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MEDICAL DEPARTMENT

UNITED STATES ARMY

IN WORL,,D WAR 11

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MEDICAL DEPARTMENT, UNITED STATES ARMY

INTERNAL MEDICINE IN WORLD WAR II

Volume 11

INFEC"TIOUS DISEASES

Prepswredi ond pubabbmke munder Owe damin"I of

Lieutenant G..ev.I L*AWAb 1). It1"Mm

UiAss in Chioy

* :skh.l Jtmn'% no" C.OA~rt* Jr.. ~W% Uti NMCA

I&jo fiw IftawI4 ,bI~dincw OI S0

U arvoned 0nl

OFFICE OF THEl SUR'GEON GEiVERAL

DFY-4RTMENT OF THE ARMY

WASHIM4'ON. D.C.. 1963
INTERSAL MIEDICINE IN WORLD WAR 11

Admwuor RdtganW Saw Bon,eAs H&d#ji of jgsfrvWm Meji snm

G~AnuJ.D G. Dlvtc~jo, M.D., C~bwm

W, PAUL HAYEMI, Jr., M.. UB*onWj Difoa

WALvan 8B4uso, WD . fiowsA~ P. Lawis, M.D.

kaxamax L BLtVtSOANW, MA). EM*NBD R. Lome, M.D.

Wowvs D. DAmisa1,g M.D. PzWM H. Loma, MA).

tuxx C. x~i~a WMU Wt~A~m S. Mwourvoma, M.D.

,OSPN. M. IIAwMALN, MD) M~ae CPnor .. (,tod

YAL& KMBESLAMD, Jr * M.D. 115MEv ME. Tuoumv. Jr., WW

Cckmai D&NCm uosaaa MC, USA (4m ogio)

GC.Lmo Joan Raot CoAiUs, Jr.. MC, USA (ex odkrio)

The IHaatnw. L Usia U*aa.4 skk4 .4ftop. .wbrolca Sov~,

CakhisI Jo"n Bow, Coi&vso, Jr.* Me, USA. burasrw

CoahmW Ri P, Ct.~ivvass MSC. USA, .r asvwojrw

(okiget It, L P4uaa. XWS, V5A. SpomW Asouisms so Iisfdi

Ljut~omaia Cok~oo. R, J Raantcvs, MC. USA. Spw*W Avma al t 04vgrvw

Major W~samn W. Ua~.ou. MSC, U"S. puetI A.tassi l~e Vir

Woutanriat Coiotawl I)Qot,*LA 1Iin.,oa, MSC. US,%. (1.4., speneW pyotrwjt.Sw?,

CNARLEE M WaIvuSM, Pk. 1), Lan4 I), (liif. lj-iWmWa 8040

14813 ouAt Colioe& Leo.. ~Eb L COLLIS&L DW-, VSA. (1.rf, I,/ukebo Aeftnhe DrhsmcA

Mispr LSU C.V fttsooa It. M.W. VSA. (1.4. Gewawet ftofwvmr en &Wew 'm

1U4saL (; lisiMs, UII,a A~hwm#A&%ihe B~wh

Library at Cocetio Cailot Card Numsbr aI-MR2
Volume II

INFECTIOUS DISEASES
MEDICAL DEPARTMENT, UNITED STATES ARMY

The volumes comprising the official history of the Medical Department of

the U.S. Army in World War II are prepared by The Historical Unit, U.S.

Aruy Medical Service, and published under the direction of The Surgeon

General, U.S. Army. Thewe volumes are divided into two series: (i) The

administrative or operational erite; and (2) the pro(eusional, or clinical and

technical, series. This is one of the volume published in the latter series.

VOLUMES PUBLISHED

ADMINISMATIVE SERIES

tloipitalization a" Evwivah, Zow of Isnerior

CLINICAL SERI

Internal Medici, in World War II:

Vol. 1. A4eivitita of MeriicLftah ~tnst

Preventive Medicine in World War It:

1'oi. Ill. Perhsohul ll..ftA &Iuawws sa Iminasuution

Voi. It" 09n m~atunric Dioe.... Tposasiwtd (1rii4% T1,ou.A Respi.

",g*.v od vinonalvy Trod#

Voi. V. Coatmirnicaohs Diatoms. Tronwimotd Thro.A 0on-tect Or By

Surgery in World War II.

'ldivtis of Swp'% 1ie I Iu nts,

11ond %P"

NOW00w'pry, U 1

0•"•pAAI 1•,ld 'Ader.vruip,

(MA. PQedi %urgrr In tA. P~avopoa Theism of Op"Wiss

(MAerpodicSre.wry i (A* Mo&iSrvesr*s Theshr of Opmevtiws

The I'Appdie Edl~Afftaeof IuvsdA

%firellaneove:

C'old bIw-g, Grounsd Tyja

D*%ads .%rkc in Warm Wo, It

Vekrinaery -%Vritv in WareU Wee' It

"Wimasd RwhAli~o
Authors

BC5WANIN M. BRAusA, M.D.

A~muoeiae pofmotm o( -%tdmi"i, John* Hopkin* Unziaucty, llakiuawt, Aid. Formaerlv

Colonel, MC, &IJS.

MVLBS P. HAILS&, M.D.

Boston, M4aw.

JoUX H. BUM*ShAD, M.D. 01000001d)

Formerly Lieutenant Colonel MC, ALS;- tg. Associate Clinical Profttuaar of Stcdiurnt

Yale University Schbool of Modkineao Now Haven. Coca.

RicummR B. Cs,,w. M).D

Aimeocate Clinical Pyofemmo, of Medicine, Univenkiy of Ilkinjis M.vdwal Schwv, Chieao,

[Ul. Lieutenant Colmone, MC, ALTS (Reti.)

WOWrU S. L)AMUIA, 4D. *, 

Clinial Proftwoer of Medicin*, Gen'getewn UravtwivetfyM k School, Waskiington, D).C. Forimerty ColoneL, MC, AUS.

toesiwo V. EMckMILAA, M.D.

Clinical Profeuaur of Medicine, L'oIvevt~y of Cablaornia school of medicin, Sma

Vrmaciww, Calif. Woynemrty Lwaegtnant Cokonet. MC, AL'S.

YALE KOISSLANSO, Jr., M).D

Pirolemor of Mathcine, Columibia Univerity College at Phyvkmucai sad &upieofs.

Sew Yorki, NY. Formeorly Colonel. MC, AV&S

HASaOto D. Lawiuss, MA).

Assiatant Clinical Irotemeor of Modicum,. Harvard Medical dchool, aind Senior Aawiate

in Medwicasi, Peter ben 19tgn OIfo liapital, PAOsto Maw. Voentery Liestesan

Coigoel, NMC, AUK,

AwosiLi. A. Liasow, M, D)

John Sllade. Ely hofe...r of Pagbology, Yawe LUaivwsry 60030Ai of Stodicine New

Itavea. Conn. Ftstawrly Lboutonajat Colonel. MC% AV1W

):&Moxv Rt. Lax*, Ph. f._ NI 1)

1"mewttus Protessur 4f vatholoy, 11of PWRO 1'hp. Ants~t te Th. Study. TrsAmment.

and Prevention of Tutabwwuilcad Vnivvvtily of Pmawylvewis, PhiAdlmmophia. Pa. E'ar.

mrly Comonel MC, AUIr*

Pasan H. Lona, %I.Dý

Chairmana ed Pyoemot, IJOP~nmmet #-f Modkicin. ftat., Laiwmiy at NOW York.

fiowsaatal Med~ical Coaat.' brihlyn, X V. fgtriodlim Cjeneve* USAR (RAt.).

1IARSS MOa t.'uS D).

Chaicoumm and hlewaxann %I- MWgg Pi4ofuwu. Owpartum~at of Pewn*U~vo Medietiw.

NOW York Univenty IWOllVw medleal Crater. Ond Vwimig Pb~y~eaa. BeI).wt

Hospital, New York. SN Y. ormarly Major. MuC. AtIK

PDSO H , MowUS,. M.D.

Atalalant Medical Ditewet (CbWe of Uodedial Swvlee). Ldsm Aadaiv Cbsaiy Gvesaal

Hospital, w4d Ammimoa*t hofwesr of Internal Medcido. Co~lsa. of Medica KvAno~ist,

L"e Ansvls. Calif Colonel. MW. lilA (a

PAULI Paess'r. M.D. (d96041d)

Formerly Calonel, MC, A CS. lat A~ms~eime PyeAmmor of M dkie*e 1914 Jobws

Hfopkins Uolvonfty Sekoo of Mdediaon, Boliame,. Md- and (Thbe. Mewdci Pcrvve.

(l~O-8),Ve4tocan Aduadn~aw tio "Ospp". POrtO "Owud. Md.
X AUTHORS

Joux R. PAUL, M.D.

Profesor of Preventive Medieine, Yale University School of Medicine, New Haven,

Conn. Formerly Cap~ain, MC (1W2Z-24); Consultant to the Secretary of War

(1941-46).

CaAaLBs A. RAGAN, JF., M.D.

Professor of Clinieal Medicine, Columbia University College of Physicians and

Stalsons, New York, N.Y. Feormetly Lieutenant Colonel, MC, AUS.

LowELL A. RANTS, M.D.

Prvfesor of Medicine, -Skanford Medical Center, Palo Alto, Calif.

WILatu A. Rj.LLY, M.D.

Clinical Professor of Pediatrics, Universiy of California School of Medicine, and Chif,

Radioisotope Service, Veterani' Adminirutitkm Hkopital, San Francisc., Calif. Colonel,

MC, llon. R., AL°S.

C'aMiS J. D. ZASAtoVna, M, ),, F A.C P.

Professor of internal Medicine amd Director, The Thoma& Hteary Simpson Memorial

Inaitute for Medical keseanh, University of Michigan, Ann Arbor, Mich. Lieulenant

Colonel, MC, USAR.
Foreword

This volume, the twenty-first to be. published in the total seracts relating

the history of the United States Army Mtedical Department in World War H1,

is the second volume to be published in the internial rnediciiie group. The

first volume, published in 1961, dealt with the activities of consultants in

medicine in all partsi of the world. T~his wecund volume deals with Some of

the infectious dimias.*i efteoulltert lit a global war. The third and tinal volumne in this g-roup, now lit preparationk, Will deal further with the Infectious

disases~ andi with general niedicine.

Of necc.*hity, asthe ediltor of the Intern4- awlicilm group poinits out lin

his prefare, swulte of the inaterial in this volume overtap' some of the niaterial In the tirs9t internal uwwdicine tvolume. It albo overlapis certain of the

material lit Otte preventivo inediine series. T'here has L**n, deliberately, sto

effort to alter the 4ituat'lim. To do *o would have. rrwuhted in rigid and artiticial disitinctionx stind would &W., hate deprivted time eadier of the bwrewfit, lit

certain InstancelI, of jpresentation. of material on the, onae su~bject front sore

than sine point of view,

As I readl tha', Ibok in mantueript, I ww% tniprr~.ed with a ttnwiibr of

cona..deratitro., 4on0M pfMiullar to thix volune, some sharod by the other volumee. Let mew li.4t '%ofla of them,

1. The wisdont of 'air plirly of utilizintg the personal ospenence. of

preusent andi former medwail #44cer%, who, as hie bftn re~peatendly Pointed out,

not only helpett to create but a)*, to rytortl the data upon whith tht# whole

history in baxedl. The author%. s4 the vnaroaA rhaptein in thr* volunte were

owlected to writo them not only hei-ause oif their entnemVw in their particular

flelds but also bowase~i they hadl had wartiam experie"Ofte in thoe. flowt More

valid sourcro could wsean-Ply be Imagined.

2. The expansion of kn#-wtldge of the etiology, chnical picture. Control,

and maonageent. of cortain diseas.'* ahout which little- zin scaW Instdance

nothint- -wax known beore the war, 1'Dw lvit tis incomplet b~ut, as ezamplao.

one might awntion miandfly fever; Q fevePr; %rrub typhito; Frill'# dorm*;

primary &typical pneumonia; and cutanemas diphtheria.

3. The remarkable uitlization of opportmanstwe for inwwaipt~g~m &Md the

sam mazn amount of valuable data that emorged frnm them. studwi. which

were often mad., under almost Intolerablo rimcditions, btwh in and out of can -

bat. In addititona to mitudie Involvistg Un~it*d States military pewwwtnnl. inicluding releamed prisoners of war, were the 4tudi"d involving Jirria Tred

Allived Military Porwmrnel, eneipii prisotwr% of war; and. nnvidlianu
X11 FOREWORD)

In this conniection one 'is imipressed with die importance and value of

the work doum. by the variou* boards, eouimissiens, and subcommtissions

appointed to Investigate, and recomniend action upon, certain aspeets of infecLious diieases. Their invest igations includedl aeute respiratory disease;

influenza and other epidemitc diseases; typhus; iteurotroplc virus diseaws:

hemnolytic streptococcal infkctiouis; airborne iiifettioiis; tuberculosis; and

malaria. When one realize* that sonte 15.00) drugs for the suppremwion and

treatmn~rt of malaria were investigated, somte cursorily and somec definiuiv'ely,

during the course of the war, otie can also relize the fruitli - activitwis and

actual 'rhao*s which inight have resulted without die guidanee of dke Board

for the Coordination of Malarial Studies.

4. The ehanging COnceptsi Of Certaint disANWS, and their management. lit

19,41, for example, no one would have dresamid rhat one of the nwat significant chapters In a volunie in the intertitl iiedicitte wrtied of the lti-tury would

concern ventereal disease. In Tecvtnber lI4AS. the treatnient of pitients ba

pitahized with ventereal diease cea*ied to be a resporxsiliility of ith genitourinary serv lev mnd 1beiAnw a resputtatbility of the medi-cal serv'ic in Army

hopipitas6. hlompitalization then gave way to ambulatory treattment. In the

("'Um of 4ifphllti-m, tterapY etolved frount the time-honored but eumrberwsone and

hazarthms nethods ith III SrýeWfal* and btArnUth-~--ini,)1raet1'-aI VenCE Under ndlativfely itatit! 6ondittoni of training and Comipleely ipmi tieAl 'in "~

to tho remudute, dweimm oi ) use penicillin for 0lit. jMsrtmiar. Tlu'ii drisaun,

madle by The Surgeon Gonerai anti applied Ariny-wide rten at a titne whent

lao. _mI nute prparationS for I)S ayin F.ft* urope were tig nmladr. 601%hed A

fer~tomm problemi with greatesteline. Trained ntanpowwer wa4 <Imt-

"4rved; ehantie.6 of evavuariof were (VA Clogged 11 tdim type of Patient; and.

"tmanV ho"CJ ta *dA wereM freedj for forwre Urgent purp.aMNO* FUn ir, Ithe use

Of jW14-11 AimpfifmA4 them trestownnmt gofnorrhem antl rodurMs tho rom~ph,

C1tion#v. arI!.ing frootg that dtlIftopw froun 23j pereeuit ini Mr3 to I jprtwnt in 1944.

'Pir vpreAd #f knoWleg0 of 41l thee &W16A0 requIred almost M*VAngel

ica) offortW'on tiftt1 part of the nie'dwal reyouvvltazt* and othet's repunuW. tot~

tho tmaintng andi imhuwtrtinartu of riwdwal iAwmrrw. No to the troops, omwtrol

ofi dliftwo was a matter sif indiirtidual Ilsjdlrtinaltium &ari to VIN'e~t~ile Me.

quirel firm comatnn~n 4upport- Fduratisn e~mmierung malaria anid its %up.

preemiyo mantagemient did not 4urvm4e until Alahbo udtortphine breru an

actuality. Thou malaria ratem foll frous z.* high a-* 1,A)O Ira IfX) per thmu

sand per annusm or higher, to neglilphle figurmo.

A caroful readIng of thtis bonk wskes clear that if thew du... h6d not

been controllod, time Vnited Statr% could havv sistred a greet milita'ry die-

"ater withcoit rvgsr4 to onemy rapabsutm*-ts Sonme -f the aisthoes frankly

aruknooWligo that luck played a part in the happy mtoufnw' anid onit did.

Th. *pdsmic of oro-ophatito did uoat tw.,sr on Okinawa until Owe Wuasd had

bean ercupwod, thouh .oporadwi fOghtmg Va.. *till gming owi a"d Iroop wmp

staging for the frmveomn of Japan. On tho oller b~a.d 11w Medical Corpo

cam jusmtihobty aomune redit for axs bilant work )ai a number of thee. dif-
OYOREWORI) X111

ferent deases. Epidemic typhus was rampant in civilian populations with

which many troops were in clow contact, but there were only 104 cases in

the United States Army and not a single death.

Otio or two comparisons with World War I figures are further proof of

the improvement of medical management of infectious diseases in World

War It: lit World War I, 46,640 deaths, 73 percent of all deaths from disease, were caused by influenza, lobar pneumonia, bronchopneumonia, bronchitis, and meaales. In World War II, in an Army over twice the Qize of

the World War I Army and mobilized over a longer period, there were only

1,285 deaths from these causes. In World War I, tuberculosis was the leading cause of disability separations; it accounted for 11.1 percent of all sep.-

rations and for 13.5 percent of all separations from disease. In World

War 11, tuberculosis was thirteenth in the list of disability separations and

it was responsible for only 1.9 percent of separations for diseas.

The prumary miLsion of the Army Medical Service is to conserve and maintain the lighting strength of the Army. After the difficult struggle for BunaSanaliadA in tim Nfew (;ukaes ,awpaigri, largvly because of the ravages of

disease, the 32d Infantry l)iviAion had to be taken out of the line for rest

and rehabilitation and it was ineffective for many uwnths. Extrapolation

of the"s facts and others atak" clear what might have happened had such

*ituatiOn.4 (!ontinued. It is to the everla.ting credit of the Medical Departient.- -supuorted 1 y undertanding line conimander- that they did not.

In retr, peAt, the Medieal Department ,ee to have acoomplished an

almolt impOsibl, t,.k. It Oade its mistakes, and, to speak bluntly, Wun. of

them %dhouhd not have been nmade. What oewe of the autdom of this book said

of malarta might vvell be iad of a numbelr of other dimseji, that the stage

otf edicatton in it were painfully alike in all theaterm and aresv. Nonethetoo, aedical jwrvonnol ,.,nmju••,d and herd in check disue that were bewihdering in both kind ind number; that offerld multiple thirultift of diag.

n•os• and diff.orntial *liagnuoun, part.-larly in their very errly tages; and

that msnmtlaea wert completely unknown and 40metipw had been modify!t

by enviroamnrnt and by tdw rhanges in the clnawial ptaure that orrurrvA

whtn non aimmu.ne twrwow raorwd aroat of nrl•ni-uty.

A.4 a au"rgM. I. &a well a* many of my eurgwas) C"fremr have, had to

Colic.ntrat. on tho r..enfal rharurtor 1f our spectA lty In dealing with combat

Casualties. Ini my nid, a* Tho Surgeon tioenral of the Army my oUtWak is

no'woerily wader and my appreciattim of tht,% book in theref¢o much 40eepr,

Quit. properly, %irw, our task I, the prvperatam of a htiory of the

Army Medtical Oppartenwt in World War 11, the chMt Pmphat,* in thta

bcmk Is a pon the normou•s dnwal military raperir.- with Infctio d,.-

ea.ee in all part.* of tho world, That drim niot mak, the vtlunw t ln valuahbl

as a teit on th~ ditsease for meutwa| tustat & wwral prartatarwwr%, and

speciahIet* in internal meiwin. I rromOeti it to them, wo. we as to nw-di.

e'V1 o&e9r of tho Army and Mher arwmwe wrv)re, awe a runpdlatirm of dtata

nAt roadily 4--meo by 01,qwte#•,
XIV FOREWORD

The nineteen authors of this volume deserve the grateful thanks of the

Army Medical Service and of the medical profession in general. For a variety of reasons, some beyond our competence, some due to our own culpability, the preparation of these and other volumes of the history has been long

delayed. It is a tribute to the sense of professional duty and the patriotism

of these former medical officers that in the midst of their busy civilian lives

they have added to their wartime service by taking the time to set down this

record, and to carry out the task with real enthusiasm. That is evident on

every page.

It is therefore my pleasure to express my gratitude to the authors of this

volume and to its editor, Dr. W. Paul Havens, Jr., and to the Advisory Editorial Board of which Dr. Garfield G. Duncan is Chairman, for a micsion

well accomplished. It is my equal pleasure to express my appreciation to

the personnel in my own office who are doing the prodigious work of producing these volumes.

LEONARD D. HEATON,

Lieutenant General,

The Surgeon General.
Preface

This is the second voluine of the history of internal medicine in World

War II. In the preface of the fitst volume, which contains the reports of

the medical consultants, is recounted the story of the development of the

organization that ultimately produced the history. Attention was called to

the early enthusiastic efforts of Brig. Gen. Hugh J. Morgan and Colonels

Walter Bauer, John S. Hunt, and Francis R. Dieuaide to implement its writing and to the subsequent formation of the Advisory Editorial Board, early

in 1952, under the chairnanship of Dr. Garfield G. Duncan and under the

overall direction of Col. Calvin H. Goddard, MC, then Editor in Chief of

the history of the "Medical Department, U.S. Army, in World War 11" and

Director, The Historical Unit, U.S. Army Medical Service. An editorial

office was established at The Jefferson Medical College of Philadelphia, and

Dr. W. Paul Havens, Jr., of that institution, was made Editorial Director.

Col. John Boyd Coates, Jr., M(C, succeeded Colonel Goddard as Editor in

Chief of the history and Director of The Historical UnitThis volume is concerned with the clinical descriptions of certain infectious disea.ss and brings into sharp focus their impacts on military activities

under a variety of circumstances in many different parts of the world. Viral,

rickettsial, bacterial, and protozoal infections are discussed, and these chapters constitute a record of the great and unique experience of our Armed

Forces with a variety of infectious di.wa.,es in a mall block of time. The

chemotherapeutic triumph of the sulfonamides in meningococcal infections

is recorded here. The great divermity of effects of various infections on mili.

tary activities is described, ranging from the relatively unimportant role of

neurotropic virus di.tises to the vast loss of time caused by respirmtory diseases, sandifly fever, and malaria. Again and again, in almost every chapter

in this volume, appear thw results of investigations initiated either by the

Armed Forces or by the various commisions working under their aegi.

Of necessity, there is overlapping of the material contained in this hook

and in volume I. However, in contrast to the more general aspects of various medical problems destribed by the ronsultantqs in the first vollume, the

chapters in this hook were ba,,d on the olhrvations of many medical officers

and were written by physicians directly concerned with the responsibilities

for the care of patients and the clinical investigation, of their di.eases. These

men, peers in their fields, were able to combine insight, judgnent. and experience in such a way that the chapters in this hook rank as outstanding records of clinical achievement. The lapse of more than 15 ypars Ietween the

experiences recounted here anti their publication in this volume does not

detract from their value or interest. Actually, much of thiq material has

Irv
X Vi PREFACE

long since appeared in our medical journals, but this book serves to bring it

together in its proper relationship with place and time in history. The delay

in publication is not unprecedented, since both the "Medical and Surgical

History of the War of the Rebellion" and "The Medical Department of the

United States Army in the World War" appeared sevenil years after the

te:'mination of the Civil War and World War 1.

For those who are concerned with military medical history, it is of interest to note that World War It was the first great conflict in which fewer

of our troops died of disease than of battle injuries and wounds. In the

Civil War, there were among Union troops approxinmtely 360,000 deaths,

an,+ of these, about 2.,Ž~5,000 were caused by various diseases. Among the

Confederate troops, it was estimated that there were not less than 0'200b,00)0

deaths, and of these, 150.1MW) were estirmated to be due to diseases. Of further interest to the medical historian is the changing importance of various

ifectims in military activity. Of the three volumes comprising the "Medical and Surgical History of the War of the Rebellion," one of them was

devoted solely to the subject of the alvine fluxes while the other two, were

de% oted, respectively, to statistics anti clinical descriptions of malaria, t yphoid

fev'er, verebrospinal fever, smallpox, and a number of olher acute infettions.

This is al*) illustrated by cownparit.om of the mortality recorded for respiratory di.aseas in "The Medical Department of the United States Army in the

World War" and in this volume dealing with World War I.

The editor wishes to express his sincere thanks to the countlessN medical

officers who made the material for these chapters available and to the distinguished authors who have written them. In addition, thanks are due

to Dr. Duncan and the entire Advisory Editorial Board for their constant

support and to Colonel Coates for his. many courtesies and vigorous asmistanceIn particular, appreciation is expresmd to Miss Eleanor S. Cooper. whose

tireless and paintaking attention to the preparation and editing of these

manuscripts was an invaluable aid in the compilation of this histor'.

The editor and the authors are also greatly indebted to Mr. E. L. Iamilton, Chief. Medical Statistics Division, Office of the Surgeon General, Mr.

A. J'. McDowell, Akwsi%tant Chief, and Mr. M. C. Rossoff. Assistant Chief,

Statistical Analysis Brunch. who not only provided essential data but also

checked and revwewpd all statistical information contained herein.

Finally, grateful acknowledgmnent is made to Mim Janie W. Williams.

Chief, Publication Section, Editnrial Branch, The Ifistorical Unit, for performing the final publbeations editing and to Mii. Rebecca L. 1lwberstein,

Chief, Editorial Section. Editorial Branch, The Historic-d Unit. for preparing the index for thil volume.

IV. , lvz~s..lr., J+u,. M.T).
Contents

Page

FOREWORD --- ------------------------- X1

PREFACE -- . - - - - - - - - - - - - - - - - - - - - - - - - xv

Chapter

I Respiratory Disea~cei (Y'ak Knieeland, Jr., M.D1.) 1

Geeralonieain- 1

Pant 1. Acute Respiratory Diseajes

Common Upper Respiratory Infection --- 2

Infuenza - - - - - - - - ---- - -- --- 9

Primary Atypical Pneumonia-.. ------- -- 16

Bacterial Pnunwonia ----- 26

Measles. - -- - ... . 12

Mumps --s-.-- 35

Infectious Mononuclisis- ----- 38

Rubella. -- - - . . . .- - - - - - - - - --- 41

Part 11. Chronic Respiratory Diseases

Chronic Bronchitis .. .. . . .......... 42

Itronchlectasis - .. --------.. . . . . . . 44

Lung Abscess ------....-------- - - -- - - -45

Spontaneous Pneumothorax ---------------------- ---.-- 40

Pulmonary Fibrosis-----------------------------.... 47

Pulmonary Emphysema--------. ... ......... 48

Malignant Dimseas of the Lungs----------------------------48

11 Sandfly Fever (William A. Reilly, M. D., Robero F. Be~mill. .31. D., and

Perin ff. Long, Mf.D.). - 49

Etiology------ ............... 52

Epidemiology-----------...------ - ...... 53

Immunity ................--------- 55

Clinical Course and Disagofsis -------- ... - -- 56

Treatment and Prevemtlion---------- --------------- 57

summary---------------------- ------- ---------- -- 57

III Dengue (RickardB.Capp@, MD.) -------------------------------- 59

Introduction.............................................fi9

Incidence ------------- --------------------------------- 60

SpdclflcOutbmks... .------------------------ ----------.--- 60

Clinical Mandwestati-n. --- ---------------------------------- 71

Scientific Inyestigation. -------- ------------------- ---------- 78

ZVU
XVIII CONTENTS

Chapter Page

IV Neurotropic Virtu Dweases (JoAh R. Paud, M.D.)-__ 79

The Arthropodborue Virus Encephalitide .------------.. 79

Poliom yelitis ---------------------------.. 91

Lymphocytic Cboriomeaiugitis ----------------------- 99

R abies ............................................. 10 1

V Q Fever (Chart" A. Ragan, Jr., M.D.) ------------------- 103

Occurrence ----------.-------.----------------------- - 103

Clinical Features .. ..-----------------------------------... 10

Epide-•-1 -----------------------------------------. I08

VI ScrubTyphus (Chris J. D. Zarafoasiw , M.D., ed ?1.W P. Baker, M.D.). inI

Cliueial Exprience ------------------------------------- 112

Pathology -------.------------------------------------ 132

Laboratory AidM in Diagnoesi--------------------------..... 133

SpeciAc Treatment ------ _----------------------.--- ---- - 136

Postwar Studies ----------------------- _-----.---- ------- 138

Summary ...........------------------------------. 139

VII The Typhus Fevers (CAW J. D. Zerqfoi, M.D.) ----------------- 143

Part I. Epidemic Typhu.

Epideniology-- -------------------------------------- - -143

(*liniesl Experience ----------------------------------------- 145

l'athoog- .........................-- _.--_----------------- 169

D~evelopment and Use of Laboratory Aide in Diagnosis -------- 179

Treatment ............................................. 192

Part II. Brill's Diseas

illstorical Note ......................... ................ .. 201

E pidemiology ................ 202

Clinial Picture ............ 202

J )iaos ----------.--- ------------------------------- -202

Part 111. Endemic (Mturine) Typhus

Epidemiology ........................... .. ... .. .. 204

Clinical Experience --------------------- .......... 205

Laboratory Aids In Diagnosis ........................ 213

Part IV. Summary

Epidemic Typhus .................................... 215

Endemic (Murine) Typhus ........................------- 221

Epilogue ------------------------------------------------. 223

VIII Rheumatlc Fever (L.weU A. Rans, M.D.) --------------------- 225

Epidemiology and Statistics.-------------------------- .. 228

Clinical Picture- ................. 229

Early Treatment and Course ------------------- - ... 232

Late Treatment and Resul.ts---------------------- 233

ReconditioninR -----------------.----------- 235

Disposition - - - -- - - 236

Control -.-.-..------------------------------- 237

RSmmarch ..---------------- -------- . 12

Summary-------------------------------- 238
OONTENTS XIX

Chapter Par

IX Meningoeoccal Infections (Worth B. Daniela, M.D.) ......- 239

H istorical N ote ----------------------------------------------- 239

Incidence During W orld W ar 1I -------------------------------- 241

Pathogenesis ------------------------------------------------- 244

Meniagococcai Bacteremia ------------------------------------- 244

Fulminant Meningococcal Bacteremia ---------------------------- 249

Meningococcal Meningitis -------------------------------------- 256

Com plications ------------------------ .------- ............- 258

Other Meningococcal Infections--------------------------------- 259

Laboratory Diagnosis ------------------------------------ ---- 260

Treatment --------------------------------------------------- 261

Pathological Findinp ------------------------------------------ 270

Treatment of Meningococcal Infections -------------------------- 271

Discussion --------------------------------------------------- 273

X Cutaneous and Other Aspects of Diphtheria (Aperill A. Liebow, M.D.,

and Jols H. Bumstued, M.D.) ------------------------------------ 275

Part 1. General Aspects of the Military Problem

Incidence ---------------------------------------------------- 275

Immunization ------------------------------------------------ 278

Part 11. Tropical Ulcers and Diphtheria

Sources and Dissemination of Information ------------------------ 279

Morphology -------------------.------------------------------ 284

Morphology in Relation to the Bacteriology of the Lesions --------- 288

Methods of Diagnosis --------------------------------------- 293

Associated Clinical Findings ------------------------------------ 295

Relation to the Schick Reaction --------------------------------- 296

Cutaneous and Extracutaneous Diphtheria ----------------------- 297

Complications ------------------------------------------------ 298

Treatment of Cutaneous Diphtheria ----------------------------- 304

Cost of Cutaneous Diphtheria to the Army ----------------------- 307

Role of Cutaneous Lesions in the Spread of Diphtheria ------------ 308

General Considerations of Diphtheria in the Tropics .--------------- 310

Association of Cutaneous and Nasopharyngeal Diphtheria in Military

Units in the Tropics ----------------------------------------- 312

Diphtheria Transmitted From Military To Civilian Populations ----- 315

Part III. A New Hemolytic Corynebacterium in Man

Part IV. Use of Penicillin in Treatment of Diphtheria

Part V. Problems Remaining for Investigation

Part VI. Summary
XX CONTENTS

('hapler POW

X1 Tuberculosis (lamond R. Long, M.D.) --- ..-- 321,

Part 1. Tuberculosis in the Army

Historical Peroptetive ----.-.... 329

Discovery of Tubereulosis lit-fore Induction 331

Discovery of Tuberculosis in the Army .... 333

Incidence and Discharge Rates ---------------.. 334

Part II. Occurrence in Oversea Arnas

Fu: ope.an Theater of Operations -.-.-.---.------------- . 339

North African and Mediterranean Theaters of O)peration .. 353

South Pacific Area------------...... 357

,4outhweit Pacific Area --- ----- - 360

Western Pacific Bame Command ------------ -------------- 362

Middle Pacific ------------------.......... 364

China-Burma-India Theater ........ .......... -.-----. 364

Alaskan Depart ment -..----.------- ..------- ..... 365

Latin American Area _. . - .. _ . . . ..- ------ 366

Middle East ... ................................ 366

Far Fast ......... ......------------- 366

Part 111. Particular Aspects of the Diwase

Extrapulnonary Tuberculosis ------ --------------------------. 367

Pleurisy With Effusion ---------------.------------.----------- 370

Spontaneous Pneumothorax -----------------------.------------ 372

Mortality From Tuberculosis ---------------------------------- 375

Part IV. Hospitalisation and Treatment in the Zone of Interior

General Principles of Evacuation- . .......... ..... 378

Specialty Centers for Treatment ------.---.----------------. 381

Orientation and Rehabilitation -------------------.------- 388

Part V. Care of Recovered and Captured Prisoners of War

Recovered Prisoners of War ----------------------... ----- 390

Captured Prisoners of War---------392

Treatment Under the Military Government in Germany ----------- 397

Part VI. Tuberculosis in British and Canadian Military Forces

Royal Navy---- -------------------------- --- _--.---- 400

Royal AirFore-- -.-.-....------------------------------ 402

Canadian Army -------------------------------------------- 403

Part VII. Significance of Army Experience for Control of Tuberculosis

XII Diagnosis and Treatment of the Venereal Diseases (PaNu Padgt, M.D.).. 409

Historical Note -----------------------------------------.. 409

Gonorrhea ------------------------------------------- 410

Nonspecific Urethrltls ---------.---------------------.-. 418

Syphilis -------------------------------------------.-------- 418

The Minor Venereal Diseases ----------------. --- - 430

Induction of Individuals With Venereal Disease. ...... ... 433

The Results .---------------------------------------- 434
CONT&NTS XXI

Chapter Palre

XIII Fort Bragg Fever (Worth B. Daniels, M.D.) ------------- 437

Recognition of a New Dies ----------------- 437

Differential Diagnosis ---------- ---- ---------------- -------- 441

Epidemiological Aspects-------------------------------------- 442

SpecilInvestigation ..-------------------------------------- 44?

Addendum ---------- I------------------- ---------------- 446

XlV Statistics of Malaria (Fred H. Mewrey, M.D.) --------------------- -449

Historical Note ------------------- -------------------------- 449

World War -I --------------------- 451

Types of Malaria----- --------------------------------- 454

Relapse in Malaria-------------- --------------- *------------ 455

Duration of Hospitalisation-------- --------------- ----------- 459

Deaths Due To Maia460

Summary ------------------- _-------- ----------- 463

XV The Suppression of Malaria (Beip~4auusaM. Baker, M.D.) -------- 465

Factors In Early Failures in Suppression of Malaria-------------- 466

Effects of Atabrine Withdrawal ------------------------ ------- 468

Effect of Suppressive Therapy on Parasite Species----------------- 469

Long-Term Clinical Experience With Atabrine Suppression ---------- 471

I.oncentratlon of Atabrine in the Blood at Levels Effective for Suppresslon ------------------------------------------------- 473

Undesirable Effects of Atabrine-------------------------------- 476

XVI Clinical Aspect. of Malaria (Harold D. Leavie, M.D.) ------- --------- 479

Predisposing Factors ---------------------------------------- 480

Prodromal Symptoms---------------------------------------- 481

Clinical Symptoms of the Acute Attack ------------------------ 481

Complications of Malaria -------------- --------------------- 484

Chronic Malaria-------------------------------------------- 487

Relapses in Malaria----------------------------------------- 488

Supporting Evidence From the Laboratory. ------------------ 489

Differential Diagnosis -------------------------- ------------- 491

summary ------------------------------------------------- 492

XVII Treatment of Malaria (Perrin U. Long, M.D.) ---------------------- 493

Introduction ----------------------------------------------- 493

Experience in the Pacific ------------------------------------- 495

Experience in the India-Burma Theater ------------------------- 498

Experience In the Mediterranean (formerly North African) Theater

of Operations -------------------------------------------- 502

XVIII Clinical Trials of Antimalarial Drugs (Harry Most, M.D.) ------------ 525

Penicillin_----------------------------------------------- 2

Heavy Metals---------------------------------------------- 526

Sulfonamides----------- ----------------------------------- 528

Cinchona Alkaklods------------------------------------------ 531

Qulnacrine Hydrochloride (Atabrine) --------------------------- 538

4-AmInoquinoline Compounds--------------------------------- 559

8-Amlnoquinollne Compounds ----------------------- --------- 579

summary ------------------------------------------------- 592

INDEX ----------------------------------------------------------- 599
XXII CONTENTS

Illustrations

Figure Pawe

I Male and female of PAhebotonss papeiakii--------------------------------54

2 Medical officers inspect water for mosquito breeding patches, Queensland,

Australia ----------------------------------------------------- 61

3 Enlisted men spray stagnant pond with kerosente guns to destroy larvae in

mosquito control, Rockhamipton, Australia--------------------------- 62

4 Conditions which favor mosquito breeding ---------------------------- 66

5 Aerial view of Manila being sprayed against mosquitoes and flies with

DDT insecticide by C-47's-------------------- ------------------ 68

6 Medical officer distributing mosquito repellent-------------------------- 71

7 Rash of dengue fever --------- ------------------------------------ 73

8 "Ulcer" eschar In toutaugamushi fever -------------------------------- 115

9 Fochar on ankle in tsutsugamushi disease---------------- ------------- 141

10 Rash of tautaugamushi disease -------------------------------------- 141

11 Maculopapular rash on third day of disease ---------------- ---------- 167

12 Capillary In derma showing swelling and proliferation of endothellum to

point of occlusion---------------------------------------------- 173

13 Finely granular capillary thromnbus, with pericapillary collection of mononuclear cells in derma------------------------------------------- 173

14 Necrosis and thrombosis of dermal capillary --------------------------- 174

15 Swelling and proliferation of endothetium of capillary in tongue ----------- 174

16 Occlusion of capillary In tongue by swelling and necrosis of endothelium. -- 174

17 Myocardium ---------------------------------------------------- 174

18 JArg cerebral nodule showing its relation to a capillarv ----------------- 175

19 Mural thrombus in subendocardial arteriole --------------------------- 175

20 Granular thrombus in arteriole in submucosa of trachea and cellular infiltrate beneath basement membrane of mucoea------------------------ 175

21 Cellular thrombus in arteriole of testis-------------------------------- 175

22 Point of attachment of base of mitral valve, with disruption of elastics,

edema (mucoid), infiltration of mononuclear cells, and production of

fibroblasts ---------------------------------------------------- 176

23 Acute interstitial myocarditis, with diffuse infiltration of mononuclear cells-. 176

24 Acute Interstitial myovitis of tongue, with infiltration of mononuclear cells.. 176

25 Small nodule of mononuclear cells in skeletal muscle attached to thyroid

gland -------------------------------------------------------- 176

26 Mononuclear infiltrate in corticomedullary junction of kidney ------------- 177

27 Focal interstitial orchitis about a dilated capillary ---------------------- 177

28 Mononuclear cells forming interstitial exudate in acute myocarditis----------177

29 Nodules In posterior lobe of pituitary identical with those In the brain and

spinal cord---------------------------------------------------- 178

30 Hyperplastia of sinusoidal endothelium of the liver and Infiltration of mononuclear cells.--------------------------------------------------- 178

31 Lung, alveolar exudate showing many rickettsia-like bodies in cytoplasm

of polymtorphonueler leukocytes---------------------------------- 178

32 Pancreas, infiltration of mononuclear cells in the Interlobular septum, dilatation of acini, and inspissation of secretion ------------------------- 178

33 Counties lit I I Southern States reporting cases of endemic typhus fever,

1922-ag and 1943-45------------------------------------------- 206

34 Typhus fever patient on U.S.A. Typhus Commission Ward, Fever Hospital.

Cairo, Egypt -------------------------------------------------- 218
CONTENTS XXIII

Pigure Pe

35 Rash in meningococcal bacteremla ------------------------------------ 245

36 Widespread ecchymotic rash in a patient with fulminating bacteremia and

hemorrhages into the adrenals ------------------------------------- 254

37 Multiple diphtheritic ulcers of lower extremity acquired in New Zealand... 285

38 Typical chronic ulcer of 4 weeks' duration -----------------.---------- 286

39 Diphtheritic skin ulcers ---------------------------------------------- 287

40 Penile ulcers ------------------------------------------------------- 288

41 Epidermophytosis superinfeeted with Corynebacterium diphtheriae .--------- 289

42 Moist, desquamative, and ulcerative dermatitis ------------------------- 290

43 Cutaneous diphtheria as seen in the India-Burma Theater --------------- 291

44 Diphtheritic paronychiae -------------------------------------------- 311

46 Toxigenic Coryanebacrium diphtheriae in skin of palms and multiple paronychlae, acquired in the Solomon Islands ---------------------------- 311

46 Exudate from diphtheritic ulcer -------------------.-----.--- 320

47 Exudate from ulcer in lesion ------------------------.------------ 3

48 Chronic ulcer of ankle containing Corynebaderium diphiheriae ............- 321

49 Diphtheritic ulcers in children --------------------.-------- ---- 322

50 CorneFbadcriunt hemolyticum colonies on blood agar --------- 323

51 Coryebadmerium diphtheriae on human blood agar ---------------------- 32,

52 Cormtebweriust henslyfticup on human blood agar ------------.-------- 323

53 Corywebacteriutm henotylicum colony as seen under low power, split lens of

microscope - ------------------------------------------------- 323

54 Corymebaceriunm hemoilticum on L6ffler's serum ------------- .-------- 324

55 Corymwbaderium diphAheria, on LAffier's serum ------------- 324

56 Poisoning by Mapharsen in treatment of syphilis ---- 421

57 Erythematous skin lesions over the pretiblal regions -------- 439

58 Generalized form of skin eruption ------------------------------------- 441

59 Lt. Col. Garfield G. Duncan, MC, explaining malaria suppressive therapy

charts to Gen. Douglas MacArthur, Queensland, Australia ------------- 467

60 Brig. Gen. James S. Simmons and Col. Arthur Fischer, GSC, inspect

cinchona seedlings ----------------------------- ------------------ 531

Charts

Number

I Incidence of sandfly fever and fever of undetermined origin in the North

African-Mediterranean Theater of Operations, U.S. Army, 1943-45 ------- 55

2 Seasonal incidence of poliomyelitis in the Army in the continental United

States compared with contemporaneous civilian rates, 1943-46 ---------- 92

3 Incidence of poliomyelitis In the U.S. Army, by selected area and year,

1940-48 ------------------------------------------------------------ 99

4 Clinical and laboratory findings in patient with "E" severity typhus fever.. 148

5 Clinical and laboratory findings in a fatal case of epidemic typhus fever-.- 150

6 Clinical course and early serological findings in a moderately severe case of

epidemic typhus In a vaccinated individual ----------------------------- 161

7 Clinical comparison of vaccinated and unvaccinated groups of typhus fever

cases among employees of the Cairo Fever Hospital, El Abbasa, Egypt. -. 166

8 Temperature chart and pertinent laboratory findings of the only known case

of typhus fever occurring among U.S. Army troops in Sicily, 1943 -------- 167

9 Effect of para-aminobensoie acid on time of death in chick embryos infected

with RickUsia prowaseki i---------------------------------------- ---- 196
XXIV CONTENTS

Number Page

10 Comparison of temperatures of 20 para-aminobenzoic acid treated patients

and 19 alternate control patients, Cairo, Egypt, 1944 and 1945 ----------- 198

11 Total reported cases of nourine (fleaborne) typhus in the United States,

1931-45 ----------------------------------------------------------- 207

12 Admissions to U.S. Army hospitals for meningococcal infections among

troops in the continental United States, by month, World War I and World

War II --------------------------------------.. . . . . ..------------ 240

13 Cae fatality ratios for meningococcal infections, by months, in the continental United States during World War I and World War 11 -.--------- 243

14 Number of cases of skin diseases and diphtheria and tonsillitis in the Afrika

Korps, 1942 ------------------------------------- ----------.-------- 313

15 Diphtheria in Germany, Norway, and the Netherlands, 1939-44 --------- 317

16 Diphtheria in France, Denmark, Sweden, and Switzerland, 1939-45 ------ 318

17 Incidence of tuberculosis in the U.S. Army in the continental United States,

World War I and World War I1 -------------------------------------- 335

18 Incidence of tuberculosis among U.S. Army troops in the United States and

overseas, January 1942 to June 1946 ---------------------------------- 336

19 Withdrawals from separation processing for pulmonary tuberculosis in U.S.

Army separation centers, July 1945 to August 1946 --------------------- 337

20 Disability discharges for tuberculosis among enlisted men in the U.S. Army,

1942-45 --------.-.--------------.------------------------------ 3_..138

21 Incidence of tuberculosis in the U.S. Army, by theater and year, 1942-45- - 361

22 A comparison of computed and actual rates reflecting savings attributed to

improved treatment of venereal disease, Army in the United States, June

1942 to August 1945 ------------------------------------------------ 434

23 Changes in therapy, incidence, and duration of treatment of venereal

disease, Army in the United States, June 1942 to August 1945 ----------- 435

24 Temperature, pulse, and leukocyte count of patient -------------------- 440

25 Malaria experience of an infantry regiment carefully followed for 34 months,

South Pacific Area, December 1942-August 1945 ------------- __.------ 472

26 Penicillin studies in three patients with vivat malaria -------------------- 527

27 Rate of disappearance of parasites during treatment of 497 acute attacks of

vivax malaria with quinacrine hydrochloride or quinine ----------------- 533

28 Relapse rates and intervals to relapse following treatment, by days, with

quinacrine hydrochloride or quinine of 250 acute attacks of rivax malaria

of Pacific origin ----------------------------------------------------- 535

21) Malaria rates in an infantry regiment under various schedules of suppression with qulnacrine hydrochloride, by week -------------------------- 547

30 Distribution of relapse in two groups of patients after treatment for acute

attacks of vivaz malaria of Pacific origin --------.--.----------------- 549

31 Comparative rate of disappearance of parasites from peripheral blood during

treatment of vvax malaria with quinine, quinacrine hydrochloride, and

chloroquine-.......------------------------------------------------- 566

32 Comparative efficiency of quinine, quinacrine hydrochloride, and chloroquine in controlling fever during treatment of delayed primary attacks of

relapses of vi'ax malaria -------------------------------------------- 567

33 Cumulative rates of relapses during a minimum of 120 days following treatment of acute attacks of niwz malaria with quinine, quinacrine hydrochloride,

and chloroquine ----------------------------------------------------- 568

34 Comparison of distribution of relapses occurring during the first 60 days

after treatment of acute attacks of vipam malaria of Pacific origin with

quinine, quinacrine hydrochloride, and chloroquine ---------------------- 569
CONTZNTS XXV

Nv mh Page

35 Average plasma levels of chloroquine during and after treatment under plans

A, B, andC C- -- ------------------------- - --------------------- 570

36 Relapse rates and intervals to relapse after treatment of acute attacks of

vionz malaria of Pacific origin with various drugs ...-.........---.-.-- 584

Tables

1 Admission rates for the various designations of Vincent's infection in the

U.8. Army during World War I and World War I I---------------------- 5

2 Admisions for primary atypical pneumonia, bacterial pneumonia, and other

pneumonia, in the U.S. Army, 1942-45 -------------------------------- 27

3 Incidence of dengue in the U.S. Army, 1942-45 ------------------------- 60

4 Incidence rates for dengue in U.S. Army personnel in New Caledonia and

Esplritu Santo, from January to August, 1943 and 1944 ----------------- 63

5 Breeding index of Aede, moaquitoes in Honolulu, T.H., from August 1943 to

August 1944 ---------------------------.---------------------------- 64

6 Incidence of dengue in U.S. Army personnel in New Guinea and adjacent

islands, January 1944 to August 1945 -------------------------------- 65

7 Incidence of dengue in U.S. Army personnel in the Philippine Islands, No-

"vember 1944 to December 1945 --------------------------------------- 67

8 Daily report of new caes of dengue at height of the epidemic in Saipan, 14

September to 6 October 1944 ----------------------------------------- 70

9 Physical signs and symptoms of 418 cases of dengue in two groups in U.S.

Army patients, 1944 ---------.-------------------------------------- 74

10 Admissions for encephalitis in the U.S. Army, 1942-45 ------------------- 84

11 Deaths due to encephalitis in the U.S. Army, 1942-45 ------------------- 85

12 Number of cases and deaths due to scrub typhus In the Southwest Pacific

Area, U.S. Army, January 1943 to August 1945 ------------------------ 114

13 Epidemic typhus in French North Africa, Egypt, and Iran, 1930-44 ------- 145

14 Incidence of epidemic typhus fever (louseborne) in the U.S. Army, 1942-45. 146

15 Serological findings and immunization record in three cases of epidemic

typhus incurred subsequent to immunlzat.on with typhus fever vaccine--- 63

16 Clinical summary of five case, of epidemic typhus fever incurred subsequent

to immunization with typhus fever vaccine ----------------------------- 164

17 Comparison of typhus in three groups at Belsen Concentration Camp,

Belsen, Germany --------------------------------------------------- 169

18 Wedl-Felix Proflae agglutination tests in epidemic typhus (case 1344) - --- 180

19 Weil-Felix Proluw OX-19 agglutination results on 1,002 sera from 203

patients with typhus fever ------------------------------------------ 181

20 Serological findings in three typhus caes with negative Well-Felix OX-19

agglutination results ------------------------------------------------ 182

21 The usual Well-Felix reactions in rickettsial diseases --------------------- 182

22 Complement fixation test results in case 1344, epidemic typhus fever ------ 184

23 Complement fixation results on 1,002 sera from 203 patients with typhus

fever -------------------------------------------------------------- 186

24 Serological findings in two cases of typhus fever with negative results in

complement fixation tests --------------------------------------------- 188

25 Serological findings in a patient with epidemic typhus fever contracted

after receiving 5.0 cc. of Cox-type vaccine ----------------------------- 187

26 Rlckettaial agglutination test rpsults In awe 1344 ----------------------- 189
XXVI CONTENTS

Numb.? Page

27 Epidemic neutralizing antibody findingh in case 1344 ------------------- 191

28 Incidence of endemic typhus fever (fleaborne) in the U.S. Army, 1942-45 207

29 Serological studies on an Americatn joldier with murine typhuis .... 210

30 Serological results found in individuals immunized with epidemic typhus

vaccine and who subsequently contracted murine typhus ---------------- 211

31 Serological findings in two cases of probable murine typhus fever occurring

in vaccinated individuals at Dakar, French West Africa. ----------------- 213

32 Serological results in an unvaceinated individual infected with murine

typhus fever(eae 1) ------------------------------------------------ 214

33 Clinical and historical information on rheunmtic fever as observed in three

U.S. Army general hospitals ------- _---------------------.------------ 230

34 Incidence and deaths due to meningoeoccal infectious, US. Army, World

War I and World War 11 ------------------------------------------- 242

35 Comparative mortality of certain mfectkma diseases in the U.S. Army, 1942-

45 ------------------------------------------------------------- 243

36 Cause of death in 300 cases of meningocuccal infection reviewed at the

Armed Forces Institute of Pathology --------------------------------- 251

37 Severity of adrenal hemorrhage and duration of life in 126 of 300 fatal cases

of meningocoeeal infection ------------------------------------------- 256

38 Duration of life in relation to severity of illness in 118 of 144 case of meningitis studied at the Armed Forces Institute of Pathology -------------- 257

39 Distribution of types of meningocorci in 1,436 eaw*s of meningocoecal infection, Fourth Service Command Laboratory, August 1942-December 1945- 261

40 Incidence of diphtheria in the U.S. Army, 1942-45 ----------------------- V6

41 Deaths due to diphtheria in the U.S. Army, 1942-45 -----------.--------- 277

42 Incidence of cutaneous diphtheria in the U.S. Army, 1944-45 -------------- 2 277

43 Schick reactions of individuals with diphtheritic tropical ulcer* in 3 infantry

divisions in the South Pacific Area ------------------------------------ 296

44 Study of influence of antitoxin on incidence of complications in diphtheria,

20th General Hospital, India-Burma Theater ........................... 305

45 Cases of diphtheria in the 27th Infantry DIvision in rest area in the New

Hebrides, 16 September-29 October 1944 ............................... 314

46 Admissions, deaths, and disability separations due to tubercular diseases in

the U.S. Army (Union only), May 1861-June 186 6- ..................... 

47 Incidence rates for tulerculosis In the Army in the European theater of

operations and in the continental United States, 1942-45 ................ 340

48 Prevalence of tubereulsis, all forms, In U.8. Army nurses in the European

theater of operations, 1942-45 ---------------------------------------- 343

49 Incidence of nonpulmonazy tuberculosis (excludes pleural tuberculosis) In

the U.S. Army, 1942-45 ............................................... 36

50 Incidence of tuberculosis of pleura and sero6brinous pleurtitis in the U.S.

Army, 1944-45 ..-.................................................. 371

51 Admissions and readmissions for spontaneous penumothorax in the U.8.

Army. 1943-46 ..................................................... 373

52 Deaths due to tuberculosi, in the U.S. Army, 1942-46 ................... 377

53 Total attack rate for malaria in the U.S. Army, by type of plasmodium,

1941-46 ........................................................... 454

54 Attack rates of malaria, all form., in the U.& Army, 1942-46 ............ 451

53 Attack rawt of vivax (tertian) malaria, in the U.S. Army. 1942-45 -------- 456

56 Attack rates of falciparum (estlvo-autumnal) malaria, in the U.S. Army,

194 ,-45 ........................................................... 456

57 Attack rates of malarise (quartan) malaria, in the U.S. Army. 1942-45 .... 457
CONTENTS XXVII

Number Page

58 Attack rates of mixed malarial infections, in the U.S. Army, I9245 - -...... 457

59 Attack rates of other and unspecified forms of malaria, in the U.S. Army,

19 4 2 - 4 5 . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . .. . .. . . . . . . . .. . . ... . . . . . .... 4 58

60 Average number of days in hospital and quarters for adniwiotn-, anid readmis-

*ions due tu malaria and fever of undetermined origin, in the U.S. Army,

1942, 43, and 1945 -------------------.------------------------- 460

61 Deaths due to malaria, in the U.S. Army, 1942-45 -. --------------------- 46

62 Deaths due to vivax (tertian) malaria, in the U.S. Army, 1942-45 -------- 461

63 Deaths due to falciparum (estivo-autumnal) malaria, in the U.S. Army,

1942-45 ------------------------------.-------------.-------------- 461

64 Deaths duo to malaria, mixed type, in the U.S. Army, 1942-45 ----------- 462

6t Deaths due to malaria, unclasified and other, in the U.S. Army, 1942-45., 462

66 Malaria eases in the Mediterranean (formerly North African) Theater of

O0erutions, U.S. Army, 1942-45 -------------------------.------------ 503

67 Experience of 32 hospitaks with malLari during the entire .riod of operation

in the Mediterranean (formerly North African) Theater of Operatiouj,

U.S. Army, to August 1944 ------------------------------------------- 504

68 Malaria cases discharged from all hospitals in the Meditrwaaean (formerly

North African) Theater of Operations, U.S. Army, 15 September 1944 to

l May 1945 .....---------- -----.------.---------------------. W55

$9 Result* of study of duration of fever after start of treatment in 28 quininetreated cames and 24 Atabrine-t4eated eases of malaria -.-.-.-- ---------- 511

70 Incidence of attaWks of marlria reported by 27 hospitals in the Mediterranean

(forrmerly North African) Theater ot Operations, U.S. Army -------------- 515

71 Incidence of relapses due to muaria repo ted by 18 hospitals ui the Mediterraiwean (formerly NortL kfriean) Theater of Operations, U.S. Army. .- -... 515

72 Malaria patiento evacuated to the Zone oa Interior from the Mediteruanean

(formerly North African) Theater of Operations, U.S. Army, 25 hospitals

repocting ....................................................... 516

73 Experimental 6.14 tents with aulfamerazine, Atabrine, and sutfapyraaine. - 5- K

74 Representative• treatment schedulta o, ehkquine- ..................... 5%

75 Relative e.fteiecy ot quinine, quiiacrmne bydroheloddi, sntd chimorquine

in troatnwnt of acute attacks of utea s malar........................ 569

76 Results of treatment in tout 1groutp of patients admlnuietrd antiltaiarl

drsup for acute attacks of e•as mslaria of PacAe origin............. 84
CHAPTER I

Respiratory Diseases

Yale Kneeland, Jr., M.D.

GENERAL CONSIDERATIONS

Diseases of the respiratory tract may be divided into two groups: The

acute infections and the chronic diseases which iay or may not be infectious.

Most of these conditions will be dealt with in this chapter, although certain

exceptions will be made. For example, in World War 11, the interrelationship of tonsillitis, scarlet fever, rheumatic disease, and nephritis was intensively studied; the subject of streptococcal infections as a whole will be

discussed elsewhere. Similarly, two chronic infections, tuberculosis and coccidioidomycosis, will be described by others. Lastly, chronic sinusitis, aerootitis, and the like, are primarily the concern of the otologist and will not

be considered here.

The acute respiratory diseases which immediately come to mind are the

common cold, influenza, and pneumonia. These are communicated by droplets and droplet nuclei and are thus allied to certain virus infections, such

as measles, which are also presumably transmitted in this way. Certain

communicable diseases of childhood will also be included here. Cerebrospinal fever and ,iphtheria, however, although their portal of entry is the

respiratory tract, will be discussed elsewhere in this volume. Clinical syndromes of unknown etiology, bizarre manifestations occurring only in localized outbreaks and not generally recognized as disease entities, are not included. This still leaves a large field for discussion.

Any general consideration of disease in World War II immediately invites comparisn with the experience "i World War I. Exact comparisons

of morbidity and mortality of acute respiratory diseases in the two wars are

not, however, possible for two reasons- First, more exact knowledge of the

dismam. led to a change mi terminology; and second, certain new concepts,

for example, that of atypical pneumonia, evolved. In spite of this, a rough

and startling comparison may be made of the 46,640 deaths from influenza,

lobar pneumonia, bronch-pneumonia, bronchitis, and measles in the First

World War,' roughly 73 percent of total deaths from di.ease. and the 1,285

dleaths from the same causes in the Second World War when an army well

over twice the size of that of World War I was mrbilizel for a longpr period.

Faetors which played a role in this extraordinary chang, in i11portai;i-e

of ti* diseas* just mentioned were the advent of sulfonamides and anti-

'Tb. M,•~IkuI Vart•ualt of the Vntotd Mate,* Army Ia the Wortal War. W*.biug1tnn- 11-8.

OGavrmqM¢t Prtntlng 0fro. 120. we, IX
2 INFECTIOUS DISEASES

biotics, the absence of pandemic influenza of the 1918 type, all apparent

change in the whole pattern of respiratory infection between the wars, and

a greater degree of immunity to certain communicable diseases in the general

population. The last was probably brought about by greatly increased communications which lessened isolation of rural areas. In addition, the almost

universal roentgen examination of the chest at induction undoubtedly lowered the incidence of chronic pulmonary diseases found in troops during

World War II.

In the following pages, the occurrence and course of each disease in

question during World War II is discussed, with emphasis placed upon problems of diagnosis, treatment, and general management which were significant

in a military sense. The chief military significance of many of the acute

communicable diseases is epidemiological, and this aspect of the question has

been exhaustively presented in other volumes in the history of the Medical

Department in World War 11.2 It is obvious that in many instances information will overlap. Some of the material will of necesity be repetitious.

Insofar as possible, proper names are avoided in the text, but where published material has been drawn upon, full acknowledgmnent is given. Other

sources employed are as follows: Preliminary data from the Medical Statistic' Division, Office of the Surgeon General; the writer's own notes while he

served as consultant in an oversea theater; essential technical medical data

sent in by various theater surgeons; reports submitted by medical con'aultants

throughout the world; and other unpublished notes, manuscripts, and memorandums in the Professional Service Division, Office of the Surgeon General.

Part I. Acute Respiratory Diseases

COMMON UPPER RESPIRATORY INFECTION

Introduction

The term "common upper respiratory infection" includes a leterogeneous

group of ill-defined conditions. In fact, it is a kind of scrapbasket which

encompasses all the acute respiratory diseases after eliminating the pneumonias and influenza. In a general way, the group includes the common

cold; nasopharyngitis which may or may not be due to the influenza virus;

infection of the pharynx and tonsils produced by certain micro-organisms,

such as the hemolytic streptococcus and Vincent's organisms; and bronchi3 (1) Medical Department. United States Army. Prrventliv Medicine In World War II. Volume

IV. Communicable Diseames Tranumitted Chiefly Through Respiratory and Alimentary Tracts.

Washington: U.S. Government Printing Oflce. 1968. (2) Medical Department. United States Army.

Prventive Medicine In World War ii. Volume V. Communicable Diseases Transmitted Through

Contact or By nitnkoowm Meana. Washington: U.S. Government Printing Offiee. 1960. (3) Medical

Department. United States Army. Preventive Medicine In World War It. Volume VI. Communicable Diseams: Malaria. (In press.1 (4) Medical Department. United Stat" Army. Preventive Medicine in World War II. Volume VII. Communicable Diseases: Artbropodborne Diseases

Other Than Malaria. (In preparatlon.)
RESPIRATORY I)ISEASES 3

tis. The latter is a loose term limited by some physicians to cases in which

dry rales are audible; that is, the asthmatic type, while others may use it to

describe an acute respiratory infection with substernal soreness and paroxysmal cough. It is probable that the viruses of common respiratory diseases,

influenza, and atypical pneumonia can all produce this clinical picture, and

it may also be the result of infection by such organisms as pneumococci or

ilemophilus i nfluetwae following a cold. InI any cases, it is not an etiological

eutit%

The common cold had been shown before World War II to be primarily a virus disease. Experimental s idies are handicapped by the fact that

only man and the anthropoid ape are susceptible to the virus, and such questions as that of immunity and whether the virus is an entity or whether

several distinct viruses exist were not settled. The Commission on Acute

Respiratory Diseases of the Army Epidemiological Board (Board for the

Investigation and Control of Influenza and Other Epidemic Diseases in the

Army) during the war undertook, under the direction of Dr. John H.

Dingle, to investigate the transmission of common respiratory diseases. Evidence was produced 4 that there are at least two viruses: One, the coryzal

type with it short incubation period, producing little if any active immunity;

the other, with a longer incubation period, giving rise to more constitutional

symptoms, often attended by fever, and conferring immunity against homologous reinoculation. The second type came to be known as "undifferentiated

respiratory disease." As the number of transmission experiments was small,

there is no information as to the relative frequency of infection with these

two agents. Recent observations by Atlas6 suggest that more viruses of

common respiratory infection may exist.

The presence of pathogenic bacteria in the upper respiratory tract adds

to the complexity of the etiology of common respiratory diseases. Purulent

complications, such as otitis and sinusitis, are due to bacterial infection, but

there is no proof of the role played by identified pathogenic organisms in the

production of subacute catarrhs, sphenoethmoiditis. and the like. The best

opinion during the war. confirmed by the use of chemotherapeutic agents in

adults, was that the average cold is a fairly pure virus disease, but that the

relationship of virus to bacteria was often not clear.

Colds are, on the whole, more serious in infants than in adults. Infants

usually develop a fever with a cold, and complications are more frequent.

SDocbes. A. R.. Mills. K. C.. and Kneeland. Y.. Jr.: Studies on the Common Cold: Cultivation

of Virus In Tissue Medium. J. Exper. Met!. 63: 559-579. April 1936.

'Comminmson on Acute Respiratory Diseases: Experimental Transmission of Minor Respiratory

Illness to Human Volunters by Filter-Passing Agents. 1. Demonstration of Two Types of Illness

Charactvrled by Long and Short Incubation Periods and Different Clinical Features. II. Immunity

in Rlnoeulation With Apnts From the Two Types of Minor Respiratory Illness and From Primary

Atypical Pneumonia. J. Clin. Investigation 26: 957-973: 974-982. September 1947.

SAtlas. L. T.: Minor Respiratory Diseases; Studies With Four Agents in Human Volunteers.

Abstract in J. Clio. investigation 32: 552-553. June 1963.

s Cecil. R. L. Plummer. N.. and Smnllih. W. 0.: Sulfadlaslne In the Treatment of the Common

Cold. J.A.M.A. 124: 6-14. 1 Jan. 1944.
4 INFECTIOUS DISEASES

Various pathogenic bacteria are more conspicuous in cultures made from

children,7 and this suggests that they may have some influence on the severity of colds even in the absence of definite purulent complications. Controlled studies made during the early war years of the use of sulfonamides

in very highly susceptible children support this concept.8

It was the writer's impression that soldiers reacted to common respiratory diseases in a manner more suggestive of childhood than of adult life.

They tended to develop fever of higher degree than that seen in general civilian life. Youth, exposure, and crowding probably contributed to this clinical pattern. Incidence of infection with the virus of undifferentiated respiratory disease may have been higher in the Army than in civilian life. Whatever the reasons, the acute phase of the common cold was apt to be more

prostrating to soldiers than to office-working civilians. However, the soldier's

convalescence was usually rapid.

Severe throat infections caused by the hemolytic streptococcus, scarlet fever,

and rheumatic fever will be discussed elsewhere. However, a certain proportion of admissions to the respiratory service of an Army hospital were

infections caulsed by this organism. Various complications to the usual sore

throat or inflammation of the lymphatic tissue are recognized, but in the

Army the most common was peritonsillar cellulitis.

The clinical picture of exudative pharyngitis is well recognized, and when

an acute tonsillitis or pharyngitis is observed showing whitish exudate, most

physicians assume it is caused by hemolytic streptococci. However, when

endemic exudative pharyngitis was studied closely by the Commission on

Acute Respiratory Diseases,9 in only about 50 percent of cases could the

hemolytic streptococcus be recoverd on culture and in only half of these

was there a rise in the titer of streptococcal antibody during convalescence

to suggest that the organism was playing an important role in the disease.

Since in only 25 percent of the cases of endemic exudative disease was the

laboratory evidence for streptococcal infection complete, the Commission

designated the other camtes as nonstrelptococcal exudative pharyngitis, and

some speculation occurred as to the possible viral origin of this condition.

Although, in the aggregate, cases of proved hemolytic streptococcal pharyngitis differ clinically from the nonstreptococcal variety, mild cases may be

indistinguishable.

Vincent's organisms may also at times produce throat lesions which resemble streptococcal infections. The appearance of a typical case of socalled Vincent's organisms differed, however, from that of a streptococcal

infection. The thick pseudomembrane and the tendency to ulceration were

7 Kneeland. Y., Jr.. and Dawes, C. F.: Studies on the Common Cold: The Relationship of

Pathogenic Bacteria to Upper Respiratory Disease In Infants. J. Exper. Med. 55: 735-744. May 1932.

8 Siegel, M. : Studies on Control of Acute Infections of the Respiratory Tract. 11. Oral Administration of Sulfadlaxine at the Onset of Acute Respiratory Illness. Am. J. Dig. Child. 66: 114-120,

August 1943.

9 Commission on Acute Respiratory Diseases: Endemic Exudative Pharyngitis and Tonsillitis;

Etiology and Clinical Characteristics. J.A.M.A. 125: 1163-1169. 26 Aug. 1944.
RESPI RATO )R Y ! I SEASHeS 5

characteristic, but differential diagnosis was not always possible, and it was

always necessary to rule out diphtheria. Vincent's stomatitis presented itself

often as only a dental problem, but occasionally the throat was involved as

well as the gunns; likewise, Vincent's infection of the throat without involvemenit of the gums was also encountered. A comparison of the admission rates

for the various designations of Vincent's infection in World Wars I and 1I

is presented in table 1.

TAntLE 1.-Admission rates for the rarious designations of Vincent's infection in the U.S. Armny

during World War I and World War 11

[Rate expressed as number of cases per annum per 1,000 average strength]

Admission rate

Diignostic terminoloty World War II

World War I

1942-45 194-43 194445

Trench mouth -------------------------------------- 0.02 0 1.94 0

Vincent's angina -------------------------------------- 1.56 0 0 0

Vincent's infection (not elsewhere classified) ------------ 0 0 2. 30 0

Vincent's infection (all forms) ------------------------ 1. 58 3. 93 4. 24 3. 73

I Enlisted personnel only.

Experience in the Continental United States

Noneffectiveness

Common upper respiratory infection was the most prolific cause of noneffectiveness in the U.S. Army. A graphic representation of its incidence in

the Army from 1925 to 1945, inclusive, would show a sharp rise around the

beginning of each year. An unusual peak was reached around the beginning of 1941, when no major general epidemic was prevalent. This military

peak was coincident with a rapid increase in mobilization, the opening of

new camps, and the hurried assembly of large numbers of unseasoned civilians.

A careful statistical analysis presented by Dr. Philip E. Sartwell in

another volume in the history of the Medical Department in World War II

shows that the magnitude of incidence of common respiratory diseases in any

area is related to the proportion of new recruits.10 It is conceivable that the

unexpected increment of respiratory infection in recruits was due to infection with the virus of undifferentiated respiratory disease; that is, the one

which leaves some active immunity in its wake. The seasoning of troops is

of military importance insofar as common respiratory diseases are concerned

as it governs the amount of noneffectiveness to be expected.

For the remainder of the war, the curve of incidence of common respiratory diseases in the United States was astonishingly symmetrical. At about

to See footnote 2 (1), p. 2.

639243--63-3
6 INFECTIOUS DISEASES

the same time during each war year, there was a recurring peak of almost

the same. dimension. Individual differences in type of disease and frequency

at various stations were cancelled out by the large numbers and wide geographic distribution.

Streptococcal infections were particularly numerous in the eastern slopes

of the Rocky Mountains and the Great Lakes area. Here, they were the subject of considerable study both in their less conspicuous form as part of the

mosaic of common respiratory disease and when they became epidemic and

were associated with scarlet fever and rheumatic fever. In cases associated

with common respiratory disease, treatment varied in different stations. The

types and amount of sulfonamides employed differed, although, when available, sulfadiazine was probably the most widely used. Controlled studies 11

in large numbers of cases indicated that sulfadiazine had no more effect

than the routine APC capsule on the duration of the febrile period or on

the length of hospital stay. In more severe cases, however, the drug seemed

to limit spread, to lessen cervical lymphadenitis, and to prevent the development of frank abscess.

A study of air disinfection directed by the Army Epidemiological Board

demonstrated that certain glycols, when vaporized, killed micro-organisms 12

and also influenza virus.13 These substances seemed wholly nontoxic in bactericidal concentration, but their efficacy was influenced by environmental

factors, such as humidity. 14 Under clinical conditions, they diminished airborne cross-infection. 15 These reports represented progress in the control of

infection, but practical limitations in the application of aerosols prevented

their use in the field. Oiling floors and bedding, another method aimed at

reduction of airborne infection, could not be shown to lower incidence of

common respiratory infection at Fort. Bragg, N.C.

In summary, common upper respiratory infection, while the commonest

single cause of military noneffectiveness, did not seriously interfere with the

training program. Prolonged disability as a sequel was almost entirely limited to the streptococcal infections. Mortality was insignificant.

Experience Overseas

Incidence.-The "transport cold" was a well-known feature of crossing

the Atlantic in wartime. Its widespread occurrence could be attributed to

11 Rusk. In. A., and van Ravenswaay. A. C.: Sulfadiazine in Respiratory Tract Infections; Its

Value in Treatment During the Winter of 1942-1943 at Jefferson Barracks, Missouri. J.A.M.A. 122:

495-496. 19 June 1943.

12-Robertson. 0. In.. Bigg, E.. Miller, B. F.. and Baker, Z.: Sterilization of Air by Certain

Glycols Employed as Aerosols. science 93: 213-214. 28 Feb. 1941.

I.3 Robertson. 0. IT., Bigg, E., Puck. T. T.. and Miller, B. F.: Protection of Mice Against Infection With Air-Borne Influenza Virus by Means of Propylene Glycol Vapor. Science 94: 612-61:.

26 Ic. 1941.

t4 Robertson, 0. n. : Sterilization of Air Withl Glycol Vapors. Harvey Loect. (1942-1943) 38:

227-254. 1943.

15 Harris. T. N.. and Stokes. J.. Jr.: Air-Borne Cross-Infection in the Case of the Common Cold.

A Further Clinical Study of the Use of Glycol Vapors for Air Sterilization. Am. J..M. Sc. 206 : 631-636,

November 1943.
RESPIRATORY DISEASES 7

the great crowding, poor ventilation, and the bringing together of troops

from many different units, thus introducing new infective strains. It was

commonplace for as high as 80 percent of U.S. troops to contract a cold in

the course of the voyage to England.

In spite of the climate in England, colder and damper than that to

which Americans had been accustomed, the noneffective rate due to respiratory diseases was considerably lower there than in the United States. The

fact that U.S. troops were seasoned when they arrived undoubtedly contributed to the lower rate. In some Americans, the cold had a tendency to become chronic, particularly during the first year overseas, but usually thereafter the men had become acclimatized, and chronic catarrh and cough were

much less marked. Individuals with a history of recurrent bronchitis were

apt to have difficulty with the English climate; in particular, any tendency

to asthma seemed accentuated. On the whole, however, the health of the

Army was excellent. and there was no undue incidence of sinusitis.

The incidence of common upper respiratory disease and influenza in the

European Theater ,of Operations, U.S. Army, pointed up the result of seasoning of troops. Lu November 1943, at the time of the epidemic of influenza A, the incidence was slightly higher than in January 1943 when influenza was not identified. After November 1943, there was a steady decline

so that in June 1944 and thereafter throughout the winter of 1945 the noneffective rate was at a very low level.

Clinical features of common upper respiratory infection in the Eurol)ean theater were not remarkable. Throat cultures yielded moderate numbers of higher type pneumococci and H. infiuenzae. The number of hemoI-tic streptococcus carriers was not large, and only sporadic cases of streptococcal sore throat appeared during the winter months. The tendency to

develop peritonsillar cellulitis has been mentioned. In 80 percent. of such

cases, the. hemolytic streptococcus could be cultivated. The remaining 20

percent. clinically indistinguishable, may represent cases of nonstreptococcal

exudative pharyngitis with an unusual degree of swelling of faucial pillars.

The incidence of common respiratory infection in the Mediterranean

(formerly North African) Theater of Operations, U.S. Army, was considerably below the average for the European theater and for the United States

in 1942 and 1943. In the summer of 1944. it was slightly higher, but at this

time morbidity elsewhere was unusually low. Common respiratory disease

presented one special problem in the Mediterranean theater-the likelihood

of its being confused with certain conditions which were endemic in the area,

particularly sandfly fever, malaria, and the preicteric stage of hepatitis.

Complications of common respiratory infections were not conspicuous, and a

total of but 10 deaths was recorded from such purulent infections as meningitis.

Incidence of streptococcal infections in the Mediterranean theater was

low. According to Circular Letter No. 16, Headquarters, North African
8 INFECTI•OUS DISEASES

Theater of Operations. Office of tile Surgeon, 22 March 11.144, subject: Prelpairatioti of Medical D)epartment Reports and Records. U.S. Army, the term

".streptotcv'eal sore tihroat" was applied oiliy to acute phar"ng itis anut tonsillitis known or ..uspected to he claused by the beta helnolytic streptococcus,

and foo0borne and milktorne outbreaks of septic sore throat. During the

l1l-month period fromi I May 1944 to 31 March 1945, inclusive, when streptococcal sore throat was relported separately, only 803 cases were reported.

Two snmall outbreaks were studied, one involving 112 men and the other, 38.

In both instances, it was thought that the streptocovcal infection was either

foodborne or milklhorne. Interestingly enough, not a single case of scarlet

fever developed as a result of these outbreaks.16

Atn acute outbreak of membranous pharyngitis in Sicily, in October

19)43. involved 96 men, 66 of whom were reported by the local civilian laboratories as having throat cultures positive for Corynebaeteriom diphtheriae.

Subsequent investigation by the staff of the 15th Medical Generai Laboratory,

Naples, Italy. threw doubt on the diagnosis of diphtheria in this outbreak,

a11d the theater consultant in medicine later expressed the opinion that in all

probability it was of strel)tococcic origin. The epidemic was explosive and

lh.1d the character of a foodlh)rne or inilkborne infection.

Vii'ent's angina (as distinct from stonmatitis or trench mouth) was reported only 990 times from the Mediterranean theater. Nevertheless, the

estiuaulted :admissions for the various types of Vincent's infection numbered

about 2,800R.

The adnmission rate for common respiratory infection in U.S. Army

F1 ores. ('China-Burnia-India, was comparable with that observed in tenperate climates, although the curve of incidence was relatively devoid of seassonal

peaks. Clinical characteristics were stated to be astonishingly sinmilar to those

noted in the lnited States, and the complications as frequent.

The Pacific area is so vast that generalizations aboit disease therein

would be dangerous. Conditions in parts of Australia are quite similar to

those in temperate regions elsewhere, and common upper respiratory infection conformed to the familiar pattent. On small tropical islands, however.

the incidence was stated to be much less under normal conditions, rising

sharply with the arrival of large numbers of troops. Studies have been reporte(d from such areas indicating that the I)acterial float was different fromn

that, noted in temperate climates. One study,1 7 for instance, included 27"2

throat and sputum cultures in which pneunimococci were found only 7 times.

It was stated in this report that pneumonia was very infrequent.

16 Report [Final). LI. Col. manlel W. Myers. MC. and Maj. Edward deS. Matthews, M1C. MTOUSA.

to omee of owe Surgeon General, subject : Respiratory Itseasem In the Mediterranean Theater of Operafi |,s, 1945.

17 Norris. R. F. : Symposium on Rtcnt Advances in .Medicine: Obhervationa on the Rpldemloiogy

and Bacteriology of Acute Rempiratory Tract Infeetions Among the Armed Forces of the Tropical South

Pacific. M. Clin. North America 29: 1418 1427. November 1944.
RESPIRATO1RY DISEASES 9

Two U.S. Navy observers "I stated that at least 50 percent of the cases

of eatarrhal fever ill ai South Pacific Area showed asthmalike inanifestalions. An eosinophilia of 8 to 10 percent was a common finding. The significance is obscure unless it is related to the high incidence of allergic disorders in the Tropics.' 9

Treatment.-Treatment of common upper respiratory infections was

symptomatic and lacked uniformity. Apart from streptococcal and Vincent's

infections, this group is not susceptible to chemotherapy. Nevertheless, it is

unquestionable that a great many viral infections were treated with sulfadiazine. The greater the experience of the medical officer, and the better his

facilities for laboratory diagnosis, the less unnecessary sulfonamides were

administered. The Professional Service Division advised that sulfonamides

should not be employed as a routine measure in the absence of definite indications. In doubtful cases, however, it seemed wise to prescribe them. If

certain indications were present, such as leukocytosis, symptoms of otitis

media, the presence of pneumococci in the sputum, or the clinical features of

acute tonsillitis, sulfonamides, and particularly sulfadiazine, were employed.

Sulfadiazine was used in the treatment of recognized streptococcal infections with prompt effect. It was likewise employed in Vincent's infection.

In the winter of 1945, studies were made, in a number of hospitals in

England, of the effect of local penicillin therapy, either in the form of a

throat spray or more frequently of lozenges containing 500 units of penicillin. Results in streptococcal infections were disappointing. The use of intramuscular penicillin was also reported in a few hospitals. Its effects in

streptococcal infection were said to resemble those with sulfadiazine. Local

and intramuscular penicillin gave striking results in Vincent's infections in

reports from England, but variable results were. obtained in a small numnber

of vases of Vincent's angina when penicillin was used intramuscularly in the

Mediterranean theater.

INFLUENZA

Introduction

The word "influenza" has been in general English usage since the 16th

century to designate irregularly recurring, widespread visitations of respiratory diseases. explosive in character and often associated with considerable

Mortality. Its recognition, until the introduction of the new serological

methods, rested upon epidemiological and not clinical grounds, and one could

not speak of an isolated case.

Good clinical descriptions of these outbreaks are available. Worldwide

attention was directed to the disease in 1889 because of its high incidence

IN Schnelerson, S. J.. and Wilson. W. A. : llumiual Feature of Respiratory Infections In a South

Pacific Area. V.S. Nay. M. Bull. 44: 1010-1012. May 1945.

19 Young. C. T.. Cook. W. R.. and Kawasaki, I. A.: Allergic Rhinitis and Asthma In Hawaii. War

Med. 3: 282 -290, March 1943.
10 INFECTIOUS DISEASES

and the relatively frequent association with fatal pneumonia during that

epidemic. The influenza bacillus, isolated by Pfeiffer from a number of those

fatal cases, was regarded for some years as the cause of the disease. Pandemnic influenza revisited the world in a more devastating form in 1918, toward the end of the First World War. Incidence was very high, distribution global, and the mortality appalling. In the U.S. Army alone, 24,604

deaths were attributed to the disease, and the number of deaths throughout

the world ran into millions." This catastrophe gave rise to a most intensive

scientific investigation of the disease which revealed that the Pfeiffer bacillus

could not be found in many typical cases of influenzal pneumonia. These

pneumonias usually had a mixed bacterial flora, among which pneunlot-o'i

and streptococci were prominent. The conclusion became inescapable that

some wholly different agent, not recognizable by ordinary bacteriologic means.

was the primary cause of the pandemic; that this agent, while occasionally

killing in a few hours, usually produced its lethal effect by paving the way

for a secondary bacterial pneumonia; and that the agent was often, though

not always, accompanied by Pfeiffer's bacillus. If this agent were not bacterial, it must be in the category of the filterable viruses.

The highest mortality of the 1918 pandemic was in the age group between 20 and 35 years. Susceptibility to the most severe form of the disease

,eeined to increase with age until about 35 years, when it fell off sharply.

This suggests that exposure to the primary agent in 1889 may have increased

resistance in 1918 and that the two pandemics were caused by the same virus.

Before and after the influenza outbreak of 1918, epidemic waves of acute

respiratory diseases occurred which were clinically indistinguishable fromn

mild cases in the pandemic. However, in these outbreaks, cases were uncomplicated and mortality was nil. These epidemics were called influenza of the

interpandemic type or simply epidemic influenza.

Intensive study of epidemic influenza during the past 15 years was begun in England where the first successful isolation of a virus capable of

infecting laboratory animals was achieved. Investigators throughout the

world have contributed to the work, the principal ones being Andrewes in

England. Francis in the United States, Burnet in Australia, and Smorodintsev in Russia. From these researches, a fairly clear pattern has emerged

although there remain distinct gaps in our understanding of the disease.

Two causative agents have been identified. Influenza A virus, the first

to be recognized, gives rise to epidemics which, in the Northern Hemisphere.

tend to occur biennially in odd-numbered years in the winter months, with

larger outbreaks every fourth year. Recent studies have shown that influenza A is a group of which the various agents are related but immunologica lyv distinguishable.

"0 The Medical Department of the United Stahis Army In the World War. Washington : Government Printing Office, 1925. vol. XV. pt. 2, p. 1:14.
RESPIRATORY DISEASES 11

Influenza B virus has appeared less regularly and less explosively and

has caused less severe epidemics. It was first identified in the United States

in 1940, and retrospective study of sera saved from the 1936 epidemic of

influenza found them to contain antibodies to this virus. Clinically, it cannot be distinguished from the disease caused by influenza A. Identification

may be by isolation of the virus or by demonstrating a rise in titer of antibody to one of the two viruses following an attack. However, in some cases

of influenza, identification of neither virus can be made. On the other hand,

during an epidemic of one type, a significant proportion of sera may later

show evidence of infection by the other type.21

Exceptions to the general statement that epidemic influenza tends to be

mild must be noted. For example, in Boston, Mass., in December 1940 and

January 1941, 66 cases of staphylococcal pneumonia with 21 deaths occurred

with coincident infection with influenza A in many of these.22 The Commission on Acute Respiratory Diseases recorded an outbreak of type I pneumococcal infection in Northville, N.Y., related to influenza B infection.2 3 In a

station such as the Army Air Force Technical School at Sioux Falls, S. I)ak.,

the already constant, rather high incidence of lobar pneumonia rose when

influenza appeared.

Active immunity acquired during an attack of influenza appears from

clinical and serological evidence to be of short duration. Complete correla.

tion between the level of serological immunity and susceptibility to the disease is not possible although the Commission found some evidence that patients with initially low antibody titer tended to be more severely ill than

those with an initially high titer. Reference will be made later to the

first large-scale attempt at active immunization of Army personnel with artificially cultivated influenza vaccine. 24

What light do these studies of influenza throw upon the pandemic of

1918? Slight epidemiological evidence that the pandemics of 1889 and 1918

were caused by the same agent and that therefore the interpandemic variety

is immunologically distinct has been mentioned. On the other hand, Shope's

work on swine influenza, a persistent disease which first appeared in 1918,

has suggested another hypothesis. The virus of swine influenza is related to,

but not identical with, influenza A virus. If it is in reality a survival in

another species of the 1918 human influenza, then one may suppose that

pandemic and interpandemic influenza are related. These questions may be

answered if another pandemic appears. Had such an event transpired during World War II, it would likely not have created the disaster of 1918

21 Lush, D., Stuart-Harris, C. H., and Andrewes, C. H.: The Occurrence of Influenza B in Southern

England. Brit. J. Exper. Path. 22: 302-304, December 1941.

22 Finland, M.. Peterson, 0. L., and Strauss, E.: Staphylococcic Pneumonia Occurring During an

Epidemic of Influenza. Arch. Int. Med. 70: 183-205, August 1942.

23 Commission on Acute Respiratory Diseases and the New York State Department of Health:

The Relation Between Epidemics of Acute Bacterial Pneumonia and Influenza. Science 102: 561-563,

30 Nov. 1945.

24 See footnote 19, p. 9.
12 INFE(CTI(US DISEASES

because complications and therefore mortality might have been very favorably affected by chemotherapy and antibiotic treatment.

For a complete account of the epidemiology of influenza during World

War 11, the reader is referred to the chapter by D)r. Thomas Francis, Jr.,

in another volume in the history of the Medical Department in World War

11?."- In the ensuing paragrap)hs, only the highlights most. relevant to the

interests of the Professional Service Division will be presented.

Experience in the Continental United States

Influenza was epidemic in the winter of 1940-41, but the major epidemic

took place at the end of 1943. It was explosive in character, but. not all Iairts

of the country were simultaneously affected. It is of interest that evidence

of infection with influenza A virus was found in three patients in May in a

station hospital in Michigan, and on 18 November, at the very beginning of

the epidemic, the same virus was recovered from two patients also in Michigan.•2t Thereafter, during the epidemic, influenza A appeared in various

parts of the country. As in other epidemics, in a number of clinically typical cases, no rise in antibody titer to influenza A virus could be demonstrated,

and there were rare cases in which influenza B virus appeared to be involved.

The epidemic was fairly widespread, both in the Army and among civilians, but like other outbreaks of the interpandemic type, the disease was of

very short duration, rather mild in character, and generally uncom)1licated.

Extensive clinical and serological studies were miade by the Commission at

Fort Bragg.27 Some of the conclusions drawn are as follows: Influenza with

typical features-sudden onset, severe malaise, painful eyeballs, flushed face,

inijected eyes, high fever, and leukopenia--occurred as a clinical entity in

only about half the serologically proved cases. Moreover, certain cases of

un(lifferentiated respiratory disease, prevalent at the time, presented the same

characteristics. In the aggregate, there were. significant differences between

undifferentiated respiratory disease and influenza, but individual cases could

not be distinguished clinically.

In some areas, the 1943 influenza epidemic assumed a slightly more

severe character. An example of this occurred at the Army Air Force Technical School in Sioux Falls where the first definite case was noted on 22

November. Following this, the incidence rose very sharply, the peak being

reached between 29 November and 1 December. Respiratory disease adlmissions per 1,000 per week for the 4 weeks beginning 14 November through

the week beginning 5 December were: 7.8, 13.7, 99.0, and 19.6, respectively.

.Altogether, 11.1 percent of the school population was affected. Age, length

25 See footnote 2 (1). p. 2.

26 Salk, J. E.. Menke, W. J.. and Francis. T.. Jr. : Identification of lnfluenzzi Type A in the Current

Outbreak of Respiratory Disease. J.A.M.A. 124: 93, 8 Jan. 1944. 27 Commisslon on Acute Respiratory Diseases: Studies of the 1943 Epidemic of Influenza A.

I1. Comparison of the Clinical and Laboratory Charaeterittic" of Influenza A and Undifferentiated

Acute Respiratory Disease ARD). An). J. IHyg. 48: 263-275. November 1948.
RESPIIRATOtRY I)ISEASES 13

of service, and duration of stay at the post had no detectable effect upon

susceptibility. Clinically, the cases were typical of influenza; throat cultures

on 137 patients showed hemiolytic strel)tooci in 17 and piceumococci in 7.

There was no evidence that tile el)idlemic engendered the sl)read of beta heniolyt ic st reptococci.

Associated peunmonitis was sai(d to be present in 5.8 percent of the

patients. In these cases, onset and symptoms were similar to the inicomplicated ones, blit the (lisease was more severe, the fever higher and of slightly

longer duration (3.2 days average), and there were rales at the bases together with X-ray changes. There was no associated leukocytosis, and silfonamides did not shorten the duration of fever. Influenzal l)Ineioniawhich this picture most assuredly suggests-has been very unconinonly found

elsewhere. In addition, at Sioux Falls, there was a sharp rise (from 1.5 to

nearly 5 per 1,0(X)) in the weekly incidenice of lobar pneumnonia. the peak

corresponding l)recisely with that of influenza.

B1 1943, the l)roduction of a vaccine tiade with artificially cultivated

influenza virus had been greatly improved, and a quantity of material containing both the A and 1, viruses was available for testing during the epidemic. Vaccination of nman with both the A and1 B viruses had been shown

not only to stimulate the production of antibodies but also to induce considerable immunity against the artificially induced disease.28 The active

immunity to type A was apparently of shorter duration than to type B, as

thoe vaccinated with the former 4 montlhs before the test were considerably

more sti.cep)tiile than those vaccinated 2 weeks before. A large-scale trial

seemed warranted. By great, good fortune, some 6.263 students in the Army

Specialized Training Program were vaccinated just before the epidemic.

The subsequent incidence of influenza was significantly less than that in 6,211

controls. the ratio being 1: 3.2.29

Evidence of influenza B infection was established in local outbreaks in

different parts of the continental Unite(i States, in the Canal Zone, Alaska,

and I awaii in the spring of 1945. The occurrence of some influenza in the

spring was reminiscent of the year 1918, and this led the chairman of the

Army Epidemiological Board to recommend that the entire Army be vaccinate(i. The proposal was approved by The Surgeon General, U.S. Army,

and was carried out in October 1945. From this uncontrolled experiment,

two conclusions30 could be drawn by comp)aring disease rates in the Army

with those of Iunvaccinated U.S. Navy personnel. The first was that mass

.1, 1 1 Francis. T'.. Jr.. Salk. J. E., Pearson. H. E.. and Brown, P. N.: Protective Effect of Vaccination Against Indueed Influenza A. Proc. Soc. Fxper. Blol. & Med. 55: 104-105. February 1944.

(2) Salk, J. E.. Pearson. 11. E.. Brown. I'. N., and Francis. T.. Jr. : P'rotective Effect of Vaccination

Against Induced Influenza B. Proc. Soc. Exlwr. 11ioi. & NM11d. 55: 106-107, February 1944.

*9 Commission on Influenza : A Clinical Fvalnation of Vaccination Against Influenza ; Preliminary

Report. J.A.M.A. 124: 982-995. 1 Apr. 1944.

.10 (1) Francis, T.. Jr., Salk. J. E., and Brace. W. M. : The Protective Effect of Vaccination Against

Epidemic Influenza B. J.A.M.A. 131 : 275-278. 25 May 1946. (2) Hirst. G. K.. Vilches. A., Rogers, 0..

and Robbins. C. L. : The Effect of Vaccination om the Incidence of Influenza 1B. Am. J. Hyg. 45:

96-101. January 1947.

G-192431. -63--4
14 INFE'TTIO)US DISEASES

vaccination had exerted a detinieitly pIroective effect in lowering mortality,

and the second, that influenza B was at better immununizing agent than infilenza A.

Experience Overseas

European theater

The history of influtenza in the U.S. Ariny in the European theater is

extraordinarily interesting in the light of what might have happened. Since

1931. epidemics had (wcurred ill England in the odd-numlbred years with a

larger wave every fourth year. Had this schedule Ibeen maillaned. .1 moderate out break wouil have occurred in .Januarv 1943 and a more severe one

in January 1945. The former would not have been serious as hospital facilities in England were more than adequate to care for alt troops then stlationed there. However, in 114.5 hospitals were already filled beyond normal

capacity. A sharp) epidemic at that time would have been extremely diffivult

to cope with and its effect upon the military situation woulh have heen

grave. It is not known why the epidemic did( not occur.

There is seldom a complete explanation of any epidemiological plhenomenon. In this instance, the events were as follows: The .January 1943

epidemic did not take place; it was delayed 10 mimoths, until November. when

a sharp, widespread epi(ernie developed. The rhythmic pattern of influenza

was thus disturbed. Late in 1.944. tlie senior co nsultant in infectious diseases,

European theater, ventured to predict to the surgeon. l7nited Kingdom Base.

that influenza would not o-cur in 1945. Partly as a result of this !rail! of

view. many hospitalized patients with trenchfoot were retained for ditty in

the theater rather than being Ixtarded home in order to increase ihe number

of available hospital beds. It reluired sorte fortitude to make tite prediction of a healthy winter front tile respiratory standpoint, but, minirdile div u.

precisely this ca(ie to pass, and the IU.S. Army went throughl the most critical period of the winter campaign with an extraordinarily low noneffective

rate (uite to respiratory disease.

Actually, the prediction was based on fairly soumd epidemiological and

inmunitological reasoning. It has fleen denionstruted that considerable imamnuity is left by epidemic influenza and that ouwbreaks of thie interpandemnic

type ot-cur at least t2 years apart. The delay in appearance of influenza in

1943 deflected what would have beet an almost intolerable extra hiulen in

19145 at a time when medical facilities were badly strained.

Observations made by English investigatorsmS on the behavior of tile

influenza viruses may be briefly suimmarized. is follows: Alt hough no epidemic occurred in the winter of 1943. a few slmnulic cas.s of influenza

showed rise in antilbly titer to infliuenza I. In flte spring and summer. a

few cases were noted with influenza A. This is a very unusual time for

MI Staart Ilanrri. C. Ii.. Govrpr. R. E.. and Mills. K, C. : InflueniR In l'rituln. 1942 43. Lanit 2:

o90 791, 25 Th'c. 1943.
RESPIRAT'OlY I)ISEASES 15

finding evid-i of influenza A infection. Then when the widespreud epidemic took place in November. influenza A was incriminated in imany -,ect iotis of the country.

Influenza in the U.S. Army paralleled this disease in the British civilian

population. The incidence of all respiratory infections in the U.S. Army

in the European theater reached a sudden peak in November 1943. with

almost as rapid a fall to a point somewhat above the preepidemic level, alld

a subsequent slower decline through the winter months. By June, at the

time of the invasion, the incidence was extremely low, and it remained low.

with much !,ss than the expected seasonal upturn, through the winter of

1945.

The great builk of the cases on whikh this curve is based fall inito lhe

category called comnnoit tipper respiratory infection. That the strikinig peak

of November 1943 represents superadded influenza is presumed because of

the explosive character of the epidemic, its clinical features, and serological

evidence. Tests were not done on a large scale in the Army, but a sufficient

number of sera from different parts of the country were examined to show

that the Army experience was quite similar to British civilian experience:

that is, a majority showed a rise in titer to influenza A virus.

In the Army, as -;th civilians in England and elsewhere, all inflmien',za

encoutntered (luring World War 11 was mild and uncomplicated. The patients were moderately, not severely, prostrated, and the disease was a short

one with a febrile course of 2 or 3 days. To all intents and purposes, puenmonia did not oc'cr. Influenzal pneumonia of the 1918 type was not se.en.

A reported increase in civilian deaths in England was found by the Ministry

of Health to be due to an increased mortality caused by sach conditions as

congestive heart failure, associated with the general rise in the respiratory

disease rate. In the U.S. Army, no deaths were attributed to influenzal

pneumonia. A few complications, such as otitis and sinusitis were obse4rved.

but they were not tispicuotis.

As for the clinical features of the epidemic. the familiar sympwlolms

were encountered in matiny H I owever. the writer wits more iilprpe.,-4l

with the widespread character of the disease than by its uniformity of behavior. As he had observed in other epidemics of influenza, a typical case

was hard to define. For example. at an airbase in East A.njrlia in Novembe-r

1943. a large number of patients were trented. but many of tht.se 1I:mi persistent colds caught on their recent trannslx1 rt voVyage. and coumnliomin ulibIer

respiratory disease confu.•sed the phictmre of sudden ottbreak of infletnz.n.

Mf editerranean theater

Maj. (later Lt. (Col.) Daiuiel W. Myers. MC. and ('apt. (later It. ('ol.)

Edward deS. Matthews, M(I. stated in their report oil respiratory dii.s-ase

33 Andtriw- . r. It . ant C.1ovirs R, K. inflitsna A" tiuibro-k of O•-otnr Dremmber. 1i4.3. IAncot 2 : 1#4 105, 22 Jl'y 1944.
16 INF~EC'TIOUS DISEASES

ill tilie .1fliterraiietin theater: "fiifliieiiza, was reportedI 11,094 times in

A'FOUSA, thus apparently making ill) 50) lperceilt of como eprtr

infections, however, it, is dIoubtful whether true influenza was encountered

in 'MTOUSA."33 The authors mention tile fallacy of miaking the dliagnlosis

solely upon clinical criteria, as the same symnptoms occurred1 inl other dliseases,

such as sandfly fever, malaria, and hepatitis, prevalent inl the theater. There

were no reports of geometric increase Iin frequency of influenza-like respinatory disease front anv organization in this theater and inicidenice of acute

coinnmon respiratory diseases remainied withini expected seasonal range. Because of lack of sufficient, indication, iniflinezal virus studlies were not attemplte'd oti a large scttle. It is noteworthy, however. that byfrthe higlh st

peak for the annual rate of common resp~iratory dlisease (nearly 300) occurdin .January 1944 only very slightly afterteepdmcoinlnzA

in England and1 the UnitedI States. It seems unlikehy that the Mediteranmeanl

theater should have completely escapedl so widlesp~readl a visitation, aild

sulperaddled influenza wvould be a logical explanation for the shape of the

curve at that time.

Other oversea theaters

Rep~ortedl adlmission rates for influenza inl the Chinia-Burmla-Inldia theater mand the Pacific areas were low throughout the war, and the curves for

commion resp)iratory iinfectioni showý% no peaks suggestive of the superadded

effect of inifluenza.

So the history of influenza during World WYar 11 stands in happy coimtrast to that of Wvorld War 1. Pandemic influenza did not occur. Owiing

to thle prolomrat ion of the epidlemic cycle in thie mnidd~le of tile war. only one

important outlhreak took p~lac'e and that at a time whmen it could he hiandled

with ease.

PRIMARY ATYPICAL PNEUMONIA

Introduction

The terilm "prwimmar-N atypical l)ilelillololia- would have evoked polite

hicomipreltenision iii the averagre nmedical practitionter about 20 yea rs ago. and

today it is one of omir cominonest (liagnPOSes.

Pnieulilonias wvere orIiginlally classified onl anl anlat oilial basis: this was

followed by a combinied aniatomic'al -ciinical approach and, also. b-v an enl-

(leavor to i(Ieiti fy them etiologieallY. These three phases were oftent liarmonious. Thus, thle Comimon type of plie'l''"l'" appearing- as a1 prim~ar'y

(disease was lobar in dlist ribut ion; it had well-definied clinlical chlaIracterist ics.

anld it was (lite to the pneumnococcus. Therefore. "lobarm pneummoiiia" was

designlated an1 anlatomuical, cli inica,1 and( et ioiorical enlt 't . As thle i(lentitifca-

;IA Se.e fqo.tnote 10(. J'. S.
RESPIRATORIY 1 DISEASES 17

tion of pnelIulococcus types became more exact, the qualification "type I

lobar pneumonia" or "type Vii lobar pneumonia" was added.

Apart from the disruption of the pattern caused by the 1918 pandemic

of influenza, lobar pneumonia had maintained a fairly consistent record for

many years in the temperate zones as primarily a winter disease with a usual

mortality of about 30 percent in cases not specifically treated. It had been

subjected to exhaustive research, and a, great deal of knowledge had been

accumulated as to the mechanisms of recovery and immunity. Tile biology

of the pneumococcus was, perhaps. better understood than that of any other

micro-organism. By 1938, specific therapeutic sera had been produced for

more than 30 types of pneunmococcus.

"Bronchopneumonia" was also originally an anatomical term. but the

classification of bronchlmopneumonias clinically was much less clearly defined.

They formed a heterogeneous group. It was known that a number of microorganisms besides the pneumococcus could cause pulmonary consolidation

of peribronchial distribution. Most of these pneumonias., however, were

secondary; that. is. they occurred as complications of other diseases or surgical operations and in the aged and debilitated. Primary bronchopneumonias were recognized, but generally speaking they were relatively uncomnmon. Occasionally, the hemolytic streptococcus gave rise to primary broncliopnieumoinia. either in sporadic cases or in localized el)idemics, wvlIenm it

often followed in the wake of measles or epidemic milkborne sore throat.

One type of virus pneumonia. psittacosis, was recognized. but was admittedly

rare. As for influenzal pneumonia, this, to all intents and purposes, had

vanished after the 1918-20) pandemic.

1n 1938, two events occurred to clange the clinical concept of pneumonia. In the first place. in England, a chemotherapeutic agent. M. & B.

693 or sulfapyridine, was introduced which was highly effective against

pl)elmmiIoc(cea l infections. Intense interest was manifested in whether sulfapyridine would supplant serum therapy as the treatment of choice in lobar

letulm(lm ia and if it would constitute a successful treatment of tie bronchopneunmonias. At almost the same time. an increasing number of primary

pneumnonias. apparently not caused by the pneumococcus and quite obviously

not susceptible to chemotherapy, were being observed. A new disease entity

was rapidly suspected.

The principal characteristics of this disease were as follows: It seemed

to have a predilection for young adults; the onset was rather gradual; the

pulmonary consolidation was patchy and often showed a migratory ten-

(lency: there was no associated leukocytosis (at least in the early stages).

and the bacterial flora of the sputum was not different from that found in

normals: some patients were gravely ill but after a variable febrile period

complete recovery took place, with a very low overall mortality; and such

slight histological material as was available indicated that the process was

an interstitial pineumonitis with a mononuclear type of exudate. Strepto-
18 INFECTIOUS DISEASES

coccus viridan. was at first thought to be the cause, but this hypothesis

failed to be substantiated. With no evident bacterial etiology, the disease

was then presmuned to be due to a filterable virus.

But was it a new disease? Hospital clinical records between 1922 and

1935 contain infrequent descriptions of single cases exactly corresponding

with the description just cited. Furthermore, beginning about 1933, occasional notations in medical literature indicate that some observers were

aware of benign bronchopulnonary infiltrations simulating tuberculosis, and

localized epidelnics of an influenza-like disease associated with mild pneumnonitis had been described. It is likely that both of these conditions were

caused by the same agent or agents of the "new disease." Atypical pneumonias more or less conforming to the same description were likewise described as occurring during the winter of 1917-18.34 The following factors

probably caused the delay until 1938 in general recognition of primary atypical pneumonia: The more numerous and severe cases observed in that year,

the more exact bacteriological diagnosis of the familiar types of pneumonia,

and the introduction of the new chemotherapeutic agents.

Most of the increasing number of papers on primary atypical pneumonia

during the ensuing years were clinical descriptions, but the research work

was going forward. Broadly speaking, it is now generally agreed that

atypical pneumonia is caused by a virus but by far the majority of cases

are not due to the identifiable viral agents, such as psittacosis, ornithosislyluphogranuloma, and rickettsia. Endeavors to transmit the agent to laboratory animals, or to cultivate it, have been, on the whole, disappointing.

The most important studies of the etiology of primary atypical pneumonia

were performed during World War II by the Commission on Acute Respiratory Diseases under the direction of Dr. Dingle. Briefly, these studies were

as follows:

The disease was successfully transmitted from man to man by bacteriafree filtrates under conditions of quarantine.35 A minority of those inoculated developed atypical pneumonia, but otlers had less severe illnesses

which might be called bronchitis or common upper respiratory infection.

In other words, there is evidence that under epidemic conditions the virus

may produce many cases of nondescript respiratory infection for each one

of frank atypical pneumonia. Under experimental conditions, the incubation period was not quite so long as the 2 or 3 weeks which had been estimated from epidemiological studies of tie naturally occurring disease.

Two serological reactions which develop during convalescence from

atypical pneumonia in the majority of cases have been discovered. One of

34 See footnote 1, p. 1.

35 (1) Commission on Acute Respiratory Diseases: Transmission of Primary Atypical Pneumonia

to Human Volunteers. J.A.M.A. 127: 146-149, 20 Jan. 1945. (2) Commission on Acute Respiratory

Diseases: The Present Status of the Etiology of Primary Atypical Pneumonia. Bull. New York Acad.

Med. 21: 235-262, May 1945. (3) Commission on Acute Respiratory Diseases: An Experimental

Attempt to Transmit Primary Atypical Pneumonia in Human Volunteers. J. Clin. Investigation 24:

175188, March 1945.
RESPIRATORY DISEASES 19

these phenomena is the cold hemagglutinin; 36 the other is the agglutinin

for a certain strain of nonhemolytic streptococcus.37 These two agglutinins

are not identical, and their significance is not clear. There is general agreement that the particular streptococcus in question is not the cause of the

disease.

Experience in the Continental United States

The concept of atypical pneumonia was still a fairly new one in the

winter of 1941, and while the disease was recognized in most university

clinics, it was not familiar to the profession as a whole. In the summer of

1941, something in the nature of a mild epidemic of pneumonia which did

not respond to sulfonamide therapy occurred in southern training camps.

At the request of the surgeon, Fourth Corps Area, a small civilian mission 38

was dispatched in October to several southern training camps, notably Camp

Claiborne, La. It reached the conclusion that this was an epidemic of atypical pneumonia. The Surgeon General accepted a recommendation from this

mission that a permanent commission be instituted for the study of the disease, inasmuch as the Army seemed an ideal milieu for such a study. This

commission, established in December 1941, continued to work throughout the

war, first at Camp Claiborne, and later at Fort Bragg. It conducted intensive clinical and scientific researches on the subject of atypical pneumonia,

as well as other acute respiratory infections.39 Among many noteworthy

accomplishments of the Commission on Acute Respiratory Diseases were the

successful human transmission experiments. 40

The characteristics of the disease as originally seen at Camp Claiborne

were briefly described by the chief of medical service of the station hospital

and two of his colleagues. 41 They reported that 262 cases occurred during

a period of 4 months with a camp population of about 27,000. In general,

these cases were mild with a short febrile course. A few more severe cases

36 (1) Peterson, 0. L., Ham, T. H., and Finland, M.: Cold Agglutinins (Autohemagglutinins) in

Primary Atypical Pneumonias. Science 97: 167, 12 Feb. 1943. (2) Turner, J. C-: Development of

Cold Agglutinins in Atypical Pneumonia. Nature, London 151: 419-420, 10 Apr. 1943.

37 Thomas, L., Mirick, G. S., Curnen, E. C., Ziegler, J. E., Jr., and Horsfall, F. L., Jr.: Serological

Reactions With Indifferent Streptococcus in Primary Atypical Pneumonia. Science 98: 566-568,

24 Dec. 1943.

38 Drx. A. R. Dochez and Y. Kneeland, Jr., of the College of Physicians and Surgeons, Columbia

University, New York, N.Y., and Dr. Colin M. MacLeod, of the New York University College of Medicine,

New York, N.Y., all members of the recently created Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army.

39 (1) Dingle, J. H., Abernethy, T. J.. Badger, G. F., Buddingh, G. J., Feller, A. E., Langmuir,

A. D., Ruegsegger, J. M., and Wood, W. B., Jr.: Primary Atypical Pneumonia, Etiology Unknown.

War Med. 3: 223-248, March 1943. (2) Commission on Acute Respiratory Diseases: Epidemiology

of Atypical Pneumonia and Acute Respiratory Disease at Fort Bragg, North Carolina. Am. J. Pub.

Health 34: 335-346, April 1944. (3) Dingle, J. H., Abernethy, T. J., Badger, G. F., Buddingh, G. J.,

Feller, A. E., Langmuir, A. D., Ruegsegger, J. M., and Wood, W. B., Jr.: Primary Atypical Pneumonia,

Etiology Unknown. (Parts I, 11, and II1.) Am. J. Hyg. 39: 67-128, January; 197-268, March;

269-336. May 1944. (4) Dammin, G. J., and Weller, T. H. (in collaboration with Commission on

Acute Respiratory Diseases): Attempts to Transmit Primary Atypical Pneumonia and Other Respiratory Tract Infections to the Mongoose. J. Immunol. 50: 107-114, February 1945.

40 See footnote 35, p. 18.

41 Moore. G. B .. Jr.. Tannenbaum, A. J., and Smaha, T. G. : Atypical lPneumionia in an Army ('anp.

War Med. 2: 615-622, July 1942.
20 INFECTIOUS DISEASES

were noted, and two patients dieti, althlough there wvas some question of

the diagnosis in one of thenm. Men over 28 years old were being released

from the Army' at this timle. Occasionally, the routine p)redischarge X-ray

in these indiviuhals shlowedl areas of infiltration resembling tuberculosis

which cleared llup quite rapidly. This, taken together with the hlumlan tranismission experiments just cited, suggests that there were p)robably many

"walking cases" of (lhe disease. The rate of 262 eases in 27,000 troops over

a period of 4 months nmay thus not indicate the true communicability. That it

mayv be, quite high under special circumstances is indicated by an occasional

rt. For examplle, onl one occasion about 40 percent of the mnen out of it

;e comipany engaged as "cleanup teamis" in at wire operat ions School

.a tracted the disease. 42

'

Shortly after the C7ommiission begranl its activities, at chiange inl termiiniology of the pnuenmonias was miade by The Surgeon General. so that thenceforward priniar atyp~ical pneumonia was rep~orted .as suchl.43 CIlinlical recognition of the dlisease becamie increasingly accurate in many hospitals, although there. is reason to believe that the officially reported incidence was

always low. A perusal of the large number of papers submitted to nUhe

.Surgeon General to be approved for p~ublication convinces one that the

clinical characteristics of the disease wvere fairly uniformn. The studenit is

referred to the original articles44 published by the Conmmission onl Acute

Respiratory Diseases for the best account of the nmanifestations and epidemniology of t he disease.

The. annual incidlence of primary atyp1ical~ pneunionia in Army camps

throughout the war was remtarkably constant. The highest. admission rate

inl the United States (8.95 petr annum per 1.000 average strength) occurred

in 194:1, although the validity of this may be questioned owving, to chlange in

(liagnostic criteria. Seasonal variations in adlmission rates were. m~ore

mnarked: with striking exceptions, rates were usually highier in the winter

monthis. Generally speaking, cases of atypic-al pneumonia showed anl iminimense. numerical prep~onderance over lobar pneumionia, rates for wvhichi were

exceedlingly low. One report, from Truax Army Air Field. MNadison. Wis..

gives this ratio as approximately 10: 1. At. Scott. Field, Blelleville, Hl., 738

cases of atypical pneumnonia were seen during a period when 24 lobar pnue- mnonias and 3' bacterial bronchiopneunmonmas ot-curred. 4

~ tJfesnBr

racks. 'Mo., 1,862 cases of atypical pneumonia were described as contrasted

with 62 lobar pneumionias occurring over the same period of time.46 These

42 ldstrom. L. G.. and Rosenberg, B.: Primary Atypical Pneumonia. Bull. U.S. Army 11. Dept.

No. 81. pp. 88-92. October 1944.

43 Circular Letter No. 19, Office of the Surgeon General. U.S. Army, 2 Mar. 1942.

14 See footnote 39 (1). (2). nnd (3). p. 19.

45 Owen. C. A.: Primary Atypical Pneumonia. An Analysis of 738 Cases Occurring During 1942

at Scott F'ie](]. 111. Arch. Int. Med. 73: 217-231, 'March 1944.

46 Van Ravenswaay. A. C., Erickson, 0. C., Reh, E. P., Sleklerski, J. M., Pottash, R. R., and

(IIl)Ie.11. : Cliniical Aspiec'ts ()f Primary Atypical Pneumonia : A Study Bamsed on 1.862 Case., Reen

at station Hjospital. Jefferson Barracks, Missouri, from June 1, 1942 to August 10, 1943. J.A.M.A.

124 : 1 -0fl 1 Janu. 1944.
RESPIRATORY DISEASES 21

cases of atypical pneumonia were said to be more severe than the average

thus far described in the Army. Two deaths resulted. Pleural effusions

appeared in 9.7 percent of cases; about one-quarter of these were large.

Between 1942 and 1945, 110,133 admissions for primary atypical pIeumonia were reported in the Army in the United States with 101 deaths as

compared to 50.807 admissions and 69 deaths overseas. Atypical pneumonia

was never of sufficient magnitude to interfere seriously with the huge training program. On the other hand, the rather prolonged course of the disease

and the lengthy convalescence often affected the military career of the individual concerned. Because of the rarity of complications and late sequelae,

chronic invalidism did not occur.

Experience Overseas

European theater

D)uring the late summer and autumn of 1942, there was a mild epidemic

of atypical pneumonia among U.S. troops in the European theater. The

incidence of lobar pneumonia was very low: in one hospital, for example,

during one of the autumn months, the chief of medical service reported 3

cases which might be called typical pneumonia and 70-odd cases which were

atypical. As in cases described in the States among military lpersonnel. these

cases were milder on the average than those presented in earlier reports from

civilian hospitals. The febrile course was shorter, being perhaps 5 to 7 days

instead of 10 to 12, and the tendency to relapse, or prolonged migratory

pneumonia, was much less pronounced. Moreover, such bizarre manifestations as erythematous skin lesions, liver involvement. pericarditis. anid so

forth, which had been noted on rare occasions in civilian outbreaks, were

not observed. A true pleuritic pain, so commonly found in lobar pneumonia.

is not a feature of atypical pneumonia. Sterile pleural effusions may occur;

when they do, they are usually small and often interlobar. Occasionally.

however, they may lpersist for an appreciable period, and in 1942 when this

was so they were conventionally considered highly suggestive of tuberculosis

It was pointed out then that a small effusion need not be regarded as tubterculous, and where there was any evidence of associated pneumoinitis, p~ast or

present, atypical pneumonia was probably the cause.

In the autumn of 1942, a board composed of an epidemiologist, Lt. ('ol.

(later ('ol.) John E. Gordon, MC: a clinician, Lt. Col. (later Col.) Yale

Kneeland, Jr., MC: and a virologist, Maj. (later Col.) Ralph S. Muckenfuss, MC, was appointed to consider the subject of atypical pneumonia. The

results of its deliberations were embodied in a circular letter, which outlined

the history and clinical features of atypical pneumonia, together with advice as to management. It was pointed out that sulfonamides were ineffective in this disease and that, if the diagnosis could be made with reasonable

certainty by a mature clinician with an adequate laboratory at his disposal,

sulfonamides were contraindicated. Where the diagnosis was in doubt, or
.)'2 INFECTIOUS DISEASES

satisfactory laboratory facilities unavailable, sulfonamnides in full dosage

were recommended for a brief but definitive therapeutic trial. Attention

was drawn to the possibly prolonged residual effects of an attack of atypical

pneumonia and to the need for a considerable rehabilitation before the

soldier returned to duty.

D)uring the winter and summer of 1943. atypical pneumonia was less

Conspicuous. The phenomenon of cold hemagglutination was described and

carefully reported in relation to a fairly large series of cases by a medical

officer in the European theater almost simultaneously with independent discovery of the phenomenon in the United States.47 Rare cases of encephalitis

complicating the pulmonary lesions were encountered in the theater. In one

fatal case, histological evidence was found at autopsy.48 In two others,

encephalitis was recognized clinically from symptoms and spinal fluid findins.49

Atypical pneumonia was not generally recognized by the bulk of the

British medical profession in 1942, although scientific investigators were

aware that a form of pneumonia, presumably of viral origin, had recently

come into prominence in America. Contacts between British investigators

and American medical officers were soon established. Professor Bedson,50

for example, tested serum from several convalescent U.S. soldiers for antibodies to psittacosis virus with negative results. Dr. C. 11. Andrewes tested

sera for antibodies to influenza virus, similarly with negative results. The

possibility that pigeons imported by the U.S. Army Signal Corps might

introduce an ornithosis-like disease in humans into the British Isles seemed

remote when it was found that native British birds were already infected. 51

It seems highly illikely that atypical pneumonia was brought into the British Isles de novo by the 17.S. Army. In fact, ward rounds in any British

Army hospital in the autumn of 1942 convinced one that the disease in a

mild form was present. Stimulated in part by American interest in the

disease,5 2 British physicians shortly began to recognize it. and in 1943 an

excellent descriptive article 5 appeared in the Laneet.

In the autumn of 1943, at a second meeting of the Atypical Pneumonia

Board (p. 21), it was recommended that routine cold agglutinin tests be

performed in hospitals, that careful records be kept, that a summary be

made of the results of the test in a large series of cases, and that informa47 See footnote 36 (1). p. 19.

4lPerrone, H.. and Wright, M. : Fatal Case of Atypical Pneumonia With Encephalitis. Brit.

M.J. 2: 63-65, 17 July 1943.

49 Hein, G. E. : Primary Atypical Pneumonia. Lancet 1 : 431-432. 3 April 1943.

50 Sir Sam Phillips Bedson, M.D., F.R.C.P., F.R.S., Consulting Advisor in Pathology, Ministry of

Health.

51 Andrewes, C. H., and Mills. K. C. : Psittacosis (Ornithosis) Virus in English Pigeons. Lancet 1:

292-294, 6 Mar. 1943.

52 Brown. J. W., Hein, G. E.. Eliman. P.. and Joules, H.: Discussion on Atypical Pneumonia. Proe.

Roy. Soc. Med. 36: 385-390. June 1943.

53 Drew, W. R. M.. Samuel, E.. and Bail, M. : Primary Atypical Pneumonia. Lancet 1 : 7f1-765,

19 June 1943.
RESPIRATORY DISEASES 23

tion be obtained as to the frequency of second attacks. Some data were collected, but no imni)ortant conclusionis coull be drawn.

The annual admission rate in the European theater for primary atypical pneumonia was 9.23 in 1942, 6.35 in 1943, and only 4.80 in 1944. Apart

from the late summer-autunin peak of 1942, these rates were considerably

lower than in the United States. This may he partly ascribed to the fact

that the virus of atypical pneumonia seems to have been less widespread and

virulent in England than in the United States. Seasoning of troops mlight

have played a role also, but one is inclined to doubt that it was very large,

since rates in the Mediterranean theater, where the troops were also seasoned, were much higher than at home for the years 1944 and 1945.

An interesting observation was made in the winter of 1945 at the 7th

General Hospital in Dorsetshire, England. Two patients were studied who

showed extremely high cold agglutinin titers with associated hemolytic crises.

One of these episodes followed a definite attack of atypical pneumonia. This

phenomenon has since been discussed in considerable detail Iy Finland and

his coworkers.54

Mediterranean theater

Available statistical reports in the Mediterranean theater do not provide

a reliable indication of the relative frequencies of lobar and atypical pneumonia before May 1944. From 1 May 1944 to 31 March 1945, inclusive, 7,142

primary pneumonias were reported, of which 5,684, or approximately 80

percent, were classified as atypical pneumonia. 55 If this percentage holds for

the entire history of the theater, it would seem that the preponderance of

atypical pneumonias over bacterial pneumonias was less than in some other

areas.

The general situation in regard to pneumonia in the Mediterranean theater as reported in 1945 (p. 8) is described in the following paragraph:

The pneumonia rate in the theater remained at comparatively low levels until January

1944 when a marked increase was noted principally in the troops based In Italy. This

increased incidence was manifested by both Base Section and Army troops, the peak level

for this season occurring in the Peninsular Base Section during April 1944 when the rate

was 38.5 per 1,000 per annum. The rate in Italy remained high until July, the Incidence

In Army falling more precipitously and at an earlier date than in the Base. In January

1945 a similar rise in pneumonia rates began, the rate in March 1945 reaching a level substantially higher than that In the preceding year. Peninsular Base Section and Fifth

U.S. Army troops participated in the rise, and once more the Incidence was highest in the

Base, attaining the surprising level of 82 per 1,000 per annum in the month of March. It

is of interest, though an explanation is not offered, that pneumonia in the Army Air

Forces reached its height in February 1945 and fell precipitously in March when Fifth

U.S. Army and Peninsular Base rates were still ascending. The case fatality rates showed

54 Finland, M., Peterson, 0. L., Allen, H. E., Samper, B. A., and Barnes, M. W.: Cold Agglutinins. 1. Occurrence of Cold Isobemagglutlnlns In Various Conditions. II. Cold Isohemagglutinins In Primary

Atypical Pneumonia of Unknown Etiology With a Note on the Occurrence of Hemolytic Anemia in

These Cases. J. Clin. Investigation 24: 451-457; 458-473, July 1945.

W See footnote 16, p. 8.
24 INFECTIOUS DISEASES

a fall rather than a corresponding rise in the years (f greatest Incidence. In 11943, 24

deaths occurred in 1,427 luneunuionas, a case fatality rate of 1.68 percent. There were

7.414 pneutuonlas and 35, deaths in 1944, a rate of 0.47 percent. lDuring the first 3 itnonths

if 1145., 3,203 pneunionlias and 6 pneumlonia deaths were encountered, a case fatality of

0.18 Iwrcent. The quoted rates included all pneumonia deaths.

If SO percent of the pneumionia was atypical its incidence was at tinmes very

high.

Clinical descriptions of the disease in the Mediterraneari theater w'erc

generally similar to those published elsewhere. HIowever, several pee'tliar

outlhreaks occllrred which excited a goodl (leal of interest and were the subject of considerable inivestivattion. rhe report of Myers and Matthew., ( p.

8) described these in some detail. ()he took place in an isolation ward of

the 24th General Holspital in the Bizerte area. Tunisia, in the witter of

1943-44. Within at 9-day period, over half the latienlts and ward personnel (13 in all) contracted miid atypical pneunmonia. A tentmate of one of

tile affected aidnien and a substitute aidman also became ill, the latter 6 days

after the first contact. The outbreak appeared to have an unusually short

incubation period anti a high degree of communicability. Its origin (0cohl(

not be traced.

D)uring the 1944--45 pneumonia season, seven local outbreaks occurred.

One, of 82 cases in the personnel of one conipany. arose in Corsica in lDecember 1944, and the remaining six outbreaks occurred between I)ecemiber

and April in separate organizations in a 5-imile radius of North Central

Itaiy. The Corsican cases were as follows:

* * * The usual duration of fever was five days, nnixiuniu temperature varyin- fro•n

100° to 105°, and recovery without serious complications ensued in every case. Diagnosis

was established by chest X-ray examination in nearly every Instance. Two hundred cold

agglutination tests were performed by Capt. Joseph HI. Swartz. utilizing the sera froin the

82_ patients and a 2 percent suspension of washed huiman group 0 erythrocytes. In two

cases agglutination was observed with a serum dilution of 1: 32. In the remainder agglutination did not occur with serumn titer greater than 1: 8. There were no circumstances

incriminating an insect vector.

The extremely high attack rate and the negative cold agglutinin tests

suggest that this was not primary atypical pneumonia. The same report

gives a description of four localized, sharp epidemics occurring near Pagliana, Italy, and totaling at least 355 cases. These constitute additional evidence of the existence in Italy of a specific and different disease entity. One

of the involved units had an attack rate of 27.7 pemcent. The disease characteristically had an abrupt onset, with an incubation period apparently

varying from 17 to 23 days. Cold agglutinins were not found, and it was

suspected that, the etiological agent might have had an insect vector, a mite,

which l mwis found in large unihbers in the area used by one of the units

involved.

Two niore outbreaks. totaling 53 cases, oc(ciirred about 10 airline miles

i torthi-itortheast of Pagliana. These cases again differed in certain noteworoly respects front atypical pneliciWnia: that is, abruptness of onset, fre-
RESL'IltATOIIY IUsE.sK25

qitent appearance of pleurit Ic pain, and absence of cold agglutinins. ('oniI)leIIlelIt lixat ion tests perfornle(l with lynx phogrxinuloma axt igen on hot lx

human and pigeon serum ( front the area) were negative for psittacosis. as

were other serological tests (Veil-Felix, influenza A iifl(l B, CoI(I agglut mm).

At tempts at virus isolation were also ixiade. Preliminary observations sug-

(rested that throat. washings from acute cases contained a filterable agent

'lIi('l1 I)roduce(l fever on guinea pig inoculation and was tranSlnissiI)le in

series. A rickettsial agent was finally isolate(l from the material. Moreover, late followup serological tests on other cases of the disease vhich develo1)ed in trool)s returnjn(r from Italy have showix that the condition was.

in fact, Q fever. It seems definitely proved that all the above cases as vell

as the so-called Balkan grippe occurring among British I)aratrOol)ers ill

Greece were Q fever.5 6

Myers and Matthews noted that true atypical pneumonia in Italy during the -inter of 1943-44 took on a rather more severe character than they

were accustorne(l to observe in Army practice. There was a large number

of severe cases, reminiscent of those describe(l in the United States in 193$.

with (vanosis, dys)nea, and extensive l)t1ll11oIlllr' involvement. Sonie of these

Cli(led fatally. Another group showed a l)rotracte(l course, " ith persistence

of l)tllnlonary infiltration beyond the expected period. In one group,5 7 55.8

per'xit of cases had residual X-ray changes after :1 weeks of illness.

IA. Col. Tr9cy B. Mallory, MC, of the 15th Medical General Laboratory. furnished the following description of his findings in the tissues of nine fatal

cases:

EI(*h of the time cases showed consolidation of more than 73 percent of the total lung

suhstaiwt'. Microscopic examination (lisclosed massive exudation into the alveoli of it

prot.'i ti-rich Ilui(1, almost free of fibrin, and containing mononuclear and red cells but few

polyniorphonuclear leukocytes. Alveolar wall thickening was observed but was minor lit

(legrt'e. In no case was there evidence of necrotizing bronchiolitis or atelectasis, lesions

characteristic of the atypical pneumonia seen in troops in the continental United $tates

during 1942-43. A serons or purulent effusion was not found in any instance.

Four of the lime evi(lenced other pathological changes unrelate(l to the pneunionia but

of stidi character and degree as to have contributed to the fatal issue. One exhibited

recent vegetations superimposed on an old rheumatic valvulitis, the second had a fresh

mnyoca rdial infarction, the third a hemnoperitoneum associated with a fractured pelvis, and

the fourth a fracture of the dorsal spine vith paraplegia. Three other cases (lisplayed

a vehf-mnarked acute mnyocarditis which was (leellied to be a complication of the pneumonia

and which undoubtedly played an important part in the outcome.

Summary

In sulumary, primary atypical pneumonia was by far the Inost common

variety of pneumonia in U.S. troops in the European and Mediterranean

*P Replratorv Dieae: Outbreaks of a Rickettdal I)Iseae Related to Q

Fevr. Bull. U.S. Army M. Dept. 5 (No. .3) : 245-246, March 1946. 7 Tlwodo,'. I'.and Zwlckel. R. E. : Clinical Aspects of Primary Atypical Pneumonia. M. Thill.

North .frIenn Theater Op. 2: 104-109, November 1944.

5..e footnote 16. p. 8.
26 INFECTIOUS DISEASES

theaters. Even so, it never became a military medical problem of any real

importance. Rates for Europe were lower than in the continental United

States, but in the Mediterranean they were sometimes higher. On the whole,

the cases were mild and recovery tended to be complete, although an average of about 30 days per patient were lost to duty. Very rarely, the individual might be left with a chronic bronchitis, sometimes of an asthmatic

type. Secondary bronchiectasis was almost unknown. Complications were

very infrequent. A few of the patients at times seemed to have some secondary bacterial infection. Such secondary infections were usually not very

clear cut, but when definite they were controlled by sulfonamides. The death

rate was almost nil.

Had the incidence of this condition been higher, it would have been a

military problem of some magnitude owing to the rather prolonged disability

incurred by the individual. This low incidence probably reflects a considerable degree of immunity in the general population. The virus, too, may be

one of rather low communicability, and the long incubation period militates

against the explosive type of epidemic spread when individuals are temporarily crowded together, as on transports.

Rates for atypical pneumonia were low throughout the war in the Pacific

area. They were also low in the China-Burma-India theater apart from a

moderate peak in July and August 1942. In the latter area, the disease picture was stated to conform with that seen in the United States except. that

an initial shaking chill and pleuritic pain were more commonly encountered.

An interesting outbreak, late in 1944, was described by the surgeon of

an airbase in India. Fourteen persons, all of whom had been in the same

hold of a troop transport arriving in Bombay. came down with atypical

pneumonia almost simultaneously a few days afterward. About a fortnight

later, there were eight secondary cases at the station.

BACTERIAL PNEUMONIA

Introduction

Lobar pneumonia due to the pneumococcus has been so closely studied

and so accurately described that it would be presumptuous to review the disease here. Medical records indicate a total of 109,882 admissions for pneumonia other than atypical as occurring in the Army from 1942-45 (table 2).

Of these, 970 patients died, giving a case fatality rate of 0.88 percent. This

is in contrast to a figure of 160,940 admissions for atypical pneumonia with

198 deaths. How many of these reported cases were actually pneumnococcal

pneumonia is impossible to state; probably the percentage was a relatively

small one. Two generalizations may be made concerning the condition in

World War II. First, the incidence was generally lower than anticipated,

particularly overseas. This low rate was simultaneously true of the civilian

population and probably reflects an inexplicable fluctuation in the character
RESPIRATORY DISEASES 27

of the disease which had begun some years before World War II. Secondly,

and perhaps for the same reason, the individual cases seemed surprisingly

mild. One is accustomed to think of lobar pneumonia beginning violently in

the classical way, with a rapid development of the complete picture of the

disease and bacteremia in about 25 percent of the cases. In the Army, the

disease (lid begin suddenly with the customary symptoms, L,-t the patient

usually did not appear as ill as one might expect; the amount of consolidation by X-ray was often astonishingly slight, and bacteremia was extremely

uncommon. It is possible that these differences were apparent rather than

real, that they were due to prompt recognition and early treatment. Nevertheless, it is the writer's belief that the essential severity of the disease was

diminished.

Other varieties of primary bacterial pneumonia were rarely encountered.

On the extremely infrequent occasions in which organisms, such as Staphyiococemi. Fr;edldnder's bacillus, and H. influenzae, produced pneumonia, they

ran true to form. Secondary pneumonias, usually on the surgical wards,

were occasionally noted, but on the whole the control of these conditions by

antibiotics was satisfactory.

TABLE 2.--Adnissions for primary atypical pneumonia, bacterial pneumonia, and other

pneumonia, in the U.S. Army, by area and year, 1942-45

[Preliminary data based on sample tabulations of individual medical records]

[Rate expressed as number of admissions per annum per 1,000 average strength]

Total Army United States Overseas

Disease category and year

Number Rate Number Rate Number Rate

Primary atypical pneumonia:

1942-45 --------------------- 160,940 6.32 110,133 7.47 50,807 4.73

1942 ------------------------ 19,891 6. 13 17,902 6.74 1,989 3.40

1943 ------------------------ 51,177 7.45 46,375 8.95 4,802 2.84

1944 ------------------------ 43,022 5.52 25,056 6.31 17,966 4.70

1945 ------------------------ 46,850 6.18 20,800 7.09 26,050 5.61

Other pneumonia:

1942-45 --------------------- 109,882 4.31 81,962 5.56 27,920 2.60

1942 ------------------------ 27,583 8.51 24,267 9.13 3,316 5.66

1943 ------------------------ 41, 161 5.99 35,735 6.90 5,426 3.21

1944 ------------------------ 23,473 3.01 14,470 3.64 9,003 2.36

1945 ------------------------ 17,665 2.33 7,490 2.55 10,175 2.19

Bacterial pneumonia:

1942-45 ------------------- 50,943 2.00 37,406 2.54 13,537 1.26

1942 ---------------------- 10,441 3.22 9,340 3.52 1,101 1.88

1943 ---------------------- 16,838 2.45 14,690 2.83 2,148 1.27

1944 ---------------------- 13,014 1.67 8,526 2.15 4,488 1.18

1945 ---------------------- 10,650 1.41 4,850 1.65 5,800 1.25

I Cases recorded as lobar pneumonia.
INFEC'TIOUS DINEJAS~ES

'Fle heiiiolvt it st veI)toetc(*Iis gives r~is-e to till occasional case of p~rimiary

pnieuilloliiia however, tile casies become ziuiiilerically 1importanlt onlly whenl foiSOM0Iii -elIS0 il te org1alisml i's widely dlist ribuited inla Iiil hi-I, hoeistt 

its is somiet ilmes fomiiio ill assoeiatio iO v ith it a li lkboriie epidemiic. Measles

anid ilitifluenlz ViruIIAse seemled to "activate" thle Iieniol't ic st reptococcus ill t he

First World War but duringj thie Second World War mleasles Was Ullmnip,0r--

tant. inl the Army and1( influenzit of the 9IlS type dIid not occur. These facets

probab~ly are related to the low incidence of st reptwoocal pnetillonia. What

&'ffect did the widespread utse of suilfonmamides have inl 1reveiiting thle st reptococcuis froim really grettinig ljimier way? n is compllex subject wimll lie conmsideredI else-wiere. together withI thlat extraordiniarily interestin hnmnn

the a jpearaiice of silfmand-eitatstrains of beta heniolyt ic st reltoeovci.

Experience in the Continental United States

Oil summilary healthI rep~orts, statistical data inl tilie Arimy with riega rd to

the piennion ins are1 un1satisfactory. After 'March 1942, the pnieuinlonmils w-ere

rep)orted under three headings: Primamry atyp)ical pneumonia, pnieumoniiia.

prim~aryan puielmmnon ia, se-ondar11y. 'file rattes for pnmeumlionia, secondary,

were generally very low. Our initerest here. is ili thle term "pnielnilomima.

primiariy."

BV definlitioni, this should( nicami anly piieummiomiia. arising de nlovo. or inl

thle course of minor tipper respiratory in fection, whichi itmmedical ofitcer c-oilsiders to be bacterial, not viral. inl origin. Presnimably , these should be

mIiaimldy pl)Cie1io(oevll, that is to say, lobar pneumonia. As might be expiected.

niledicvil records based onl tile conisolidated statistical health report (WD) Ml)

Forml S~ah) contain nil eniormuous amount of error, resulting froml the na-,t iril limnitations of this source of information.

F~or exampjle. at (Camp Iee, 'a., between 6 Novembler 1943 and 3 'March

1944, 1.5 cases of pneuimonia, were reportedl; 147 designatedl pnieimfouitil, primuary. and 8 atypic'al Imietui~moliiu. This seettied of sflicfiient interest to wvarrant further invest igat ion. The D ireetor., C1 ommuission on) Pnleuumnonill, Ariumy

EpidlemniolOgrical Board, visitedl Camp Lee and1( studliedI records omi 97 poemsmuonmla Cases 11dillitted shice I January 1944. Ini his opinion, 58 of these were

aitypical pneumon ia, and only 8 were lob ar pnueumnonia. The rema i nder -on -

sistedl of 6 olefinlitel% streptwoocal cases, 1:3 doubtful streptococeal cases, iW

prob~ably bacterial pnuemnon ias fromi wh ichi no organiiismn was isolated, and 2

staphylococcal cases.

Thlere were several reasons for this woeful dlegree of inaccuracy. One, of

course(1, was the failure of many clinicians to think clearly along etiological

linies; another was lack of interest and experience onl the part of thle labo~ratory; andl last. Niut not. least, wats the registrar's liahit of making uip the statist ical health relport from tile mlorningl~ report which wats usually Compililed

byv a nurse. There is, therefore. little to be, gained fromnia discussion of the

overall iiicnlemice of so-cal ledl nlieuliumominl. primarmy, ats reported onl leriohici
RESPIIRATORY D ISEASFEs S9

sunlnlary reports. In contrast, considerable information is mnade available

fronm the tabulations of final diagnoses from inlividual iiedical records

(table 2).

The low incidence und mortality of lobar pneunmonia in the Army mtay

be illustrated by two figures which, although not strictly comparable, d(o

give a crude index of affairs. The death rate front lobar pneumonia, is give-.

in the official history of the First World War as 2.59 per 1,000 per year, or

259 per 11)M,000 per year, for the period 1 April 1917 to 31 December 1919.

Preliminary .nAry figures in World War 11, 1942-45. give tile death rate for

the bacterial pneutmonia in the United States as less than 2 per 100,000 per

year.

lobar pneuimonia was mildly epidemic in the United States at timles,

but only in certain localities. Epidemic conditions never became generalized.

The most conspicuous instances of this were in the Sixth Service Command

where, the rates for plenmnumia were significantly higher than in other service

commands. These high rates were entirely contributed by Air Forces personnel, the rate for Army Service Forces being not. uissimilar to that iII

other regions. Accordingly, the mutter was investigated by the consultant II

medicine of the Sixth Service Conmand and the director of the Commission1

on Pneumonia who reported a number of interesting figures. For examiplh,

rate-; for commorn respiratory disease the week of 20 October 1944 at three

airfields were 150, 111. and 83 its comnl)ared to 55 and 64 in two service caII ps.

Similarly, the pneumonia rates were :12, 41. and 55, comipared to 7 and 3.

"These reported pneunionias included both lobar pneumonia and aty I)ici

pneumonia. The exact proportion of the two varieties was hard to determine. At one field between I January and 8 December 1944. 215 cases of

primary pneuimonia were relorted as a,,ainst 396 atypical pneumonia cases,

but when tlhe investigators studied the individual medical records rather than

tile statistical health report they found that at the three airfields p)rimary

pnelmllnollia was being solmewhat overdiagnosed at tile expense of atypical

l neuninia. Nevertheless.,. it was obvious that lobar pneumonia was unusually

prevalent.

At one field, pneumetn cceits typ)ings had been performed in 160 cases.

In these, type VII was present in 18.1 percent of cases, types I and II each

in 14.4 percent, ,) that these three together accounted for nearly half the

cases. The prominence of type VII seenis a little surprising; whether it was

also suchi a notable offender at the other two fields is unknown.

A careful attempt wvas made to discover the reasons for this unusual

incidence of respiratory infection including pneumonia. In the final analysis, the most striking difference between life at. the air station and in the

service forces was that the former involved men being together in classrooms

al (lay.

.\nother interesting example of the behavior of lobar pneumonia was

relx)rted at the knry Air Force Technical School, Sioux Falls. Coincident
30 INFECTIOUS DISEASES

with the peak of a sharp epidemic of influenza in November 1943, and extending for about a fortnight afterward while the influenza was rapidly subsiding, the rate for lobar pneumonia (already rather high) rose to an unprecedented level. For the week of 3 December, it was 4.8 per 1,000. In

72 cases, pneumococci were isolated and typed. Of these, 17 proved to be

type II, 9 type V, 6 type I, and 5 type VII. The rest were scattered or

untypable. Later in the winter, during a controlled experiment on sulfadiazine prophylaxis at the same station, it was noted that the drug appeared

to reduce significantly the incidence of lobar pneumonia, although the result

was not as striking as in the case of streptococcal infections.

In harmony with all experience elsewhere, the treatment of lobar pneumonia with sulfadiazine was highly satisfactory, and complications were very

infrequent. In this connection, it is interesting to review the role of serum

therapy. At a conference on pneumonia held at the Office of the Surgeon

General in January 1944, the subject of classification was discussed at length.

Therapy was also considered, and it was agreed that antipneumococcus serum

may be lifesaving in cases of drug-resistant pneumonia. Shortly thereafter,

a remarkable variation in the actual use of antipneumococcus serum in various hospitals was uncovered in a survey by the Professional Service Division.

A good many hospitals had never used serum while in others it had been

employed surprisingly often. The opinion of all the service command consultants ill medicine was then sought. The great majority agreed that serum

was necessary in only very exceptional instances and that it could, if necessary, be obtained from local sources. In other words, the consensus was that

antipneumococcus serum could be discontinued in the Army drug lists; in

this, the Chief Consultant in Medicine, Office of the Surgeon General, and

the National Research Council concurred on 15 May 1944. The advent of

penicillin as an addition to sulfonamides had much to do with influencing

this view, which would have been considered mildly revolutionary a few

years earlier. The efficacy of treatment of lobar pneumonia with sulfonamides alone is shown by a report of 454 cases over a period of 3 years with

only 4 deaths.59 In the last year of this study, 92 cases were treated without

a single death.

An important study of immunization against lobar pneumonia by injection of specific capsular polysaccharides was started in September 1944 ait

the Sioux Falls Army Air Force Technical School 11 where the pneumonia

rate had been very high; over 1,500 cases had occurred in the preceding 2

years. Of these, 34.9 percent were due to type II pneunmococcus. More than

8.000 men were injected with a single dose of a mixture containing polysaccharides derived from pneumococcus types I, II, V, and VII with a strik59 Adamson, W. B.: Lobar Pneumonia. Air Surgeon's Bull. (No. 11) 1: 21, November 1944.

6o MacY -od, C. M., Hodges, R. G., Heidelberger. M., and Bernhard, W. G.: Prevention of Pneumococcal Pi. umonla by Immunization With Specific Capsular Polysaccharides. J. Exper. Med. 82:

445-465, December 1945.
RESPIRATORY DISEASES 31

ing subsequent immunity to pneumonia caused by these types as compared

with a similar control group. The carrier rate of these four types was also

significantly reduced, but no effect was noted against infection with, or the

carrier rate of, other types.

Hemolytic streptococcal pneumonia was comparatively uncommon. Some

cases were seen, however, which conformed to the pattern set in the First

World War; that is, an abrupt onset of the pneumonia with symptoms of

pleurisy and the rapid development of a massive effusion. Such effusions

were characteristically thin but, of course, infected. The opportunity to use

local penicillin therapy was seized, but the cases were not sufficiently numerou.s to draw any final conclusions as to its efficacy. Early in 1944, one statioin hospital in the Third Service Command reported 5 such cases, together

with 10 other pneumonias, believed to be streptococcal, which did not have

associated empyema. At about the same time, six cases were present in another hospital in the same service command. These numbers, however, were

quite unusual. Other varieties of bacterial pneumonia were occasionally

encountered, but not with sufficient frequency to merit particular comment.

Bacterial pneumonia never became a serious problem in the United States,

and its response to sulfonamides and antibiotics completely changed its significance as compared with the First World War.

Experience Overseas

European theater

The incidence of bacterial pneumonia in the European theater was extremely low, and the mortality almost nil. This small fatality rate can be

ascribed, in part at least, to early diagnosis and satisfactory response to

treatment.

Empyema following lobar pneumonia was very inconspicuous in the

Second World War. When it occurred, it was ordinarily the result of delay

in the institution of treatment, the pneumonia at times having been unsuspected. Other complications were exceedingly rare.

The typing of pneumococci was always difficult overseas. This was no

doubt in part due to lack of training of laboratory technicians. However,

it also appeared to be a fact that the available typing serum was weak.

There were a number of scattered cases of bronchopneumonia in the

European theater, particularly in the spring of 1944, in which the differential diagnosis between atypical and bacterial infection was in doubt. Clinically, these cases resembled atypical pneumonia, but the sputum was more

purulent than one expects in that disease and contained a pathogenic organism. These cases occasionally showed a moderate, although not a dramatic,

response to sul fon am ides. They may have represented instances of secondary infection superimnl)sed on a pIeuimionia originally of viral origin.
32 INFECTIOUS DISEASES

Mediterranean theater

Preliminary data on pneumonia in the Mediterranean theater indicate

that there were 17,715 admissions for these diseases during the period 1942-

45. Of these, 12,908 were reported as primary atypical pneumonia, and 2.443

(approximately 14 percent) were regarded as bacterial pneumonia. There

were 74 deaths, and of these, 28 were due to bacterial pneumonia. Presumably, the bulk of the bacterial pneumnonias were pneumoc-ceal, and p1nenmococcal lobar pleumonia is estimated to have caused about one-third of the

deaths from pneumonia that occurred in the theater.

Other types of bacterial pneumonia were occasionally noted in the Mediterranean theater but in insufficient numbers to warrant discussion. A small

number of cases in which a green streptococcus was cultivated frout blood

and sputum are recorded. Str. c,;.dan.. pneumonia was a clinical rarity. but

had been previously observed. It is possible to speculate on the relation of

this condition to atypical pneumonia, with the strel)tococcus in time role of

secondary invader, b)ut no proof of such relationship exists.

The standard treatment of lobar pneumonia was sulfadiazine. which

yielded satisfactory results. Penicillin was tried in a limited number of cases

and found to be effective. Occasionally, in a severe case, both agents were

used. Serum therapy was only recommended in very exceptional cases.

MEASLES

Introduction

Measles (rubeola) is a highly communicable virus disease with a stereotyped clinical pattern which is universally familiar. Susceptibility to measles

is considered to be almost universal, and one attack, in the majority of persons. confers lifelong immunity. In urban communities, it is more or less

epidemic in the early spring of each year with a greater number of cases in

alternate years. Approximately 102,000 cases of measles occurred in tile U.S.

Army in the First World War, with 2.370 deaths. Associated infections were

a cause of serious illness, prolonged invalidism, and death. In World War I1,

by contrast, the total number of cases was 60,809, with only 3.3 (lealths. in spite

of the fact that the Army was about four times as large and the duration

of the war twice as long. The seasonal peak for measles during World War I1

occurred in late winter or early spring. but during World War I peak incidence due to mobilization occurred in the late fall of 1917. This is of sufficient importance to warrant considerable discussion.

UIn'oniplicated measles is almost never fatal. The gravity of the condition lies in complications caused by certain inicro-organisms. Baeterial

infections due to )Ineunococcus, C. d/puttherie. H. ;nfqiinzeie, Mycob,ictPi tn,

hlberiiclo.x;,. and most particularly the hemniolytic strel)tococcus. are descril)ed.

The most frequent and serious complications of measles are pneumonia

and otitis media. In the First World War, there were 93.629 admissions due
RESPIR ATORY DISEASES 33

to nIea.sles among enlisted mIei ill the (olit ineiint'i I nited States and Furope

of which bronchopneumonia and lobar pneumonia were comiplications of

measles in 6.283 cases, with 2.186 deaths. Similar data for the entire Army

are not available. Suppurative pleurisy, undoubtedly secoilary to pneunnionia.

occurred in 645 cases with 268 deaths. There were 3.926 instances of otitis

media. but only 122 of these patients died. Careful studies of the bacteriology

of these complications in(icated that the hemiolvtic streptococcus was the

causative agent in nearly every case. One may ask how this secondarv infection comes about. D)oes it occur in a carrier of streptococcus who becomes

infected with measles.? I)oes one catch the streptococcus along with the virus

of measles or does one become secondarily infected as a result of living in a

highly contaminated environment after contracting the measles? It seems

likely that all these mechanisms play a part. At one hospital in the First

World War, for instance, the carrier rate for hemolytic streptococcus rose

steadily on measles wards from 11 percent on admission to 57 percent in

patients who had been on the ward from 8 to 16 days. If noncarriers of

streptococculs with measles were carefully segregated from carriers at tile

time of admission, the difference in complications was striking, the rate being

6.4 percent in the noncarriers as opposed to 36.8 percent in the carriers. While

the mechanism of secondary infection might not always be clear in the individual case. it is safe to conclude that. during a measles epidemic in a training

caimp. the hemolytic streptococcus b)ecame widely distributed.

Following a measles epidemic with much complicating pneumonia, primary streptococcal pneumonia made its appearance in some camps. The cases

were severe, with a high incidence of early suppurative pleurisy, and a high

case fatality rate. This disease also spread to the civilian population. It

seems likely that rapid passage from individual to individual through the

mediation of measles enhanced the essential infectivity and virulence of the

hemolytic streptotoccus.

Epidemiological studies of measles in the First World War also have an

interesting bearing on more recent events. In such a station as Camp Pike,

Ark., which drew its recruits from the rural regions of Alabama, Arkansas,

Louisiana, Mississippi, and Tennessee, the rate was enormously higher than

in camps drawing from urban areas. Thus, the admission rate for measles

among white enlisted men at Camp Pike was 164.67 per 1,000 per year, compared to 7.27 at Camp) Dix, N.J. For white and colored enlisted men coinbined. the admission rates were 142.05 per 1,000 per year for Camp Pike and

7.73 for Camp D)ix. Moreover, as might be expected, the incidence of measles

was highest in recruits less than 2 months in camp. Thus, it was essentially

a disease of country boys coming for the first time in their lives into a densely

crowded environment.

The only tenable explanation of the much lower rates for measles in the

Seconmd World War is that the number of susceptibles was much smaller.

There is no question that a great change in habits of life occurred in rural
34 INFECTIOUS DISEASES

America between the two World Wars. In 1910. rural districts were fairly

well isolated; it was the "horse and buggy era"; the facilities of travel were

limited; people stayed on the farm. By 1935, all this had chang ed. There

was a moving picture house in nearly every village; schools were larger, and

education was more centralized. As a result, the counti, boy growing up in

this decade had far more opportunity for exposure to the exanthemata of

childhood with a consequent reduction in susceptibility rate at the time of

induction into the Army. Although there is no firm statistical basis for this

conclusion, one cannot avoid feeling that it must be correct.

Complications of measles were much less conspi(uous in World War II.

Undoubtedly, this was related to the low incidence of the disease. Where

cases are sporadic, rather than epidemic, the widespread dissemination of

virulent streptococci is unlikely to take place. Moreover, the use of sulfadiazine in cases with threatened or actual complications unquestionably served

to modify the picture. Part of the small number of deaths were probably due

to secondary infection; some may have occurred as a result simply of overwhelming virus infection or complicating encephalitis.

An average of about 13 days was lost to duty for each case of measles.

Experience in the Continental United States

Most of the measles in the Army took place in the United States for the

reasons just mentioned; that is, that it is essentially a disease of unseasoned

troops first entering military life. Actually, 54,388 cases occurred in the

United States as contrasted with 6.421 overseas. The largest number and the

highest rates were reported in 1943, although in the civilian population the

absolute numbers of cases were about the same in 1942, 1943, and 1944. As

in the First World War, the disease was seasonal, but the peaks were much

lower. In other words, while the total number of cases was considerable,

measles never became a really serious military problem.

The relative insignificance of complications is illustrated by a report of

400 cases of measles at the Station Hospital, Fort Sill, Okla., in which otitis

media occurred but 6 times.6 ' Three hundred of these were given sulfonamides, but 100 control cases were untreated. No difference was noted in the

clinical course of the treated as opposed to the control cases.

Suppression or modification of measles following exposure by the injection of convalescent serum or immune globulin are established procedures in

pediatric practice. Measles in the Army. however, never was sufficiently serious to warrant the generalized use of these measures. Similarly, no attempt

was made to apply the principles of active innmunization, although interesting preliminary studies, under the direction of the Commission on Measles

61 Haerem, A. T.: Treatment of Measles and Mumps With Three Well-Known Sulfonamides. Mil.

Surgeon 92: 306 309, March 1943.
RESPIRATORY DISEASES 35

and Mumps, Army Epidemiological Board, indicated the immunizing value

of artificially cultivated measles virus.6 2

Experience Overseas

Measles rates in the European theater were low, a total of 2,554 cases

being reported. The disease was sporadic, and nothing in the nature of a real

epidemic ever developed. Clinically, the cases presented no unusual features.

Sulfadiazine was administered to most of the patients for several days during

the acute phase. Only one death was attributed to the disease.

Between 1 January 1943 and 31 March 1945, 612 cases of measles with

no deaths were reported ill the Mediterranean theater.

MUMPS

Introduction

Of the so-called comimunicable diseases of childhood, mumps (epidemic

l)arotitis) was the most common in the U.S. Army. There were 103,055 cases

recorded between 1942-45 compared with approximately 237,000 during the

First World War. for a much smaller number of men over a shorter period

of time. This marked reduction was greater than that for measles, the comparable figures being 60,809 and 102,000, respectively.

No exact explanation of the reason for this is possible, but a plausible

hypothesis suggests itself. As has already been pointed out in the section on

measles, a change in the living habits of rural America probably permitted

more exposure in childhood and resulted in fewer susceptibles of military age.

Measles is more highly communicable than mumps; therefore, when measles

occurs under conditions of military life, where opportunity for spread of epidemic disease is excellent, it is likely that a higher percentage of the nonimmunes will contract measles than mumps. Thus, the proportionate decline

in the incidence of the two diseases during the two World Wars might be

expected to be greater in measles, the highly communicable disease, thaln in

mumps, the disease of lesser communicability.

Complications

Mimtips is a specific virus infection with a particular tendency to localizationi inl the parotid glands. In the majority of cases, these are the only organs

clinically affected. However. a number of other glands and structures are

ordinarily spoken of as complications, although they are probably better

regardled as additional manifestations of the virus infection. Generally speak62 1 ) Stokes. J., Jr., O'Neil, G. C., Shaffer, M. F.. Rake, G., and Marts, E. P.: Studies on Measles.

IV. Results Following Inoculation of Children With Egg-Passage Measles Virus. J. Pediat. 22: 3 -18,

January 1943. (2) Marls, E. P., Rake. G., Stokes, J., Jr., Shaffer, M. F., and O'Neil, G. C. : Studies

on Measles. V. Results of Chance and Planned Exposure to Unmnoditied Measles Virus In Children

Previously Inoculated With Egg-Passage Measles Virus. J. Pedlat. 22: 17-19, January 1943.
36 INFEC'TIOUS DISEASE8

ing, these (c)ipl icat lolls are It roublesomie. but not part icularly seriolu. Mumps

is es•sentially a nonfatal disease. and in the First World War the only deaths

Occurred as a result of infrequent se.olldar1y infections, such as l)nleuonil.

At that tinie, the case fatality rate where mlpllll)S was the primary cause of

admission was 0.0)8 percent. As there were only live deaths from nitimps

reported for tiie entire U.S. Army during the Se.onid World War, it can be

seen that even the cited low figure was markedly reduce(].

Perhalps the most striking of these so-called comnlplications is orchitis

which develops as a rule when the parotitis is subsiding. Rarely it is said

to be tile only manifestation of lnmulmps. II a recent study of tile disease in

civilian life. orchitis is stated to occur in IS percent of cases of niuni•s. and

ili about one-sixth of these tile conlition is bilateral.6 3 Ill over 5.0 percent.

sonlle atrophy is Said to result. hut ensuing sterility is clainmed to he rare.

probably because the cases tire unilateral. and even in bilateral cases with

atrophy a sufficient amount of sperniatogenic tissue is left intact. re authoi's

of this paper recomnmentid surgic.al deconipression in severe cases, a procedure

which was tried at tinmes in the Armny during World War It with allegedly

good resuilts. 64 It seens likely that conplaratively few cases are sufficiently

severe to require such an operation. It is reported to cause remarkable relief,

liowever. in patients with very marked swelling, intolerable pain, and high

fever.

lPancreatitis may be another complication of nuinl)s. 11ow often it occurs"

is impossible to say. The clinical diagnosis is occasionally made on the basis

of thle appearance of upper abdominal pain, nausea, and vomiting during tile

Course of mumps. 'lnfortunately, there would appear to be no means of

laboratory confirmation, for a study at Canpl) Adair. Oreg.,6

e showed that the

level of blood diastase was elevated in 73 percent of cases of muml)s. Only

15 percent of these had any symptoms of pancreatitis, and it was a"ssulmed

that the diastase originated in the affected salivary glands rather than in the

pancreas. Ih any event, pancreatitis is an unpleasant rather than a serious

C.oIlm)l icat ion.

The virus of mumps can also cause meningoencephalitis which manifests

itself as a rule by headache, sone stiffness of time neck, and increased cell

count in the spinal fluid. Although more severe central nervous system manifestations can occur, this comiplication is usually a rather m1ihl one of short

duration. Complete recovery is the rule.

In World War 1. mumps was third in order of importance as a cause for

noneffectiveness; in World War I1, with less than half the number of cases.

it was obviously less important. However, as the average number of days lost

63 Wesnelhoeft. C., and Vose. S. N.: Surgical Treatment of Severe Orchitis In Mumps. New England J. Med. 227: 277-280. 20 Aug. 1942.

64 (1) McGuinness. A. C.. and Gall, E. A. : Mumps at Army Camps in 1943. War Med. 5: 95--104.

February 1944. (2) Nixon, N.. and lAowN. 1). B.: Mumps Orchitis; Surgical Treatment. Air Sturgeon's

suill. 2: 152-154, May 1945.

65 Zelman. S. : Blooll DIAiatap, values in .Mumllts anti Mumps Pancr'atitis. Am. J.M. Se. 207 : 461-

464, April 1944.
RESPIRATORY DISEASES 37

to duty for each case was about 18 during World War II, it remained one

of the major causes of noneffectiveness among the acute infections, being surpassed only by hepatitis, common respiratory diseases, the pneumonias, gonococcal infections, malaria, syphilis, and derinatophytosis. Mumps usually

begins in the late autumn, and there is a slow development of the epidemic

during the winter and spring. It is not as explosive as measles. On the other

hand, the incidence may rise sharply when a unit with sporadic mumps is

closely packed in together for a long period of time, as happens on a transport on a protracted sea voyage."

Experience in the Continental United States

As with other so-called childhood commniiicables, the greatest incidence

of mumps occurs in the first months of Army service. Mumps occurred at

some time in all Army camps and, at times, was sufficiently prevalent to be

called epidemic. One such epidemic at Camp McCoy, Wis., was reported in

detail by McGuinness and Gall. During a 7-month period, 1,378 cases were

treated in the station hospital. The slow evolution of the epidemic is noteworthy, the peak of 194 cases not being reached until the 17th week. One

group of soldiers was predominantly from the rural areas of the South. This

group, roughly equal in size to the other group from the industrialized North,

contributed 84 percent of the cases. Nearly half the companies in the northern group had but one case each, whereas in one southern company 19 percent

of the men contracted the disease. Orchitis occurred in slightly over 36 percent of the cases in this epidemic as compared to 15 percent of some 250 to 300

cases in an epidemic in two large cam[F. in the Fourth Service Command.

This relationship was borne out elsewhere; that is, the larger the epidemic,

the higher the incidence of complicating orchitis. Orchidotomies were performed in 83 cases at Camp McCoy with what were described as good results.

An attempt to ward off orchitis by enforcing '2 weeks of bed rest was a failure.

The complication appeared to be as frequent as in ambulatory patients. Of

the entire series of mumps cases. one-third were moderate in degree, and onethird severe. Clinical meningoencephalitis was uncommon.

Other interesting observations were made elsewhere in regard to orchitis.

For example, no relationship between incidence of this complication and preceding gonorrhea 67 could be found. Generally speaking, treatment with convalescent serum was found ineffective in preventing orchitis," except in a

small series treated with serum drawn from convalescent orchitis cases. Here,

there was an apparent reduction in incidence to 4.2 percent from an average

of about 20 percent.

0 Dermon, H., and Le Hew, E. W..: A Mumps Epidemic in a Small Task Force. Am. J.M. Sc. 208:

240-247, August 1944.

67 See footnote 66.

68 Bailey, W. H., and Haerem, A. T. : Some Observations on the Efficacy of Convalescent Serum

in Mumps. Mil. Surgeon 90: 134-139, February 1942.

6392431-63---5
38 INFECTIOUS DISEASES

No advance in tv'eatment of unconmplicated in :-,,s was recorded. At one

station hospital in the Third Service ('omnnand, .t'. 1)inizing did not appear

to ameliorate symptoms 1;9 in a small series of cases.

On the whole, it may be stated that, while not infrequently bothersome,

lnlpllllI)s did not coinstitute a very serious military problem.

Experience Overseas

As in measles. munmps was more conmmon in the United States than overseas. although tile difference was less marked. About nine times as many

cases of measles were reported at home as abroad; about four times as many

cases of nnumps were reported. This difference is presumably due to the lower

(olnunicability of mumps. The disease tended to be mild in the European

theater. It was somewhat more comimon in Negroes than in white troops.

A number of complications, particularly orchitis, was observed, but they did

not prove very troublesome. It was the writer's impression that bed rest had

little influence on the likelihood of development of orchitis.

Routine lumbar punctures were done on a number of consecutive cases

of mumps, at the 30th General Hospital,70 Nottinghamshire, England, and in

about half of themu the spinal fluids showed pleocytosis. On the other hand,

only 10 percent of the cases showed clinical evidence of nmeningoencephalitis.

This indicates that the central nervous system is affected by the virus much

more often thanm was formerly believed but that in most cases the infection is

asyniptomatic. In this connection, it is worth remarking that a, very occasional cas, of mild encephalitis without mumps was seen in an individual

from .a unit in which the disease was epidemic. It was suggested that such

cases were actually mumps meningoencephalitis without parotitis. This may

well be true. although there was, of course, no way of verifying the diagnosis.

The question of length of quarantine of patients was considered by the

infectious disease board. The board suggested that isolation of the individual

case could be terminated as soon as all evidence of swelling had disappeared

and there was no fever or other manifestations. This resulted in considerable

shortening of hospital stay for tile mild cases and, as far as one could tell,

produced no untoward consequences.

From 1 January 1943 to 31 March 1945, inclusive, approximately 1,700

cases of mumps were reported in the Melditerranean theater.

INFECTIOUS MONONUCLEOSIS

Introduction

Infectious mononucleosis is a fairly common disease which affects males

somewhat more than females and which shows a predilection for people under

69 Potter, tl. W.. and Bronsteln, L. II. : Some Clinical Cbaracteristics of Mumps, and the Effect

of Belladonna in Treatment; A Study Made at the Station Hospital. Fort George G. Meade, Maryland.

Ann. Int. Med. 21 : 469-474, September 1944.

.o Kirkland, H. B., and Brown. J. W. : Mumps Complicated by Meningo-encephalitis. ETO Medl.

Bull. 9: 9-10, September 1943.
RESPIRATORY DISEASES 39

30 years old. A survey at Harvard University, Cambridge, Mass., in 1944,

indicated that it caused 1.5 percent of all student admissions to the infirmary.7 '

Therefore, one would expect to encounter it quite often in the Army.

It was frequently recognized in tile U.S. Army, but it is probable that

the reported incidence is considerably below the actual. Infectious mononucleosis presents itself in a number of clinical forms and is often sufficiently

vague in character to escape detection unless one is on the alert. The classical

form with sore throat, enlargement of the upper deep cervical lymph glands,

palpable spleen, and rather prolonged fever, is easily recognized, either immediately or during a workup to exclude such conditions as syphilis or Hodgkin's

disease. On the other hand. it is probable that nearly 20 percent of patients

have no abnormal lymph gland enlargement. In some cases, the presenting

feature is an ulcerative throat infection of the Vincent's type, from which

Vincent's organisms are obtained. There may be an associated stomatitis.

A small percentage of patients will have jaundice, which may be confused

with infective hepatitis of the ordinary type. Some cases show a skin eruption which may be purpuric or resemble German measles. Mumps also may

be simulated. Evidence of meningoencephalitis is found on rare occasions.

Lastly, some of the cases are extremely mild and therefore likely to be dismissed as undifferentiated respiratory infection.

In connection with jaundice, a study at the Station Hospital. Boca Raton

Army Air Field, Fla., is worthy of mention.72 Serial liver function tests

performed in 15 consecutive cases of infectious mononucleosis showed some

evidence in every case of deranged liver function, although clinical jaundice

was not present in any of the cases. Since World War I1, it has become recognized that the cephalin flocculation reaction is almost invariably positive in

mononucleosis. It has, in fact, become a useful ancillary aid in diagnosis.

The etiological agent of infectious mononucleosis is still unknown, but is

not believed to be any of the several microbes which have been described in

the past. It may well be a filterable virus, although transmission experiments

have usually been unsuccessful. Nor has the mode of transmission been established. It is apparently infectious, and occasional, localized epidemics with

a high incidence have been described. The communicability would seem to

be usually rather low as many of the cases are sporadic, without history of

contact. Moreover, cases are treated on an open ward in most hospitals, and

the disease does not appear to spread under these circumstances. If it is true

that infection is widespread but that most of the cases are subclinical, then

the phenomenon of apparent low communicability would be explained.

Infectious nmononucleosis is a benign disease with a mortality that may

be considered nil, though death may result fromt conditions complicating the

71 Contratto, A. W. : Infectious Mononucleosis ; A Study of 196 Cases. Arch. Int. Med. 73: 449-

459, June 1944. 12 Cohn, C., and Lidman, B. I. : Hepatitis Without Jaundice in Infectious Mononucleosis. J. Clin.

Investigation 25: 145-151, January 1946.
40 INFECTIOUS DISEASES

disease, :is has been recotrtded ill se\'i'1 epo)o'tt.73 The diseas-e may persist for

several weeks and retluire considerable additional time before convalescence

is coimplete. Sixty pericelit of a series of cases in the Army spent more than

3 weeks in the hospital.

Experience in the Continental United States

During 1944, it bec:|me clear thiat inl certain areas in the Fourth and

Eighth Service Comnmands infectious muomnionucleosis wits being more frequently

reported than formerly an(d was presumably mildly epidemic. An extensive

clinical stoudV at a station hospital in tile Eighth Service Command reviewed

tile findings in some 556 cases occurring over a period of about a year.74

Several points of interest. were noted in this excellent reWPrt. The disease was

fouinid in more than the ant icipated number of Negroes, in whom it was formerely thought to be rare. Skin manifestations occurred in 16 percent of all

the cases, at higher figure than has been commonly recorded. I1n 23 percent

of 223 patients on whom cardiograms were taken, sonme abnorntality was

noted. usually of the T-waves. Six percent of the patients were jaundiced,

but unequivocal meningoencel)halitis occurred only once. The authors also

noted 14 cases in which there was radiographic evidence of lneuimonitis, a

complication which has received scanty attention in the literature. The rest

of the clinical manifestations conformed to the varied picture which has

already been described. The blood counts were typical, and heterophile antibody tilers of 1 : 112 or higher were noted in most of the cases. Very few had

titers below 1: 56. False-positive Kaithn tests were only noted in 8 of 263 cases,

and the incidence of other false serological re4,ct.ions, that is, Weil-Felix,

Widal, cold agglutination, wits exceedingly low.

In contrast, what was described as an epidemic of 91 cases of infectious

mononoucleosis in the Caribbean Defense Command occurred in the autumn

of 1944. Of these, 48.7 percent showed an exanthem, and the titer of heterol)hile antibodies was remarkably low, in the majority being below 1:28.

A Weil-Felix reaction of above 1: 160 wits found in half the cases. Moreover, there were numerous other transient serological reactions, such as the

Kahn, Widal, and cold agglutinin tests, a finding which has been noted in

typhus,. Histological studies of at few excised glands were made at the U.S.

Army Medical Museum. Washington, I).C., and the findings were not typical

in all of theni. Altogether, there is a strong suspicion that this outbreak may

have been rickettsial in nature.

In summary, it may be stated that while infectious mononucleosis was

fairly common, it was not a serious medical problem in the continental

United States. It is estimated from sample tabulations that about 21,000

73 (1) lBernstein. A. : Infectious Mononucleosis. Medicine 19: 85-159, February 1940. (2) Custer, IR. P., and Smith. E. 1.: Pathology of Infectious Mononucleosis. Blood 3 : 830-857. August 1948.

74 Weehshi-r, 11. F., Rosenblum. A. H1., anld Silts. C. T. : Infectious Mononucleosis; Report of an

Epidemic In an Army Post. Ann. Int. Med. 25 : 113. July; 236, August 1946.
RESPIRATORY DISEASES 41

cases occurred in the total U.S. Army during the period 1942-45, of which

about 15,000 were in the continental United States.

Experience Overseas

Sporadic cases of infectious mononucleosis were observed in the European

theater throughout World War II where the case rate was about one-half that

in the United States. At one time, the disease was mildly epidemic in an area

of East Anglia, where a considerable number of cases was reported among

Army Air Force personnel, and also among the personnel of the 2d Evacuation Hospital. In one of these, a most unusual complication occurred, spontaneous rupture of the spleen. The patient recovered following splenectomy.

This epidemic was not of sufficient magnitude significantly to affect military

operations.

As might be expected in any disease with such varied manifestations,

very unusual clinical cases were observed. One patient, for instance, had a

severe thrombocytopenic purpura during the acute phase of the disease.75 The

writer saw a patient who was nearly exsanguinated owing to hemorrhage from

an ulcerative pharyngitis. Ile recovered following transfusions and penicillin

therapy. This indicates that the associated Vincent's infection in mononucleosis may be a dangerous complication. No useful purpose is served in

multiplying these remembered clinical curiosities.

RUBELLA

Rubella (German measles) is the mildest of the exanthemata of childhood. Unlike the others, it is almost wholly uncomplicated, and the mortality

rate is usually stated as nil. The disease is highly communicable, but the

symptoms are so trifling and the resulting disability of such short duration

that its only importance is its nuisance value. Clinically, it may cause some

difficulty in differential diagnosis as it can be mistaken for other diseases,

such as measles, infectious mononucleosis, drug eruptions, scarlet fever, or

even syphilis.

Although the diagnosis is purely clinical, it seems probable that German

measles in its usual form is recognized with some accuracy by clinicians of

wide experience. However, the differential diagnosis between it and measles

may be difficult for others less experienced. This point is brought up because

of certain peculiarities in its reported behavior during World War II. In

the first place, unlike measles and mumps, rates were higher than in World

War I. This is difficult to explain unless the low rates for the First World

War resulted from marked under reporting of a trifling malady. Secondly,

seven deaths were ascribed to German measles, and the average days lost to

duty (9) was not much lower than the number lost owing to measles (13 days).

T5 Lloyd, P. C.: Acute Thrombocytopenic Purpura in Infectious Mononucleosis; Report of a Case.

Am. J.M. Sc. 207: 620-624, May 1944.
42 INFECTIOUS DISEASES

Lastly, there was a striking peak in the incidence of German measles in 1943,

the year of tile highest rate for nleasles. All these facts create tile Suspicion

that cases of measles were being reported as German measles. The most importaiit differentiating points are the diffei'etit modes of onset of the two

diseases, and the exanthein of true measles.

There were 135,83,0 cases of German measles rel)orted in W1orld WVar It.

of which 125,5,30 occurred in the United States. If these figures are accurate.

it caused inore noneffectiveness than measles. It was an inconsequential

malady, of extremely benign character, and presented no clinical features

worthy of discussion. However, the interesting observation made in Australia

during the Second World War that German measles occurring in the first

2 months of p)regnancy is associated with i a high incidence of congenital malformations of the iiewborn 76 was ol)bviously devoid of military significance.

Part II. Chronic Respiratory Diseases

CHRONIC BRONCHITIS

"Chronic bronchitis" is a rather loose diagnostic term which does not

usually indicate a clear-cut pathological or, for that matter, clinical entity.

One variety is the chronic cough of older men, usually more marked in winter. Some of these individuals may have occasional wheezing rales; in

others, there are no noteworthy physical signs. X-rays of the chest may

show somie exaggeration of the bronchial markings, but often the diagnosis

is a presumptive one based on the observation of a chronic cough. As the

individual grows older, he may develol) varying degrees of emphysema with

its attendant effects on respiratory physiology. Cigarette smoking and

chronic disorders of the upper respiratory tract are most assuredly contributing factors to the condition. Because of the age distribution of Army personnel, this type of chronic bronchitis was more often seen on the officers

wards. In some climates, it tended to get worse. It was the writer's impression, for instance, that elderly officers coughed more in England than they

had at home. Dampness, unheated billets, and excessive smoking undoubtedly contributed to this. It has also been remarked that in a tropical climate.

such as Panama, soldiers with a history of recurrent acute bronchitis tend

to (le•velop) chronic bronchitis. 77

The nmanagement of these cases was largely a matter of appraisal. In

the author's experience, it was almost always impossible to persuade an

officer stationed overseas to stop smoking. If the condition were deemed

76 Swan, C., Tostevin, A. L., Moore, B., Mayo, H., and Black, G. H. B.: Congenital Defects in

Infants Following Infections Diseases During Pregnancy, With Special Reference to the Relationship

Between German Measles and Cataract, Deaf-Mutism, Heart Dlsease and Microcephaly, and to Period

of Pregnancy In Which Occurrence of Rubella is Followed by Congenital Abnormalities. M.J. Australia 2: 201-210, 11 Sept. 1943.

77 Cohen. A. G. : An Early Form of Chronic Bronchitis In Panama. War Med. 5: 105-108, February 1944.
RESPIRATORY DISEASES 43

incompatible with atny kind of duty, the patient was boarded home. At

times, it was possible to effect a change in his working and living conditions.

On the whole, however, there was little in the way of medical treatment

which could be offered. Diag',.)sis of ehronic bronchitis was sometimes used

as a handy means of returnir , home elder!y officers who had outlived their

usefulness in an oversea theater.

A just appra;Sal of the IiIll)ort' tliCQOe o'fnirouic bronchlitis in the Army

is difficult. It never seemed to be a major problem, and yet preliminary data

based on sample tabulations indicate that the disease was responsible for

about :14,000 admissions during the l)eriod 1942-45. Nearly half of these

occurred overseas. nhe figure seems extraordinarily high and, l)erhal)s, indicates that the diagnosis wits freely tsedo designate any case of chronic

cough.

Mustard gas is a recognized cause of chronic bronchitis. Hadi this or

other irritating inhalants been c(mployed in any of the camlpaigns, the disease might well have become a major p)robllenm. During World War II. virtually the only individuals at risk were those engaged in the manufacture of

mustard gas. A few cases were reported.78

Asthma.-The dividing line between (-hronic l)ronchitis and asthma is

oftelm not very .lealr cut. In younger individuals, chronic bronchitis is often

of an asthmatic character; that is, it, ina. be really a imanifestaiion of asthma

of the endogenous or intrinsic type. These asthmatic bronchitides tended to

get worse overseas. 7

9 Moreover, it is interesting to note that, in one series

of 28 asthmatics whose initial attack occurred in thie Army, in 23 it developed overseas.8 0 This is presumably related to heavy pollination in certain

tropical areas. At the same tinme, intrinsic asthma was aggravated during

the tropical rainy season.

Trhe management of asthma in the Army is fraught with discouragement. In civilian practice, one can perform an exhaustive study and. depending, upon the findings, endeavor to modify the external environment or

to exert influence on the patient, by either improving his respiratory disease

status or actually rendering him less sensitive. None of these is feasible

during a military campaign. save in very exceptional instances. The clinical

manage1ment of -Isthlnma. apart from symp)tomatic treatment, consists principally in appraisal. By observing the patient. over a consi(lerable period of

time, the medical officer tries to answer the following questions: Is this

man capable of full duty? Of limited duty? Should he be boarded home

from an oversea theater or, if at home, separated from the service?

Most medical officers believed that very few asthmatics, no matter how

mild their disease, were fit for combat duty. Exertion and dust, for in-

"78 Morgenstern. P., Koss, F. R., and Alexander, W. W. : Residual Mustard Gas Bronchitis ; Effects

(it Prolonged Exposure to Low C.on'entrations of Mustard Gas. Ann. Int. Med. :.6: 27-40. January

1947.

79 See footnote 19. p. 9.

m4) Alford, R. I. : DIspos4tion of Soldiers With lJron.hlal Asthma. J. Alle rgy 15: 196 202, May

1944.
44 INFEC'TiOUS DISEASES

stance, tended to produce some shortness of breath in these individuals even

when the asthma did not seeim to be clinically active. On the other hand,

many such individuals could be retained on a limited duty status either

overseas or at home. It must be added, however, that this was partly dependent on the man's willingness to serve. Asthma undoubtedly has a psychosomatic aspect, and if a relatively mild asthmatic wished to get himself

sent home from an oversea theater, he usually succeeded in doing so. Mild

asthma often got worse overseas. Thus, asthma was one of the leading mnedical causes for return to the Zone of Interior. The disposition of asthimatics

in thie Vinited States may be indicated by a report of 100 consecutive patients,

of whom 71 were discharged from the service.

BRONCHIECTASIS

In young individuals, bronchiectasis may be a progressive and disabling

disease. The likelihood of such a person being accepted for military service

is extremely remote, and it has been stated that bronchiectasis was the most

common form of chronic nontuberculous lung disease discovered on induction

examination. However, bronchiectasis of a milder type, essentially cylindrical rather than saccular, may be discovered in a soldier who has previously been in reasonably good health. The pathogenesis of the condition is

somewhat obscure, but the lesions may arise apparently as a result of sinusitis. following pneumonia, or in older individuals as a consequence of chronic

bronchitis. Bronchiectasis by itself does not necessarily produce any physical signs or X-ray changes. It is likely, therefore, that the disease is overlooked on occasion. Undoubtedly, if more bronchographic studies were performed, it would be more frequently recognized.

Bronchiectasis has been termed the most common chronic pulmonary

disease in the U.S. Army.81 As evidence of this, the authors reported 95

cases investigated bronchographically, mostly for slowly resolving pneumonia. Of these, 37 showed frank and 24 minimal bronchiectasis. No

bronchiectasis was found in 34 patients. Two other reports might be cited,

both from station hospitals in the Third Service Command: At Fort Belvoir, Va., 33 cases were discovered during the course of a year 82-14 were

said to be severe, 9 moderate, and 10 minimal. At Fort Eustis, Va., the

diagnosis was made 40 times over a 15-month period; 9 patients were studied because of chronic cough, and the rest were admitted with a diagnosis of

atypical pneumonia. When resolution failed to occur in 4 to 6 weeks, bronchographic studies revealed the true condition. Only 23 of the entire series

81 Evans, W. A., Jr., and Galinsky, L. J.: The Diagnosis of Bronchiectasis in Young Adults;

Prebronchographic Roentgen Manifestations Observed Among Military Personnel. Am. J. Roentgenol.

51 : 537-547, May 1944.

82 Thompson, T. E., Jr., Cawley, F. C., and Seltzer. A. : A Study of Bronchlectasis at Station

Hospital, Fort Belvoir, Virginia. M. Ann. District of Columbia 13: 93-97, March 1944.

8s Grier, G. S., III: Importance of Bronchography in Cases of Unresolved Pneumonia. Arch.

Int. 'Med. 73: 444-448, June 1944.
RESPIRATORY DISEASES 45

gave a long history of chronic cough. These patients did not show the typical textbook picture of severe bronchiectasis with wasting, foul sputum,

clubbed fingers, and so forth. The disease was obviously in a much milder,

or earlier, stage. The author of this study did not believe that these slowly

resolving pneumonias were primary atypical pneumonia, but rather that

they were of the variety long recognized as occurring in conjunction with

symptomatic flareups of bronchiectasis. Some internists believe that chronic

bronchiectasis is at times a rare sequel of severe atypical pneumonia. For

instance, the disease was believed to follow atypical pneumonia in no less

than 17 of 33 cases admitted during a 9-month period to the Percy Jones

General Hospital, Battle Creek, Mich.s 4 However, a review of the case

reports given in this paper leaves serious doubts as to the diagnosis of

atypical pneumonia. Flareups of pneumonitis are a common feature of

bronchiectasis, and the differentiation of these from primary atypical pneumonia is extremely difficult. Van Ravenswaay and his associates85 stated

that bronchiectasis occurred as a sequel to atypical pneumonia at Jefferson

Barracks in 11 of 1,862 cases. This question is not yet entirely settled. On

the other hand, dilated bronchi, which later reverted to normal, have been

shown in a few patients convalescing from atypical pneumonia.8 6 The condition was termed "pseudobronchiectasis."

It is estimated that the disease caused more than 6,000 admissions in the

period 1942-45, four-fifths of them in the continental United States. When

the diagnosis was established, it was ordinarily a cause for separation from

the service.

A certain number of cases were treated surgically during World War IlI.

For example, in 1943, 25 lobectomies were performed at Fitzsimons General

Hospital, Denver, Colo., with 2 deaths.

LUNG ABSCESS

The possibility that a person with a chronic lung abscess could pass the

induction X-ray and physical examination is so slight that cases of this

condition observed in the U.S. Army presumably developed in the service.

Acute lung abscess is by no means uncommon in civilian practice; such

cases follow ,. fairly well recognized clinical pattern, and a considerable

percentage, perhaps nearly half, recover spontaneously without surgical

drainage. The remainder will become chronic if not drained. Acute abscesses of this type coming on de novo, so to speak (in the absence of such

predisposing factors as dental extraction and tonsillectomy) were very rarely

encountered in the Army. The reason for this is not entirely clear unless

it be the generally low incidence of bacterial pneumonias. Lung abscess

84 Kay, E. B.: Bronchiectasls Following Atypical Pneumonia. Arch. Int. Med. 75: 89-104,

February 1945.

85 see footnote 46, p. 20.

86 Blades, B., and Dugan, D. J.: Pseudo Bronchiectasis Following Atypical Pneumonia. Bull.

U.S. Army M. Dept. No. 70, pp. 60-68, November 1943.

639243"--63--6
4fl INFECTIOUS DISEASES

developing after surgical procedures also seemed unexpectedly rare. It is

the writer's impression that many of the lung abscesses seen in tile Army

were in battle casualties.

The disease is estimated to have beenl responsible for about 500 admissions in the 1942-45 period, with 16 deaths.

SPONTANEOUS PNEUMOTHORAX

Tihe sudden appearance of air in the pleural cavity not due to penetrating wounds of tile chest wall or endotrael!1' ....... i is known as spontaneous pneunmothorax. It was formerly tli, related to tuberculosis.

Now, however, while it is known that sl iiiaueous pneumothorax may occasionally occur as a complication of frank pulmonary tuberculosis, it is also

recognized that the great majority of cases take place as a result of rupture

of a suipleural bleb and have no relationship with tuberculosis whatsoever.

Interestingly enough, rupture often takes place quite independently of physical exertion.

In many instances. pneuniothorax is a recurrent disease. Recurrences

were formerly thought to be uncommon, but it now seems likely that if more

frequently recognized by general practitioners their incidence would rise.

For example, a report from the Station Hospital, Seymour Johnson Field,

Goldsboro, N.C.,8 7 points to a highly suggestive history of one or more previous episodes in five out of seven carefully studied cases.

Spontaneous pneunlothorax is most frequently encountered in relatively

young males and gives rise to characteristic physical signs only if the

amount of escaped air is large enough. Roentgen examination, however,

as a rule is unequivocal; and if chest X-rays are routinely taken of individuals giving a suggestive clinical history (there is almost invariably some sudden chest pain at the onset followed by varying degrees of dyspnea), the

condition should not be overlooked. Pneumothorax is rarely complete; in

probably three-fourths of the cases, the collapse is less than 50 percent. so

that the number of cases not detectable with assurance on physical examination is high. Following spontaneous pneumothorax, fluid may occasionally

appear. but these effusions are small.

In the usual course of events, there is aI single leakage of air which will

be absorbed in the course of time. On1 the other hand, there may be recurrent leakages (luring the reexpansion period, or the pneumothorax may be

permanent due to an open fistula. Such cases require the attention of the

thoracic surgeon. Another clinical variety is the so-called tension pneumothorax wherein so much air escapes (often aided by a valve effect in the

rent pleura) that dangerously high intrathoracic pressures are produced.

Fortunately, this is a rare happening, but when it occurs, it may constitute

a real medical emergency. The patient is extremely dyspneic and cyanotic,

47 P'ease,. I. P., Steuer, L. G., and Chapman, A.: Spontaneous Pneumothorax In Soldiers. Bull.

U.S. Army M. Dept. No. 82, pp. 102-107, November 1944.
RESPIRATORY DISEASES 47

and his gasping respirations only serve to aggravate the situation. In such

instances, the quick release of air by means of a needle plunged through the

chest wall is lifesaving. Lastly, the rare phenomenon of hemopneunothorax

might be mentioned. Here, bleeding occurs from the torn pleura, sometimes

on a large scale.

There were 3,831 admissions for spontaneous pneumothorax to U.S.

Army hospitals between 1942 and 1945. It was about twice as common at

home as overseas. The vast majority of these cases were of the uncomplicated benign type, and in about 10 percent was the condition a cause for

separation from military service. Recurrence was the reason for most of

the discharges. The average duration of hospitalization was in the neighborhood of 2 months, so that neither in terms of man-days lost nor manpower permanently lost did the disease constitute a serious medicomilitary

problem. The four deaths attributed to the condition were presumably due

to tension pneumothorax.

In 1944, at the suggestion of the National Research Council, a booklet

on spontaneous pneumothorax was prepared for general distribution by Dr.

James J. Waring.8

a In this, he advocated conservative therapy, with emphasis on hospitalization, bed rest, and the avoidance of air transport. Dr.

Waring also discussed the indications for thoracotomy, chemical pleuritis in

the recurrent cases, and the disadvantages of these procedures. In general,

he advised an individualized approach to each case.

PULMONARY FIBROSIS

Diffuse fibrosis of the lungs may follow granulomatous diseases, such

as tuberculosis, fungus infections, sarcoidosis, and beryllium poisoning. It

is also a serious occupational hazard of those exposed to the inhalation of

silica dust. The preinduction X-ray screening of U.S. Army personnel in

World War II made it highly improbable that individuals with any significant degree of pulmonary fibrosis would be accepted for military service.

Moreover, the conditions leading to its development were not a feature of

army life, so that, apart from a certain amount secondary to chronic pulmonary tuberculosis, it was never a feature of medicomilitary practice. It

might be added that the only generalized fungus infection with a fairly

high incidence in the Army, coccidioidomycosis, is not a recognized cause

of diffuse pulmonary fibrosis.

Peculiar instances of rapidly progressive pulmonary fibrosis whose

etiology is entirely obscure have been recorded in the literature. Notable

among these is the report of Hamman and Ricl.8 9 It is of interest that four

88 Waring, J. J.: Spontaneous Pneunothorax. Office of Medical Information, Division of Medical

Sciences, National Research Council, July 1944.

89 (1) Hamman, L., and Rich, A. R.: Acute Diffuse Interstitial Fibrosis of the Lungs. Bull. Johns

Hopkins Hosp. 74: 177-212, March 1944. (2) Eder, H., Hawn, C. V., and Thorn, G. W. : Report of

a Case of Acute Interstitial Fibrosis of the Lungs. Bull. Johns Hopkins Hosp. 76: 163-171, April 1945.
48 INFECTIOUS DISEASES

cases thought to resemble those described by Ilamman and Rich were observed in the U.S. Army in New Guinea in 1944. Of these, one patient

finally recovered while two were evacuated and lost to followup study.

One canie to autopsy.

PULMONARY EMPHYSEMA

Chronic pulmonary emphysema was occasionally noted in the U.S. Army

in the older age groups, particularly among officers. It was less common

than in civilian practice, probably owing to the generally higher standards

of health prevailing in the Army. It was said to be responsible for about

750 admissions in the period of 1942-45, most of them in the continental

United States.

MALIGNANT DISEASE OF THE LUNGS

The incidence of malignant disease generally in the U.S. Army is very

low, owing to the age group involved. Moreover, a survey of 15 million

Army man-years in the 20- to 40-year age group made in 1944-45 indicated

that the incidence in this group was lower than among civilians.'0 The

reason for this difference is not apparent. In any case, cancer occurs with

expected frequency in the older age group, again particularly among officers.

As a measure of the importance of malignant disease of the lungs in

military medicine, the following is cited: Bronchogenic carcinoma is estimated to have been recognized 200 times during the period 1942-45. There

were 91 cases of all forms of malignant diseases of the lungs identified at

Letterman General Hospital, San Francisco, Calif., between 1944 and 1950.

This represented almost exactly I per 1,000 admissions.9 1

90 Lindsey, D., and Cohart, E. M.: Incidence of Cancer in American Males; 15.000,000 Man-Years

of Aggregate Experience, United States Army, 1944-45. Cancer 3:: 945-959, November 1950.

91 For the surgical aspects of diseases of the chest see Is~ades, Brian B., Carter, B. Noland, and

DeBakey, Michael E. : Surgical Aspects of Diseases of the Chest. In Medical Department, United States

Army. Surgery In World War II. Thoracic Surgery. Volume II, ch. XI. [In preparation.]-J. B. C., Jr.
CHAPTER II

Sandfly Fever

William A. Reilly, M.D., Roberto F. Escamilla, M.D., and

Perrin H. Long, M.D.

The diagnosis of sandfly fever was not made as frequently as it should

have been, because of an unfamiliarity with the disease and a certain reluctance on the part of medical officers to make the diagnosis solely from the

clinical picture.'

Sandfly fever, also known as Phlebotomus fever and pappataci fever,

attained importance in Allied and Axis forces in the Mediterranean (formerly North African) Theater of Operations, U.S. Army, in World War II

by incapacitating large numbers of men for periods of 7 to 14 days, or

longer. This disease was known to be endemic in the Mediterranean littoral

and was first recognized in U.S. forces in North Africa toward the end of

April 1943. Although not reported as such in the statistical health report

(WD MD Form 86ab), the first patients were seen at the 77th Evacuation

Hospital then situated near B6ne, Algeria. At that time, typical cases were

described, and a careful study vas made of the relation and importance

of meningeal irritation to the general findings in the disease. The patients

had come from the U.S. II Corps which was then engaged against the enemy

in northern Tunisia. At the same time that these patients were being studied and the disease recognized in the 77th Evacuation Hospital, an increased

incidence of influenza was observed by the medical services of the other

e-vacuation hospitals within the corps area and also a sharp increase in the

number of cases of F.U.O. (fever of undetermined origin) was noted in the

statistical health report for April 1943. While no careful search for sandflies was conducted by trained entomologists during that period, it is known

that sandflies, Phfcjbotorus papafasii., were captured and identified as sucl.

in northern Tunisia by certa_,1i British medical officers and by members of

the hygiene section of the Brit,:h First Army.

While knowledge concerning the incidence of sandfly fever in U.S.

forces in North Africa during the summer of 1943 is obscured by the fact

that the diagnosis was infrequently made and doubtlessly most of the cases

were classified as F.U.O., the disease is known -o have occurred frequently

in the region of Tunis, Mateur, Ferryville, and Bizerte in Tunisia; also

1 Letter, Lt. Col. Perrin H. Long. MC, Consulting Physician, Office of the Surgeon, Headquarters,

NATOUSA, to the Surgeon, NATOUSA, 24 Aug. 194:1. subject: A Report Upon Medical Services in

Sicily.

49
50 INI'E(TI(JUS DISEASES

around Orani and Algiers in Alger a.2 (Cases of the endemic disease were

noted iii members of the Allied forces iii Algiers and, in at least one

inistanice, a fairly extensive outb~reak occurred among memibers of a signal

corps det achmnent, which was situated just ouitsidle thle city. InI this outbreak,

hie disease was thought to lbe dlengue utili it review of the cliniical finding

in the disease revealed ý.i absence of secondary rises in fever. An entomiological survey of thle area of this (let achmient established tilie presence of

miany sandtlies of thle variety 1'. papalaii.~n

Ai review oif the plan~is for the amplhib~ious o1)erat ionl in Sicily Which dealt

with the professional services shiows that sandily fever was considered ai

likely threat. to manpower (luring the Battle of Sicily anid thlat the peak of

the disease would he reached after 1 August 194:1. This prediction wvas

more than realized, lbecause the (disease wvhich had been contractedl in North

Africa be-iriu to make it s appearance onl D-day in Sicily, and, while no

cases of the disease wvere reported in the statistical health report for

NATroITSA (North African Theater of Operations, U.S. Army) for July

1943, in reality, there were hundreds of cases of sandfly fever in thle troops

in Sicily during that monthI. This lack of reporting was (Ile to the dliffidence that medical officers then showed in making the diagnosis of the (isease froin tilie clinical find~in~gs alone.3

D~espite the reportinlg of bult 104 e'ases. thle (lisease reached epidlemic proportions iii Sicily because, it was at f-avorable simimer for thle. propagation

of sandflies, the type of figltingl Was froii village to village, native hiabitations were used as billets, and discipline in respect to the use of nets and

insect repellents was poor. Sampling studiesi noade in division clearing

companies and evacuation hospitals during the. first 2 weeks in August produced clinical evidence ttat a mninimumi, at least 25 percent, of the cases

(liagnosed as F.IT.O. should have lauen diagnosed as sandfly fever. During

the latter half of the month of August and the first half of September, this

same percentage probably prevailed.

Trhe invasion of Italy by way of the beaches atit Salerno (all area in

Which sandlflies were commonl) was attended by a large number of cases of

sancifly fever. This iiivasioni w;s spearheaded by the .36th In~fantry lDiVi2 11n May 194:1, shortly after Von A4rmin's army was driven out of Tunis, contact was possible

with U.S. Army Forces In !he Middle V'a .g i-gypt) and the Persian Gulf Service C:ommand (Iran-Iraq).

Rep,,rts of the extensive outbreak.ý ýiit.ý,!' fever there. which occurredl ini U.S. personnel, were

beginning to be available althoug~h :-I wax' nl-,"ýeft that In theme areas, too, medical officers were loath

to make the diagnosis, preferring F. ý '' -rlizenza.

'I An analysis of the possible exteill -i andifiy fever cases In the Sicilian campaign, nearly all of

which were probably erroneou~sly' dliagnose4d am malaria or conservatively labeled F.U.O., was the Rubject of a special report miade by Mij. (later Lt. Col.) Albert B. Sabin, MC. In September 1943. This

repport was subsequently published in part by Major Sabin, Lt. Col. Cornelius B. P~hilip, MC, and

h~r. John R. Paul. The conclusion reached by Major Sabin was that sandfly fever was probably responsible for as many, If not more, cases of fever as malaria. (I. Letter, Maj. Albert B. Sabin, 16C, to

chief Surgeon, Seventh Army : Col. Daniel Franklin, 7 Sept. 1943, subject: Estimate of Extent to

Which Sandfiy Fever Was and Is a Problem Among Ameprican Forces In Sicily. 2. Sabin, A. B., Philip,

C. B.. and Paul, J. R.: Phiebotomus (Pappataci or Sandfly) Fever: A Dlisease of Military Importance:

gamnmary of Existing Knowledge and Preliminary Report of Original Investigations. J.A.M.A. 125:

60.3 606, 1 July 1944.)
SANDFLY FEVER 51

sion. a unit which had had little experience with sandfly fever and hence

was ,comprised mainly of susceptible persons. Again, as in Sicily. the

tro•i, , iade use of buildings both as strong points during the fighting and

subsequently as billets, and discipline in the use of nets and repellents was

poor. Because of certain command difficulties, it was impossible to have an

adequate study made of the F.U.O. cases in Fifth U.S. Army hospitals during September and early October, so that an approximation of the number

of cases of sandfly fever was not made, although from the rather meager

data at hand it seemed probable that the incidence of the disease in the Fifth

U.S. Army during this period was similar to that experienced by the Seventh U.S. Army in Sicily.

In 1944, in Italy, the situation in respect to the diagnosis of sandfly

fever was considerably improved, and the figures for that year were much

more representative of the actual incidence of the disease than they were in

1943. However, it must be recorded that, even after an indoctrination campaign had been conducted in the diagnosis of sandfly fever, there were many

medical officers who, because a specific diagnostic test for this disease did

not exist, preferred to make the diagnosis of F.U.O. Frequent examples of

this failure to make the proper diagnosis were encountered in the monthly

essential technical medical data reports, in which medical officers, after having describd classical examples of the disease, would state that although

sandflies are known to exist in this area, the faet that none of the patients

had seen the insects and few if any gave a history of having been bitten by

sandflies, the diagnosis of sandfly fever could not be definitely established

and that, hence, the cases were classified as being F.U.O.

In MTOUSA (Mediterranean Theater of Operations, U.S. Army), during the winter of 1944 and spring of 1945, an intensive campaign of education was carried out in respect to the clinical findings in sandfly fever. The

effect of this campaign became evident because the incidence of sandfly fever

as reported in the statistical health reports for May, June, and July, 1945,

reflected the true incidence of the disease.

While the literature upon disease in the Wehrmacht was scanty, it was

known that German troops based in the Mediterranean area suffered from

sandfly fever. Hallmann' 4 in 1941, deseribed an outbreak of sandfly fever

that occurred in German soldiers who were stationed in the islands and the

Greek mainland near Athens. The majority of the cases of the disease were

seen in July and August, and it was estimated that 20 percent of all the

troops in the area had the disease during this ti- e. In a reportr printed in

Berlin in 1944,5 an analysis of 5,890,000 records for admissions to hospitals

for sickness in the German Army from 1 September 1939 to 31 March 1943

was made. Of the admissions recorded in this report, 1,062,920 were for

.Hallman: Beltrag zum Pappatacifleber 1941 auf der Balkanhalbinsel. Deut. trop. Ztschr. 43:

64-68, 1 Feb. 1943.

5 DIe Infektionskrankheiten im jetzigen Kriege. Anlage zu Der Heeres-Sanititslnspekteur. Nr.

8715/44 geh. (WI G) Prdif Nr. 50. Berlin, den 28.8.1944.
52 INFECTIOUS DISEASES

infectious diseases. Sandfly fever (Pappatacifieber) was 13th on the list as

a cause for admission with 4,941 cases recorded without any deaths and with

an average period of hospitalization of 13.4 days. Inasmuch as the Wehrmacht had a large number of troops stationed in the Mediterranean and Black

Sea littorals in 1941. 1942, and 1943, it is astounding that but 4,941 cases of

sandfly fever were recorded. It is especially surprising when one considers

that in this study no mention was made of the existence of F.U.O. The

truth of the matter probably lies in the fact that during this same period a

total of 159,890 cases of "grippe" were recorded from hospital reports. It is

likely that many cases of sandfly fever were reported incorrectly under this

diagnosis.

ETIOLOGY

It was established in 1908 by Doerr, Franz, and Taussig 6 that the causative agent of sandfly fever is a filterable virus and that the midge, P. papatasii, is the vector of this disease. This finding was confirmed by other observers 7 and also by Sabin, Philip, and Paul. Sabin and Paul studied the

disease in Sicily after the end of the Sicilian campaign in 1943. As a result

of their studies, they obtained the following information regarding the virus

of sandfly fever:

Virus is present in the blood of patients 24 hours before the onset of fever and during

the first 24 hours thereafter: it is no longer demonstrable 48 hours after onset. It may

be passed serially in volunteers by parenteral inoculation although the intracutaneous

and Intravenous routes were more effective than the intramuscular or subcutaneous routes.

Attempts to recover virus from the spinal fluid obtained In the first 2 days of the experimentally produced disease were unsuccessful. The virus survived in the frozen state at

Dry Ice box temperature or in the lyophilized state in an ordinary refrigerator for

6 months. The size of the virus as determined by filtration through gradocol membranes

appeared to be not larger than 25 to 37 mpt, although the low titer of virus (1,000 minimum infectious doses per ml. of serum) suggests the possibility that it might be even

smaller. Unsuccessful attempts were made to inject embryonated eggs and a wide variety

of species including young baboons (Papio hamadryas) and monkeys of the following

species: grivet (Cercopithecus griscoviridis), vervet (Cercopithecus acthiops pygerythrus),

red African hussar (Cercopithecus [Erythroccbus] patas), Macaca radiata and Macaca

mulatta (rhesus). The rodents included young white mice, wild gray mice, Syrian hamsters, Egyptian desert rats (jerboas), rabbits, guinea pigs, and cotton rats.

As cited by Warren and Johnson,s Sabin also showed that there was more

than one strain of sandfly fever virus. Volunteers who had been inoculated

6 Doerr, R.. Franz, K., and Taussig, S.: Das Pappatacifleber. Leipzig und Wien: Franz Deuticke, 1909. "7 (1) Birt, C. : Phlebotomus Fever in Malta and Crete. J. Roy. Army M. Corps 14: 236-258, 1910.

(2) Birt, C. : Sand-fly Fever In India. J. Roy. Army M. Corps 15: 140-147, 1910. (3) Tedeschi, A.,

and Napolltani, M.: Experimentelle Untersuchungen uiber die Aetiologle des Sommerflebers. Centralbl.

F. Bakterlol. 57: 208-211, 1911. (4) Shortt, H. E., Poole, L. T., and Stephens, E. D. : Sandfly Fever

on the Indian Frontier; A Preliminary Note on Some Laboratory Investigations. J. Roy. Army M.

Corps 63: 361, December 1934; and 64: 17, January 1935. (5) Sbortt, H. E., Poole, L. T., and

Stephens, E. D. : Note on Some Experiments With Sandfly Fever Blood and Serum. Indian J.M.

Research 23: 279-284, July 1935. (6) Moshkovsky, Sh. D.: Studies on Pappataci-Fever. Med.

Parasitol. and Parasitic Dis. Moscow 5 (No. 6): 823-862, 1936.

8 Warren, R. 0. Y., and Johnson, J. W., Jr.: Sandfly Fever in NATOUSA. M. Bull. Mediterranean

Theat. Op. 3: 160-164, May 1945.
SANDFLY FEVER 53

with a strain of virus obtained from a patient in the first day of his illness

in Caserta, Italy, developed typical sandfly fever; they were not subsequently

protected by this attack against an inoculation with the Sicilian strain of the

virus.

EPIDEMIOLOGY

It is believed that P. papatasii is the chief vector of sandfly fever ill

NATOUSA. The adjacent shores and islands of the Mediterranean, Adriatic, and Aegean Seas which were included in the North African and Mediterranean theaters have long been known as favorable breeding places for

the moth midges of the genus Phl ebotomus. The hilly and rocky terrains of

Algeria, Tunisia, Sicily, Sardinia, Corsica, and Italy and the adobe or stone

houses which (lot these areas give rise to what was aptly called "tile classical

sandfly situation," by Maj. Marshall Hertig, SnC. The female sandfly by

choice seeks rocky places, cracks in masonry, buildings, stone walls, or rubble and caves in which to lay its eggs; the adult midges seek outdoor shelter

in caves, cracks in stones an(d buildings, and under the eaves of buildings. A

cool, shaded, slightly damnp environment is ideal for the life of this insect.

Sandflies rest during the day and feed during the night. The female

alone bites, an act which she performs persistently and viciously; a meal of

blood is necessary for proper ovulation (fig. 1).

The incidence curves of sandfly fever and F.U.O. in NATOUSAMTOITSA from January 1943 to December 1945 are presented in chart 1.

The first cases of sandfly fever were reported in August 1943 although the

disease was recognized in North Africa as early as April 1943. In 1943, the

peak monthly rate (September) was 7.9 per 1,000 per annumi, a rate doubtlessly far below the actual rate, because the vast majority of cases of sandfly

fever were reported as F.U.O. Since careful studies were not made upon any

sample group of cases of F.U.O. in 1943, there was little information about

the correct diagnoses at the time of the final disposition of these patients,

and it will never be known what percentage of patients diagnosed as having

F.U.O. during the summer of 1943 were in reality suffering from sandfly

fever. It is to be remembered, however, at this point, that many cases of

malaria were also classed as F.U.O. in 1943 and that the total rate does not

primarily represent undiagnosed cases of sandfly fever.

The incidence curve during 1944 more closely approximated the true incidence, since medical officers were beginning to have some familiarity with

the disease and hence were more prone to make the correct diagnosis. In an

interesting study of F.U.O. 9 made by Maj. Emil C. Beyer, MC, it was found

that a diagnosis of sandfly fever was made at the final disposition in 2.4

percent of 450 cases initially undiagnosed upon admission as F.U.O. during

the months of June, July, and August, 1944. However, in this same group,

9 Beyer, E. C.: Fever of Undetermined Origin. M. Bull. Mediterranean Theat. Op. 3: 208-209,

June 1945.
54 INFECTIOUS DISEASES

FIoUID 1.-Male aind female of Phlcbotoimns papataxii, the vector of sandfly fever. (Sabin,

Philip, and Paul. J.A.M.A. 125: C63-606, 1 July 1944.)
SANDFLY FEVER 55

CHART 1.-Incidence of sapdlty fever and fever of undetermined •rigin in the North

African-Mediterranean Theater of Operations, U.S. Army,1 1943-45

(Preliminary data based on summaries of statistical health reports]

[Rate expressed as number of cases per annum per 1,000 average strength]

rATE

225

200 A

ITS'

150 FEVER OF UNDETERMINED ORIGIN

too

75

I

500 I t I

so I

26 .- SANOFLY FEVER .

5I -

0 1 _______ M J S D 1 J S 0 M J S 0

1943 1944 1945

I The North African Theater of Operations was redesignated the Mediterranean Theater of

Operations on 1 November 1944.

the diagnosis of F.U.O. or of febricula appeared in 8.4 and 10.7 percent,

respectively, of the final dispositions made during that period. Thus, the

etiology of 19.1 percent of the patients having fever was in doubt at the time

of their final disposition, and it is possible that many of those patients may

have had sandfly fever. That this is probable is evidenced by a further

study of the diagnoses which were recorded at the time of the final disposition of a similar group of patients, which was made by Major Beyer during

January 1945. In this group only 8.9 percent were discharged with a final

diagnosis of febricula or F.U.O. It is unknown how many times the original diagnosis of F.U.O. was changed to sandfly fever in the statistical health

reports, but on the basis of these figures, there is a possibility that about 10

percent of the patients originally diagnosed as having F.U.O. in the summer

and early fall of 1944 had sandfly fever.

The incidence curve of sandfly fever for 1945 probably represented the

incidence of this disease quite accurately as the rates for F.U.O. were at low

levels in comparison with corresponding months in 1943 and 1944.

As will be noted from chart 1, cases of sandfly fever made their initial

appearance in NATOUSA-MTOUSA in April and gradually built up to a

peak in September; following this, there was a rapid decline within the next

2 months. Thus, the epidemiological pattern of the disease reflected accurately the life cycle of P. papata-ii.

IMMUNITY

A natural resistance to sandfly fever apparently does not exist, and a

large percentage of susceptibles develop the disease if left unprotected in an
56 INFECTIOUS DISEASES

endemic area. Livschitz 1r reported thar, practically 100 percent of experimentally inoculated volunteers who had had no l)reVious contact with the

disease were found to be susceptible, while Sabin, Philip, and Paul stated

that approximately 95 percent of their volunteers contracted the disease following their inoculation with virus. This same high rate of susceptibility

was observed in U.S. forces when they were introduced into NATOUSAMTOUSA, and instances were recorded in which 80 percent of a command

contracted the disease in certain areas around Caserta. These observations

were similar to those made by Cullinan and Whittaker 11 in the Middle East,

where rates for sandfly fever of approximately 1.000 per 1,000 per annum or

more were recorded in other ranks in two British general hospitals which

had been located in areas in which sandflies were abundant and in which

sandfly fever was epidemic.

It was recognized also that second, third, or even more attacks of sandfly

fever could occur in the same individual and even the same epidemic season.

Livschitz observed that the initial rate of attack of the natural infections in

a group of 1,076 persons, who were newcomers in an endemic area, was about

50 percent and that 22.8 percent and 0.9 percent, respectively, of 416 persons

who had recovered from an initial infection had second and third attacks of

the disease within the same epidemic season. Cullinan and Whittaker reported that 15 percent of the noncommissioned officers and other ranks in

two British general hospitals had second attacks (and some even third attacks) of sandfly fever during a period of 3 months in which these men were

exposed to the disease in an epidemic area.

While there can be little doubt that an immunity to sandfly fever generally results from an attack of the disease, the observations which have

just been recorded suggest that at times the immunity may not, be solid.

However, Sabin's investigations,' 2 previously mentioned, indicated the existence of at least two different strains of virus and suggested the possibility

that second attacks within the same epidemic season or later may have been

the result of an infection with a different strain of virus rather than waning

immunity from the first attack.

CLINICAL COURSE AND DIAGNOSIS

Sandfly fever in NATOUSA-MTOUSA was characterized by the sudden onset of fever, headache and severe retro-orbital pain, photophobia, generalized aching, malaise, and chilly and feverish sensations. Anorexia. nausea, and vomiting occurred in some patients. The face was suffused, the

conjunctivas and scleras injected, and not infrequently pressure over the eyeballs caused pain. At times, a very faint pink erythema was present over

10 LivschItz. J. M.: Studies on Pappataci Fever. Med. Parasitol. and Parasitic Dim. Moscow 6

(No. 6): 938-943. 1937.

11 Cullinan. E. R., and Whittaker, S. R. F.: Outbreak of Sandfly Fever in Two General Hospitals

in the Middle East. Brit. M.J. 2: 543-545, 30 Oct. 1943. 12 See footnote 8, p. 52.
SANDFLY FEVER 557

the shoulders and thorax, and the spleen was palp)able in a small percentage

of patients. Many of the patients had relative bradycardia. Tihe fever lasted

from 1 to 11 days, averaging 4 days, and was followed by a variable period

of asthenia. In one large group of patients, the period of hospitalization

ranged from 1 to 25 days, averaging 6.2 days. Leukopenia was present in

most cases at the time the patients entered the hospital with the lowest counts

being recorded in the immediate postfebri!e period. The differential count

was characterized by a relative or absolute increase in the lymphocytes (often

with the appearance of large atypical forms) and an absolute increase in

many patients in the younger types of the polymorphonuclear cells.

It is not unusual that the disease caused diagnostic difficulties in medical

installations in MTOUSA. In its milder aspects, it simulated the milder

forms of influenza. At times, the onset was similar to that of malaria, infectious hepatitis, or primary atypical pneumonia, and it required much aid

from the laboratory to differentiate promptly and accurately between these

diseases and sandfly fever.

On occasion, the occurrence of nuchal rigidity in patients with signs and

symptoms characteristic of sandfly fever made the differential diagnosis bebetween this disease of aseptic meningitis difficult.1 3 Because of the lack of

specific serological tests, the diagnosis of sandfly fever could not be made in

patients with evidence of meningeal irritation and pleocytosis of the spinal

fluid, and it could not be proved that sandfly fever virus caused the aseptic

meningitis syndrome. In experiments with volunteers, Sabin, Philip, and

Paul did not believe that it occurred in any of 150 volunteets.

It is evident that, at times, the diagnosis of sandfly fever was difficult

and that it required much clinical acumen and confirmation by the laboratory. However, too often in MTOUSA, the reluctance to make the diagnosis

resulted from intellectual slovenliness and from the ease with which, for

diagnostic purposes, the disease could be classified as F.U.O.

TREATMENT AND PREVENTION

The treatment of sandfly fever in NATOUSA-MTOUSA was purely

symptomatic in type.

It was found in NATOUSA-MTOUSA that the prevention of sandfly

fever was dependent upon the precautions taken by the individual against

being bitten by sandflies and upon environmental control measures aimed at

the eradication of sandflies.

SUMMARY

Sandfly fever was a problem of great importance to the U.S. Army in

NATOUSA-MTOUSA, and it was responsible for much loss of manpower

during the summers of 1943 and 1944.

13 See footnote 8, p. 52.
58 INFECTIOUS DISEASES

Due to the variations in the clinical picture of sandfly fever, and because

specific tests for establishing its identity were not available, medical officers

were often reluctant to make the diagnosis of this disease on the basis of

their clinical findings. As a result, many thousands of cases of sandfly fever

were probably recorded as F.U.O., and hence, the data recorded in the statistical health reports from NATOITSA-AITOUSA regarding this disease

were inaccurate.

Sandfly fever could have been prevented in the areas in which the disease was endemic if the proper individual precautions for the prevention of

this disease had been observed and if a program for the environmental control of sandflies based upon the use of I)DT (dichlorodiplenyltrichiloroethane) sprays had been instituted.
CHAPTER III

Dengue

Richard B. Capps, M.D.

INTRODUCTION

Dengue is an acute febrile illness caused by a filterable virus transmitted by mosquitoes. It was tirst described by David Bylon in 1779 under the

niame of joint fever.' Since then, the disease has come to be recognized as

common in many parts of the world, and a number of extensive epidemics

have been described..2 Bancroft," in 1906, was the first to suggest that transmission might be due to Aedes aegypti. This was conclusively established by

Cleland, Bradley, and McDonald in 1916 and 1919,4 Siler, Hall, and Hitchens

in 1926,5 and Simmons, St. John, and Reynolds in 1931.6 Subsequently, it

was demonstrated that Aedes albopictus, Aedes scutellari., and Aedes hebrideus 7 can also serve as insect vectors. That the etiological agent was a filterable virus was first proved by Ashburn and Craig in 1907.8 In 1929, Blanc,

Caminopdtros, Dumas, and Saenz 9 found that certain species of monkeys

could be infected with the virus and could thus serve as a natural reservoir.

This was confirmed by Siminons, St. John, and Reynolds in 1931.

Although dengue is a nonfatal disease, it may assume considerable military importance because of its tendency to occur in massive outbreaks resultin- in incapacity of large numbers of men. This type of epidemic is favored

by the introduction of nonimmunes into an endemic area as so often occurred

1 Pepper, 0. 11. Perry: A Note on David Bylon and D)engue. Ann. M. Hist. , : 363-368, September 1941.

2 Sabin, Albert B. : Dengue. In Viral and Rickettsial Infections of Man. 2d edition. Philadelphia : J. B. Lippincott Co., 1952, pp. 556-568.

3 Bancroft, T. L. : On the Etiology of Dengue Fever. Australas. M. Gaz. 25 : 17, 1906.

4 (1) Cleland, J. B., Bradley, B., and McDonald, W. : On the Transmission of Australian Dengue

by the Mosquito Stegomyia Fasciata. M.J. Australia 2 : 179-184, 1916. (2) Cleland, J. B., Bradley. It.,

and McDonald, W. : Further Experiments in the Etiology of Dengue Fever. J. Hlyg. 18: 217, October 1919.

5 Siler, J. F., Hall, 31. W., and Hitchens, A. P. : Dengue: Its History, Epidemiology, Mechanism

of Transmission. Etiology, Clinical Manifestations, Immunity and Prevention. Philippine J. Se. 29:

1-304. January-February 1926.

6 Simmons, J. S., St. John, J. II., and Reynolds, F. H. K. : Experimental Studies of Dengue.

Philippine J. Sc. 44: 1-251, January-February 1931.

7 (1) Daggy. R. H. : Aedes 8cutellari8 hebrideus Edwards; A Probable Vector of Dengue in the

New Hebrides. War Med. 5: 292-293, May 1944. (2) Mackerras. I. M. : Transmission of Dengue

Fever by Aedes (Stcgomyia) scutellaris Walk. in New Guinea. Tr. Roy. Soc. Trop. Med. & Hyg. 40:

295-312, December 1946. (3) Fairley, N. Hamilton: Medicine in Jungle Warfare, 26 Feb. 1945.

[Official record.] (4) King, Willard V.: Notes on the Vectors of Dengue in New Guinea, February 1946.

[Official record.]

8 Ashburn, P. M., and Craig, C. F.: Experimental Investigations Regarding the Etiology of Dengue

Fever. J. Infect. Dis. 4 : 440-475, 1907.

9 Blanc. G., Caminopktros, J., Dumas. J., and Saenz. A. : Recherches Exp~rimentales sur la Sensibilit6 des Singes Inf~rieurs au Virus de la Dengue. Compt. rend. Acad. d. Sc. 188 : 468-470, 4 Feb. 1929.

5"
60 INFECTIOUS DISEASES

during tWorld War II. Since prophylactic measures were limited to mosquito control and since this was difficult to accomplish during combat, the

disease was a definite military hazard throughout World War I1 in practically all areas of the Pacific and Asiatic theaters.

INCIDENCE

The incidence of dengue in the U.S. Army during World War II, by

theaters of operations, is shown in table 3. It is evident that the disease was

largely restricted to tie Pacific and Asiatic theaters, although scattered cases

were reported from each of the other theaters. The lack of a specific diagnostic test raises a question as to the validity of the diagnosis, especially

where sporadic cases were reported. On the other hand, many cases were

undoubtedly not recognized and were reported under the diagnosis of

"fever of undetermined origin." It seems probable that the actual cases exceeded those reported. Finally, it should be noted that the incidence remained

low throughout. 1945. This was presumably due to improved mosquito colltrol measures, although in certain areas an increased percentage of immunes

may have also been a factor.

TABLE 3.-Incidence of dengue in the U.S. Army, by area and year, 19142-45

[Rate expressed as number of cases per annum per 1,000 average strength)

1942-45 1942 1943 1944 1945

Area

Num- Num- Num- Num- Numher of Rate her of Rate her of Rate ber of Rate her of Rate

cases eases cases cases Cases

Continental United States ----- 35 0.00 (1) (1) 12 0.00 14 0.00 9 0.00

Overeas:

Mediterranean --------------- 97 0.07 (I) (1) 82 0.19 13 0.02 2 0.01

Africa-Middle East ---------- 8 .05 4 .70 1 .02 2 .04 1 .02

China-Burma-India ---------- 7,753 17.92 143 25.14 1,150 24.96 4,050 25.39 2,410 10.84

Southwest Pacific ------------ 48,632 28.45 3,9'23 58.51 5.778 2960 26,580 47.96 12.351 13.78

Pacific Ocean Area ..--------- 27,365 23.67 12 .08 11.931 40 42 14.200 35.98 1.222 3.76

North America --------------- 1 .01 1 .02 i) (1 ) () () ') ()

Latin America --------------- 203 .53 117 1.14 39 .32 33 .38 14 .19

Total overseas ------------- 84.059 S.60 4.20 8.18 18,981 12.15 44.878 12.82 16 000 3.86

Total Army ----------------. 84.094 3.46 4.200 1.38 18,993 2.82 44.S92 5.9S 16.0OM 2.25

present in the area; no STroops cases reported.

NOTE.-0.00 indicates a rate of less than 0.005 per annum.

SPECIFIC OUTBREAKS

Australia

In March, April, and May of 1942, an extension epidemic of dengue occurred amoig U.S. Army troops stationed in Northern Territory and Queens-
'1111141 X1. J 1II.v ICIiiId Gc i iill MC.~*I l(wIIlI Tra 1joI H4 l IIru

N11' . 1. 44i I.IrigI I'(,~ J( 011( 1. I ( 4Is ý 11 %xa 1 I Kr.rI If I(I I 'hi \ .I 1g o j I,, -4 1\u t:1 k I\%I w ~- .

I A '\C II.
1\1-JA I Jill S III>] ýý,j

Ili p .- Ild it 11 lilt, I r- rý ;w ill 111l'i ,I[. it,

,\(.XN I Ichridl.- mid 'all"I'mill

A It v\ICII-I\ 1, C1,141vilil.. 40, d oll_-lilt, :I I H ýN; I I I I I I 11of \\ci.II

F-dwil:1 r ;11141 A .".I)l it I

1.1-pro-cill - I." I w I vi I I I it, I I: I -o

V ( w -1.\ cr:1 Ill, m l Il- w il( w I I I lit. I )II-of 14 1111, 1, ),[ I I I, I I I I I I, I'l, Iro I w ell

lit 11" :1 lirl-f-d Ill,, (,f I .

Ili .1 Illit., It I lit, o p id i-Ill W -1 11 1 o ll 11111

it - 111.\ o I I f n I I -:11111 1 ý1 ;.]III :Ili li'lT if I I I' I I I I I [I

A I I I Ill, 'I )I I 1 :1 1 lilt*- . 110 ,1114 1 111-.. 1 Ill .- :Ili 1 1111111

11 1 1 It'll lit - I 11:1 111( 1 1 it 1 111:1 1

I %'It I I lit 1112 ' :lI)IW (I\ IIII:III'I

1) d lol. rill. If

A ll-fil-I lilt, I, I 1,111w :I- till,

11" I'llIT 0 11 :it I 11ý- 11:1-1' 11111'11112 fillMA,11ý., V ''.6
DENGUE 63

TABLE 4.-- Incidence rates for dengue in U.S. Army personnel in New uCaledonia and Espiritu

Santo, .front January to August, 1945 and 1944

[ Rate expressed as number of eases per annum per 1,000 average strength]

New Caledonia Espiritu Santo

Month

1943 1944 1943 1944

January_ %.. 1 1I - 1

February- 65 15 441 1

March 186 120 1,095 0

April -- -.. 645 56 1,713 0 May .------------------------.. 317 16 1,531 0

June -.-------.---- 66 5 909 0

July ..... . .. . . ... - 30 1 245 0

August------------------------i 3 1 82 (

A less severe epidemic occurred at New Caledonia in 1943, as shown in

table 4. The wide distribution of breeding places for A. aegypt; and the

lack of preventive measures by the resident population contributed to the

persistence of the outbreak. The incidence of infection in military personnel would undoubtedly have been much higher if it had not been for intensive

mos(qufito control measures carried out by the base malaria control unit. An

epidemic was avoided, although cases developed during the 1944 rainy season.

Hawaiian Islands

In 1943, dengue appeared in Honolulu, T.H., in epidemic form for the

first time in over 30 years. The evidence suggested that the disease was

imported from Suva, Fiji Islands, where an epidemic was in progress. Two

commercial airline pilots were hospitalized with dengue in Honolulu early in

July 1943, shortly after arrival from Suva. One of the pilots was ill upon

arrival whereas the other did not develop symptoms for several days and

was not isolated by hospitalization until he had passed through the infectious

period.15 Three weeks later, two civilian cases appeared in the Waikiki

Beach area of Honolulu, and, 12 days later, two cases occurred in Army

personnel in the same section. 16 Measures were taken immediately to prevent

an explosive outbreak, consisting chiefly of an extensive program of mosquito

control. Also, proper screening of patients in hospitals and in homes was

made mandatory, and large areas of the City of Honolulu were placed off

limits to troops. Although 1,355 civilian cases were reported through 31 December 1943, only 56 cases occurred in military personnel.

'5 Gilbertson. W. E. : Sanitary Aspects of the Control of the 1943-1944 Epidemic of Dengue Fever

in Honolulu. Am. J. Pub. Health 35: 261-270. March 1945.

Ifl History of Preventive Medlcin,. United States Army Forces, Middle Pacific, pp. 231-21.'5. [Official record.]
04 INFECTIOUS DISEASES

In order to render effective neasures for control of mosquitoes in militarv areas, it was necessary to have adequate control in the surrouiding

civilian areas. Toward this end, the Army gave all possible assistance to

civilian agencies. A medical officer was attached to the territorial board of

health to make an epidemiological study of all new cases. Fifty enlisted

men were assigned to spray the buildings and to eliminate breeding places of

mosquitoes in homes where there were cases of dengue. Trucks, ladders, and

sp)raying equip)ment were made availabl,, for use by civilian agencies. In

September 1943. it became necessary to extend the program for mo.nquito

control to include the entire City of honolulu. The program was supervised

by the 1 .S. Public Health Service, and labor was provided by a medical

service c+i.Oraany. I Ionolulu was divided into 3 districts and subdivided into

77 inspectho zones, each of such size that one man could thoroughly cover

his zone every 10 days.

Aed~s mosquitoes were found breeding in all varieties of containers that

could hold water, such as tin cans, bottles, barrels, jars, flower vases and cups,

tanks, tubs, tires. storm drains, catch basins, unstocked fishponds, abandoned

cesspools, an(l cisterns. Breeding places were also encountered in waterholding plants, such as spider lilies, pineapple lilies, and ape plants and in

rotted-out holes and crotches in poinciana, algarroba, haole koa and guava

trees, bamboo and banana stumps, and the larger water-holding pockets in

traveler's palms. Other unusual breeding places were in fallen paln fronds

and the holes of lava-formed rocks and pockets in emerged formations of

coral reef. It is striking that in over one million inspections, on only four

occasions were ground pools found to be breeding places for Aedes mosquitoes. Since both A. a.gypti and A. albopictus have short flight ranges (up

to 200 yards), it was only necessary to extend control operations to the

fringes of the inhabited areas.

The effectiveness of these measures is shown in table 5. It will be noted

that the breeding indices of Aedes mosquitoes were satisfactorily reduced. It

TABLE 5.-Breeding index of Aedes mosquitoes in Honolulu, T.H., from August 1943 to

August 1944

Year and month Index I Year and month Indexs

1943 194.4

August ------------------------ 5. 7 January --------------------- 1.0

September --------------------- 1.7 February -------- -- ---------- 1.9

October ------------------------ 1. 1 March -----------.------------- 3. 5

November ---------------------- .9 April --------------- ----------- 1.8

December ---------------------. . 2 May ---------------- ---------- 1.0

June ---------------------- - 1. 1

July -------------------------- .7

August --------------- -------- .8

I Percentage of premises inspected in which .ledes larvae were found.
DENG U E 65

is interesting that the critical index or thresllold of iipl)ortance for dengue

was 3.0 or less, which is considerably lower than the value of 5.0 which is

generally accepted as the critical point for yellow fever.1 7

New Guinea and the Philippine Islands

From the onset of operations in New Guinea and adjacent islands, dengue

was an inm)ortant cause of noneffectiveness of troops.1 8 Table 6 shows the

case rates for the years 1944 and 1945; separate rates for this area are not

available for the year 1943. It will be noted that the incidence was highest

during January and February, which are the months of heavy rainfall. Dur'-

ing the first 6 nmonths of 1944, the case rates for dengue exceeded those for

TABLE 6.-Incidence of dengue in U.S. Army personnel in New Guinea and adjacent islands,

January 1944 to August 1945

[Rate expressed as number of cases per annum per 1,000 average strength]

Year and month Number of cases Rate

1944

January -----------.-------------------------.----------- 3,137 197.6

February ------------------------------------------------ 2,849 J64. 1

March ---------------------------------------------- 2,469 90. 6

April ---------------------------------------------------- 1,848 68. 0

May _-- 1,970 66. 1

June --------------------------------------------------- 2,756 61.2

July ---------------------------------------------------- 2,613 60. 1

kugust -------------------------------------------------- 1,571 33. 6

ber ---------------------------------------------- 1,828 Sptem 30.5

October -------------- --------------------------------- 1,102 21.5

November ----------------------------------------------- 935 23. 5

December ----------------------------------------------- 1,001 23. 2

Total --------------------------------------------- 24, 079 54.2

19415

January ------------------------------------------------ 640 24.6

February ----------------------------------------------- 576 25.8

March -------------------------------------------------- 597 25.5

April --------------------------------------------------- 468 30. 5

May---------------------------------------------------- 353 27.3

June --------------------------------------------------- 208 15.3

July. ---------------------------------------------------- 48 G. 9

August ...------------------------------------------------ 222 9.2

Total- -------------------------------------------- 3, 112 21.5

"17 Soper, F. L., and Wilson, D. B. : Species Eradication; A Practical Goal of Species Reduction in

the Control of Mosquito-borne Disease. J. Nat. Malaria Soc. 1 (No. 1): 5-25, 1945.

is See footnote 7 (3), p. 52.
maulariai. It Will be noted that lit 1945 thle rate., remiained low. even during

thle raiiiii season)I. Thisi lp'siiliiablYl was dlile 1(iii)rO& Impoe iis(jliii 0conItrVol

andlt to anlll ii&Ttil~t percet'Iiir2e () ol1111(! iiiiiiniie. :inll~ ilitarv per-.oiiiiel. A S

OCCII rrle(I vlsewhiere. sd i-] k i w, it 01111 k1s a )l)aI'v(CI I Iiii ert a Iit il lii t '. lim t a) dv in1

lie 1ItolI la IId ni a I Id I Ia k ai It'us. III Illie 1 '~l(ai i te Ilt- ratit ()f0 (lt-' lle~I t(

malairia was, 4 :1U"

411iii44 1breed'4ing'. A\. D iscardedt, raili-tilieti

A I Pi 4 4 27T5 8, 9,1: A,

lii -New Gu~ll&ine, the~ vector appeared to beC I. 8c?1t/('/bIx,-,x' I1. (Ie~fy/)/;

are rare ill this, area. This Increasedl tilt, poleml~t' of inlosqulito cmbnt ol. j)(b

cauklse of the grevater varietv of lweedol ny pla-e- eplll~oycol byN A. i/las

g.4). lIn addition, thle, (Jai-litin jug habitS of thiS Species Iladep 1(individual

prioteiv Iturei~ts measV( iievessarv* alI all llourIS. p.ýe(ec alIV inl Slunleol jjIllurlp areaS.

Tril si izat ion inl tle. PhilIipjpinles is of p a rticul a r Intderest 1)ecallse it ilhiust rates thle effecti veness of measures for conitrollinhg ilosyjUitoes. Prior to

WXorld W~ar 11, deugzue had~ always been a, problemn among- A rmiuv forces stat joned ill thle P idiippiiies. R~eplacemnent's IreqiteulvolitIN cnracteid thle dlisealse

within a few imonthis after arrival. ConlsequlentlY. Wil li the peigof the

(Vi liIii igli for FPvoccutlollt01. a sTI'0l5s sitll WIiOl Was5 aiit liipated. espeia)'11lly

if, Quarterly Rep'ort, Su~rgeonf, I Ccorps. 5041t14w4st l'1wi-ic Arsvo. I Apr. 1 944-31) .June 1944.

21) See footnote 7 (4), p. 52.
DENGUE 67

during the rainy season in areas of dense population. However, in spite of

the presence of large numbers of noninimunes and the appearance of cases

throughout the Philippine Islands, no real epidemic outbreaks developed.

The case rates are shown in table 7.

TABLEt 7.-Incidence of dengue in U.S. Army personnel in the Philippine Islands, November

1944 to December 1945

[Rate expressed as number of cases per annum per 1.000 average strength]

Year and month Number of cases Rate

1944

November -.... - 652 39.8

December -----.------------------------------------- 1,360 49. 1

1945

Ja n uary _ . ---- ----. --. --. -------. --. -----... . ... 1,033 32. 1

February. 893 24. 8

March ---------------- _ 1,214 25.7

April--- --.------------- 857 19.9

May ---.--------------- -------- ------------------ - 913 19.6

June ----- 839 13.4

July-------------------- ----------- 930 16.4

August 1,140 15.2

September -------------------------- 439 7.9

October -------------------------------------------------- 294 6.3

November ---------------------------------------------- 285 6.3

December ---------- ------------------------------------ 89 4. 1

Total for 1945 ------------------------------------- 8,926 15. 7

Total ..----------- _.-.-------------------------- 10,938 17.9

Effective mosquito control was achieved by attaching malaria units to

all forces operating in the Philippines. In addition to the usual control

measures which were carried out on an intensive scale, area spraying with

DDT (dichlorodiphenyltrichloroethane) from airplanes was carried out extensively over Manila (fig. 5) and other populated centers on Luzon Island

during the early months of 1945.21 The houses of natives adjacent to concentrations of troops were also sprayed with DDT.

It is of interest that reports from this area indicated considerable variation in the clinical picture. Thus, many cases showed only a single peak in

temperature, and in many instances the disease was quite mild. The difficulties in diagnosis, particularly during the first few days of illness, were

21 Essential Technical Medical Data, U.S. Army Forcps in the Far East, for March and April 1945.

Inclosure 1:3, subject : 1)DT Spraying in luozon.
4'''' ' I 144V I I I , , )I it TI. lic44 q-4 Iil4('' o \\ .I:1 I4''1t4 II( ) l'V( ItIIIII III IY (4111 h41 I 4t I \ IlZl4It 
DENGUE 69

of rubble resulting from the total destruction of villages and scattered dwellings, a multitude of wells, cisterns, vats, troughs and rainwater-collection

facilities as well as an immense quantity of tins, shell cases, et cetera." The

difficulties encountered in controlling mosquitoes during and immediately

following the assault phase of a campaign are sufficiently great under ordinary circumstances, but in this instance they l)roved to be insurmountable.

This is illustrated by counts made of the number of mosquitoes found biting

a single human during 10-minute periods. Thus, between 16 August and

10 Sel)tember 1944, counts made in the late afternoon near the vicinity of

towns or villages showed from 5 to 36 specimens of A. aegypti and from

2 to 16 specimens of A. albopictus as well as 1 to 7 specimens of other species.

Counts made at night showed as imany as 42 specimens of still other species.

Effective control of mosquitoes only became possible when a supply of

DI)T arrived on 3 Septemlber 1944. Area control was employed by spraying 5 p)ercent D)DT and kerosene from airplanes. It was found that small

planes were inadequate and that it was necessary to use C-47's because of

the size of the area involved. Between 12 and 22 September, 8,600 gallons

of the mixture was sprayed over a total of approximately 15,000 acres, an

average of approximately two-tenths of a pound of DDT per acre. In

addition, DDT residual spray was used in all tents and living quarters of

hospitals. 23 This was accomplished with a truck-mounted power spray unit

for chemical decontamination provided by the Chemical Warfare Service.

The effectiveness of these measures is shown in table 8. The number of

new cases began to decrease significantly about 1 week after the aerial spraying of DDT was started. After the first of October, the number of new

cases was less than 10 percent of the niumber which occurred at the height

of the epidemic. Although the preliminary summary reports show only 10,834

cases of dengue for the entire Pacific Ocean Area during August, September,

and October, 1944, it is reliably estimated that there were 20,000 cases on

Saipan alone.24 This discrepancy was probably due to a high percentage of

cases that were cared for in quarters and were not officially reported.

The effectiveness of these measures in controlling the mosquito population was clearly demonstrated by observations on the "biting rate" per

minute. Thus, surveys made before and after spraying by airplane indicated

a decrease up to 98 percent. In addition, it was generally agreed by troops

that. there had been a tremendous reduction in the mosquito population.

This was further substantiated by surveys of breeding places of mosquitoes

made before and after DDT spraying. Finally, the effectiveness of these

measures is indicated by the marked decrease in new cases of dengue which

occurred before the end of the rainy season and at a time when susceptible

troops were still arriving on the island.

23 Letter, Deputy Surgeon, Headquarters, U.S. Army Forces, Pacific Ocean Areas. to Surgeon,

Pacific Ocean Areas, 30 Sept. 1944, subject: Measures Used for Control of Dengue Fever on Saipan.

24 Annual Report, Eighteenth Medical General Laboratory, Pacific Ocean Areas, 1944. Inclosure 5

thereto.

639243v-63-7
70 INFECTIOUS DISEASES

TABLE 8.---Daily report of neuw cases of dengue at height of the epidemic in Saipan, 14 September

to 6 October 1944

Date Number Date Number

1944 1944/

September 14 ----------.------- 393 September 26 ------------------- 1i 62

15 ------------------- 426 27 ------------------- 87

16-294 28 ------------------- 79

17 ------------------- 306 29 ------------------- -71

18 ------------------- 289 30 ------------------- -44

19 ------------------ 275 October 1 ------------------ 36

20 ------------------ 230 2 - --------- 33

21 ------------------ 137 3 ------ -------- 27

22 ------------------ 137 4 ------------------ 28

2:3---------------------112 5 --------------------- 32

24 ------------------- 93 6 ------------------ .23

25 ------------------ 81

China-Burma-India

Although dengue was endemic in most of the China-Burma-India

theater, the majority of cases among U.S. troops occurred in the region of

Calcutta, India. The highest incidence appeared between July and October

with the peak varying according to the dates of the monsoon.25 During 1942,

1943, and 1944, the dengue rates were approximately the same; namely,

25 per 1,000 per annum. However, in 1945, the rate dropped to less than

half. Although the explanation for this is not entirely clear, it is felt that

the improvement was largely due to the work of malaria control detachments

whose measures were directed towards Aedes mosquitoes as well as the

Anopheles mosquitoes. In addition, antimosquito supplies and equipment

were more readily available in 1945 and individual protective measures were

better enforced (fig. 6).

One small but sharp outbreak of dengue which occurred in the China

theater illustrates the military importance of this disease as follows: During

September 1945, after V-J Day, an epidemic was reported in Hankow,

China, which was said to have affected F) percent of the population of the

city. When American forces occupied the airport, 40 of the first 48 men to

arrive contracted dengue within 5 to 10 days. 26 Because of this situation,

it was first recommended that operations from Hankow be suspended. Subsequently, however, they were considered essential. Intensive measures for

25 Van Auken, H. A. : A History of Preventive Medicine in the United States Army Forces of the

India-Burma Theater, 1942 to 1945, p. 317. (Official record.1

"26 Essential Technical Medical Data, U.S. Forces, China Theater, for October 1945.
1*.M. Arm.\~

II 4 1 1iiI) . A I ri 444 l -I I c11 I ij l iv l Ii' I 1 ifL 1)" 1i Ii I' lis li es 4,111,,1 114" 10 1 1r.l14441111V. :114 It't4l~l:I 141il ill 4 iss i 41114. I.lt 111:11 1ill f r4t ill-i V I 1(4444III a f. ditrh

Il/4t I :1 It. 41) hill I j444Il 4-ol 1 411 144'- I 4: ;fil i41 I 1:1 i'411 prlv-il. t: 11 pr41 1144 11:1 IIi 41 .k- 4 14I II ii lt11 41 1*4)11 (I*4I ,-' - 1\ I4''I 1'l I ii aii: V 1v II -tMVV I Thel

1 I' I I' II I It' I
72 INFECTIOUS DISEASES

and pro'ide a coinl)rehensive background for the military cases described

in different parts of the Pacific area. These were likewise of varying severity

and symptolnatology,' 2 9 and in some instances, because of lack of specific

laboratory tests, the diagnosis could be only denguelike fever 30 based on

sylni)tomatology and epidemiological considerations.

Characteristically, the onset of dengue was sudden, accompanied by fever

and sometimes by a chill. The fever was of two types-saddleback and

single phase. Patients were usually admitted to the hospital within a few

hours of onset of the disease, with a templerature ranging from 990 to 104' F.

which persisted for at least 2 or 3 days.31 Over half the patients then had a

remission in which both the fever and symptoms practically disappeared.

This remission lasted 1 or 2 days and was followed by a second rise in

temperature and return of symptoms. These, in turn, subsided rapidly on

the fifth to seventh day of illness. In patients who did not exhibit this

saddleback type of fever, symptoms and fever were largely the same but

persisted for several days, regressing gradually from the third to the eighth

day of illness.

Dizziness, prostration, and extreme weakness in the legs were frequent

presenting symptoms. Frontal or occipital headache, generalized aching

especially in the back and joints, and pain in and around the eyes developed

early. Anorexia, was common and was often accompanied by nausea and

sometinmes by vomiting. Occasionally, mild abdominal pain was noted.

Many patients complained of insomnia and restlessness, and these symptoms

frequenitly persisted into convalescence.

Flushing of the face and neck and scleral injection were common. Two

tlypes of rash were observed. One, an enanthem, appeared within the first

12 hours. if at all, and consisted of pinpoint-sized, discrete, glistening vesicles

on the posterior half of the soft palate. Star-shaped redness developed

beneath these within 24 hours. This rash was morbilliform; it faded during

the period of remission and did not recur with the second rise in temperature. The other type of rash was an exanthem (fig. 7). Seventy-nine percent of the patients in one group had this rash on admission to hospital.

It could be mild (a few discrete, light pink, morbilliform spots on the sides

of the thorax, inner surfaces of the upper arms, and in the lumbar region)

or severe when it presented unbroken, erythematous areas covering the face

below the forehead, neck, shoulders, and thorax. The morbilliform charac2 (1) Diasio, J.S., and Richardson, F. M.: Clinical Observations on Dengue Fever; Report of

100 Cases. Mil. Surgeon 94: 365-369, June 1944. (2) Kisner, P., and Lisansky, E. T. : Analysis of

an Epidemic of Dr'ngue Fever. Ann. Int. Med. 20: 41-51, January 1944.

30 (1) Fairchild. L. M.: Dengue-Like Fever on the Isthmus of Panama. Am. J. Trop. Med. 25:

397-401, September 1945. (2) Johnson, J. A., Jr., Martin, W. B., and Breslow, L.: Dengue-Like

Fever on Okinawa. Bull. U.S. Army M. Dept. 5: 306-311, March 1946.

31 (1) See footnote 29, p. 72. (2) Cavanagh, J. R.: Dengue; Observations on the Disease as Seen

in the South Pacific Area. War Med. 4: 549-555, December 1943.
''.3

AlFIt P ' I.,AI S

I:htt ia t-:m m h' mo a k
74 INFECTIOUS I)ISEASES

ter became apparent at the edges of the confluent areas, notably the lower

half of the upper arm, upper part of the abdomen, and thoracic extensions

of the axillary spaces. This rash also faded during remission but recurred,

usually in less intense form, with recrudescence of fever. When it extended

to the palms of the hands and soles of the feet, it was frequently followed

by itching.

The incidence of adenopathy wias highly variable and, when present, it

most commonly involved the cervical nodes, 32 persisting through the second

phase of fever and subsiding gradually during convalescence. Bradycardia

was usually present and first appeared after the second day of illness, sometimes lasting into convalescence. Leukopenia was present early, with an

average reduction in number of white blood cells to 5,450 per cubic millimeter. By the fifth day of illness, the average count numbered 3,500 cells

per cubic millimeter, with a relative lymphocytosis. Atypical lymphocytes

with vacuolated cytoplasm and coarse granular inclusions were commonly

seen. The symptoms and signs of disease in two groups of patients in the

U'.S. Army are recorded in table 9.

TABLE 9.-Physical signs and symptoms of 418 cases of dengue in two groups of

U.S. Army patients, 1944

Condition Australia South Pacific

(percent) (percent)

Physical signs:

Fever -------------------------------------------------- 100 97

Saddleback ------------------------------------------ 55 66

Single temperature rise ------------------------------- 45 30

Intermittent temperature rise --------------------------- 0 0

Afebrile --------------------------------------------- 0 3

Rash ----------------------------------- -------------- 79 37

Flushing of face (initial phase) ----------------------------- 33 26

Tongue coated -------------------------------------------- 53

Bradycardia (after 2d day) ------------------------------.-------- 97

Scleral injection ---------------------------------------- 89 26

Eyeball tenderness to pressure ---------------------------- ----45

Adenopathy -------------------------------------------- 100 17

Cervical --------------------------------------------- 94 193

Epitrochlear ------------------------------------------ 90

Ipguinal -------------------------------------------- 80

Laryngeal or oropharyngeal vascular congestion ------------ 17 11

Leukopenia -------------------------------------------.------------ 100

Red blood cell count ---------------------------------- Normal Normal

Febrile albuminuria ------------------------------------ 8

Symptoms:

Feverishness --------------------------------------- 100 97

Chills or chilliness -------------------------------------- 54 32

32 See footnote 29, p. 72.
DENGUE 75

TABLE 9.-Phys*iC1 signDs and eyisaptoms of 418 cases of des•guc in two groups of

U.S. Army patients, 1944-Continued

Condition Australia South Pacific

(percent) (percent)

Symptoms-Continued

A ches and pains ..---- ----------------------- 99

H ead a ch e .. . . . .. .. . ..... .... . . . . .. . .... ... .. . . ... . .. 9 4 6 9

General aching -------- .- ------------------------------ - 75 35

Lumbar backache ------------------------------------ 89 43

Orbital pain ----------------------------------------- 74 25

Anorexia ------------------------------------------------- 85

Loss of taste ----------------------------------------- 55 ------------

Bitter taste ---.------------------------------------- 45 4

Weakness (early) ---------------------------------------- 29 14

Insomnia ------------------------------------------------ 53 6

Coryza (fleeting) ------------------------------------------ 24

Sore throat (mild) --------------------------------------- 12 3

Stiff neck ---------- ------------------------------------ --- 14.........

Dizziness and nausea ---------------------------------------- 29 -.....

Constipation -- --------------------------------------- 2 2

Pruritus ----------------------------------------------- 20 3

Photophobia ------------------------------------------.------------- - 5

Total number of patients ---------------------------- 100 318

1 Of those %ith adenopathy; 16 percent of the total group (318 caes).

Source: (1) Diasio, J. S., and Richardson, F. M.: Clinical Observations on Dengue Fever; Report of 100 Cases. MR.

Surgeon 94: 365-369, June 1944. (2) Kisner, P., and Lisansky, E. T.: Analysis of an Epidemic of Dengue Fever. Ann.

Int. Med. 20: 41-51, January 1944.

The disease ran its course in 6 to 10 days (average hospital stay 71/2 to

9 days) with complete recovery. In general, symptoms tended to abate with

the fever, but during convalescence some degree of neurasthenia manifested

by muscular weakness, lack of ambition, mental depression, insomnia, and

anorexia was almost invariable. These usually disappeared in 7 to 14 days,

but sometimes lasted much longer.3 3 Recurrences were rare and could probably be explained as re-infections.

Occasional complications of dengue were observed, including hemorrhagic nephritis, trismus of the jaw, arthritis of hip, suppuration of glands,

persistent bradycardia, and purpuric manifestations. 3 4 Urogenital complications were also occasionally observed. Dull testicular pain and impotence were not infrequent during convalescence, and the latter was

attributed to generalized weakness.3 5 In one group of 141 patients, 8 men

33 (1) See footnotes 29, p. 72; and 31 (2), p. 72. (2) Hyman, A. S.: The Heart In Dengue; Some

Observations Made Among Navy and Marine Combat Units In the South Pacific. War Med. 4: 497-

501, November 1943.

3u See footnote 31 (2), p. 72.

35 Weyrauch, H. M.. and Gas., H.: Urogenital Complications of Dengue Fever. J. Urol. 55:

90-93. January 1946.
76 INFE("TIOUS DISEASES

(5.7 percent ) had late inivolveinient of Ihe urogenital tract, including orchitis,

with subsequent atrophy of the testis and repeated bloody seminal emissions. Rare neurological complications following dengue were described by

Kaplan and Lindgren 3 who 'reported palsy of the facial, palatine, long

thoracic, ulnarr. peroneal, and sciatic nerves.

l)engue may be confused with rulnella because of the rash and because

of the type of cervical adenopathy observed. Other diseases frequently considered in differential diagnosis included scarlet fever, infectious monoiiucleosis, malaria, viral pIeumonia, inluetinza, and occasionally meningitis.

A knowledge of the epidemiology of dengue and its clinical course was

helpful in early diagnosis.

Sufficient. discrepancies in signs and symptoms existed in certain outbreaks of denguelike fever to question the diagnosis. In 32 cases from

Pana1,, 37 the symptoms and course of the disease were similar to dengue

except that the typical rash was not seen, bradycardia did not occur, and

the incidence of lymphadenopathy was low. I)efinite diagnosis was inmpossible because of lack of laboratory methods. Many of the patients observed

in Okinawa in 1945 likewise had most of the diagnostic signs of denigle.38

The clinical picture presented by these cases was remarkably uniform.

Specifically noted was the sudden onset, with chilly sensations, rapid rise

in temperature, headache, pain on movement of the eye, postorbital pain,

photophobia, generalized aching, periarticular soreness, conjunctivitis,

lymphadenopathy, bradycardia, and heinatological changes. However, it

"was pointed out that the short duration, relative infrequency of recrudescence

of fever and symptoms, and the absence of rash in these patients were against

the diagnosis or' dengue. Later, Sabin. 39 on the basis of failure to produce

dengue in four human volunteers inoculated with serum from five of these

patients, suggested that this outbreak may have been leptospiral meningitis.

The treatment of dengue was symptomatic. Codeine (Q,/ to I gr.) and

acetylsalicylic acid (10 gr.) usually sufficed for relief of pain'40 and phenobarbital (11/2 gr.) was employed for insomnia and restlessness. Morphine

was rarely required.

SCIENTIFIC INVESTIGATIONS

The military importance of d(engue became evident early in World

War II. As a result, the Commission on Neurotropic Virus Diseases, Army

Epidemiological Board (Board for the Investigation and Control of Influenza an(d Other Epidemic Diseases in the Army), became interested in

36 Kaplan. A.. and Llndgreqn. A. . : Neurologic Complicationis Following Dengue. U.S. Nay. M.

Bull. 45: 506 510. September 1945.

37 See footnote 30 (1), p. 72.

. See footnote :10 (2). p. 72.

39 Sabln. A. B. : Researeh on lDengue During World War It. Am. J. Trop. Med. 1 : 30 50. Jantiary 1952.

40 See footnote 31 (2). p. 72.
DENGUE 77

promoting research in this field with the specific objectives of producing

a protective vaccine and, if possible, of developing a specific diagnostic procedure. Neither of these was available before World War I1, for up to that

time the virus had not yet been definitely propagated in animals or in

tissue culture. Lt. Col. Albert B. Sabin, MC, was the central figure in the

series of studies which provided pertinent key information. Detailed reports

of his findings are available elsewhere. 4

' The following summarizes those

finding'; especially pertinent to military medicine:

1. Proof of the existence of multiple immunological types. Seven strains

of dengue virus were isolated from patients who contracted their illness in

Hawaii, New Guinea, and India. Serum obtained during the first 48 hours

of the disease was shipped to the United States under refrigeration and

inoculated into volunteers who had never resided in areas where dengue is

endemic. Subsequently, studies of transmission by mosquitoes were conducted with A. aegypt. The existence of separate strains was demonstrated

both by studies of cross-immunity and through virus neutralization tests

using immune serum. At least two immunologically distinct types of virus

were identified. It was shown that the Hawaiian strain, one of the four

New Guinea strains, and the two Indian strains were identical. Thus, two

separate strains were detected in New Guinea.

2. The long persistence of immunity to homologous types of virus. It

was found that homologous immunity persisted for at least 18 months under

conditions which precluded reinforcement of immunity by subclinical reinfection. leterologous immunity was observed but persisted for only about

2 months.

2. The modifications of the clinical manifestations of the disease which

result from reinfection with a heterologous type of virus at various periods

after the primary attack. It. was shown that a superimposed heterologous

infection produced marked variations in the course of the disease depending

upon the time which lapsed from the primary infection. A short febrile

illness of 2 days' duration with or without rash, lymphadenopathy, or other

characteristic manifestations occurred under these circumstances. In these

experimental cases, the virus, recovered from the blood showed conclusively

that the observed disease actually was dengue. This knowledge readily

explained the many cases reported of the transitory acute illnesses which

could not be specifically identified, particularly from New Guinea. This

explanation is confirmed further by the fact that two of the New Guinea

samples of serum from individuals with this type of illness produced the

41 (1) See footnotes 2, lo. 50: and 39, p. 76. (2) Sabin, A. B., and Schlesinger. R. W.: Experimental Studies on Hluman and Mouse Adapted IDengne Virus. Paper presented at joint meeting of

American Society for Experimental Pathology and Anmerican Association of Immunologists, Atlantic

City, N.J.. 13 Mar. 1946. (3) Letter. Maj. Albert B. Sabin, MC. to Preventive Medicine Service, OCice

of the Surgeon oe,..ral. :3 Aug. 1944. subject: Isolation of Several Strains of Dengue Virus From

Serum of Patients With Various Types of Fevers in New Guinea. (4) Sabin, A. B., and Schlesinger,

R. W. : Production of Immunity to Dengiie With Virus Mlodifled by Propagation in Mice. Science 101

640 642. 22 June 1945.
78 INFECTIOUS DISEASES

clas•sical picture of dengue when inoculated into nonimmune volunteers in

the United States.

4. The demonstration that type-specifh iMimunity to dengue is associated with neutralizing antibodies for the virus. It was shown that the

demonstration of neutralizing antibodies can be employed for diagnostic and

epidemiological survey purposes. iey shioui prove to be of great value

in the future.

The r. propagation of dengue virus in mice. Sabin finally succeeded in

propagatting the virus in mice. In the course of a number of passages, the

virus underwent a mutation since it lost its capacity to produce severe illness in man but retained its capacity to produce a rash. A mousebrain

extract of this modified virus was found to afford complete protection against

the naturally acquired disease. A single mousebrain was shown to contain

at least 10M0OW imunuizing doses which led to the preparation of an effective lyophilized vaccine. Viifortunatelv, large-scale field trials were not

undertakeii because the opportunities for testinig the vaccine ceased with

the ending of the war.

6. Investigrationis of del)gule, conducted by Colonel Sabin in Panama,

showed ,learly that dengue has occurred there since 1941 and suggested that

the interior of Panama may be an endemic focus of the disease.

In coniclisioll. it should be pointed out that the history of dengue during World War II reflects great credit on the V.S. Army Medical Department. Like sonie other virus diseases, dengue was promoted to the category

of an illness diagnosable by laboratory means and preventable.
CHAPTER IV

Neurotropic Virus Diseases

John I!. Paul, M.D.

The group of diseases designated as neurotropic virus diseases in this

chapter has been selected, for practical reasons, on a somewhat arbitrary

basis. They include acute infections with the viruses that cause the arthropodborne virus encephalitides: poliomyelitis, rabies, and lymphocytic choriomeningitis. It is with some aspects of the clinical and epidemiological story

of these virus infections, as they occurred in military personnel in World

War II, that this chapter is concerned.

Numerically speaking, the recognized military cases of neurotropic virus

infections have been insignificant, but from other standpoints these diseas&_

have proved to be of some military importance. In the first place, any

virus disease that attacks the central nervous system easily acquires a bad

reputation. Furthermore, as a group, the mortality is apt to be high and

the stigma of injured brain function accompanies them. In the case of

poliomyelitis, not only does this disease carry a more serious prognosis

when it occurs ir young adults (of military age) than in children, but when

a permanent Army post is involved, this disease presents a threat to dependents who may happen to be living within the epidemic area. And

finally, as far as the arthropodborne virus encephalitides are concerned, any

mosquitoborne disease is of military significance.

Early in World War II, the Medical Department of the U.S. Army recognized that this relatively new group of diseases might pose a number of

problems, and to forestall them, Circular Letter No. 74 was issued on this

subject by the Surgeon General's Office on 19 March 1943. This circular was

followed by War Department Technical Bulletin (TB MED) 212, issued

16 January 1946. The bulletin reviewed information bearing on the common neurotropic virus diseases of man, including classification and diagnostic features. In addition, the bulletin described the circumstances under

which the then available diagnostic procedures could be profitably utilized.

THE ARTHROPODBORNE VIRJS ENCEPHALITIDES

The arthropodborne virus diseases comprise a group whose membership

has expanded greatly since the war, but even in 1941 the recognized members were eastern and western types of equine encephalomyelitis, St. Louis

encephalitis, Japanese B encephalitis, and Venezuelan encephalitis. Others

of less importance to IT.S. Forces included Russian spring-summer encepha639243-.63_.-S 79
SO) INFFCrOUS usDIS.sEASF

lit is ( andu other types from Russia and Siberia ) some tNypes from A frica,

aZiII loulping ill fronm Eniglanid. These wvinllot ibe -oiisidlertd here.

,rthe number of mmilitarYvcases of this group) of disekases which occurred

ill World War. ItI turnedl out to be few indeed. but besidles the reasons already

given that these few cases deserve attention hiere Is t hat research Initiated

and proimoted by tilet Preventive Mledicinle D ivision, O)ffice of the Surg'eon

G( meral, .11d thle Army Epidemiological Board jHoard for tile Invest igationl

amd (Coutrol of Iniflueniza amnd O t her Epidemic D iseases inl the Armyi i), conltrihuted materially to the addit ion of knowledge aboult thes-e implort ant infect ions (luring World War 11.

Military History Prior to World War 11

In view of thle fact that 11o imemiber of this gr-oup of ar-thlrolx)(lIwine

viruis eilceeplialit ides hadI been dliscoveredl. nor hmad the dliseases which they

caulse b~eenl recogrnizedl as stiedl prior to the 1930's. there is nothinig abouti

them in the mnedical history of World War 1; nor had there beent in the

post-World War I period any experience by the Armed Forces with these

agrents or with the (diseases they cause. If cases of this group of illnesses

hadl occutrred andl at tractedl attencttion in 1917j-18. thley would probabl y have

I been 1listedl undier thle miiiscel laneouis group) of "encephialitis, type undeter11iined" or perhaps as -ep~idem~ic encephalitis." D)uring the last year of

World War I and the years immediately following, t'-.e type of encephalitis

most frequeiily encountered in1 military pop~ulations was enlcephalitis letharEc oth erwise known as Von Econonio*s disease. The records fronm World

WVar I show SO admissions, and at least 79 secondary cases of encephalitis,

reported for the period from I April 1917 to :11 D)ecemnber 1919 inl thle total

V.S. Army of approximately 4 miillion.' In this group, 274 deathis occurred,

giving It caIse fatality ratio of ablout 17 percent. The chtances that a large

petr(&'ilt age of these cases were examplles of encephalitis lethlargmica aregod

H owever. as filie e~tiological agent of that (disease was ntever establhishmed. one

('lhiot sp)eak wit hi any1 confidence that it was actually a viruis (lisease an~d

therefore dleserves d1iscussion here. Fu rthermnore and fort unately. the incideiice of encep~halitis lethargica began to dlecline in the midtwenities. both in

the 1 niiteol States and hii Europe. BY 1930, to all intenits andl purposes,

classical cases of this dlisease had (disappearedl. so for the pre~sen~t at least, we

nieed not p~mursue thle discuissioni about it further. except to point out that

other niew typ~es of encephalitis were soon to supplant Von Economno s disease.

It was during the 19 30's that thle art hropodblorne viruis encephialitides

cainle under scrutinyv, the first recognition of any member of the group being

that of the virus of western equinie encephialonimvehitis. isolated with some

(litlichilt , . from a sick htorse in California in 1931 bv D)r. Karl F. Mtever of the

University of California. San F~rancisco. Later. I~r. Carl TenBroeck. of the

I T~he Alpiical IDeimIrtflis-it of the Unlited Stiutem A rmy in the w~orld Wanr. Wambiinigton:Goen

menit Printing Offioe. 1925). vol. XV. ptt. 2. ppi. 90) 1 :18. i
NEUROTRO PIC' VIRUS DISIEASES 81

Rockefeller Institute of Medical Research at Princeton, N.J.. found that

strains of the equine encephalomyelitis viruses could be. separated into eastern

and western tylpes. The "disease" for which these viruses were responsible

was regarded at that time primarily, if not entirely, as one of horses. A

manifest interest by the Army in this matter accompanied the report in 1934

by 1t. ('ol. (later Brig. (Gen.) Raymond A. Kelser, VC, that these viruses

could be transmitted from horse to horse by certain species of mosquitoes.

A second chapter in the story was written when it was found that this

type of illness affected man. In 1933, a severe outbreak of human encephalitis

occurred in and about the city of St. Louis, Mo. More than 1,000 human

cases were reported with about an 18 percent mortality. The virus of St. Louis

encephalitis was isolated in this epidemic more or less coincidentally by Drs.

Ralph S. Muckenfuss and L. T. Webster. Although sick horses received little

notice during this epidemic, some of the investigators, including Maj. (later

Brig. Gen.) James S. Simmons, MC, thought that St. Louis encephalitis

might be related to one of the equine encephalitides and attempted to infect

horses with the St. Louis virus. The assumption was correct, and the failure

to substantiate it experimentally at that time might have been due to the fact

that the horses used were from the St. Louis area and they could well have

been immune to the disease.

It was also at about this time (1933-34) that U.S. investigators began

seriously to compare the St. Louis epidemic with the existing situation in

Japan where endemic encephalitis had appeared in parts of the home islands

almost every summer since 1871. In 1924, there had been a particularly bad

epidemic, and clinical studies had made it possible for the Japanese to distinguish their diseases from epidemic encephalitis of the so-called A type (Von

Economo's disease). For this reason. Japanese epidemic encephalitis has

been termed type B encel)halitis. The el)idemIhc of i924 had spread through

a wide area resulting in a heavy mortality among 6,000 reported cases.

During the period from 1924 to 1937, outbreaks occurred almost every summer

in Japan, resulting in a total of some 21,000 reported cases for that period

with the heaviest concentration of cases occurring in the region of the Inland

Sea. Similar recurrent appearances of summer or autumn encephalitis were

known to have been reported from the Ryukyu Islands, as well as from

Formosa, Manchuria, and the far eastern maritime districts of Soviet Russia.

Opinion in Japan was divided as to the means of spread, and by 1938. although one group had suspected that it was mosquitoborne, the balance of

Japanese medical opinion held to the view that it was spread from the respiratory tract.

By 1938-39, relations betiveen Japanese medical science and that of the

United States could hardly be described as close and shortly thereafter ceased

altogether. Consequently, the up-to-date story on current Japanese views as

to how their type of encephalitis was transmitted and just where this disease

could be expected to appear was not readily available to medical intelligence

officers during the war years.
82 INFECTIOUS DISEASES

The next development in this story took place iM the United States in

1938. with tie appearance in Massachusetts, Rhode Island. and Connecticut

of a less extensive outbreak of acute encephalitis involving both man and

horses. 'Tihe causative virus was identified as eastern equine encel)halonmyelit is

virus. It also became apparent that here was a group of diseases that not

only infected both man and horses, but peralps other animals. More or less

coincidewtally, the discovery in 1937 of the spring-summer type of encephalitis in the forested. far eastern regions of the U.S.S.R. and the demonstration

that it was caused by a new virus which was tickborne. all indicated the existence of a large group of related agents extremely widespread geographically

and with a variegated group of insects (arthropods) as vectors and several

mammalian hosts. To this group were soon added other stra'ins of virus from

South America (notably Venezuelan encephalitis). amid subsequently several

from Africa.

Early in the 1940"s. information about these diseases was accumnumlatinig

at a rather rapid rate. although much of it was still theory. Birds had been

found to be infected, which made the epidemiological picture still more complicated. Eventually. the epidemiology of some of this group of diseases. as

they occurred in the United States, was worked out largely through the efforts

of lDr. William McD. Hammon at the University of California, San Francisco.

From his work, the concept gradually emerged that, in this country at least.

this group of infections. many of which were inapparent, was primarily one

of birds and that the severe infections in man, horses, and other animals were

what might be called casual, though spectacular, accidents. Apparently, the

avian infection could be very widespread numerically but was mild, causing

little more than a viremia in certain members of the avian family. It was

transmitted to various species of both birds and mammals usually through

the agency of COdex. mosquitoes.

Thifs then was the background in 1941 with regard to the "new" neurotropic virus infections with which the U.S. Army might be confronted if it

should engage in global combat. The threat was appreciable in that any mosquitol)orne disease recalled the destructive effect which malaria, yellow fever.

or dengue had had upon troops in the field in the past. In addition. a numnber of potential theaters of war, such as ,Jap)an. Manchuria. and elsewhere.

were listed as endemic or epidemic areas and might possibly turn out to be

hotbeds of infection by one of the worst members of the group. Japanese B

encephalitis. These potentialities were further emphasized by an epidemic of

western equine encel)halomyelitis which swept over a large section of Western

Canada and many areas in the Western United States. including the Dakotas,

Montana, and Colorado in the summer of 1941. Thousands of civilian cases

occurred, although the number of U.S. Army l)ersonnel involved in this epidemic was insignificant. However. in Canada where it was estimated that

there were more than 5,000 cases. mostly in Saskatchewan and Manitoba. the

epidemic had also involved certain training areas where Canadian troops were

stationed. and during the summer of 1941. a number of cases occurred in the
NEUROTROPIC ViIl'S l)ISEASEMS 83

Canadian Army. 2 It hardly could be questioned in the autumn of 1941 that

here was a new disease of potential military importance to U.S. troops.

Diagnosis.-It is important to mention here that not only in 1917-18 but

in the subsequent 25 years the clinical diagnosis of encephalitis proved to be

a loose one indeed, covering a number of different entities. In another voltime in the history of the Medical Department in World War II, Sabin

states: 3

Clinical records from civilian as well as military medical practice indicate that the

diagnosis of encephalitis is commonly made whenever clinical manifestations suggestive

of cerebral disturbance (ranging from mild lethargy to coma, from slight delirium to

complete disorientation, from restlessness to convulsions) are associated with an otherwise undiagnosable febrile illness. The diagnosis is not infrequently made when the syndrome of aseptic meningitis is associated with what may be interpreted as lethargy or

unusual restlessness. It is made not only when the cerebral distuibance is associated

with pleocytosis. but also in its absence, and indeed not infrequently when toxic encephalopathy is associated with certain bacterial infections.

In the period 1941-46. and subsequently, the exact method of making a

diagnosis of this group of virus diseases was by immunological and virological tests. Some of these became available during and immediately prior to

World War II. However, the utilization of these tests, which included neuitralization or complement fixation tests on matched specimens of sera. was

more or less in its infancy and hardly more than half a dozen laboratories in

the U nited States capable of carrying them out. 4

Experience During World War II

Most, although not all, of the apprehension about arthropodborne virus

encephalitides proved to be unnecessary, for when the Second World War was

over the incidence of these infections in military personnel turned out to be

small. There were no large wartime epidemics in the United States involving

the civilian population compared to those at St. Louis in 1933 and in the

Northwest in 1941.

The final experience in World War II with these diseases both as to

num)er of recognized cases, incidence rates, and deaths ascribed to encephalitis is listed in tables 10 and 11. It is clear that the figures suffer somewhat

fronm the inaccuracies of diagnoses which are apt to beset all figures on the

incidence of the encephalitides, infectious or otherwise. As just mentioned,

Sabin has pointed out that the clinical diagnosis of any kind of encephalitis

"2 Report. Commission on Neurotropic Virus Diseases, Board for the Investigation and Control of

Influenza and Other Epidemic Diseases in the Army, 1 Dec. 1941-1 May 1942.

": Sabin. Albert B. : Encephalitis. In Medical Department, United States Army. Preventive Medicine in World War 11. Volume VII. Communicable Diseases: Arthropodborne Diseases Other Than

Malaria. [In preparation.]

4 Better known laboratories readily available to the Medical Department of the U.S. Army for the

diagnostic purpose of these diseases, in 1941-45. ineiuded that of the Army Medical School, Washington. D.C., the G. W. Hooper Foundation of the University of California in San Francisco, the Rockefeller Institute for Medical Research in New York City (both of which facilities were made available

through the Commission on Neurotropic Virus Diseases of the Army Epidemiological Board), and a

few other laboratories, also connected with the Army through that Board.
84 INFECTIOUS DISEASES

without the assistance of serological tests is notoriously difficult. IIn view of the

fact that such immunological tests were not available ill many of the cases

occurring in military personnel during wartime, the data in tables 10 and 11

must be regarded as being approximate rather than definitive. It should be

noted, however, that the rates for infectious encephalitis were higher in 1944

and 1945 in the Pacific than in Europe. This is what should have been expected because, except for the presence of tickborne lhussian sprilig-sulilmner

encel)halitis in Czechoslovakia and in eastern Austria, the arthropodborne

encephalitides as they are now known to occur in man are almost entirely

absent from Europe.

TABLE 1O.-Admissions for encephalitis in the U.S. Army, by diagnosis, selected area, and

year, 1942-45

[Preliminary data based on sample tabulations of individual medical records]

[Rate expressed as number of admissions per annum per 1,000 average strength]

1942-45 1942 1943 1944 1945

Number Rate Number Rate Number Rate Number Rate Number Rate

Infectious encephalitis: I

Continental United States ---------- 187 0.01 44 0.02 65 0.01 43 0.01 35 0.01

Overseas:

Europe-------------------------- (72) 0.02 (1) 0.01 (6) 0.02 (20) 0.01 (45) 0.02

Pacific-------------------------(107) .03 (1) .00 (5) .01 (41) .04 (60) .04

Total overseas------------------ 247 0 02 4 0.01 14 0.01 94 C.02 135 0.03

Total Army --------------------- 434 0.02 48 0.01 79 0.01 137 0.02 170 0.02

Postvaccinal encephalitis: 2

Continental United States -----------(3) (3) (3) 3) (3) (3) 1 0.00 --------- 0.00

Overseas:

Europe ------------------------ (3) (3) (3) (3) (3) (3) ......... 0 ---------- 0.00

Pacific ---------------------------- (3) (3) (3) (3) (3) (3) (6) .01 (5) .00

Total overseas ------------------- (3) (3) (3) (3) (3) (3) 6 0.00 10 0.00

Tetal Army -------------------- (3) (3) (3) (3) (3) (3) 7 0.00 10 0.00

Encephalitis. other and undetermined: 4

Continental United States ---------- 953 0.06 272 0.10 355 0.07 21 0.05 115 0.04

Overseas:

Europe ---------------------------- (89) 0.02 (9) 0.11 (10) 0.04 (20) 0.01 (50) 0.02

Pacific ---------------------------- (138) .04 (7) .03 (17) .04 (19) .02 (95) .07

Total overseas ------------------ 394 0.04 26 0.04 101 0.06 97 0.03 170 0.04

Total.Ary-------------------- 1.47 0.05 298 0.09 456 0.07 308 0.04 285 0.04

I Includes infectious encephalomyelitis and Japanese B type encephalitis as well as other types of infectious encephalitis. Excludes lymphocytic choriomeningitls.

2 Includes postvaccinal encephalomyelitis.

3 Data are not available.

4 Includes encephalomyclitis, other and undetermined. Excludes lymphocytic choriomeningltis.

No'rM.-Figures in parentheses are subtotals.
NEURMTROPIC VIRLS DISEASES 85

TABLE I 1.-Deaths due to encephalitis in the U.S. Army, by diagnosis, selected area of admission, and year of death, 1942-45

[Preliminary data based on tabulations of individual medical records]

[Rate expressed as number of death4o per annum per 100,000 average strength]

1942-45 1942 1943 1944 1945 Diagnosis and area

Number Ratet Number Rate Number, Rate Number Rate Number Rate

Infectious encephalitis: '

Continental United States ---------- 9 0.06 2 0.08 2 0.04 3 0.08 2 0.07

Overseas:

Europe ---------------------------- (4) 0.09 ---..... 0 --------- 0 (1) 0.06 (3) 0.13

Pacific -------------.------------- (3) .10 ------- 0 --------- 0 (2) .20 (1) .07

Totaf.)verseas --.---------- - - 12 0.11 1 0.17 --------- 10 6 0.16 5 0.11

Total Army --------------------- 21 I0.08 3 0. 0i 2 0.031 9 0.12 7 0.09

Postvaccinal encephalitis: S ,

Total Army --------------------- (3) (3) (3) .(L) (3) () ---------- 0 ---------- 0

Encephalitis, other and undetermined: 4

Continental United States ----------- 57 0.39 7 0.26 20 0.39 23 0.58 7 0.24

Overseas:

Europe --------------------------- (15) 0.34 --------- 0 (1) 0.37 (4) 0.24 (10) 0.42

Pacific ---------------------------- (19) .61 (2) .90 (1) .21 (3) .31 (13) .92

Total overseas ------------------- 55 0.51 2 0.34 1 0. 65 15 0.39 27 0.58

Total Army----..---------------- 112 0.44 9 0.28 31 0.45 38 0.49 34 0.45

'Includes infectious encephalomyelitis and Japanese B type encephalitis as well as other types of infectious encephalitis. Excludes lymphocytic choriomeningitis.

2 Includes postvaccinal encephalomyelitis.

3 Data are not available.

4 Includes encephalomyelitis, other and undetermined. Excludes lymphocytic choriomeningitis.

NOTE.-Figures in parentheses are subtotals.

No sizable epidemic due to one of the known encephalitic viruses was

ever recorded in U.S. Forces stationed within the United States during the

period 1942-45. However, a possible outbreak, of which the agent was never

identified, occurred during the summer of 1941, when 12 mild cases of encephalitis developed in a force of unknown size maneuvering near Sabinal,

Tex.- Sporadic cases of proved arthropodborne virus encephalitides occurred

in western training areas during 1942-45, but the incidence never reached

anything comparable to that experienced by the Canadian troops in Manitoba

in 1941. Clinical descriptions of these sporadic cases in U.S. troops apparently did not differ from the usual textbook descriptions, and no unusual findings are known to the author.

Outside the confines of the United States, a single case due to one of the

exotic South American types of the neurotropic viruses was recorded of a

5 Woodland, J. C., and Smith, E. M.: Acute Encephalitis; Mild Epidemic Observed at Station

Hospital, Fort Sam Houston, Texas. J.A.M.A. 120: 358-361, 3 Oct. 1942.
86 INFECTIOUS DISEASES

U.S. Navy seaman in Trinidad in 1943. It proved to be due to the virus of

Venezuelan equine encephalitis.6

By far the most important group of cases, however, which occurred

during the Second World War took place inl an oversea theater. This was the

small but important outbreak identified as Japanese B encephalitis which

involved both natives and troops on the island of Okinawa in the summer

of 1945.

In the spring of 1945 and at the time of the occupation of islands north

and northwest of Guam, the Medical Department recognized that U.S. troops

were entering territory where Japanese B encephalitis might be endemic. For

this reason, knowledge of the disease was summarized for use by medical

officers in War Department Technical Bulletin (TB MED) 181, July 1945.

Japanese B encephalitis had been previously reported as recurring not only

in Japan proper but in the Ryukyu Islands, Formosa, Korea, eastern China,

in certain of the far eastern maritime districts of the U.S.S.R., and in Manchuria. However, it was uncertain whether the Japanese B virus was the

sole etiological agent of encephalitis within all these areas.

The epidemic occurred during a combat period on the island of Okinawa

and has been well described by Sabin,7 so that his account need not be repeated here. It may suffice to say that the occupation of Okinawa, representing, as it did, a very strategic area, had been achieved in April 1945, and

during the entire spring and early summer months, fighting continued sporadically on the island. Encephalitis first appeared among the native population early in July. The first native patients with severe encephalitis observed by American medical officers in the Ryukyus were seen by Lt. L. M.

Miller, MC, USNR (of the local military government) on 8 July 1945 on

Heanza Shima, a small island about 2 miles east of Okinawa. During the

following 3 months, 127 patients were seen by military government medical

facilities on the two islands; 66 of the 91 patients found on Okinawa were

admitted to the isolation hospital for observation and treatment. The etiological agent of the disease was first established by the results of complement

fixation and neutralization tests and by recovery of the virus from a fatal case.

Two groups of workers participated in these identifications. The civilian

cases were first identified by Hodes, Thomas, and Peck," of the Naval Medical

Research Unit No. 2, then established on the island of Guam, and subsequently,

military cases were identified by Lt. Col. Albert B. Sabin, MC,9 member of

the Commission on Neurotropic Virus Diseases, Army Epidemiological Board.

This achievement by American medical officers in recognizing clinically and,

6 Randall, R., and Mills, J. W. : Fatal Encephalitis In Man Due To Venezuelan Virus of Equine

Encephalomyelitis in Trinidad. Science 99: 225-226, 17 Mar. 1944.

7 (1) Sabin, A. B. : Epidemic Encephalitis in Military Personnel; Isolation of Japanese B Virus

on Okinawa in 1945; Serologic Diagnosis, Clinical Manifestations, Epidemiologic Aspects and Use of

Mouse Brain Vaccine. J.A.M.A. 133: 281-293, 1 Feb. 1947. (2) See footnote 3, p. 83.

8 Hodes, H. L., Thomas, L., and Peck, J. L.: Cause of an Outbreak of Encephalitis Established by

Means of Complement-Fixation Tests. Proc. Soc. Exper. Biol. & Med. 60: 220-225. November 1945.

9 Sabin, A. B. : Outbreak of Encephalitis on Okinawa in 1945: Preliminary Report on Status as of August 27, 1945. J. MR. Med. in Pacific 1: 79-84, November 1945.
NEUROTROPIC VIRUS DISEASES 87

subsequently, in identifying the etiology of Japanese B encephalitis was accomplished under arduous combat conditions and was indeed a noteworthy

event, both in military medicine and in the history of this disease in general.

At the time the disease was discovered, the island was the most important

advanced base in the Pacific area. Large forces of U.S. troops were already

assembled for the projected invasion of the home islands of Japan scheduled

for the autumn. It was reasonable to assume that these troops were and

would be susceptible to neurotropic virus disease to which they had never

been previously exposed. and the danger of an epidemic was therefore a matter of great concern to the Medical Departments of the Army and the Navy.

The news of the epidemic of "a dread Japanese brain disease" on Okinawa

had also spread among the troops with demoralizing effect.

It is hard today to appreciate the difficulties which confronted medical

officers at that time, but the story of these difficulties has been well documented

by Lt. Col. William I). Tigertt, MC. and Dr. Hammon.' 0 They pointed out

that in 1945, available information about the presence of the disease on Okinawa was meager. Although Japanese B encephalitis had been stated to

occur on Okinawa, the figures were difficult to assess since cases of epidemic

cerebrospinal meningitis, encephalitis lethargica, and malaria with cerebral

symptoms were also reported, usually with the diagnosis made on clinical

grounds. Furthermore, relatively few Japanese physicians had practiced on

the island of Okinawa before World War II. and public health reports were

fragmentary and incomplete there. Only later did it become known that

Iimura had reported 68 cases of Japanese B encephalitis on Okinawa in 1933

(cited by Tigertt and Iamnmon) and that, in 1937, Takagi and others (cited

by Tigertt and Hammon) had shown that most of the human sera collected

on Okinawa contained neutralizing antibodies.

Mosher 11 has described how the situation was handled on Okinawa in

July and August 1945. The investigation of encephalitis was assigned to the

Military Government Research Center, and on 18 July 1945, an isolation hospital for the study of the disease was opened at Gimbaru. By direction of

the commandant of the U.S. Military Government, all native patients with

cerebrospinal symptoms suggestive of encephalitis were referred to the research center from all parts of the island by field dispensaries, hospitals, and

other medical units established to care for the natives. Dispensary personnel

were instructed in the recognition of the disease, and in some areas native police

assisted in finding the sick. A visiting nurse program was instituted by some

of the dispensaries. While these nurses were largely untrained volunteers,

they facilitated in some degree in case finding and in referral of cases to the

hospitals. Between early July and October, a total of 91 natives of Okinawa

1o Tigertt, W. D., and Hammon, W. McD.: Japanese B Encephalitis: A Complete Review of

Experience on Okinawa, 1945--1949. Am. J. Trop. Med. 30: 689-722, September 1950.

ii Mosher, W. E., Jr. : Japanese "B" Encephalitis; Epidemiologlcal Report of the 194. Outbreak

on Okinawa. U.S. Nay. M. Bull. 47: 586-593, July-August 1947.
88 INFE('TIOUS DISEASES

were diagniosed as having encel)halitis, the mnorbidity being 2.S per 10.000,

as compared with 44.7 for the Ileanza-Hainahika Islands.

Among U'.S. military pelrlsonnel, between July and mid-September. 38

military patients exhibited a variety of clinical manifestations and were investigated by serological methods for the diagnosis of Japanese It encephalitis.

Of these., only 11 yielded unequivocal evidence of the specific infection. Two

of Ihe eleven died, and autopsy revealed cerebral lesions compatible with the

diagnosis of viral encephalitis. It is highly probable that more than 11 cases

occurred.

In a report of the outbreak by Lewis and his associates,12 which represents perhaps the first extensive clinical description of Japanese encephalitis

made by U.S. physicians. the symlptonmatology of the disease was described

as it occurred among Okinawan nativ-es. The clinical features of the cases

in U.S. military personnel, as observed both on Okinawa, and subsequently

in Korea, have been well documented in War Department Technical Bulletin

(TB1 ME)) lS on Japanese B encephalitis, issued on 6 April 1947.

Although the clinical features of Japanese B encephalitis do not seem

to differ materially from those of St. Louis encephalitis and western equine

encel)halomvelitis, which were already in 1945 well described in U.S. textbooks of medicine, it may be worthwhile to mention something here of the

clinical picture of Japanese encephalitis as it appeared on Okinawa. Most

important for diagnostic purposes was the appearance of the following

signs during the course of an acute febrile illness: Mental confusion, disorientation, purposeless movements, speech disturbances, and complete aphasia. Varying degrees of lethargy might be plresent ranging from abnormal

somnolence to complete coma in patients who also exhibited high fever

and nuclhal and spinal rigidity. As a rule, there was a period of 2 or 3

(lays before the appearance of any signs suggesting involvement of the

nervous system. During this time, headache and low-grade fever were the

only symptoms. Generalized convulsions of the grand real or petit mal type

were occasionally the first signs of involvement of the nervous system, with

stiffness of the neck and back, and other signs already mentioned, coming

later. Flaccid paralysis, suggesting involvement of large numbers of lower

motor neurons in the spinal cord or medulla, was not seen. Localized spastic

paralysis was seen only once among 15 patients, although generalized rigidity

was present in the more severe cases. Dissociated eye movements were seen

in only one patient. and diplopia did not occur. Pupils were usually contracted and reacted poorly to light: a sticky exudate was not infrequently

seen about the eyes. The reflexes were variable and by themselves of little

aid in differential diagnosis. The abdominal reflexes were usually absent

while the tendon reflexes were most exaggerated: only occasionally did they

become diminished or absent. Babinski's sign was rarely elicited.

12 Lewis, L., Taylor, H. G., Sorem, M. B., Norcross, J. W., and Kindavatter, V. H. : Japanese B

Encephalitis; Clinical Observations In an Outbreak on Okinawa-shima. Arch. Neurol. & Psyeblat. 57:

430-463, April 1947.
NEUROTROPIC VIRUS DISEASES 89

As a rule, the fever lasted from 7 to 11 days. It was high after the

appearance of nervous signs and frequently remittent, although it is uncertain to what extent the administration of antipyretics may have affected

the temperature curve. A relative bradycardia was invariably present during the febrile phase with a pulse rate of about 50 to 60 being common after

defervescence. In fatal cases, death due to encephalitis occurred within the

first 2 weeks and, as a rule, during the first 7 days after onset.

Convalescence was slow. Lethargy and incoordination, tremors and

nervousness, and occasionally distinct personality changes persisted for some

weeks after defervescence. Subsequently, it became apparent from observations by Japanese physicians aind by neurological consultants from the

United States that residual symptoms from this disease were noted in only

a small percentage of patients.1 3 These did not grow progressively worse

as in the sequelae in encephalitis lethargica.

As to laboratory findings in the blood and spinal fluid, during the acute

phase of the disease, the. white blood cells in the former were likely to be

increased in the range of 10.000 to 25.000 cells per cubic millimeter of blood,

with a definite increase in the number of mature and immature neutrophiles.

Cerebrospinal fluid was clear, under normal or occasionally increased pressure. and pleocytosis, ranging from 22 to 1,450 white blood cells, was present

in all of the military patients whose illness was definitely proved to be due

to this infection. The cells were. as a rule, predominantly mononuclear,

although in at least two of the group polymorphonuclear leukocytes predominated; spinal fluid sugar and chloride were in the normal range. Protein was normal or only slightly increased early in the disease, while during

convalescence a 3 or 4 plus Pandy reaction was not uncommon.

In American military personnel, poliomyelitis and "aseptic meningitis" 14

offered the greatest problems of clinical differential diagnosis. Among the

children and natives of older age groups, tuberculous meningitis proved to

be another important differential diagnostic consideration. Of aid in the

diagnosis was the use of neutralization and complement fixation tests and

virus isolation from fatal cases. It was fortunate indeed that, during the

13 DIuring World War II. and when this disease was first encountered, a subject of great interest

was whether the military cases of Japanese B encephalitis would result in any residual deficiencies

in nervous function after the acute stage of the disease had been passed successfully. This was a

matter which should call for preferably long-term followup observations. One postwar study which

can be mentioned is embodied in a report to the Surgeon General's Office by Dr. Charles D. Aring.

Professor of Neurology, University of Cincinnati. Ohio, made under the auspices of the Army Epidemlological Board in 1948 (published in Arch. Neurol. & Psychiat. 62: 759-765, December 1949). Dr.

Aring examined 19 late cases of Japanese B encephalitis in Americans at the 361st Station Hospital

In Tokyo, as well as 12 late cases among Japanese. In only 1 American out of a total of 19 did he

feel that it was possible that the patient was suffering from residua, and even In this case It seemed

probable that the signs were attributable to an emotional disorder apart from his recent acute dise•se.

It was Dr. Aring's opinion that once the "dangerous period" had been passed without the appearance

of crippling neurological signs, the patient would go on to good recovery, with the possible exception

of the develooment of parkinsonlsm, which had been reported in Japanese cases as an occasional

occurrence.

14 Several years later, it was shown that leptospirosis was the cause of at least one outbreak of

"aseptic meningitis" in troops on the Island of Okinawa.
90 INFECTIOUS DISEASES

combat conditions on Okinawa in the summer of 1945, not only were laboratory facilities made available for the carrying out of these tasks but that

personnel were also available to do the tests and to interpret them. Thii

is a type of frontline scientific medicine which deserves special mention in

any military history.

Medical officers were aware that there was no specific treatment for

Japanese B encephalitis, but the following supportive measures were carried out. During the period of coma, nutrition was maintained by gavage

or by the parenteral administration of fluids and the use of vitamin supplements. As depletion of body protein was sometimes extreme, plasma or

amino acids were given.

Other special and general methods were used as a means of preventing

decubitus ulceration. The careful use of sedatives during periods of restlessness and irritability, with frequent changes of posture of comatose patients. tracheal aspiration, catheterization when indicated, and similar routine

procedures constituted almost all the therapeutic measures.

The treatment of complications with chemotherapeutic agents was

regarded as of parar.mount importance, particularly with reference to pneumonia.

The pathology of Japanese B encephalitis was also described on the

basis of material studied from the Okinawan epidemic. An excellent report

was made by Lt. Comdr. H. M. Zimmerman, MC, USNR, from the Naval

Medical Research Unit No. 2,5 and, with the help of the Army Institute of

Pathology (now the Armed Forces Institute of Pathology), Washington.

D.C., another report was made by Haymaker and Sabin.16 Involvement of

the brain proved to be very extensive.

For preventive measures, the reader is referred to Sabin's chapter on

encephalitis in another volume in the history of the Medical Department

in World War I1.17 It is enough to say here that the use of mosquito control

and a mouse-brain formalin (inactivated) vaccine were tried on Okinawa.

In summary, therefore, and in retrospect, it would appear that during

World War II after considerable preparation with regard to the arthropodborne virus encephalitides this group of diseases turned out to be less of a

threat as a military disease than had been anticipated, but in this respect

there was feeling that the Armed Forces had been lucky. In any event,

considerable was learned about arthropodborne virus encephalitides which

constituted a group of what might be called new diseases as far as the Medical Departments of either the Army or the Navy were concerned. The first

contact by American troops with a most important member of this group.

namely, Japanese B encephalitis, became a landmark of some prominenceViZimmerman, H. M.: The Pathology of Japanese B Encephalitis. Am. .. Path. 22: 965-991,

September 1946.

16 Haymaker, W., and Sabin. A. B. : The Topographic Distribution of Lesions in Central Nervous

System in Japanese B Encephalitis; Nature of the Lesions, With Report of a Case on Okinawa. Arch.

Neurol. & Psychlat. 57: 673-692, June 1947.

17 See footnote 3, p. 83.
NEUROTROPIC VIRUS DISEASES 91

in the military history of virus diseases. That the disease should have been

promptly recognized, and the agent isolated by medical officers from the

Army and the Navy working close to the combat areas, was a noteworthy

achievement. Subsequent to World War II, important additions were made

to knowledge about this disease, as a result of experiences in the army of

occupation in Japan,18 but the introduction to this story came in July and

August of 1945 on the island of Okinawa.

POLIOMYELITIS

Just prior to the onset of World War II, it was generally agreed by

medical officers in the Army that poliomyelitis was not a disease of military

significance. This was based on the very low incidence of poliomyelitis in

U.S. Army forces during and in the years immediately following World

War I. It seemed justifiable to continue to regard this disease essentially,

if not exclusively, as a disease of early childhood and not, to any appreciable

degree, as a disease of men of military age.

By 1945, however, it was abundantly clear that this opinion needed

revision, for although the number of cases of poliomyelitis which had occurred in the Army during World War II was not very great (in the

neighborhood of about 1,000 covering the 4 war years), the disease had

been responsible for many problems. The degree of crippling was high;

the percentage of bulbar cases was high; the mortality was high; and the

element of panic which poliomyelitis caused, either in outbreaks or in single

cases within military units, had proved to be appreciable. Not only had

this been so within the confines of the United States but, with the exception

of the European Theater of Operations, U.S. Army, the incidence of poliomyelitis had been considerably greater in troops abroad than at home

(p. 9 9 ).

The statistics with regard to the prevalence of poliomyelitis in U.S.

Army personnel preceding and during World War II have been admirably

18 It will not be within the scope of this chapter to discuss postwar outbreaks of arthropodborne

virus encephalitis or the experience with this disease by troops occupying Japan during the 2 years

immediately following 1945. Three cases did occur in U.S. troops in Korea in 1946, one of them fatal.

These occurred among 1,500 Americans stationed in an isolated camp near Kunsan (Sabin, A. B.,

Schlesinger, R. W., Ginder, D. R.. and Matumoto, M.: Japanese B Encephalitis in American Soldiers

In Korea. Am. J. Hyg. 46: 356-375, November 1947). No cases of encephalitis were found in the

native lIopIulation coincidentally. Subsequently (1946-55), Korea has experienced at least two large

outbreaks of Japanese B encephalitis.

Also during the summer of 1946, an outbreak of illness among U.S. Marines stationed In Tientsin,

China, which at first was thought to be encephalitis and later regarded as poliomyelitis, led to certain

Investigations by Sabin and his coworkers (Proc. Soc. Exper. Biol. & Med. 65: 183-187, June 1947)

which revealed that extensive previous inapparent infection with Japanese B encephalitis virus existed

among the populations of Shanghai and Tientsin, where no epidemics of encephalitis had been observed.

The survey method employed by Sabin was one which had been followed by Japanese in Japan and

elsewhere, for some years: namely, by determinhig the presence or absence of neutralizing antibodies

for the virus of Japanese B encephalitis in large numbers of sera collected from various age groups

of the local population living in various locations. It was, however, one of the first of many subsequent

examples of the use of the serological antibody survey by U.S. Investigators as a means of outlining

the geographic distribution of epidemic encephalitis in what might be called unknown territory.
92 INFECTIOUS DISEASES

CHART 2.-ueasonal invidenc• of poliomniceitis in the Atrmiy in the contii(IntaL United States

compared wcith eon tcutporaecocous virilian raftes during the secoid half of each year,

1943-.J6

[Rate expressed an number of camNs per annum per 100.000 average strength, by weeks]

RATE 1943 1944 RATE

75 78

60 s60

48 4

At CIVILIAN

15 A

0 -

* I

S/tCIVILIAN 

J•

0 \

so #, ARMY. 3

i I A i A \ Is

75 14

I *-

I01 '

45l ____- __________, I i4

1948 I946

Source: Health of the Army, vol. I, Report No. 3, 30 Sept. 1946.

reviewed by Sabin in another volume in the history of the Medical Department in World War II.19 The attempt will not be made, therefore, to duplicate Sabin's figures to which the reader may be referred. There are, however, certain epidemiological points which deserve mention even at the

expense of reiteration because they represent new information about this

disease acquired as a result of military experience. Primarily, it became

apparent during the years 1941-45 that men of military age, born and

brought up in the United States during the 1920's and 1930's, were more

susceptible to poliomyelitis than their fathers had been in 1917-18. This

was unexpected. The military rates for 1943-46 within the United States

19 Sabin, Albert B.: Poliomyelitis. In Medical Department, United States Army. Preventive

Medicine In World War II. Volume V. Communicable Diseases Transmitted Through Contact or By

Unknown Means. Washington: U.S. Governaeait Printing Office, 1960. pp. 367-400.
NEUROTROPIC VIRUS DISEASES 93

are shown in chart 2. In comparing the curves recording A.rmy and civilian

incidence, respectively, in chart 2, one should recall that the civilian populatII contains a much higher percentage of susceptibles (children) than does

the military population In terms of actual rates, the average civilian overall annual rate for poliomyelitis per 100.000 in the United States for 1940-47

was about 10. Triis includes all ages, all months of the year, and both para-

,-tic and nonparalytic cases. It can be compared with the annual rate for

•. Army troops in the Inited States for the period 1940-47, which was

,t. 3 per 100,000.

Another point that came out of the military experience was that in 1941

;iere was little appreciation that l)oliomnyelitis could be a tropical disease

,,f any importance, or that it amounted to much in subtropical areas. Local

civilian 1)ublic health statistics within the great majority of tropical areas

had for years reported a dearth of epidemnics and a very low incidence of

poliomyelitis in the native-born inhabitants.20 Therefore, it was naturally

thought that this disease should not be of particular danger to troops in

such areas. It was not long, however, before it became apparent that poliomnvelitis could exist in poorly sanitated tropical or subtropical areas as a

hidden disease, hitherto unsuspected. Later. by the copious use of hindsight,

one could surmise that this might have been predicted on the basis of prewar

experience with poliomyelitis in the Philippines. As early as 1936, Lt. Col.

(later Brig. Gell.) Charles C. Hillman. MC. had reported an interesting

observation, which was to be repeated frequently during World War II.

III his account 21 of an outbreak of poliomyelitis which occurred in Manila,

Philippine Islands, in 1934, he described 17 l)atients withl poliomyelitis who

were admitted to the Sternberg General Hospital in Manila; of these, 3

cases were in military personnel, the remaining 14 being in dependents.

Coincidentally. the number of cases in the local Philippine civilian population was small, presumably represented by only Atine cases. Colonel Hillinan

comlmented on the fact that, considering the vast preponderance of natives

to American-born people in the community, there was indeed a striking discrel)ancy between the poliomyelitis incidence rate in the civilian population

and that of the Americans. However. the extraordinary degree to which

the immunity of the young adults in the two populations might differ was

not appreciated at that time.

The idea should not be conveyed here that the Medical Department of

the U.S. Army was indifferent at the beginning of World War II to the

threat of poliomyelitis as a possible problem in military medicine, for this

was not the case. During the summer of 1941, the Office of the Surgeon

General of the Army prepared a statement about poliomyelitis and recomnliendations for its control in the Army. Again in 1943. at the request of

20 Sin(ce 1945. many epidemics of poliomyelitis have jein reported from tropical areas (Paul, J. R.,

Ramirez Corria. F., and H1orstmann. D. M. : Analyses From a Tropical Epidemic of Poliomyelitis Which

Occurred in Florida and Cuba in 1946. Am. J. Trop. MePd. 29: 543-554, July 1949).

21 1lllman, C. C. : Poliomyelitis In the Philippine Islands. Mu1. Surgeon 79: 48-58, July 1936.
94 INFECTIOUS DISEASES

The Surgeon General of the Army, the Division of Medical Sciences of the

National Research Council sponsored a discussion by outstanding authorities

in the field of p)oliomyelitis, which again resulted in a number of recoinmendations used by military officers. These recommendations are recorded

by Sabin in another volume in the history of the Medical Department in

W1orld War 11.22

Perhaps the first theater in which this disease became an appreciable

problem was that of the U.S. Army Forces in the Middle East in 1943. Observations regarding the seriousness of poliomyelitis in British troops within

the area during 194142 had already been mnade in 1943.23 The situation was

later reviewed by Caughey and Porteous in a postwar report of their experiences which includes a description of anl epidemic of poliomyelitis which had

occurred in 194041 in New Zealand troops stationed in Egypt.24 Similar

British observations were recorded in India with comments on the fact that

poliomyelitis was particularly severe in foreign troops in India, whereas at

the same time it seemed to be both uncommon and not severe in the natives

there.

This early British experience in the Middle East was later shared by

U.S. troops in North Africa, Egypt, and the Middle East generally during

the suimlner of 1943. This joint experience has been described 25 with particular reference to the high rate and high fatality of poliomyelitis in U.S.

troops in contrast to its apparent rarity in the native adult Egyptians.

Comment was also made on the absence of epidemics of poliomyelitis in the

local native population and the fact that the only examples of the disease

which did appear in the local population were in infants.

There was considerable difficulty with the diagnosis of poliomyelitis in

U.S. troops stationed in this area during the summer of 1943. Medical officers had not been prepared for this disease and were very loath to accept

suspicious cases as poliomyelitis. This may be understandable in that, at

least at that period, the clinical picture of poliomyelitis in adults had received scanty treatment in American textbooks of medicine. At the 38th

General Hospital near Cairo, Egypt, this author, in consultation, saw at

least a dozen cases of poliomyelitis, several of which were fatal. In the

majority of patients, the disease was characterized by insidious onset with

2 or 3 days of malaise, relatively little fever, but severe pain in the back.

This is in some contrast to the textbook picture seen in children with an

acute onset with fever and usually a biphasic course. Fortunately, at the

38th General Hospital, a virus laboratory had been established in the sum22 See footnote 19, p. 92.

23 Van Rooyen, C. E., and Morgan, A. D.: Poliomyelitis; Experimental Work in Egypt. Edinburgh M.J. 50: 705-720, December 1943.

24 Caughey, J. E., and Porteous, W. M.: An Epidemic of Poliomyelitis Occurring Among Troops

in the Middle East. M.J. Australia 1: 5-10, 5 Jan. 1946.

25 Paul, J. R., Havens, W. P., Jr., and Van Rooyen, C. E.: Poliomyelitis in British and American

Troops in the Middle East; Isolation of the Virus from Human Faeces. Brit. M.J. 1: 841-843,

24 June 1944.
NEUROTROPIC VIRUS DISEASES 95

mer of 1943. Monkeys were obtained locally and from Eritrea, where they

had been trapped by members of the Army Veterinary Service, and the isolation of poliomyelitis virus by monkey inoculation with material from a

number of these cases during the summer of 1943 supported the diagnosis. 24

In the care of these patients, there is little to record other than the fact

that here, as elsewhere in areas remote from the linited States, tank respirators and other respiratory aids were seldom available. As a result, poliomyelitis patients who developed severe respiratory paralysis promptly died.

From the epidemiological standpoint, it was here in the Middle East

that the idea first emerged that the phlenomena which had been observed by

Hillman in the Philippines in 1934 was one which could be repeated in a

number of different areas. particularly in cities located in the tropics where

sanitation was primitive. In other words, among the native-born infants

and young children in these areas, poliomyelitis was apt to be endemic with

an exposure rate so high that the infection was almost universally acquired

by natives in infancy and was almost universally unrecognizedl. Consequently, by the time the native child had reached the age of 2 or 3 years,

he had had the disease (rarely in either paralytic or nonparalytic form), but

commonly in inapparent form and had thus acquired some immunity. This

immunity rate among the adult natives was high as opposed to the visiting

troops from northern Europe, the United States, Canada, Australia, and

New Zealand whose exposure to poliomyelitis at home had not been so heavy

during infancy. When these troops entered these areas, poliomyelitis came

to the surface, as it were, because of heavy exposure of a moderately susceptible population coming into an infectious environment. As a result, not

only were appreciable numbers of cases of poliomyelitis acquired by the

susceptible members of the "immigrant" troops, but small epidemics in U.S.

trool)s were precipitated now and again of which notable examples appeeared

in 1944 and 1945 in the Philippines.

It would also appear that the same unsanitary conditions and proximity

to native populations, which gave rise to high attack rates of bacillary dysentery and infectious hepatitis, were also associated with an increased incidence

of poliomyelitis. Thus, poliomyelitis and these other diseases did not often

occur among the troops in various primitive, tropical or subtropical, regions

where the military installations were "beyond the range and influence of

native villages." But where, as became particularly evident in the Southwest Pacific Area and in the Philippines, U.S. troops moved into the midst

of congested native villages and towns with sanitation of the worst possible

order, poliomyelitis appeared in unexpectedly high numbers of cases, along

with the other infections whose etiological agents were known to occur predominantly in human feces.

26 Report. Commigsion on Neurotropic Virus Diseases, Army Epidemiologieca Board. to Office of

the Surgeon General, U.S. Army, May 1944. subject: Report of the Middle East Expedition of the

Virus Commission.
96 INFECTIOUS DISEASES

III tile Philippine Islands. for instance, the story was typical. Prior

to the invasion of the islands in 1944, tie attacking force had spent a month

on board ships without the appearance of a single case of polionivelitis.

But shortlv after the occupation of Leyte began in October 1944, cases

appeared. and this was followed by a relatively high incidence of the disease. According to the statistical health report, 39 cases of poliomiyelitis

occurred, during the months of November and December 1944, in a force

which varied from an initial strength of about 200()000 to a little over 300.000

at the end of the year. In the next year. there were 245 cases (for all of

1945) in a force with an average strength of around 600,000. Sabin states

that there is good reason to believe that this does not include all the cases.

Studies on the disease here were reported by the virus team of the 19th

Medical General Laboratory. Leyte.-'7 It was noted by them that there was

no uniform history of the increase of upper respiratory infections in units

involved, but several of the patients had had diarrhea or dysentery subsequient to arrival on Leyte. Nonparalytic cases were also recorded; several

of theem caused considerable difficulty in diagnosis. Coincidentally, no evidence of poliomivelitis appeared aniong the Filipinos so that in the Philippine Islands poliomyelitis was considered to be a disease of white people.

In retrospect, the observations point to the fact that the local population

in Leyte was the hidden reservoir of the virus.

Another outbreak in the Southwest Pacific was investigated at Laoag

Army Air Base in 1945 by Lt. Col. Adam J. French, MC.28 Twenty-two

cases occurred, most of them during the month of May, with at least eight

paralytic cases. Here again, it was not an isolated explosive outbreak but

rather a group of cases resulting from what seemed to be continuous expostire to a reservoir of virus.

Apart from the incidence of poliomyelitis in various oversea theaters,

the incidence of poliomyelitis in troops in the continental United States was

appreciable (chart 2). As a rule, most of the cases were sporadic examples

of the disease which were not followed by outbreaks in the units in which

they appeared. However. there were several small, sharp. and moderately

serious epidemics in the United States during the period 1941-46. These

epidemnics have been discussed with care by Sabin in another volume in the

history of the Medical Department in World War 11.29

The first of these was an epidemic in San Antonio, Tex.. in December

1942.30 Although only 3 cases, I of themn fatal, occurred in soldiers in the

vicinity of Fort Sam Houston, San Antonio, there were a number of cases

27 Report, 19th Medical Service D)etachment (General laboratory). to Chief Surgeon. Headquarters,

U.S. Army Services of Supply, Southwest Pacific Area, 28 Ic. 1944, subjoet : Poliomyelitis and Other

Virus Diseases in the Tacloban-Palo-Dulag area of Leyte.

28 Ietter. Lt. Col. A. J. French. MC, to Chief Surgeon. U.S. Army Forces, Western I'acific, 25 June

1945. subject: Investigation of Poliomyelitis Outbreak at Lamig Army Air Base.

29 See footnote 19, p. 92.

30 Paul, J. R. : Preliminary Report on time Poliomyellls Epidemic in San Antonio, Tex.. SeptemberDecember 1942. (Official record.]
NEUROTROPIC VIRUS I ISEASES 97

among the families of officers mid men stationed in that area, 11 of which

were admitted to the Brooke General Hospital at Fort Sam Houston. This

outbreak cause~d considerable concern locally anmd served as an illustration

of the manner in which poliomyelitis can indirectly become a morale problem

when it suddenly appears in the families of military personnel living on a

large military post in this country.

A second outbreak, which was well describied, occurred in a training unit

designated as the STAR (Specialized Training and Reassignment) unit at

Pasadena College, Pasadena. Calif. The STAR unit consisted of approximately 800 men among whom an explosive ep)idemic occurred in mid-August

1943, just after 310 of the men had left for duty at Indiana University,

Bloomington, Ind. The first case, which ended fatally, occurred on the

train, and subsequently, there were 16 other cases compatible with the diagnosis of paralytic or nonparalytic poliomyelitis in the group which went to

Indiana. Among the men remaining at Pasadena College, there was only

one case.

Another epidemic occurred at Fort McClellan, Ala., in the spring of

1945, which was apparently the only example of an outbreak of poliomyelitis

in an isolated Army camp in the continental United States. Seventeen cases

of paralytic poliomyelitis occurred within a brief period of 2 months, yielding a paralytic attack rate of approximately 0.57 per 1,000 men. All the

cases were in soldiers.

These last. two small outbreaks which occurred in Army personnel in

the United States were both explosive localized types, suggesting primary

infection from a common source over a limited period of time.

The incidence of poliomyelitis among American troops in the European

theater was of the same order of magnitude as in the United States, except

that no outbreaks were recorded.

Diagnosis

During World War II, poliomyelitis proved to be a disease of some

significance within several theaters. This had been more or less unsuspected by medical officers, snme of whom went to considerable lengths to

determine whether the case of acute paralysis seen in North Africa, for

instance, in 1943, might be due to some cause other than poliovirus. One

of the reasons for the difficulties in making the diagnosis seemed to have

been that at that time, in the mid-1940's, the average medical or pediatric

textbook description of acute poliomyelitis described the picture of the

juvenile case characterized with initial signs and symptoms of acute fever

(often in two bouts), headache, vomiting, and stiff neck. Textbook descriptions of adult cases were few, and there was little awareness that adult cases

could present a picture, quite different, from the juvenile case, of insidious

onset, often with little fever in the first few days and often with severe

pain in the back. Consequently, it was with some reluctance that the diag-
98 INFECTIOUS DISEASES

nosis of poliomyelitis was made by medical officers in areas where poliomyelitis was said to be rare and where there was the possibility of the occurrence

of one or more unusual diseases of local origin which might simulate poliomyelitis. This reluctance to diagnose poliomyelitis, because it was a disease

that was not supposed to occur in certain parts of the world and not supposed to occur in soldiers, is understandable. By early 1944, cases of poliomyelitis in military personnel were becoming more familiar in the Mediterranean area, and the diagnostic problems were soon resolved.

Treatment

It would not be profitable to review the various kinds of treatment which

patients with paralytic poliomyelitis received under widely differing circumstances in different theaters of war and in different kinds of hospitals. During and immediately following World War I1, current ideas as to the

symptomatic and supportive therapy of poliomyelitis were undergoing certain

clanges. The abandonment of the prolonged and rigid splinting of paralyzed limbs was taking place, and the tendency was more in favor of the use

of shel] casts to protect the weakened or paralyzed limb rather than its fixation. Actually, the degree to which rigid splinting of paralyzed limbs during

acute phases of the disease was carried out must have differed conside'al lv

in different places. Another innovation was just beginning to be us, (L This

was the application of moist heat to the limbs and body in the painful stages

of myelitis, the so-called Sister Kenny method, which also called for the

reeducation of muscles early in the postfebrile period.

Considerable improvements were to be made in the decade following

World War II in the development of various mechanical breathing aids for

supporting patients whose life was threatened because of respiratory inpairment as a result of paralysis to the respiratory muscles. During World

War IL, however, the main respiratory aid was the tank respirator, known

as the Drinker respirator. This was a large, heavy piece of apparatus, bulky

and difficult to transport. It was not standard equipment of many general

hospitals. Nevertheless, a number of these tank respirators were available

for hospitals in the United States, and occasionally, the emergency transportation of a tank respirator to a distant area was achieved. In retrospect

and taking all things into account, it is not believed that loss of life due to

the failure of availability of respiratory aids was a serious situation.

Oversea patients with residual paralysis were eventually evacuated to

hospitals in the Zone of Interior where they could have orthopedic supervision and undergo a regimen of rehabilitation before discharge from the

Army. This latter phase represents a different but important chapter in the

handling of these cases.

In summary, therefore, it can be said that, before the close of World

War II, it had become apparent that, with the exception of northern Europe,
NEUROTROPIC VIRUS DISEASES 99

the rates of polionmyelitis for U.S. troops stationed abroad were higher than

in the United States, and in some instances far higher (chart 3). In this

chart, the rates are indicated at which poliomyelitis appeared in U.S. Arnmy

troops, which were low in the United States and the European theater, were

higher in the Mediterranean, the Middle East, and China-Burma-India theaters, and higher still in the Philippine Islands.

CHART 3.-Incidence of poliomyelitis in the U.S. -truty, by selected area and f/car, 1940-48

(Rate expressed as number of cases per ai mim per 1,000 average strength]

RATE

CHINA

UNITED EuRoPE MEDITER- MIDDLE PACIFIC PHILIPPINE

TATES RANEAN EAST OCEAN JAPAN I DIA ISLANDS SURMA N KOREA KO A

INDIA

1.0

0.9

08

0.?

06

0.5

04

0.3

0.2

0.,0 . . . . . . . .. . ... . . . . .

4•0 '42 '44 '40 46 42 44 46 46 45 45 44 '4"6 4 6 '44 '45 4 '4? '46 s*4

Source: Paul, J. R.: Poliomyelitis Attack Rates in American Troops, 1940-1948. Am. J. Hyg. 50:

57-62, July 1949.

Unexpectedly, therefore, this military experience has added a good deal

of knowledge to the epidemiology of poliomyelitis in general 31 but relatively

little to other aspects of this disease. This was because of the small number

of cases and the insufficient volume of clinical material.

LYMPHOCYTIC CHORIOMENINGITIS

The story of this disease in World War I has been presented by Rasmussen and Smadel in another volume in the history of the Medical Department in World War 11.32 From their review, it appears that lymphocytic

chorionieningitis, which had been a popular diagnosis during the late 1930's,

31 (1) Paul, J. R.: Poliomyelitis In Japan. Am. J. Hyg. 45: 206-218, March 1947. (2) Sabin,

A. B.: Epidemiology of Poliomyelitis; Problems at Home and Among Armed Forces Abroad. J.A.M.A.

134: 749-756, 28 June 1947.

32 Rasmussen, Aaron P., Jr., and Smadel, Joseph E.: Lymphocytic Choriomeningitis. In Medical

Department, United States Army. Preventive Medicine in World War II. Volume V. Communicable

Diseases Transmitted Through Contact r. iy Unknown Means. Washington: U.S. Government PrintIng Office, 1960, pp. 363-366.
100 INFECTIOUS DISEASES

proved to be a nnuch less conunon disease anmong U.S. military personnel

than had been originally suspected.

Early ill the war, this disease, which will be referred to here as LCM,

had been considered of sufficient importance to deserve detailed mention in

Circular Letters Nos. 107 and 74, 21 October 1941 and 19 March 1943, respectively, pertaining to neurotropic virus diseases; later, these circulars were

followed by TB MEI) 212, 16 January 1946. In all of these summaries, it

was pointed out that exact diagnosis was desirable and that aids to the

clinical diagnosis of LCM were available in the form of complement fixation

tests, which could preferably be performed for diagnostic purposes on

matched samples of sera.

These directives reflect the fact that the clinical diagnosis of LCM was

being made all too freely in the early 1940's and that the term had become a

catchall to embrace the majority of cases of acute aseptic or lymphocytic

meningitis of undetermined etiology. This explains the report of admission

to Army hospitals of 758 cases of LCM in which the diagnosis was based

on clinical criteria alone during the period. However, from the laboratory

studies, reported by Rasmussen and Smadel (in which only 31 of 276 suspected cases were proved to be caused by LCM), it appeared that only 1 in 10

of these 758 cases reported in the Army were actually caused by the virus

of LCM, giving an estimated overall incidence of 76 cases during three of

the war years, 1943-45.

The problem of differential diagnosis on clinical grounds in cases of

aseptic meningitis was in the early 1940's, and still is, very appreciable,

particularly as the list of diseases which were considered in differentiating

LCM from lymphocytic meningitis in military personnel was long. It included mumps meningoencephalitis, nonparalytic poliomyelitis, central nervous system syphilis, tuberculous meningitis, acute encephalitis of a variety

of causes, tetanus, brain abscess, rabies, lymphocytic meningitis associated

with malaria, and infectious mononucleosis. At that time, the syndrome

associated with infections by a number of Coxsackie and Echo viruses was

not known, and it is highly probable that such cases were also included under

the term "acute benign lymphocytic meningitis." Furthermore, the syndrome of acute, benign lymphocytic meningitis encountered in leptospirosis was also not appreciated, and it is reasonable to suppose that such cases

occurred because of their subsequent detection in areas where troops were

stationed during World War II.3

In brief, then, it appears that although many cases of LCM were diagnosed clinically during the war, actually this disease was uncommon. The

introduction of serological methods and the notification of medical officers

that such methods were available did much to clarify this situation. It is

quite clear that in many theaters of operations it was difficult to have the

3-3 Professional History of Internal Medicine in World War II, 1 Jan. 1940 to 1 Oct. 1945, The

Panama Canal Dept., vol. 1, pp. 162-171. [Official record.]
NEUROTROPIC VIRUS DISEASES 101

special type of laboratory determinations performed, such as the serological

diagnostic methods described in Circular Letters Nos. 107 and 74, and TB

MED 212.

Nevertheless, it was gradually brought home to medical officers, in this

country at least, that here was a disease of which, if loosely diagnosed, one

could find many examples, but if rigidly diagnosed, particularly with the

use of the complement fixation test, 90 percent of the cases could be eliminated. The fact that these tests were more readily available to physicians in

the Medical Department of the Army than to many physicians in civilian

practice indicates that here was a situation with certain educational potentialities.

In retrospect, therefore, it would seem that LCM did not prove to be a

disease of military importance in World War 1I. The number of proved cases

were few and scattered and, apparently, there was nothing special or consistent about, the circumstances under which they occurred. One noteworthy

feature about LCM during World War II was, however, that through the laboratories of the Army Medical Department Professional Service Schools,

Army Medical Center, Washington, D.C., and a few other special laboratories, this proved to be one of the first of the virus diseases of the central

nervous system in which an exact etiological diagnosis could be established

by serological methods. Others in the group soon followed.

RABIES

Rabies among military personnel during World War II was rare and

sporadic. In the U.S. Army, 1941-45, seven rabies deaths were reported on

individual medical records, five occurring in the United States and one each

in Panama and the Philippine Islands. Of the five patients who died in the

United States, one had contracted the disease in Italy but had not reported

for treatment until after returning to the United States.

This author reviewed three case reports of patients who had contracted

the disease in the United States-one at Jefferson Barracks, Mo., in December

1941; one in Washington, D.C., in November 1943; and one at Chanute Field,

Ill., in January 1944. The first two cases were due to dogbites; the third,

to the bite of a skunk.

In the three case reports reviewed, there were no special features with

regard to the history, clinical course, and treatment. The incubation period

in two of the patients, one of whom received a full course of antirabic

inoculation, was from 3 to 6 months; whereas, in the third patient, who was

bitten on the lip and who had received but three injections of vaccine, it

was about 5 weeks. Once symptoms started, the course was rapidly downhill

with death in 3 to 4 days. Initial symptoms included malaise, anxiety, and

drowsiness. These were soon followed by nausea, pain in the shoulders,

increasing stupor, rapidly developing flaccid paralysis, and pharyngeal and
102 INFECTIOUS DISEASES

laryngeal spasm. Paraldehyde and Avertin (tribromolthanol) were employed as sedatives.

l)espite the farflung activities of the U.S. Army during the course of

the war, the only areas other than the United States in which the disease

was contracted were, as just mentioned, Panama, the Philippine Islands, and

Italy. rhis is extraordinary from the standpoint of the exposure which

might have existed in North Africa and in the Middle East generally, but is

of course not remarkable for Gteat Britain and France in the European

theater.

('ol. John E. Gordon, J[C, 34 in a report from the European theater,

noted that it was a novel sensation in the experience of most American physicians to be able to look with complete equanimity on the occurrence of a

dogbite. Rabies had been so long absent from Great Britain by reason of

the stringent quarantine practiced in that country that no need existed for

administration of antirabic vaccine after bites by dogs or other animals. The

last rabies in Great Britain occurred at the time of World War I.

The rabies situation in France was almost as favorable, for apparently

iio definite cases of rabies had been detected in animals for some years, and

no lumman had died from rabies in France for 16 years.

Rabies was, however, reported in Berlin, Germany, in 1945, and occasional infections among animals were recognized in northwestern European

countries. Most American medical officers consequently returned to traditional l)ractice in the management of dogbites sustained in these areas.

Rabies transmitted by bats was a disease known to the Army, but was of

no military significance since it did not produce human cases. This battransmitted disease is the cause of paralysis in livestock, principally cattle.

It made its first appearance in Trinidad, in 1925, where, for 11 years thereafter, focal outbreaks reoccurred in cattle, with about 1.000 cases occurring

annually. The rigorous control measures which were brought to bear in

Trinidad and Venezuela are described by Maj. Richard T. Gilyard, VC.35

34 Gordon. John E. : A History of Preventive M•edleine in the European Theater of Operations,

U.S. Army, 1941-45, vol. II, pt. III, p. 51. [Official record.]

35 Gllyard, R. T. : Bat Transmitted Paralytic Rabies. Cornell Vet. 35: 195-209, July 1945.
CHAPTER V

Q Fever

Charles A. Ragan, Jr., M.D.

OCCURRENCE

Q fever first appeared among Allied troops in 1944 and 1945 when

several sharp outbreaks occurred in the Mediterranean (formerly North

African) Theater of Operations, U.S. Army.1 That it was not identified

immediately was doubtless related to the fact that this rickettsial disease had

first been described in 1937 ,` and that, with the exception of laboratory infections,3 the disease had been reported only from Queensland, Australia, as

occurring naturally in human beings. The author was present as Chief,

Medical Service, 15th Field Hospital in Italy, when some of the first military

patients were seen, and it must be confessed that there was no realization

at that time that an unusual situation was developing. In retrospect, it is

of interest to reflect upon the interplay of serendipity, error (a single positive Weil-Felix reaction), and the presence of Maj. Frederick C. Robbins, MC,

in Naples that led to the realization that we were dealing, not with common

primary atypical pneumonia, but with Q fever, appearing naturally in a

locality far distant from Queensland. Subsequently, the disease was recognized in southern Italy, Greece, and Panama. Since World War II, Q fever

has been recognized in California.4

Apennines outbreaks.-The 15th Field Hospital was set up in December

1944 as a three-platoon unit acting as a medical evacuation unit behind the

U.S. II Corps in the Apennines north of Florence. The hospital was studying

the feasibility of early return to duty of patients with various psychosomatic

problems related to combat fatigue. In addition to such patients, there were

others with trenchfoot, infectious hepatitis, and primary atypical pneumonia.

1 Unless otherwise noted, the material presented in this chapter was taken mainly from a series

of articles which appeared In the American Journal of Hygiene, volume 44, July 1946, pp. 1-182.

2 (1) Derrick, E. H. : "Q" Fever, A New Fever Entity; Clinical Features. Diagnosis and Laboratory Investigation. M.J. Australia 2: 281-299, 21 Aug. 1937. (2) Burnet, F. M., and Freeman, M.:

Experimental Studies on the Virus of "Q" Fever. M.J. Australia 2: 299-305, 21 Aug. 1937.

3 (1) Cox, H. R.: A Filter-Passing Infectious Agent Isolated From Ticks. III. Description of

Organism and Cultivation Experiments. Pub. Health Rep. 53: 2270-2276, 30 Dec. 1938. (2) Dyer.

R. E.: A Filter-Passing Infectious Agent Isolated From Ticks. IV. Human Infection. Pub. Health

Rep. 53: 2277-2282, 30 Dec. 1938. (3) Hornibrook, J. W., and Nelson, K. R.: An Institutional Outbreak of Pneumonitis. I. Epidemiological and Clinical Studies. Pub. Health Rep. 55: 1936-1944,

25 Oct. 1940. (4) Dyer, R. E., Topping, N. H., and Bengtson, 1. A. : An Institutional Outbreak of

Pneumonitis. II. Isolation and Identification of Causative Agent. Pub. Health Rep. 55: 1945-1954.

25 Oct. 1940. (5) Lillie, R. D., Perrin, T. L.. and Armstrong, C. : An Institutional Outbreak of Pneumonitis. III. Histopathology in Man and Rhesus Monkeys in the Pneumonitis Due To the Virus of

"Q" Fever. Pub. Health Rep. 56: 149-155, 24 Jan. 1941.

4 Clark. W. H., Lennette. E. H., and Melklejohn, G.: Q Fever in California. III. Aureomycin in

the Therapy of Q fever. A.M.A. Arch. Int. Med. 87: 204-217, February 1951.

103

639243--63-9
104 INFECTIOUS DISEASES

Radiological facilities under the direction of Capt. Stanley M. Wyman, MC,

were excellent.

in late February 1945, an officer front Headquarters Company, 339th

Infantry, was admitted with high fever and general malaise without localizing symptoms, a, picture suggrsting the preicteric phase of infectious

hepatitis. A roentgenogram of the chest at admission was interpreted as

normal. A mnacular erythematous rash appeared transiently, and typhus

was then considered in differential diagnosis, because several of the medical

officers in the 15th Field Hospital had had duty in North Africa and had

seen the disease in native populations. For this reason, a Weil-Felix test

was done and was reported as positive in a significantly high titer from the

2d Medical Laboratory iii Florence. Shortly thereafter, a second roentgenogrami of the chest revealed an area, of pneumonic consolidation, and a presumptive diagnosis of primary atypical pneumonia was made.

Within the next month, 32) additional members of Headquarter(s Counpany, 339th Infantry, were admitted with febrile illness, and 20 inore patients

from this unit were seen in other Fifth U.S. Army hospitals withi similar

symptoms. Major Robbins of the 15th Medical General Laboratory in Naples

came to investigate the reported positive Weil-Felix reaction. From the

blood of one of the patients with pneumonitis, a strain of rickettsia characterized as Rclkett8ia burneti was isolated by inoculation into guinea pigs

and subsequent transfer to chick embryo yolk sac. This was established as

the Hlenzerling strain. Sera were obtained from 28 patients during acute

illness and convalescence, and convalescent samples were obtained from 25

other patients. Complement-fixing antibodies to the hfenzerling strain were

found in the sera of all 53 patients.

A second outbreak, originating in the same vicinity, was observed in

April 1945 in the 3d Battalion, 3062d Infantry, involving 267 patients of

whom 80 were personally observed in the 15th Field Hospital. Sera of the

acute disease and convalescence were obtained from 29 unselected cases, and

a rising titer of complement-fixing antibodies to the HLenzerling strain was

demonstrated. The Paige strain of R. burnwti was isolated from one patient

in this group. In this epidemic, 70 percent of the patients not personally

observed were reported as having atypical pneumonia or pneumonitis, and

the remainder had diagnoses of fever of undetermined origin, infections

hepatitis without jaundice, or upper respiratory infection. Occasionally, no

final diagnosis was made.

In a survey carried out by Major Robbins, Lt. Col. Ross L. Gauld, MC,

and Capt. (later Maj.) Frank B. Warner, MC, several localities appear

to be epidemiologically implicated in the high incidence of disease seen in

these two outbreaks. Insects in the presumed areas of infection were numerous but no specific rickettsial vectors were discovered and the spraying of

DDT (dichlorodiphenyltrichloroethane) did not modify the pattern of the

outbreak in the 339th Infantry. An incubation period varying from 14 to
Q FEVER 105

26 days, with a peak at 19 to 20 days, was suggested by this epidemic. No

cases developed in medical personnel caring for these patients. It was noted

that the implicated areas were dusty, but no attempt was made to recover

the reckettsia from dust. Rickettsia was successfully recovered from dust in

California by DeLay, Lennette, and DeOme in 1950.5 High complementfixing antibody titers to the Henzerling strain were found in a group of

civilians from the epidemic area. Several other outbreaks, which were similar in their clinical and epidemiological features but not proved serologically,

occurred in small units in northern Italy and Corsica. All outbreaks seemed

to be related to dusty habitations.

Laboratory outbreaks.-In June, July, and August, 1945, a laboratory

outbreak of 20 cases developed in the 15th Medical General Laboratory in

Naples. This epidemic was well documented by Major Robbins and was

shown to have originated in the room of the laboratory where the Henzerling

and Paige strains were being studied in guinea pigs and embryonate hens'

eggs. The Seale strain of R. burneti was isolated in this epidemic, and

rickettsiae were isolated from 16 of the 20 patients as early as the second

day of disease and as late as the eighth. Complement-fixing antibodies to

the I-enzerling strain of rickettsia were absent in sera taken before the 7th

to the 13th day of disease but were present with later specimens. The peak

of the antibody response was reached on about the 21st day with a tendency

to diminish after the 30th day. The disease contracted in the laboratory

appeared to be somewhat more severe than that seen in the field, possibly

owing to a greater initial exposure to the infectious agent; however, four

patients, proved to be harboring rickettsia and sick with fever and malaise,

developed no roentgenologic evidence of pneumonia.

Outbreaks originating in Greece.--During the outbreaks north of Florence, it was learned that an epidemic of 40 cases of pneumonitis had appeared in one company of a battalion of British paratroopers who had come

to Rome, Italy, from Athens, Greece, in January 1945. The outbreak appeared to have developed in Athens, and the men recalled exposure to dust

in an abandoned silk mill used as a bivouac. Dr. J. Caminopetros of the

Pasteur Institute in Athens had obtained from the blood of patients with

"Balkan grippe" an agent producing a transmissible febrile disease in guinea

pigs. Guinea pig blood was sent by him to the Commission on Acute Respiratory Diseases, Army Epidemiological Board (Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army),

and from this, a rickettsia strain similar to R. bhinet; was isolated at the

Commission laboratories at Fort Bragg, N.C. A laboratory outbreak caused

by the "Balkan grippe" strain of Q fever occurred in the personnel in this

laboratory before the rickettsia had been definitely characterized from the

material sent from Greece. As was so often the case with these epidemics of

5 DeLay, P. D., Lennette. E. H., and DeOme, K. B.: Q Fever in California. II. The Recovery of

Coxiella Burnett from Naturally-Infected Air-Borne Dust. J. Immunol. 65: 211-220, August 1950.
lot; INFECTIOUS DISEASES

Q fever, the diagnosis was made in retrospect. Convalescent serum obtained

from 35 of the British paratroopers who had been sick in Athens and Rome

and sera from 43 well soldiers of the same battalion were tested for agglutinating antibodies to the "Balkan grippe" strain at Fort Bragg. Significant

elevations were found in 29 of the 35 recovered cases, while only 9 of 43 men

who had not been ill showed a high titer. Presumably, therefore, the epidemic in British paratroopers represented an infection with the "Balkan

grippe" strain contracted in Athens.

Outbreak in Zone of Interior.--An outbreak of Q fever was observed at

Camp Patrick Henry, Va., in May and June 1945, after approximately 7,500

troops returning from southern Italy had disembarked. The disease was

apparently confined to five squadrons of an air force group. Careful case

finding in one squadron revealed 143 patients-an attack rate of 38 percent.

Agglutinating antibodies to the "Balkan grippe" strain of R. burneti were

found, as were complement-fixing antibodies to the Australian strain, but

no organism was isolated. The outbreak seemed to be related to a particular

bivouac area, at Grottaglie Air Base near Taranto in southern Italy. Again,

no cases developed in medical personnel caring for these patients.

Other outbreaks.-A single case of pneumonia was studied in Panama

from which a strain of rickettsia similar to R. burneti was isolated. The

British Army in 1944 had observed in the Mediterranean area several sharply

localized epidemics of "atypical pneumonia" characterized by a high attack

rate-up to 50 percent of a unit. These may have represented Q fever, but

no serological proof for this was obtained.

CLINICAL FEATURES

Mode of onset.-In northern Italy, the disease was characteristically sudden in onset and the exact hour was frequently known. At Camp Patrick

Henry, in contrast, 70 percent of the patients noted a gradual onset. These,

however, .represented the milder cases discovered by careful case-finding

studies and would not have been observed in the Apennines epidemic in which

only patients with complaints sufficient to require hospitalization were seen.

The early symptoms were nonspecific---chilliness, sweats, general malaise,

weakness, fatigue, muscular aches, frontal headache, and anorexia. Pain in

the chest when present was variable in intensity, ranging from a vague to a

definitely pleuritic character.

Symptoms.-Although the onset was usually sudden, it was seldom severe

enough to cause prostration, and the patient often continued duty for 12 to

72 hours. The nonspecific symptoms persisted and became more pronounced

with the ensuing rise in temperature. Frank rigor was seldom experienced.

Frontal headache was common and severe, as in many rickettsial diseases,

and a majority of the patients complained of retro-orbital pain aggravated

by coughing. Anorexia was the only common gastrointestinal symptom. A

moderately dry cough frequently developed on the fifth or sixth day but was
Q FEVER 107

not an outstanding feature. Approximately 20 percent of the patients who

were carefully observed raised small amounts of blood-streaked sputum.

Vague pain in the chest of the type described at the onset persisted, but true

pleuritic pain was not common and was rarely severe, responding to aspirin

and codeine therapy.

Physical findings.-Temperature on admission ranged between 1010 and

1050 F. The curve was irregular, extremely sensitive in a transient fashion

to salicylates, and persisted from 4 to 15 days. It returned to normal by

lysis with an occasional crisis. Slight relative bradycardia, normal respiratory rate, and absence of cyanosis and dyspnea were usual. A cutaneous

rash was seen only in the first patient. Physical findings in the chest were

normal or only minimally altered. Crepitant rales and slight diminution of

breath sounds or dullness were occasionally noted, after the roentgenogram

called attention to abnormalities. Coryza and pharyngitis were not encountered although vesicles on the pharyngeal mucuous membrane were noted in

the epidemic in British paratroopers. Splenomegaly was rare save in the

British paratroopers who also had generalized glandular enlargement. Herpes

simplex was not observed. Nuchal rigidity of moderate intensity was seen

occasionally, but in six patients, lumbar punctures yielded normal spinal

fluid. Guinea pigs inoculated with one of these fluids obtained from a patient

in the Apennines outbreak had a transmissible disease, but serological proof

for its rickettsial origin, that is, cross-immunity, was not obtained.

Roentgenological flndings.-The pneumonic infiltration as seen in roentgenograms was characteristic. Its incidence in all the outbreaks was not

determined, but 80 percent of the proved cases in the Naples laboratory outbreak and 90 percent of those at Camp Patrick Henry showed such infiltration. The shadows were homogeneous, of a ground glass appearance and

patchy in distribution, involving only a small portion of a lobe. Atelectasis

with shift of an interlobar septum was frequently seen. In Italy, in most

instances, lesions of a single lobe were observed, but occasionally, two lobes

were affected. At Camp Patrick Henry, 60 percent of the patients had multilobar involvement. Lower lobe involvement predominated. There was no

correlation between the extent of involvement demonstrated by roentgenogram and the severity of the disease. The roentgenogram of the chest on

admission was frequently clear, with shadows appearing on the third or

fourth, and occasionally as late as the sixth, day of the disease. Shadows

consistent with small amounts of pleural fluid were seen in approximately

10 percent of the patients. The roentgenographic changes tended to be persistent and, frequently, were still present when the patient was discharged

after an average stay of 22 days in the hospital. Resolution occurred by a

gradual clearing of the involved area.

Course and convalescence.- With defervescence, the symptoms rapidly

subsided leaving only weakness, which varied with the severity of the disease.

The duration of asthenia ranged from a day to 3 weeks. Loss in weight
108 INFECTIOUS DISEASES

commensurate with a febrile illness associated with anorexia was usually

observed. No deaths, no recurrences, and only one possible complication were

seen in military personnel. The complication was a severe esophagitis in one

patient in the Naples laboratory outbreak. The great majority of patients

returned promptly to full duty.

Laboratory findings.-Increase in numbers of leuk(o'ytes, polymorplhonuclear leukocytosis, and anemia were not observed. The urine was normal

except for occasional mild albuminuria at the height of fever. The erythrocyte sedimentation rate was moderately rapid during the acute phase of illHess and became normal promptly after recovery. Blood cultures were sterile; enteric agglutinations, Proteus OX-19, OX-2, and OX-K agglutination

(save in the original Apennines patient), coccidioidin skin tests, and throat

cultures were negative. Cold agglutinins, antibodies to influenza A and B,

treatment with the sulfonamides or penicillin were noted.

Treatment.-Treatment was symptomatic, and no beneficial effects of

treatment with the sulfonamides or penicillin were noted.

EPIDEMIOLOGY

The Henzerling strain isolated in Italy, the "Balkan grippe" strain from

Greece, and the strains isolated in the laboratory outbreak at Fort Bragg and

in Panama were similar in immunological specificity (complete reciprocal

cross-immunity) to the rickettsia isolateI ;,N Dyer 6 (the American strain)

although there were great variations in the sensitivity of the antigens. Crossimmunity between the Australian 7 aid American strains had previously

been demonstrated. It therefore seems reasonable to assume that the rickettsial disease seen in the Mediterranean area and in Panama characterized

by pneumonitis was Q fever. The relationship of Q fever to the usual form

of primary atypical pneumonia was investigated serologically, and it was

found to be close in endemic areas such as Caserta, Italy, but not in nonendemic areas such as the Eastern United States.

Mode of transmission.-In the original cases from Australia, plleuionitis was not mentioned. The disease, there, is tickborne to cattle with a

reservoir in bandicoots. The infection in man is aberrant, and the Australian

workers postulated that the inhalation of dried tick feces present on the hides

of cattle was the route of infection in human disease. Pneumonitis was first

recognized in the laboratory epidemic at the National Institute of Health,

U.S. Public Health Service," and in retrospect, it appears that this was probably a dustborne rickettsial infection. No insect vectors were implicated in

the Italian or Greek disease, but dusty habitations were. noted. Retrospectively, in view of the isolation of rickettsiae from dust in California, 9 it

C, .*e footnote 3 (2), p. 103.

7 See footnote 2 (2), p. 103.

s See footnote 3 (3), p. 103.

: See footnote 5, p. 105.
Q FEVER 109

seems fair to assume that pneumonic Q fever may represent aii infection in

which the pulmonary infiltrate represents the primary lesion, as does the

eschar in fl&vre boutonneuse and rickettsialpox.

Military significance.-The military implications of this disease can be

far-reaching. It occurs in sharp outbreaks and, although rarely fatal, can

completely incapacitate an entire unit for combat. A satisfactory form of

prophylaxis was not at hand during the war years. Since World War II, it

has been shown that oxytetracycline (Terramycin) and chlortetracycline

(Aureomycin) are effective in the treatment of Q fever. 10 The avoidance of

dusty bivouacs in habitations w-here sheep, goats, or cattle have been kept

may help, and disturbing of such dust by vigorous procedures should particularly be avoided.

I0(1) Stokes, M. G. P.: Q Fever In Britain. Brit. M. Bull. 9: 231-233. 1953. (2) See footnote 4. p. 103.
CHAPTER VI

Scrub Typhus

Chris ]. D. Zarafonetis, M.D., and Myles P. Baker, M.D.

Scrub (or miteborne) typhus is an acute febrile disease caused by infection with Riekettdia tsutitgatu,8hi. Clinically, it resembles other rickettsial

diseases with an abrupt onset characterized by chilly sensations or rigors,

followed by fever, headache, malaise, and later a rash. The differential diagnosis may be established early by finding the primary sore or eschar at the

site of infection, often with associated satellite or generalized lymphadenopathy; at a later stage, some cases may be distinguished serologically. Scrub

typhus is also called tsutsugamushi disease, tropical typhus, rural typhus,

Japanese river fever, and Kedani fever.1

The earliest description of the malady in the Japanese literature was

written by Hakuju Hashimoto in 1810, while the first English report was

made by Palm in 1878. Mites were suspected as the probable vectors as early

as 1879. The field mouse, Mierotu, moiwtebelli, was implicated as an important natural reservoir of infection in 1918.

During the 20 years before World War II, careful research work, notably

in Malaya and Sumatra, had indicated that tsutsugamushi disease was not

limited to Northwestern Japan, Formosa, and the Pescadores Islands, where

the Japanese had by 1931 definitely established its rickettsial etiology. The

clinical picture, pathology, and epidemiology were shown to be fundamentally the same in Sumatran mite fever, in the scrub typhus of Malaya, the

endemic typhus of New Guinea, the coastal fever of North Queensland,

Australia, and in cases reported from Burma and Indochina. The common

pattern could be traced in spite of wide variations in mortality and frequent

failures to find the primary eschar. Prior to the experience of World

War II, however, the only species of mite proved by animal experiments to

be the vector of tsutsugamushi disease was the trombiculid mite identified by

Japanese workers. Other mites had been highly suspected in Sumatra and

Malaya, but conclusive proof had not been furnished. Similarly, the principal reservoir host of the trombiculid mite had not been incriminated elsewhere than in Japan and Malaya. Definitive work on the mite-rat complex,

in New Guinea and Burma, remained to be done.

This identification of scrub typhus, as it was commonly called in the

Armed Forces, with tsutsugamushi disease of the Japanese removes it from

the list of strictly tropical diseases, for Japan can scarcely be considered

I Blake, F. G., Maxey. K. F., Sadusk, J. F., Jr., Kohls, G. M., and Bell, E.J.: Studies on Tsutsugamushi Disease (Scrub Typhus, Mite-Borne Typhus) in New Guinea and Adjacent Islands; Epidemiology,

Clinical Observations and Etiology in the Dobodura Area. Am. J. Hyg. 41 : 243-373, May 1945.

111
112 INFECTIOUS DISEASES

within the tropics. It was, ill fact, little known outside Japan as late is

1942. Its distribution is known to us now only as indicated by the accident

of human infection with le. tsutsugamu hi. With the advent of large-scale

jungle warfare, scrub typhus became an important medical problem to troops

in the Far East. Indeed, approximately 6,000 cases were to appear in U.S.

Forces alone during the campaigns that followed the outbreak of war with

Japan.

As military operations progressed in the Southwest Pacific and in

Burma, U.S. Armed Forces passed into and through areas hitherto scarcely

studied as to prevalent diseases and lived there under field conditions very

unlike the customary sheltered life of the white planter of prewar years.

One immediate result was a wider appreciation of the geographic area of

distribution of this disease. Until then, such places as Bougainville and

Goodenough Islands, the Schouten Islands, and Netherlands New Guinea, or

Luzon and Mindoro Islands in the Philippines, had not been reported as

sites of scrub typhus. Medical officers became acquainted at first hand with

the clinical picture and pathology of the disease and hadm opportunity to compare it with other rickettsial infections, notably epidemic typhus. Opportunity was afforded for thorough study of its epidemiological and entomological aspects in the field and laboratory and for the institution of preventive

measures.

CLINICAL EXPERIENCE

Southwest Pacific Area

In this region, Gunther had by 1940 collected 105 cases of a disease which

he labeled "endemic typhus," chiefly from the Wau area in the mountains

south of the Markham Valley in northeast New Guinea.2 The clinical picture was described by him at length, the similarity to tsutsugamushi disease

emphasized. Diagnostic agglutinations with Proteus OX-K were reported.

The patients were white men who had been clearing jungle areas. Scattered

cases were reported from New Britain Island and the coastline of northeast

New Guinea west of Finschhafen. The disease was, then, well known when

American and Australian Armed Forces moved into New Guinea in the

spring of 1942.

THE FIRST PHASE: ORIENTATION (1942)

The first cases.-Typhus fever was first recognized among our troops in

the Southwest Pacific as an isolated case, reported from northern Queensland

in March 1942. Eight cases were reported from the Port Moresby area of

Papua late in September 1942, and subsequently, a few cases appeared in the

Milne Bay area at the eastern extremity of Papua.3 During the summer

2 Gunther, C. E. M.: A Survey of Endemic Typhus in New Guinea. Med. J. Australia 2: 564-573,

30 Nov. 1940.

3 Essential Technical Medical Data, Southwest Pacific Area, for February 1944.
SCRUB TYPHUS 113

and early autumn of 1942, combat operations in Papua were primarily the

assignment of Australian forces. At the close of the year, Lt. Col. S. W.

Williams, of the 2/9th Australian General Hospital at Port Moresby, was

able to report a prelimiiaary study of 300 cases of scrub typhus. 4 Within 10

miles of Port Moresby, the disease was rare, considering the large number

of troops concentrated there; all but a handful of these cases developed under

combat conditions along the Moresby-Buna track, the so-called Kokoda Trail.

This early Australian experience tallied closely with the prewar description

of the clinical picture given by Gunther. Emphasis was laid on the following points:

Among the first hundred patients there was only one death; among the

second hundred, exposed to the hardships of living conditions while following

the Japanese retreat over the Owen Stanley Range, there were three deaths.

In cases observed during December 1942, chiefly from the Buna-Gona combat

area, the mortality was "nearly 10 percent." These soldiers, too, were spent

by weeks of campaigning in the mountains and fighting around Buna.

Early diagnosis was not found a simple matter. Eschars were noted in

only 60 percent of the cases. As experience was to show, they should be

sought in covered parts of the body. Similarly, the rash was observed in

about 60 percent only. Generalized lymph node enlargement was the most

useful diagnostic sign in distinguishing the disease, in the early stages, from

malaria. Even so, the diagnosis, in absence of eschar and rash, might well

remain in doubt until the appearance of blood agglutinins for Proteus OX-K

on about the 9th or 10th day of fever. It was noted that patients with

scrub typhus fever may appear deceptively well during the first week, only

to develop serious pulmonary, circulatory, and neurological symptoms in the

second week of fever.

American troops were soon presenting examples of those diagnostic problems that proved to be scrub typhus. The majority of men who were to

engage in combat in the Buna-Gona area were flown over "The Hump" of the

Owen Stanleys, were set down at Dobodura airstrips, and went into battle

late in November 1942. Patients with scrub typhus began to appear in December in Port Moresby hospitals, evacuated thereto by air. In January 1943,

there was a sharp rise in the number of reported cases of scrub typhus in the

Southwest Pacific Area (table 12). The case fatality rate for 1943 was 5.5

percent per 100 cases. In 1944, over 4,000 cases of scrub typhus were reported

with a case fatality rate of 3.8 percent. Durinig the first 8 months of 1945,

the number of cases was less than those reported for the same period in 194:3,

with a case fatality rate of 5.4 percent. Owing to the exigencies of the military situation, soldiers convalescing from scrub typhus were evacuated to

general hospitals on the Australian mainland, with the result that any compilation of case material was rendered impracticable. Medical officers in hos4 WIlliams, S. W.: Scrub Typhus in Papua. Preliminary Report. A Description Founded on

Observation of 300 Cases by the Medical Staff of an Australian General Hospital, 5 Jan. 1943. [Official record.]
114 INFECTIOUS DISEASES

TABLE 12.-Number of casex and deaths due to scrub typhus in the Southwest Pacific Area,

U.S. Army, January 1943 to August 1945

[Preliminary data based on unit summary reports]

Period Cases Deaths

1943

January ------------------------------------------------ 92 4

February ----------------------------------------------- 62 1

March --------------------------.----------------------- 45 5

April --------------------------------------------------- 55 2

May --------------------------------------------------- 64 0

June ----------------------------------------------------- 79 5

July ---------------------------------------------------- 83 6

August ------------------.-.----------------------------- 81 3

September ---------------------------------------------- 95 5

October ------------------------------------------------- 93 4

November ----------------------------------------------- 67 3

December ------------------------------------------------ 119 13

Total --------------------------------------------- 935 51

1944

January ------------------------------------------------- 75 9

February ----------------------------------------------- 104 16

March -------------------------------------------------- 184 8

April --------------------------------------------------- 75 12

May -------------.------------------------------------- 130 4

Juie_ --------------------------------------------------- 212 15

July ---------------------------------------------------- 647 9

August ------------------------------------------------- 1,759 32

September ---------------------------------------------- 757 38

October ------------------------------------------------- 251 10

November -------------------------------------------- -- 113 6

December ----------------------------------------------- 89 6

Total --------------------------------------------- 4,396 165

1945

January ------------------------------------------------ 100 5

February ------------------------------------------------ - 66 2

March -------------------------------------------------- 45 4

April --------------------------------------------------- 32 2

May ----------------------------------------------------- 15 2

June ---------------------------------------------------- 43 2

July --------------------------------------------------- 20 1

August --------------------------------------------------- 11 0

Total ---------------------------------------------- 332 is

Grand total --------------------------------------- 5,663 234
SCiRUB TYPHUS 115

pitals of the Advance Base. becoming familiar wAith clinical features of thle

textbook picture of the dlisease, cultivated a high index of suspicion of scrub)

tVpluIIS inl the case classified as fever of undetermined origin withi no evidence

of mualaria. no letikocvtosis. no clinical response to Atabrine ( quinacrine hydrochiloride) or qutiini ine. and wit Ii generalized ivupih node en largenment.

E~schars were more carefuily soulght foi, and ulcers, wvitliout a seat). were

found inl the groins and axilla (figr. 8). By the time thiat agglutinins for

FIGURF S.-"'1 ler' es('har oil right axilla ill tsutsugmnmshi fever on1 151-1 day of illness,

34Md Station IFospital, IDohodura area, Papua.

Proteus OX-K appeared inl the blood, the templerature curve had becomie

(liagniostically chiaracteristic in cases without othier diagnostic sigris. Onle

temp~erature chart (often makinig upl the bul1k of the recordl evacuated with

thle convalescent) could be superimposed onl anothier, so alike were they.

Ill 4)I1e series of cases,'. tile tempera ture Nvas usua1;lly INPJ to lIP* F. onl the first day

of illness. There Nvas a r~ise ill temuperatuare wvithin 24 hou41rs to 1(Ni* to 1030 F'., and durin", tile days that followed. the 4-hoiuriy chart showed a swing-ing- temuperatulre wvith daily

remnissionls fro OW1 fl to 1040 F. throug-hout tile illnes4s. subsiding- by 1 vsis on thle 14th to

17th dlays. fit the molre severe vases. for the first 3 to 5) days a remlittent type of fever

Was seenl, followed by a sustainled fever iup to 1030 F'. until recovery or death. Inl soiiw

fatal eases a remnittent fever ra ilgi g from11 990 to 10W0 F'. was recorded. A temperature

wh~ichl did not rise above 1030 F. was seen inl a few fatal cases.

The first necropsies.-Inexperience with the (disease and lack of any specific treatment lent p~articular interest to the p)athologist's finldinigs inl thle first

5 Wilia~ms. S. W.. Sincla ir A. J.. M.. an 14 Jackson. A. V. :Mite-Iiorne ( Scrub 1Typihus hi Pa.pult

anti th*e 'Mandalte'd rTerritory- of New Gtiinva :14*II(rt of 628) Cnai's. Med. J ustraliat 2: 52.52-539.

18 Nov. 1944.

63t9243'-63~---1
116 INFECTIOUS DISEASES

seven necropsies performed in December 1942 and January 1943 at Port

Moresby by ('apt. (later Maj.) Austin J. Corbett, MC1.6 Ile reported three

groups of findings, as follows:

1. An acute diffuse inyocarditis. with perivascular and interstitial infiltration with plasma cells, macrophages, and lymphocytes, as a constant and

characteristic finding. Damage to the myocardial fibers varied in degree.

Arteriolar walls showed thickening, degeneration, and intramural round-cell

in flit rat ion.

2. In the lungs, alveolar septa were infiltrated with mononuclear cells

in a perivascular arrangement, and the vascular endothelium. within the septa

was swollen and fragmented.

3. In the brain, perivascular proliferation of glial cells and infiltration

with lymphocytes were observed; the endothelitun of smaller blood vessels

was swollen, and several vessels showed intramural round-cell infiltration.

Cardiac findings and prognosis.-The finding of a diffuse myocardial

lesion at autopsy, and the occasional finding of gallop rhythm and "soft"

heart sounds on physical examination of the precariously balanced patient iu

the second and third weeks of fever, gave rise to much concern about the convalescent's prognosis. In the rear hospitals, in Australia, convalescents were

examined carefully for evidence of residual cardiac damage and insufficiency

and were found to have none. Pending the accumulation of enough data to

support a general policy of sending all but the most hard-hit cases back to

duty. the majority of convalescents were returned to duty following maximum

hospitalization benefit.

THE SECOND PHASE: INVESTIGATIONS (1943)

A second phase in U.S. Army experience with scrub typhus began in the

summer of 1943. The occurrence of cases from month to month, without seasonal incidence, was unremitting among combat and service troops, which

were increasing in number as the bases were developed along the north coast

of New Guinea to Finschhafen. The New Guinea hospitals had become more

stabilized, facilitating the study of cases. This period saw clinical and epidemiological studies carried out by a group of investigators, headed by I)r.

Francis G. Blake, working under the auspices of the United States of America

Typhus Commission, and it saw also the development of preventive measures

to protect troops from scrub typhus.

Clinical study.-It will be noted in table 12 that cases were diagnosed

without letup during the spring and summer of 1943. Base B, which included

Dobodura and Oro Bay, Papua, became a hive of activity with ever-increasing

numbers of troops moving into camp areas in the base. Between 1 August

and 1 I)ecember 1943, 248 patients with scrub typhus were admitted to Base B

hospitals. The mortality in these cases was 2.4 percent. From a study of a

group of 20 cases. most of them at the 363d Station Hospital, I)r. Blake and

6 Corbett, A. J.: Scrub Typhus. Bull. U.S. Army M. Dept. No. 70. pp. 34-54, November 1943.
SCRUB TYPHIUS 117

his collaborators constructed an exemplary word picture of the disease, as

follows: 7

The characteristic early symptoms and physical signs of mite typhus at onset and

during the first 5 to 7 days of the disease are headache, apathy and generalized inalaise.

fever, relative bradycardla, anorexia, conjunctival congestion, lyinphadenitis, often rtgional, and eschar. Although the diagnosis may be suswe.ted from the general symptoms

and physical signs together with a normal or low leukocyte count. only the presence of

a typical eschnr iý sufficiently pathognomonic to establish the diagnosis at this stage of

the disease. oquently, the whole body surface should be scrutinized in detail with

adequate Ii unless this Is done, the eschar may be easily overlooked if It Is located

in the less Y accessible areas.

Commonly, lwtween the fifth and eighth days a characteristic macular or maculopapular rash appears on the trunk and may later spread to the extremities. It should

be borne In mind, however, that although the development of a rash tends to confirm the

suspected diagnosis, rashes sufficiently similar to that of mite typhus to cause confusion

may at times occur In dengue and other infections.

The subsequent course of tsutsugamushi disease after the first week may be relatively mild, with no recognizable evidence of the more serious aspects of the disease, and

with a total febrile period of 12 to 14 days: or moderately severe with signs of pneumonitis and encephalitis and recovery by lysis early in the third week; or severe to extremely severe with febrile course of approximately 3 weeks' duration. Symptoms and

signs of more severe pneumonitis and encephalitis are constant. Evidence of peripheral

circulatory collapse are common and signs of myocarditis may appear. Hepatitis and

nephritis sometimes complicate the picture. Thromboses and cerebral or gasti-ointestinal

hemorrhage may take place. Death is not infrequent in these severe cases, particularly

in older individuals, but the majority recover by lysis during the latter half of the

third week.

Laboratory studies have confirmed the already known fact that the Well-Felix test

becomes positive for Proteus OX-K about the 12th to 14th day of the disease in the

majority of cases but that not all patients develop agglutinins for this organism in a

diagnostic titer of 1 in 160 or higher. Rickettsia orientalis (tsutsugamushi) may readily

be recovered from the hlood of patients during the acute stage of the disease by the

intraperitoneal Inoculation of 0.2 to 0.3 inl. of blood into white mice. Both of these

laboratory procedures, If positive, establish the diagnosis, but a negative Well-Felix test

for Proteus OX-K does not exclude mitehorne typhus.

The total leukocyte count, usually within the normal range during the first week but

sometimes showing a leukopenla, tends to increase during the second week. In cases

progressing favorably, this leukocytosis is commonly due In large part to a progressive

Increase in the absolute number of lymphocytes.

Limited observations on the blood chemistry of the miteborne typhus of New Guinea

have shown that hypochloremla, a moderate but not critical reduction in serum albumin.

a rise in serum globulin, and a diminution in plasma fibrinogen tend to occur during the

height of the disease.

The treatment of mite typhus consists primarily of complete bed rest, good nursing

care. adequate diet, fluid and salt Intake. and the judicious and selective use of symptomatic drug, supportive, and oxygen therapy only when specifically Indicated. Penicillin

is Ineffective.

Blake and his coworkers particularly emphasized the localization above

thigh level of the eschar, or primary ulceration, present in all 20 of their cases.

This is in contradistinction to the bites of mites causing scrub itch, on the

7 See footnote 1, p. 111.
118 INFE('TIkUS L)ISEASE-S

ankles and shins. This observation talliedl With that Of tile Aulstralianls lit

Port More5I)V (65~ percent onl a1rins axilla. neck, and trunk). They enipha -

sized1 further (1) the ab)sence of SighIS of right -Sided lheart failure, (2) tile

Ipictitre of at true rickettsial ptieunlionit is. With Which physical signs and findings at auitopsy tire in keeping. and (3) the relat ion of cyanosis and pulmhlolnary

congest ion to plhiehhhi)fl it is. rat her thanl to myvoca rdijal inisufficiency.

Du)ring the spring and~ siummer of 1943. Aulstralianl patienits Were held at

tile Areneral hospitus ill Por1t Moresibv N. as American p~atients were not, making

possib1le (certain olbservat ions oil 620, cases 8~ that add~edI to the clinical picture.

signlficalitly. as re'gairds course1. 11 few vasies were recognized in~ amibuilato~ry paltien1ts

not sick enough to go oiff duty, lout later showing agglutinins to 1'rot its (X-K of 1: 125

or higher (takenitas at mini muml di~kigMOios C titer in this series). No relapse of fever

aitt rihutalole to the* rickettsial infection was tiliserveol. Amiong symptoms, iuatules were

notedl 1)2 fihe soft palaite. Ill a55,0V'it toi~l With t lie typica'Il rash over tile body.

lit the severe Pt 4e*1MS Ciirtllitvaseltila aibnormialitieos such as faint systolic murmurs.

tic-tile sounds.1 gallop rhyt hin, tachycardia. hypotension, andl pulsus alterinans were occals11ionlVy obhservetl. Alt-asumrelienits. of venouIls presstire and electrocardiographic study did

not speatk for inyocandial insufficienicy or clinically fIeinlons-trahile nlyocardlltls. Hlearts

examiniol~4 microscopicailly In patients dying in the sixth wveek of complications not referMblo to circulatory appal~raltus showed no infiltration or tihrosis.

('vnoii I ' anrd increasedl respi ratory rate accomlipanii le the (level opmen t of abnormal

physical signs lit thle lung-., which did not include those of consolidation unless there was

secomidary infection, atelectasis, or infarction. Pulmonary Infarction was a late comiplicaitioni to be reckoned wvith.

lit the severely Ml, mental symiIJtoiIs uniiforiiily appeared fromt about the 6th to the

10th day :apathy was more common than restless irritability and Insominia. Nerve dleaftiess wats p~resent in 1*1 cases, and) could ble expected to be transient, lasting only at week.

l'areszis of the shoulder girdle umuscles an(1 sensory changes in arus and legs were ohs;erved uluring covlsec.Treniors of thle hands appearing lin the dhifficult second week

were rare b~ut striking, in one instance simulating the tremor oif parkinsonismn. Examilnations of cerebrospinal thild (60) revealed anl increase lIn pressure (about 160 tuiu.) lin

less thani half the individuals tapped: Increase lin lymiphocyte count was Infrequent

(7 calse's).

Mortality continued tol vary mumch (luring the period of Investigaltionl It rose fromt

1 to 2 percent lin the first 200 cases to 2A5 percent lin the next 154) cases, comprising soldiers

exhatusted by weeks (of Jungle comubat, and)( handicappedl by slow evacuation. For the next

27T6 cases, mortality wvits 7.2 percent. This varying mortality gives at fairer picture than

thle overall figure for (01) cases. 9.T percent.

Tf. prior to evacuation, the* soldier was seriously Ill bly the sixth day, or had already

had( 6 days of fever, it was thought wiser, if possible, to treat him "wvhere he lies," rather

than subject hinm to evacuation. Most patients were treated in convalescence in the expectinmvy that they wvouldI be fit to return to dluty wvihin 12 weeks from onset of their Illness.

Lipman. C'asey. Byron, and Evans rep~orted a study of 200 lpatients observedl at the 362(i Station Hospital in Base B1 between F~ebruary 1943 and

February 1944.9 The clinical picture in their cases conformed with Biake's.

T[heir extensive experience permitted observation of complhicationls that shouhld

8 See footnote 5, p. 115.

HI Lip~man. It. L., Casey, A. V., Byron. R. A.. and Evans. R. C. : Serlib Typhus: Resuilts of ai Stndy

of the* Cases of Two Hundred Patients Admitted Too and Trreaited At a Station Hospital Between

Feb. 9, 1943, and Feb. 4. 1944. War Med. 6: 304-315, November 1944.
SHRUB TYPHUS 119

be borne in mind; that is, pleural effusion, 5 percent; periplheral neuritis.

uhnar. 5 percent; thrombophlebitis, 5 percent; and pulmonary and splenic

infarction, each 2.5 percent. The mortality in their 200 cases was 10 percent.

They emphasize the point made by the Australians at Port Moresby. that

coill)at troops who will or must disregard early symptoms of scr-it) typhus

are those with whom it goes hard. The older age group tolerated the onslaught of scrub tyl)hus less well than did those younger. Six of the thirteen

officers in this series died; four of the six were over 35 years of age. In

therapy, these authors recommend the following: (1) A lumbar puncture for

relief of meningismus and cerebral symptoms associated with an elevated

sp)inal fluid pressure, (2) treatment of incipient and established peril)heral

vascular failure with oxygen and intravenous plasma, and (3) penicillin for

secondary bronchopneumonia complicating the rickettsial pneumonitis.

Irons and Armbrust, at the 3d Medical Laboratory in Base B. extended

their observations on the Weil-Felix reaction to a series of 74 cases of scrub

typhus.'0

Of this series, 86 percent developed blood agglutinins for Proteus OX-K.

Controls with other febrile diseases gave negative reactions. In general, however, the incidence, maximum titer, and duration of the reaction were inversely proportional to the severity of the disease. Only 2 of the 7 fatal cases

showed a positive Weil-Felix reaction during their clinical course; the maximum titer was 1: 80. Patients with less than 18 days of fever were more

likely to develop a titer of 1: 160 or over thmn were those with longer febrile

periods. The initial Weil-Felix reaction occurred at approximately the 17th

day of the disease, after the peak in severity of clinical manifestations, or

during obvious clinical improvement.

Accordingly, the authors concluded that the Weil-Felix reaction is of no

value in prognosis. For diagnosis, no absolute level could be given, but a rise

and fall in serial tests proved helpful in some cases. That a negative reaction

does not exclude scrub typhus was indicated by isolation of the causative

inicro-organism in some cases with no OX-K titer.

Epidemiological study.-In addition to delineating the clinical features

of scrub typhus, Blake and his coworkers clarified the epidemiological background of the disease, as follows:

An analysis of the occurrence of cases among American forces In an advanced base

area near Buna on the northeast coast of New Guinea indicated that, although the disease

was contracted in widely scattered localities, some were more dangerous than others. It

also indicated that the exposure to Infection was associated with activities which brought

men into intimate contact with field conditions, such as those which prevail in bivouacs

or in establishing camps. During the period of this study in the I)obodura area. the

environments in which human infections were known to have originated were kunal grass

fields. in which natural conditions were undisturbed at the time of occupation. From the

time distribution of onset of cases of the disease it was clear that maximum risk was

experienced during the first week or two following arrival of a unit in a new area. This

1o Irons. E. N., and Armbrust. C. A.. Jr.: Relation of the Well-Felix Reaction to the Clinica!

Course of Ttutmugamushl Disease. Bull. U.S. Army M. Dept. 5: 85-95, January 1946.
120 INFEC'TIOUS DISEiASES

risk decreased prlogressiLvely so that after the fourth or fifth week the Incidenve i*e4amie

spoiradic or ceasedl entirely. and the site (couhld Ile occiu)ied with Impunity thereafter.

D)ecline Ili the attack rate could not 1e explainei asi (due to the accuiuulathiion of

Inlnlune Individuals. It therefore was pr•ibaibly dliue to deireaseil exposure to bites of

sole Slpeltes of hlrvlal miiltes that serveil ais vet-tors. Diecrease in expoisure wais corrlhited

uwith progressive changes produceil by "eveliopmenit and uise of thie callipsite. Evidfently,

the voldihtins thus created were uinfavorable to eointinuedl activity aind survival of tile

vector s-pecies.

In alttemllintig tp Idhentify this vector species. collect ihons1 of larval inite, were Iule

not onily lit boetilitles -wh'ere eases hlad originatlled a ndl extensive envirolilinmenital changes

taken place, hlut al0-4 In hl(ol it ie'is where the etili'•nineient appeteilre to hte sinmilar hut where

the natural condilitions elimineiia l Uneli-d.tum'lled.

*I , * * *! *l *

* * * th~ i'ra).semitioins made are ('oili.t*•bm llwith tile ihiyothesis that either TrontNieul fltchhe'i ior T'romnbivid'a tralchi. tor- lotht, .ay serve its vettors Ili this area. Furtherniore. b%' 141y lii4Se Ililoculatih ino , R. oric,,ttfli was recovered front two ptools of inites

('T. iethcri) m'oilec-tee frlon twoe, liandijoeiits. Brain tlissue front tlies.e saile alnimnalls,

iljeceted! intoe white nmhke falM toi produhýe ia rI'kettsial Infehtion. In view of this inegltive

result and the fact tlhl genmertlhi-to-t~enntlol transfer of R?. orienatalix occurs in ninitel

the evidence do4es not inc-ilmlilnate the I'tiillliceoot as a reservoir host.

Tiis concept (of bivouacs |ind the establishmiient of campsites as the backgroulind of scriui) tyVphuis was entir'ely in keeping with U.S. Army experience

during 1943. elsewhere than at 1)obodura. On 5 Septeniber 1943. the 503d

Parachute Infantry Regiment jumped in the Markham Valley terrain which

includted muehi open grassy country with kiinai grass prevailing. The regimnent remaineiti ini jungle comnbat for about 12 days. By October. 37 caises of

scruill typhus had appeared.1 ' For tihe niext 5 to 6 months, cases contilued to

occur ais areas were developed around the Nadzab airstrips northwest of Lae

in northeast N'ew Gut|inea.

Outbreaks.-In November 1M43. an elpideimic of scrub typhus broke out oil

Goodenough Island, north of PapUia. chiefly in a hospital area sitUated in

kunii grass. For the first few nights after arrival in the area, personnel lived

under condition•, prevailing in the field. This was a serious outbreak. Seventy-five cases occurred on the island over the slib.eqlent 4 months, most of

them in December. The mortality, 25 percent, was utniquely high alnd cannot

be adequately explained with the knowledge at h]and. The patients were not

in combat and were not exhausted when stricken. With each successive

beachhead taken. cases of scrub typhus develolped. The landing att Cape

(lloucester in the Bismarck Archipelago was made in D)ecember 1943. At the

30th Evacuation Hospital, 104 cases were reported in Februairy with 5 deaths:

in March, there were 151 cases with 8 deaths. The mortality was 8.3 pelreint

for these New Britain cases. more in keeping with the IDobodura series.12 It

is well to note. however, that in the first 3 tuonths of 1944 the 363d Station

Hospital at I)obodura had 60 cases of scrub typhus. of which 9 ended fatally,.

a mortality of 15 percent. in contrast to atn average of 7.1 percent for the

11 See footnotp 3, 1). 112.

12 Quarterly Report. Surgeon. 30th Evacuation IHotpital (Semnimobile). Southwest Pacific Area,

1 Jan.-31 Mar. 1944.
SCRlU B TIY111it'S 121

l)obdllIIra regioll.13 Eight of the deaths occurred in the first 35 cases admitted

after transfer from tile combat areas several hundred miles to the west. The

patient sick with scrub tyl)plls did not tolerate evacuation well.

Following tile lahding at Saidor in northeast New Guinea in January

1944, 61 cases developed in March, 59 of them among troops oil patrols or

bivouacked in a combl)at area. At Aitape, on the northwest coast, the samle

story held true: Landings on 22 April and 33 cases of scrub typhus in May,

52 ii little, and continued incidence in ,July and August. Headquarters. 32d

Infantry l)ivision. proffered the comnnents that the cases deveh)led in fairly

well identified areas. or in troops on patrol. that withdrawal from tile l)eriilieter to cleared areas caused a dwindling of cases. and that uncleared kunai

grass and low sites where kunai grass and underbrush are mingled are dangerous. At Hollaidia in Netherlands New Guinea. there were scattered

cases; 43 of the 140 reported for the Sixth U.S. Army in lJunle originated

there. It is worthy of note that the new staging area for tile 3-2d I)ivision at

1ollanhdia was burned over before troops were allowed to move into it in

September. Ihlring the ensuing month, there were no cases reported from

this area. An engineer aviation battalion that moved into Ilollandia late in

April reported 24 cases with 7 deaths ill May and June, "due to sleeping in

kunai grass, since no tents or cots were available the first month." The small

Wakde Task Force that captured this island with its important airstrip in

May reported a few cases in the third and fourth weeks of .June.14

It is to be noted that task force units were becoming familiar with the

type of terrain to be avoided and the dangers of sleeping on or near the

ground in ulnleared areas likely to harbor infected imites. Meanwhile, active

measures for personnel protection of the soldier were in preparation.

THE THIRD PHASE: PEAK OF INCIDENCE AND CONTROL MEASURES (1944)

The subsequent epidemics at Owi and Biak (in the Schouten Islands)

and at Sansapor (in Netherlands New Guinea) mark a third period in Army

experience with scrub typhus, in which (1) the disease first assulmed proportions serious from a mnilitary point of view, (2) new ecological types of foci

appeared, and (3) procedures. long-planned, were directed at energetic control of tile epidemics.

Outbreaks.-('ases first developed on Owi. a small island off the southern

shore of Biak, about 10 to 14 days after arrival of units of the Army Air

Forces early in June. During July and early August. as much as onefourth to one-third of the effective personnel of two air force squadrons on

Owi were hospitalized for scrub typhus. On nearby Biak. there were 107

13 Kohlis. G. M.. Armbrust. C. A., Irons. E. N., and Philip. C. B.: Studies of Tsntsuganmushi Disease

iSerub Typhus. Mite-Borne Typhus) in New Guinea and Adjacent Islands: Further Observations on

Epidemiolog3y and Etiology. Ani. J. Hyg. 41 : 374-396. May 1945.

14 41 )Quarterly Report, Surgeon. Sixth U.S. Army. Southwest Pacific Area. 1 Apr.-30 June 1944.

(21 Quarterly Report. 32d Infantry Division, plus attached units. Southwest Pacific Area. 1 July-

.':o lept. 1944. (3) Quarterly Report. 1913th Engineer Aviation Battalion. Southwest Pacific Area.

1 Jan.-31 Mar. 1944.
122 IF'~U IEu:

ca1ses inl tile I S6th Infant rv within 41 days, of 1)-day, :12 of them from one

cotlipipan eiigalget i~tro ill thle island1( liills.'-5 Certain units were unable

to funct ion effectively limit ii replacements were sec-ured. ()wi anid Milk tire

corallinle, with bare ridges andi por-ous outcrop~s. very little swamlpy land,

no kinni flats. and few open grassy areas. Even where there is little top)-

soil. as onl ( wi. denlse undi(erb~ruish, ferns, andt manly 1imni1letse rottinig logrs

p~rovidle cover and moisture for miites. With New Guinea experience ats

p~recedlent. scrub typhus wats not expected inl this type of terrainl. The first

cases were relatively mild. eschars were infrequent, and these fevers of unldetermin ted orig~in were not directly recogniized as scru) tvlpIus. They were

thjought onl (wi to h~e (elengue fever until typical cases of selrub1 typ);lus ap-)

pearedl, anld rilled n10-iosui toes were found to he scarce. Thel* risk onl Owi

lay inl thle slowniess inl clearing of camipsites. A contributing factor wits tile

necessity for using aill available bulldozers for the construction of airstriips.

Men leaving clothes on rotting. logs. when swimmmimnng inl the ceann, may also

have contributed. Onl Biak. severe fighting inl uncleared areas, seekinig coverin thick underbrush. and( patrollin~g.,Iall contributed to exposure to the inlfected linites.

Members of the U.S.A. Ty'phius Commnission arrived at Owi soon after

sct-il) typhuls was recognized. and1( encouraged tile speedy clearing of canilpsites and sand(ing of tent floors. together with imp~regnation of clothiini.

Enmulsions of (limetllyl plithialate were miade available and all personnuel were

equipp~ed1 with treated clothing within 2 weeks of arrival of the repellent."'

The fall inl incidence inl thle various iuuits expressed the sunm of the effect of

control measures. Onl Biak. similarly. tile 41st Infantry IDivision wats inl

imp~regnatedl clothing b~y tile second week ili Augis and camp areas were

cleared. The scrub typhus rate fell appreciably inl the latter p~art of All4vllit. 'I'l IhIa)SOr-l)i~lgly interestil SolrV of tile dlevelopmen~tt anld inlstitiution of p)revent ive measures against sc rub typhus are recounted inl another

volumie in the history of the Medical D~epartiient inl World War I I.18

The Owi-Biak outbreak inicluded at least 1,084 cases, which passed

thrlough thle 92d Evacuat ion H ospital. 'File mortality, 0.7 percent, wats low.

and1( mmany~ cases were imilder than had been the e. )erec n1au. 9 N

ill effects wvere noted froml the airt evacuizt ion to Nmdzab or Finschhanfen of

con1vallescent s 5 da vs or niore after (lefervescence.

The Sansapor task force landed at the western extremity of New Guinea

in) Fss.'nttin rechnical 'Mtiedicl Data. U.S. Army, 5terviees of Suppily, Sootiw.st 1'neltie Ar.ez.. for

Segpt-mbh.r 1944.

16 Le'tte~r. Lt. Cot. Cortiells It. Philip. SnC, to Surgeon. U.S. Army Fo.rces tit the Far East. 5 Au.%t.

1944. sti)J4*(t :scrub Tiyj'hiis on Owl and Biak Islands.

IT Monthly Manata ry Repmort. 41st Infaint ry Division. (Iffic,. of Surgeon. 'Sout hwest I'nefite Are'a.

October 11944.

Is Philip. Cornelius It. :Scrub Tyimliti and Scrub Itch. fit 'Medlial Depajurtmecnt. Unitedl Sta tes

A rmy. P'reventiv Med** .'icine it, l Worldl WaJr 11. Voi u 114 VII. (7oni mu Iicla,4 toI is'ame so: Art hrop.. luorne'

D isea ses O ther Than ' Malarina. [lit prep ara~ tion.]

111na rt.'rly Report. Surgeon. !)'2.1 Evaunflo i~n Ilomulital 4 Senilniobilo), * Sothwest Ineitle Arell.

I .July-341 %4-plt. 1944.
SCRUB TYPHUS 123

on 30 July 1944.20 On 6 August, the first case of scrub typhus developed,

an unusually short incubation period. The outbreak was explosive (136

cases by D+13) and a cause of serious depletion in strength. In one battalion, 17 percent (125 cases) were stricken. Impregnated clothing appeared

to be definitely protective, when used. In all. about 931 cases (data are incomplete) were reported in the course of 53 (lays at Sansapor, with a mortality of 3.4 percent. Attempt was made to avoid a long 1,200-mile air

evacuation until patients were afebrile. This led to much congestion at the

one functioning evacuation hospital but was doubtless the better part of

wisdom in view of the earlier experience in the Cape Gloucester and Aitape

operations. At Sansapor, it was noted that areas of infection were found

particularly in abandoned plantations or native gardens filled with a rank

growth of grass. These areas, as at Owi-Biak, represented a different type

of focus from those seen theretofore, and apparently in this instance a highly

infected type, to judge from the high incidence of eschars and the recovery

of R. tqtits ug(imu•8i from white mice injected with material from each of

three lots of rat mites.

Convalescence and disposition.-The base hospitals to which (he New

Guinea cases were evacuated continued, over the course of the 20 months

from January 1943 to August 1944, to determine the disposition of convalescent cases. Many ambulatory convalescents complained on admission of

rapid heart rate and shortwindedness on slight exertion. Some litter cases

were slow to mobilize themselves. At the 105th General Hospital in Australia, Levine carried out observations on 130 convalescents and found no

evidence, by physical examination, electrocardiogram, roentgen examination,

or by measurements of vital capacity or venous pressure, of persistent myocardial damnag(e. 21

Exercise tolerance tests gave mediocre results, which could be contributed

to, commonly, by a prevalent anxiety state. Patients whose heart rates were

rapid prior to a road march returned from a 5-mile march with normal

heart rates. Such a functional test appeared more reliable than a "Schneider

index" determination. Of this series of 130 patients, 117 were returned to

full duty.

A critical evaluation by Howell of the 233d Station Hospital, at Nadzab,

of electrocardiograms in 190 convalescents from scrub typhus (92 percent

within 1 to 4 weeks after subsidence of fever) and 10 acute cases revealed no

significantly abnormal electrocardiographic patterns.2 2 There were minor

deviations from normal, to be sure, and these were all too often exaggerated

in importance by the unwary observer. But they were no more frequent than

2 (1) See footnote 13. p. 121. (2) Quarterly Report, Surgeon, Headquarters, Sixth U.S. Army,

Southwest Pacific Area, 1 July-30 Sept. 1944.

at Levine, H. D.: Cardiac Complications of Tsutsugamushi Fever (Scrub Typhus) ; An Investigation of Their Persistency. War Med. 7: 76-81, February 1945. 22 Howell, W. L. : Absence of Electrocardiographic Changes in Tsutsugamushi Fever (Scrub

Typhus). Report of 200 Consecutive Cases. Arch. Int. Med. 76: 217-218, October 1945.

639243--63-11
124 INFECTIOUS DISEASES

have been found in a -eries of tracings from approximately 500 healthy

ybung adults.

In the summer of 1944, at the instig-ation of Col. Bruce P. Webster,

MC, then Surgeon, Base E, a reconditioning program for s,. ab typhus convalescents was set up at the 90th Station Hospital. Three hundred and

twelve unselected and successive patients were classified on admission with

regard to their capacity for exercise.- 3 Only 8 percent were considered to be,

properly, bed cases. These patients had been evacuated chiefly from OwiBiak, Sansapor, and Aitape. They had averaged 4 weeks prior hospitalization. In rare cases, there was residual hypesthesia and deafness. Tachycardia, tremors of the hands, and giddiness were frequent. At the completion of a purposeful. graded reconditioning program, 303, or 97 percent, were

returned to full duty, after an average of 1 month in this hospital. These

patients were symptom free on discharge, the majority with weight regained.

Nine patients were evacuated to the rear because of associated disabilities,

niot referable directly to scrub typhus.

This policy of returning the scrub typhus convalescent to duty was thus

supported as experience with the disease increased in 1944. Few such soldiers

were subsequently evacuated for inability "to stand the gaff" of field duty.

Technical Memorandum No. 10, Headquarters, United States Army Forces in

the Far East, dated 29 August 1944, declared it official policy (1) that in

patients who have safely reached convalescence from scrub typhus, complete

recovery is to be. expected. (2) that permanent physical defects resulting

from thie disease are exceptional, (3) that physical reconditioning, with unequivocal reassurance that there is no residual heart damage, will expedite

recovery of stamina, and (4) that patients who require a month or more of

full] physical reconditioning should be transferred for that purpose to the

newly established training center at Oro Bay.

The concept. of the part that the myocardial lesion plays in scrub typhus

had thus changed materially from that which prevailed early in 1943 when

the first cases were observed, precariously ill, and at post mortem. Berry.

Johnson, and Warshauer.2 4 reporting experience with 85 cases and 110 convaleseents in two New Guinea station hospitals between 20 December 1943

and 20 June 1944, drew the following conclusions:

1. Clinically, there is no severe irreversible myocardial damage.

2. Peripheral vascular collapse in the severely ill patient poses the therapeutic problem, not myocardial failure; the clinical picture is analogous to

that of shock and should be treated accordingly.

3. Circulatory symptoms in convalescence are no more pronounced than

after any severe infection.

23 Romeo, B. J.: Convalescence From Scrub Typhus. Bull. U.S. Army M. Dept. 6: 167-173,

August 1946.

24 Berry, M. G.. Johnson, A. S., Jr., and Warshauer, S. E.: Tsutsugamushi Fever; Clinical Observation in One Hundred and Ninety-five Cases. War Med. 7: 71-75, February 1945.
SCRUB TYPHUS 125

4. The patient should not be given the impression that he has any heart

disease.

The soundness 9f this policy was borne out by the report 25 from one

general hospital in the Zone of Interior that examination of such patients as

were returned from overseas with the diagnosis of myocarditis following scrub

typhus fever definitely indicated their disability to be that of neurocirculatory

asthenia.

Settle, Pinkerton, and Corbett 26 reviewed the pathological changes from

55 fatal cases of scrub typhus occurring in American troops in Papua, Netherlands New Guinea, and adjacent islands. They reassert that generalized acute

vasculitis was a constant finding. But they note that although myocarditis

was present in all cases, it was severe in only about half the patients, more

commonly in those dying relatively early, between the 9th and 12th days of

illness. They suggest that in these severe cases myocardial failure may contribute to fatality; yet they elect to emphasize the generalized vascular lesions

and the concept that patients with rickettsial vasculitis may die of peripheral

circulatory collapse. They draw attention to a similar conclusion of Woodward and Bland 27 from their cases of epidemic louseborne typhus in the

Mediterranean Theater of Operations, U.S. Army.

IN THE PHILIPPINES (1945)

In the Philippine Islands, scrub typhus appeared sporadically during

U.S. Army operations 2 8 but never to the degree of military importance it had

assumed at Owi and Biak, and might have done at Sansapor had enemy resistance been more taxing. Scrub typhus had not been identified in the Philippines prior to World War II. Toward the close of the Leyte campaign, late

in 1944, 3 cases were reported from the northern end of the island. Fifty-one

cases were reported from Samar, where units of the Army did extensive patrol

duty after the invasion of nearby Leyte. On Mindoro, experience with scrub

typhus followed the typical course: Invasion in December 1944, the first case

admitted to hospital 12 days after the initial landing, and the bulk of the 100

cases reported in January and early February. Sporadic cases continued for

the next 3 months.

On Luzon, rare cases were identified from the mountainous country east

of Manila during the fighting in February 1945. Diagnosis was based on the

finding of classical eschars and a positive Weil-Felix reaction with the OX-K

strain of Proteus. A cluster of three cases appeared early in May in one in25 Benjamin, J. E., Porter, R. R., and Dreisbach, R. H. : Sudden Death in Patient Supposed To

Have Myocarditis Following Scrub Typhus. Bull. U.S. Army M. Dept. 4: 235-238, August 1945.

26 Settle, E. B., Pinkerton, H., and Corbett, A. J.: A Pathologic Study of Tsutsugamushi Disease

(Scrub Typhus) With Notes on Clinlcopathologic Correlation. J. Lab. & Clin. Med. 30: 639-661,

August 1945.

27 Woodward, T. E., and Bland, E. F.: Clinical Observations In Typhus Fever, With Special

Reference to the Cardiovascular System. J.A.M.A. 126: 287-293, 30 Sept. 1944.

28 Essential Technical Medical Data, U.S. Army Forces, Pacific (for Western Pacific Area), May

and June 1945.
126 INFECTIOUS DISEASES

fantry reginment engaged in battle in the nmountains west of Baguio. A rising

titer of OX-K agglutination was pre,,elt ill all thiree ca,.s. All had a typical

rash and clinical course, and one had an eschar. Beginning on 9 May 1945,

cases of scrub tvyhus were recognized in a reginent engaged in a beachhead

landing in the Blicol Peninsula in the southern end of Luzon. Six cases

developed in the course of a week and four more in the following fortnight.

Eschars were. present in only 2 of the 10 cases. but clinical course. rash. and

rising (X-K titers were diagnostic. During the combat of Negros in late

April andl May 1945, six cases appeared in two infantry units. all with eschars.

These reported data on approxinmately 180 cases are inevitably incomplete,

for they do not include patients evacuated from Luzon for other medical

reasons who developed scrub typhus en route to or after arrival at New

Guinea base hospitals. Statistical reports on Southwest Pacific Area scrub

typhus for 1945 include 258 cases tip to 1 June (table 12) with a mortality

of 5.8 percent. There was nothing unusual in the clinical picture of the cases

in the Philippine Islands. Plasma and blood transfusions were used more

frequently than in New Guinea days, to forestall or alleviate peril)heral

circulatory collapse. The number of cases so treated, however, did not pe!rnit

any c(,m)arative study. In the focal areas of infect ion studied, as on Mindoro

and Negros, cogon grass was prevalent. This was probably not so near

Baguio. Bearing in mind the Owi-Biak experience, the U.S.A. Typhus Commission warned that any environment harboring rats infested with Trombiculae that will accept man as a casual host can be a potential source of human

infection.

Tie Philippine experience with ..crub typhus made it clear that when man

exposes himself to field conditions wherein he may become an accidenial host,

scrub typhus will appear sporadically, and unpredictably, in hitherto unreported districts.

South Pacific Area

Before the war. scrub typhus had not been recognized in the Solomon

Islands. The first case was identified on Bougainville in December 1943.

Nine more cases developed in January 1944. All had been exposed in a

bivouac area on the bank of the Laruma River. Sporadic cases, 11 in number,

each after exposure in the same area, developed in the course of the next 6

months. In all but two of these cases, agglutinins for Proteus OX-K developed in a titer of 1: 160 or higher.

An interesting outbreak of mild scrub typhus developed on Bougainville

in a Fijian force of 750 who were bivouacked in a meadow of coarse grass

between riverbank and jungle at the former site of a native village.29 From

14 to 22 days later, 49 patients were in hospital with a fever that averaged

11 days' duration. An eschar typical of scrub typhus was found in all cases,

and was above the legs in 32 (65 percent) of them. Generalized lymph node

29 Anderson, W. L., and Wing, W. M.: Tsutsugamushi Disease (Scrub Typhus) ; A Clinical Study

of 49 Cases. War Med. 8: 163-166, September 1945.
SCRUB TYPHUS 127

enlargement was constant; the eruption was present in 45 percent (22 patients). Bradycardia was the rule. Tachypnea was not observed. In these

Fijians, in whom malaria could be excluded, the splenic enlargement was

made out in the course of the second week in approximately 40 percent.

Proteus? OX-K agglutinins were present in 24 cases, or about 50 percent;

only 5 had titers of 1: 1.200 or over; 19 ranged from 1: 50 to 1: 200. Two

weeks later, another patrol of the same strength wearing clothing impregnated

with dimethyl phthalate bivouacked in the same area with no resultant cases

of scrub typhus. Two months later, an unprotected patrol went into the

same area. After they came out, 23 cases of scrub typhus appeared. The

available evidence suggests that this was a localized focus of mild scrub

typhus.

India-Burma Theater

Before the outbreak of hostilities in 1941, there had been considerable

interest in Indian Army Medical Services in cases diagnosed as "fevers of

the typhus group." It had become clear that there were two types in the

Simla hill country: (1) The nmurine or flea typhus case, developing agglutinins

for Proteus OX-19, occurred under urban conditions, such as the bazaar

sections of the cantonmen~ts, and (2) scrub or mite typhus, with agglutinins

for Proteus OX-Kingsbury strain, occurred sporadically or in explosive focal

outbreaks in units living under field conditions, particularly in scrub jungle.

Attempts to establish the presence of rickettsial infection in a larval mite had

not been made, nor had it been possible to isolate a strain of OX-K typhus

in a, wild rat. The rodent reservoirs of mite typhus in India were not established. The disease had been known to exist in Burma since 1932.

The late months of 1943 marked a period of orientation in this disease

for U.S. Army medical officers. During November, a group of 22 febrile

patients were admitted to the 20th General Hospital at Ledo, Assam.30 The

fever was intense, associated with generalized lymphadenopathy, mild conjunctivitis, and on occasion a nonpetechial rash, appearing on the fifth to

eighth day. Small ulcers or crusted papules were found and thought to mark

the bite of the infecting insect. The fever lasted 8 to 20 days. The first WeilFelix reactions were negative, save for a few agglutinations of OX-K in low

titer. However, these patients, mostly Chinese troops in active training for

jungle warfare, were considered likely cases of scrub (mite) typhus. In

Shingbwiyang, Burma, on the Stilwell Road, 50 cases, entirely similar, had

appeareu in November. By 1 February 1944, 352 cases had been reported,

35 of them Americans, the remainder Chinese, all from units living under field

conditions along the Stilwell Road. Two centers of infection where troops

had been in training were incriminated, one of them the center of the jungle

training area of the '2d Chinese Division, the other a campsite much fre30 Letter, Maj. D. S. Pepper, MC, Assistant Chief, Medical Service, 20th General Hospital, to

Surgeon, Base Section 3, China-Burma-India Theater, 9 Dec. 1943, subject: Report on Investigation

of "C.B.I. Fever."
128 INFECTIOUS DISEASES

quented by Chinese troops. All American soldiers with scrub typhus had

been living in the jungle. By December, the clinical picture had taker. on a

definite and characteristic pattern, in every way conforming to the picture

of scrub typhus already familiar in the Southwest Pacific Area and to the

descriptions of tsutsugamushi fever in Japan. Eschar, rash, fever curve,

circulatory symptoms and signs, pneumonitis. and encephalitic manifestations were observed. Agglutinations in high titer for Proteus OX-K were

found.

It was noted that the foeal areas from which most of these Chinese cases

came were not occupied by an appreciable number of troops until October

1943. During each of the last 2 weeks of November, there were 40 cases, and

this rate rose to 60 per week through December. Incidence dropped off

sharply in early January, following rather closely the movement of troops

out of the area.

Earlier, in the autumn of 1943, a British unit in the India-Burma theater

had 121 cases in an outbreak that began 9 days after moving into an area for

training exercises. 3' The epidemic subsided directly after the area was left,

with cases continuing in the unit for about 2 weeks. The description of their

cases was in all respects similar to the Chinese and American groups.

Captured Japanese reports revealed that the enemy in Burma was encountering the same disease, which they called eruptive fever. They recognized similarity to tsutsugamushi fever but did not find the eschar frequently

enough to warrant making this diagnosis in Burma. Their mortality rate

is not given save in the comment--"very low." This incidence among the

Japanese is all the more interesting in the light of our repeatedly negative

reports about scrub typhus in enemy troops in New Guinea.

The subsequent story of scrub typhus among American troops in Burma

is described in a comprehensive report by Sayen, Pond, Forrester, and Wood

front the 20th General Hospital.," Up to July 1945, there were 726 cases

reported from the India-Burma theater in U.S. Army personnel with 52

deaths. a mortality of 7.2 percent. Among U.S. Army troops, 535 cases were

carefully studied at the 20th General Hospital; 472 of these Americans were

acutely ill on admission. There were 27 deaths, giving a mortality of 5.7

percent.

Saven and his coworkers point out that a more intelligent understanding

of the severity of scrub typhus is gained from grouping their cases according

to the circumstances surrounding the successive outbreaks. Among 113

Amnerican soldiers from Services of Supply units installed along the Ledo

Road who developed the disease sporadically, the mortality was approximately

4 percent. Among 105 patients who were evacuated by air from active jungle

combat in the mountains north of Myitkyina, Burma, from March to May

1914, the mortality was 16 percent. This group, exhausted by the stress of

31 Blumgart, Herman L., and Pike, George Al. : History of Internal Medicine in India-Burma

Theater. Chapter on Scrub Typhus. inclosure 5 thereto. [Official record.]

32 Sayen, J. J.. Pond, H. S., Forrester, J. S., and Wood, F. C.: Scrub Typhus in Assam and

Burma ; A Clinical Study of 616 Cases. Medicine 25 : 155-214, May 1946.
SCRUB TYPIIUS 129

fighting, and stricken with scrub typhus, was in an area from which evacuation was difficult. The mortality of only approximately 1.5 percent among

177 cases evacuated in the autumn of 1944 from troops undergoing jungle

training north of Myitkyina must be related to speedy hospitalization in the

forward area, and early evacuation to a general hospital. This group was

in far better physical condition than the combat troops of the second group.

In a fourth group of 77 cases, evacuated from combat south of Bhamo, Burma,

in January and February 1945, the fatality rate rose again to 7 percent.

Evacuation for this group was as difficult as for the Myitkyina combat group,

marching after onset of fever again being unavoidable. The patient's

pretyphus state of health and quality of early care were vital in prognosis.

The typical march of symptoms developed in all of these cases. Effort on

the part of Sayen and his coworkers to classify the cases according to severity

warrants quotation, as follows:

In the average case of scrub typhus, during the first week there were no signs by

which the probable outcome could be determined. Occasionally a high fever at this time

indicated a severe course. During the second and third weeks, however, certain phenomena appeared which justified placing the patient in "severe" or "grave" groups with

respective mortalities of approximately 25 and 50 percent. However, until the disease was

definitely on the decline one could not be sure that these features would not appear.

Consequently, the diagnosis of "mild" or "moderate" scrub typhus, which carried practically no mortality, was not justified until defervescence was established. * * *

A case of scrub typhus was assigned to the "severe" group on the basis of any one

of the following:

(1) An alarming increase of the general evidences of illness in the second week.

(2) More than the usual amount of fever: Over a week of peaks to 1040, or 105°

for more than 2 days.

(3) Frank clinical signs of dysfunction of an important organ:

(a) Signs of "typhus pneumonitis": Respirations 36 per minute for 2 days, cyanosis of the skin.

(b) Signs of meningoencephalitis: Severe delirium; meningismus.

(c) Signs of nephritis: Azotemia over 50 mgm. percent, isosthenuria, heavy albuminuria and cylindruria.

(d) Marked enlargement of the heart or sharp T-wave inversion in the electrocardiogram.

(e) Pitting edema with or without ascites.

(f) Multiple hemorrhagic phenomena.

The appearance of any of these phenomena indicated that statistically the patient's

chances of survival had been reduced from 19 in 20 to about 3 in 4.

A severe case of scrub typhus was considered in the "grave" group on the basis of

one of the following findings:

(1) A steady increase of illness during the third week.

(2) Very high fever: 1050 for 5 days or 1060 for 2 days.

(3) Signs of severe dysfunction of more than one vital organ, or evidence of severe

Inflammation of the central nervous system and the lungs. Of these, the most common

were the following:

(a) Extensive pneumonitis: Persistent cyanosis out of oxygen [tent] ; respiratory

rate 50 per minute for 2 days, or over 36 per minute for a week.

(b) Encephalitis: Malignant restlessness, Cheyne-Stokes respiration, a convulsion,

coma.
130 INFECTIOUS DISEASES

(c) Severe nephritis: Anuria.

(d) Tachycardia exceeding 130 per minute.

The appearance of these phenomena indicated that, statistically, the patients' chances for

survival were 25 to 50 percent. We have never seen a patient recover whose cyanosis

was unrelieved by oxygen or who had persistent hyperpnoea, pulmonary edema, or coma

lasting 24 hours.

In their discussion of the classical signs, laboratory findings, and treatment of scrub typhus, Sayen and his coworkers bring out the following interesting points that tally with or supplement findings recorded in the Southwest

Pacific Area.

1. The finding of an ulcer or papule that later became a typical mite

ulcer 1 to 14 days prior to onset of symptoms was not uncommon. The

presence (60 percent of 200 cases) or character of the eschar or ulcer had no

relation to the severity of the disease, or to the OX-K titer. In only 27 percent was the primary lesion on the thighs or below.

2. Increasing generalized enlargement with, usually, tenderness of the

lymph nodes was an early development in all but 6 of the 200 patients, and

was, in fact, the most constant of the main diagnostic clinical signs.

3. The eruption (71 percent of cases) involved the trunk always, the face

in 15 percent. Generally of 4 to 9 days' duration, it might outlast the fever.

A few rashes were florid or purpuric. There was no relation of the rash to

the severity of the disease.

4. Ophthalmoscopic examination revealed engorgement of retinal veins

in 67 p)ercent of cases in the first and second weeks, progressing to bilateral

edema of the retina and optic nerve head in 36 percent, with retinal hemorrhage and exudate in a few instances. Retinopathy of this sort was absent in

other febrile disease, and was actually helpful in the early diagnosis of

atypical cases, latar confirmed by the OX-K agglutination reaction.33

5. Bronchial rales, changing in location, appeared in "mild" and "moderate" cases, did not of themselves indicate a rickettsial pneumonitis.

6. Brief periods of gallop rhythm were not evidence of a prognostically

important degree of interstitial myocarditis.

7. Agglutination titers for Protemi8 OX-K of 1: 100 were not seen except

in scrub typhus. About half of a series of 200 cases failed to have this

"diagnostic" titer. It was helpful diagnostically in isolated atypical cases.

In epidemics, a "clinical" diagnosis was generally made before agglutination

became positive (about the 14th day, on an average).

8. Cerebral malaria was the disease of chief importance to exclude in

differential diagnosis of the case without conclusi,,e signs of scrub typhus.

9. Roentgen examination of the chest in scrub typhus cases often failed

to indicate the extent and severity of the rickettsial pneumonitis. Intermittent

dyspnea at rest, then persistent tachypnea, and cyanosis relieved initially by

oxygen comprised a march of signs more valuable than physical findings in

33 For a further discussion of the ocular manifestations of scrub typhus (new and original work)

see Medical Department, United States Army. Surgery in World War II. Ophthalmology and Otolaryngology. Washington: U.S. Government Printing Office, 1957, pp. 141-144.--J. B. C., Jr.
SCRUB TYPHUS 131

the chest or roentgen examination in establishing the presence of pneumonitis.

10. Cardiac enlargement, sharp T-wave inversion with or without RS-T

elevation (11 percent of 61 cases suspected of cardiac complication), and

persistent gallop rhythm were not found to be necessarily evidence of ill omen.

Dangerous rickettsial myocarditis could not be diagnosed, prior to final collapse, save by inference of precedent. No patient with T-wave inversion

died; three cases who had tracings before death showed no electrocardiographic abnormality.

11. Spinal fluids in 27 patients with signs of mieningeal irritation were

under increased pressure (average 230 mm. of water). Ten had increase in

cells, generally lymphocytes; three had a polynuclear pleocytosis with negative

cultures. Spinal fluid protein levels were elevated (68 to 156 mg. percent, in

four cases).

12. Convulsions occurred in 12 patients, of whom 3 were not considered

dangerously ill until the convulsive seizure.

13. Spontaneous diuresis late in the febrile course, or at the onset of

convalescence, was observed in 38 percent of 200 cases; the largest diureses

were seen in the sicker patients with edema (10 percent of face, hands, shins,

and feet), and with ascites. It constituted a reassuring prognostic sign.

14. Hypochloremia was little modified by parenteral saline therapy. Return to normal blood chloride levels occurred in convalescence, regardless of

therapy.

15. In convalescence, thrombophlebitis and pulmonary embolism were

occasional complications. Pleurisy developed in 10 percent of 200 cases;

effusions, if present, were small, sterile; fever lasted only 4 days, and evidence

of p)leurisy was generally gone in a week.

16. In treatment.-(1) The mildest appearing case in the first week

should be prepared by absolute bed rest for an unpredictably severe ordeal

in the second week. (2) An adequate number of experienced nurses is of

vital importance to see that small frequent feedings are taken, fluids pushed

(minimum of 3 liters daily), and severely ill patients protected. (3) Salt

administration can be overdone; it may aggravate edema. (4) Oxygen should

be given by mask preferably; when given by nasal catheter, it did not, in the

average case, relieve cyanosis. (5) Rectal paraldehyde, 30 cc. in oil, was the

best sedative for "malignant restlessness," and might make it possible for the

cyanotic patient to tolerate oxygen by mask, and prevent exhausting exertion.

(6) Digitalis was not used. (7) Penicillin was of no avail save in the presence of a complicating bronchopneumonia. (8) The concept of peripheral

circulatory collapse was not raised; intravenous plasma was not used with

this in mind. (9) Intravenous fluids were given when indicated, carefully,

and without untoward incident.

As experience with scrub typhus increased, confidence grew in the convalescent's ability to cope with the demands of duty. Patients with mild and
132 INFECTIOUS DISEASES

moderate cases (less than: 3 weeks of fever) were informed soon after defervescence that they were returning to their units and were gradually reconditioned for discharge about 3 to 4 months from the onset of illness. Patients

who had been gravely ill were evacuated to the Zone of Interior. The severe

cases were appraised individually. Of the last 300 cases, 82 percent were

returned to full duty. No evidence of residual myocardial damage was detected during reconditioning.

PATHOLOGY

Although a number of reports 34 dealt with the pathology of scrub typhus,

the most comprehensive study was performed at the Army Institute of

Pathology (now the Armed Forces Institute of Pathology), Washington, D.C.,

by Maj. Arthur C. Allen, MC, and Dr. Sophie Spitz.3 5 These workers undertook to study the lesions not only of scrub typhus, but also of louseborne

typhus, Rocky Mountain spotted fever, and Q fever in order to dletermine

whether the various rickettsial diseases could be differentiated histologically.

After careful study of the histological preparations and protocols of 78 cases

of scrub typhus. 24 cases of epidemic typhus, 12 cases of Rocky Mountain

spotted fever, and lung sections from 2 cases of Q fever, the authors made

the following observations:

1. The primary lesion, or eschar, is considered to be provoked by the combined action

of the secretion of the larval mite anti the inoculated rickettsiae. it is suggested that

the absence of the eschar in certain instances of scrub typhus may be due to variations

in cntaneous imlnmunity.

2. Interstitial pneuenonitis of a marked degree is common in scrub typhus in contrast

with epidemic typhus and Rocky Mountain spotted fever. The histologic picture of the

interstitial pneuumonitis of scrub typhus is indistinguishable from that of Q fever, rheumatic fever, toxoplasmosis, and viral pneumonia.

3. It is concluded that the amount of hepatic damage as noted histologically d(os not

warrant the presumption that hypoproteinemia Is due to hepatic insufficiency.

4. Early, acute, diffuse gIomnerulonephrltis Is common in scrub typhus, epidemic

typhus, and Rocky Mountain spotted fever. The indirect rolc of the rickettsiae in the

pathogenesis of the gloinerulonephritis is indicated.

5. The focal encephalitis or nodule of scrub typhus is qualitatively similar to that

of epidemic typhus and is in contrast to the "microinfarct" of Rocky Mountain spotted

fever. The nodules of scrub typhus and epidemic typhus are practically limited to the

gray matter, whereas the encephalitis of spotted fever involves the white matter preponderantly.

6. Contrary to the generally held Impression, there is a sparsity of histologically evident vascular damage in scrub typhus. Arteritis is exceedingly slight in scrub typhus In

contrast with epidemic typhus and Rocky Mountain spotted fever. Accordingly, it is

suggested that the designation "diffuse vasculitis" when applied to scrub typhus represents

an oversinplification not justified by the morphologic evidence.

7. It is concluded that the peripheral circulatory failure in patients with rickettsial

diseases Is a complex phenomenon which cannot be explained solely on the basis of

34 See footnotes 5, p. 115: and 26, p. 125.

35 Allen, A. C., and Spitz, S. : A Comparative Study of the Pathology of Scrub Typhus (Tsutsugamu.sh) )isease) and Other Rickettsial Diseases. Am. J. Path. 21 : 603 681, July 1945.
SCRUB TYPHUS 133

morphologic damage of vessels. The contributory role of the adrenal gland in the circulatory failure is suggested.

8. The evidence of lymphoblastic origin for the cells characterizing the interstitial

Infiltrate Is presented. The identification of the large "basophilic macrophage" with the

"acute splenic tumor cell" is su ;gested and the evidence pointing toward the association

of these cells with an allergic response is given.

Finally, Allen and Spitz proposed a much broader pathological concept

of the rickettsioses than that generally held at the time of their studies, as

follows:

From the pathologic point of view, the rickettsloses have long been regarded as a

form of diffuse vascular disease. Surely, this impression is almost inescapable after a

study of epidemic typhus and spotted fever. However, the histology of scrub typhus

may perhaps warrant a change in the direction of emphasis. Although focal, more or

less bland thrombophlebitis in scrub typhus is not uncommon, actual arteritis occurs

rarely, and, in our series, was never of the fibrinoid variety seen in louse-borne or tickborne typhus. Moreover, the arteritis of scrub typhus does not seem to be a lesion sui

generi8, but, rather, appears to be secondary to an extension of the periarterial infiltrate

into the wall. This interpretation was made previously by Kouwenaar. Yet, notwithstanding the disparity in the histologic evidences of vascular damage, there are basic

clinical, etiologic, and, in many respects, immunologic similaritiec, between scrub typhus

and the other rickettsioses. Therefore, perhaps, a re-evaluation of the significance of the

pathologic changes is in order. A close analogy to this problem is found In a nonrlckettsial disease-acute disseminated lupus erythematosus (Libman-Sacks disease). The prominence of the degeneration of vessels in many organs led initially to the concept that this

entity was a diffuse vascular disease. However, further studies prompted a broader

concept; namely, that disseminated lupus erythematosus was in effect a disturbance of

collagen, be it of a vessel, a cardiac valve, or a serous membrane. Moreover, the histologic and clinical pictures were such as to suggest a hyperergic reaction. The analogy

may be extended by reference to periarteritis nodosa and to the arteritis that follows

administration of sulfonamides. In other words, in the over-all view of the pathologist,

the more remote, possibly hyperergic effects of the rickettsiae-the effects of the adrenal

gland, on the glomeruli, and on the production of interstitial inflammation-assume more

importance than the direct damage wrought by the localization of the rickettsiae.

LABORATORY AIDS IN DIAGNOSIS

The Weil-Felix reaction.-In 1929, Fletcher, Lesslar, and Lewthwaite,"

while studying two forms of tropical typhus, discovered a serological difference which proved to be of considerable diagnostic value. They found that

sera obtained from cases of rural typhus agglutinated in high dilution suspensions of the Kingsbury (K) strain of Proteus, in contrast to sera in urban

typhus cases, which agglutinated the Protens OX-19 micro-organisms. Subsequent studies showed the rural form to be the initeborne scrub typhus and

the urban form to be murine (fleaborne) typhus.

During World War II, the WYeil-Felix reaction was extensively employed

in the laboratories of U.S. Army medical installations. Observations at the

Virus and Rickettsial Diseases Laboratory, Army Medical Center, Washing-

.36 Fletcher. W.. Lesslar, J. E.. and Lewthwalte, R.: The Aetiology of the Tsutsugamushi Disease

and Tropical Typhus In the Federated Malay States. Tr. Roy. Soc. Trop. Med. & Hyg. 23: 57-70,

June 1929.
134 INFECTIOUS DISEASES

toll, D.C., clearly ind~icated the Prott'us OX-K agglutination was not elicited

by sera fronm other rickettsial dliseases, and was, therefore, a Valuable diagnostic aid1 for scrub typhus.37

'Meanlwhile. ZarafolletiS. 3S4 working in the Cairo laboratory of the U.S.A.

Typhus C1ommnission. carriedI out a series of studlies in typhns-vaccinated individiials to (determhine what serological effects may resuilt from vaccination

alone. Onilv one instance of OX-K agglutination was found, and there was

no0 Change in titer following booster vaccination, Ile concluded that typ)hus

Vac*cination dlid not cause an increase in OX-K antibodies.

Pro/Cus OX-K agglutination tests were also performed on serial blood

specimens, front 104 acutely febrile patijents who liitd been p~reviouisly vacciflatedl with Cox-type epidemnic typhus vaccine. No anaminestic reactions were

dletectedl in these studlies.

The finial phause of these observations was concerned with the serological

findings in typhus fever patients who developed their illness despite prior

Vaccination with (1ox-type epidemic typhu~s vaccinep. 391 Again, such patients

were found not to develop agglutinlins for suspensions of J'roteis OX-K.

Thtus. ther'e appeared to be no) needl to modlify the Iprevionsly held interp~retation of risingv OX-K titers, that this finding was essentially specific for

scrub) typhus. However, in tests onl sera from 5il cases of louseborne relapsing

fever. Zarafonetis. Ingraham, and l er~ry 40 found that all p~at ients had Proteus

OX-K titers of 1: 40 or more in at. least one serumi specimen. The titers

ranged fromn 1: 40 to 1: :2.560. These workers suggested, therefore, that "since

there is considerable overlapping in thz. geograp)hic distribution of tsutsugamiushi disease and louseborne relapsing fever, it becomies. necessary to interpret

Weil-Felix OX-K results with caiition, particularly when atyp~ical cases of

either (disease are in question."

Complement fixation tests.-At the "~itset and wvell into World War 11,

the 11Veil-Felix Proteus OX-K agglutination test was the only available serological test of value in the (diagnosis of scrub typhus. It was fortunate that

this nonrickettsial antigen appeared to be specific for scrub typ)hus with the

single excep~tion of louseborne relapsing fever that has been noted. In view

of important, p)rogress in the development of specific ricket~tsial antigens for

use in compIlemuent tixat ion and agglutination tests for other rickettsia] (iseases. it was anticipated that similarly successful results would follow with

37 Plotz, HI.. Wertman, K., and Bennett. R. L.: The Serological Pattern In Epidemic Typhus Fever.

It. The Well-Felix Reaction. Division of Virus and Ricicettmiai Diseases, Army Medical School, Army

Medical Center, Washington, D.C.. 1944. [Official record.]

." (1) Zarafonetis. C. J. D.: Serologic Studies In Typhus-Vaccilnated Individuals. 1. The Effect

of a Stimiulating Dose of Typhus Vaccine on the Well-Felix and(l omplement-Fixing Antibodies.

J. Immunol. 51 : 365-374. November 1945. (2) Zarafonetis. C. J1. ID.: Serologic Studies In TyphusVaccinated Individuals. 11. The Effect of Non-Typhus Fevers on the Well-Felix and ComplementFixing Antibodies. J. Immunol. 51 : 375-.19R, December 1945.

30 Zarafonetis. C. J. D., Ecke, R. S.. Yeomans. A.. 'Murray. E. S., and Snyder, J. C.: Serologic

StudiesA in Typhus-Vaccinated Individuals. 11l. Weil-Felix and Complement-Fixation Findings In Epidemic Typhus Fever Occurring In the Vaccinated. J. Immnnol. 53: 15-30. 'May 1946.

40 Zarafonetis, C. J. D., Ingraham. HT. S., and Berry. J. F.: Well-Felix and Typhus ComplementFixation Tests in Relapsing Fever. With Spe-cial Reference to R. proteus OX- K Aggluutination. J. Immunol. 52: 189-199. March 1946.
SCRUB TYPHUS 135

scrub typhus antigens. Bengtson,4 1 at the National Institute of .Aealth, U.S.

Public Health Service, was the first to prepare satisfactory complement fixing

antigens from infected eggs by a technique similar to that used for epidemic

typhus. Additional experience, however, revealed that there were significant

antigenic differences between various strains of It. t8ut8qaiu.V.h. Because

of these differences, diagnostic complement fixation tests on human sera require the use of several antigens prepared from different strains of 11. t8ut8ugynm,8hi. Thus, while the complement fixation test became available for scrub

typhus, its use was limited essentially to research laboratories during World

War II.

Isolation and identification of strains.-Diagnosis of scrub typhus by

isolation of strains is, of course, absolute in contrast to the presumptive nature

of serological tests. Isolation of strains is also desirable for laboratory comparison of immunity relationships between strains, for possible vaccine production, and for the preparation of antigens for serological tests. In addition,

strains may be used in the laboratory evaluation of chemotherapeutic agents

proposed for the treatment of scrub typhus. To these ends, therefore, strain

isolations were carried out by several groups of workers in World War I1

and returned to adequately equipped laboratories for pertinent study.42

Prior to these efforts, attempts to isolate and serially transmit tsutsugamushi disease in laboratory animals gave negative results in the hands of

many investigators. Japanese workers had been successful with rabbits, using

intraocular injections. Mice were later found to be readily susceptible but

were, unfortunately, not available for use in the field laboratories. Guinea

pigs were susceptible to many tsutsugamushi strains, but apparently not to

others. This was the situation in January 1944, when the Imphal, Ceylon,

and Calcutta strains of scrub typhus were received in the Cairo, Egypt, laboratory of the U.S.A. Typhus Commission. These strains had been maintained at the district laboratory in Calcutta and at the Haffkine Institute in

Bombay, India, by British workers and were forwarded to Brig. Gen. Leon

A. Fox, Field Director, U.S.A. Typhus Commission, by Lt. Col. M. H. 11.

Sayers, RAMC. The strains were received in rabbits, infected intraocularly,

and were maintained for several passages in rabbits. The infectivity of these

strains for two desert rodents, namely, Gerbillus pyramiduwrb and Gerbillu.x

gerbillus, was then tested.43 They were found to be highly susceptible to

infection with R. t8utsugamru.hi and were, therefore, a suitable substitute in

the absence of a supply of white mice. Since these rodents were plentiful, it

41 Bengtson, LA.: Complement Fixation in Tsutsugamushi Disease (Scrub Typhus). Pub. Health

Rep. 61: 895v-900, 14 June 1946.

42 (1). See footnote 1, p. 111 ; and 13. p. 121. (2) Philip, C. B., Woodward, T. E., and Sullivan, R.

R. : Tsutsugamusbl Disease (Scrub or Mite-Borne Typhus) in the Philippine Islands During American

Reoccupation in 1944-45. Am. J. Trop. Med. 26: 229-242, March 1946. (3) Letter, Lt. Col. M. H. P.

Sayers, R.A.M.C., Assistant Director of Pathology, 14th Army, Calcutta, India, to Brig. Gen. L. A. Fox,

U.S.A. Typhus Commission, Cairo, Egypt, 4 Jan. 1944.

4.1 Zarafonetis, C. J. D. : The Susceptibility of the Rodents, Gerbillux pyramidum and Gerbillus

gerbillus, to Experimental Tsutsugamushl Infection (Scrub Typhus). Proc. Soc. Exper. Biol. & Med.

59: 113-116, June 1945.
136 INFECTIOUS DISEASES

was possible to accelerate e number of studies in scrub typhus at the U.S.A.

Typhus Commission laboratories at Myitkyina as well as in Cairo.

Growth of the etiological agent of scrub typhus in the yolk sac of developing chick embryos was accomplished by a number of workers.4 4 This was an

important method of experimental vaccine and antigen production.

SPECIFIC TREATMENT

The treatment of scrub typhus includes both general and specific measures. The general supportive measures consist of nursing care, diet, maintenance of fluid and electrolyte balance, and the management of complicating

diseases or conditions. These aspects of therapy have been adequately indicated in the reports that have been cited.45 Here, consideration will be limited

to specific measures, such as the use of immune serum, antibiotics, and chemotherapy.

Serotherapy.-Hyperimmune rabbit serum was found to reduce the mortality of experimental scrub typhus in mice.46 Human convalescent serum,

however, was without effect on the clinical course of scrub typhus even when

given during the first week of illness. 47 Since there are wide differences in

the antigenic pattern of various strains of R. t8utsugamushi,48 it may be that

only homologous antiserum would be effective therapeutically.

Antibiotics.-Although penicillin and streptomycin proved to be valuable

for certain complicating bacterial infections, these antibiotics had no significant specific effect on the etiological agent of scrub typhus. Since the war,

the newer broad-spectrum antibiotics have been used with signal success in

rickettsial infections.

Chemotherapy.-In a report to the Division of Medical Sciences, National

Research Council, dated 26 December 1942, Drs. John C. Snyder, J. Maier,

and C. Russell Anderson, first demonstrated an antirickettsial effect of PABA

(para-aminobenzoic acid) in mice experimentally infected with murine (fleaborne) typhus. This led to extensive clinical and laboratory studies and to

experimental trials of PABA in animals infected with R. tsut8ugamu.8hi.

Gerbilles proved to be of great value in this connection. Snyder and Zarafonetis, 49 and Murray with these authors 50 demonstrated conclusively that,

44 (1) See footnote 39, p. 134. (2) Bengtson, I. A. : Apparent Serological Heterogeneity Among

Strains of Tsutsugamushl Disease (Scrub Typhus). Pub. Health Rep. 60: 1483-1488, 14 Dec. 1945.

(3) Lewthwaite, R., and O'Connor J. L.: Prophylactic Vaccine Against the Tsutsugamushl Disease.

Second Report on an Attempt to Prepare a Vaccine From Hens' Eggs Experimentally Infected. Virus

Laboratory, Commonwealth Serum Laboratories, Melbourne, Australia, 1943.

45 See footnotes 1, p. 111 ; 9, p. 118; and 32, p. 128.

46 Topping, N. H. : Tsutsugamushl Disease (Scrub Typhus) ; The Effects of Immune Rabbit Serum

in Experimentally infected Mice. Pub. Health Rep. 60: 1215-1220, 12 Oct. 1945.

47 (1) See footnote 9, p. 118.. (2) Hay, C. P.: Scrub Typhus at Port "X." J. Roy. Nay. M. Serv.

30: 127-135, July 1944.

SSee footnote 44 (2).

49 Snyder, J. C., and Zarafonetis, C. J. D. : Effects of Para-Aminobenzole Acid in Experimental

Tsutsugamusht Disease (Scrub Typhus). Proc. Soc. Exper. Blol. & Med. 60: 115-117, October 1945.

6 Murray, E. S., Zarafonetis, C. J. D., and Snyder, J. C.: Further Report on Effect of ParaAminobenzoic Acid in Experimental Tsutsugamushl Disease (Scrub Typhus). Proc. Soc. Exper. Biol.

& Med. 60: 80-84, October 1945.
SCRUB TYPHUS 137

properly administered, PABA significantly reduced the mortality of experimental scrub typhus in gerbilles. PABA was effective against strains of

R. tsutsugamuhi that had come from widely separated regions including

India, Ceylon, and New Guinea. On the basis of their observations, these

workers strongly recommended a clinical trial of PABA therapy in human

beings.

Such an opportunity presented itself to Tierney, 51 of the Cairo Unit of

the U.S.A. Typhus Commission, in 1945. Working at the 20th General Hospital, in Ledo, Tierney carried out a controlled study on 18 patients with

scrub typhus. He administered sufficiently large doses to obtain adequate

blood concentrations of PABA and found that the treated patients had fewer

complications and shorter fever than a comparable group of untreated subjects.

Although there are now improved means of administering large doses of

PABA, 52 and PABA has itself been supplanted by the newer antibiotics as

the treatment of choice in scrub typhus, these early studies were of great

significance to those concerned with the scrub typhus problem. Lack of an

effective vaccine, the insidious vector, the widespread distribution, and a

significant mortality rate, all made scrub typhus an important medical problem affecting morale in ',he field. Furthermore, several prominent investigators succumbed to infections acquired during the course of laboratory investigations with R. tsutsugamushi. The search for an effective therapeutic

agent for scrub typhus during World War II was stimulated by an awareness

of these factors.

Immunization.-Information regarding the degree and duration of immunity following an attack of scrub typhus was fragmentary, even at the

close of World War II. From the available data, it appeared that a strong

and lasting immunity was induced by the disease, and considerable support

was added to this belief by animal studies in several laboratories. 53 Indeed,

these observations indicated that animals experimentally infected with one

strain of fl. t8utsugamnu.8hi are resistant for some months, at least, to inoculation with both homologous and heterologous strains. Studies in progress at

the end of hostilities, however, revealed that a number of strains of R. t8utsugamushi had important antigenic differences as judged from cross-neutralization tests 54 and toxic neutralization tests,55 as well as from study of the com51 Tierney, N. A.: Effect of Para-Aminobenzoic Acid in Tsutsugamushi Disease. J.A.M.A. 131:

280-285. 25 May 1946.

52 Zarafonetis, C. J. D.: Clinical Use of Para-Aminobenzoic Acid. Texas 3. Med. 49: 666-672,

September 1953.

53 (1) See footnotes 1. p. 111; and 13, p. 121. (2) Bell, E. J., and Plotz, H.: Infection and Immunity Following the Intracutaneous Inoculation of Scrub Typhus. Proc. Soc. Exper. Biol. & Med. 59:

143-144, June 1945. (3) Zarafonetis, C. J. D., Snyder, J. C., and Murray, E. S.: Immunity Following

Para-Aminobenzoic Acid Therapy in Experimental Tsutsugamushi Disease (Scrub Typhus). Proc. Soc.

Exper. Blol. & Med. 61: 240-242, March 1946.

54 Bell, E. J., Bennett, B. L., and Whitman, L. : Antigenic Differences Between Strains of Scrub

Typhus as Demonstrated by Cross-Neutralization Tests. Proc. Soc. Exper. Biol. & Med. 62: 134-137,

June 1946.

55 Smadel, J. B., Jackson, E. B., Bennett, B. L., and Rights, F. L.: A Toxic Substance Associated

With the Gilliam Strain of R. orientalis. Proc. Soc. Exper. Biol. & Med. 62: 138-140, June 1946.
138 INFECTIOUS I)ISEASES

plement fixation antigen.5G From the observations and from efforts to

produce an effective vaccine, it became evident that much remained to be

learned regarding the immune response to the various scrub typhus strains.

Vaccine studies.-In view of the apparent immunity conferred by all attack of scrub typhus in man and confirmed in the animal work just noted. it

was hoped that a satisfactory vaccine could be developed for scrub typhusl i as

had been done for epidemic typhus. Several laboratories turned their attention to this problem. Fulton 5'1 at the National Institute for Medical Research

in London prel)ared vaccines fronm the lungs of infected mice and cotton rats.

lie found some p)rotectionl was afforded )by intraperitoneal vaccination to intra peritoneal challenge. Similar observations were iiiade by Sinadel. Rights,

and Jackson 58 at the Virus D)ivision of the 1st Medical (General Laboratory,

814th Hosp)ital Center. Paris. France. and by Plotz, Jlennett. and Reagan 59

at the Medical Department Professional Service Schools. Washinggton. D).C.

The subcutaneous administration of these vaccines induced no resistance to

infection.

Vaccine suspensions were also prepared fronm infected yolk s.acs of developing chick embryos.'e However, these l)reparations failed to confer imnmunity in a" wide series of tests. It appears that the ether-extraction method.

which was so valuable in the production of epidemic typhus vaccine, had some

inexplicably deleterious effect when applied to suspensions of R. tsutsugam.ush i.

POSTWAR STUDIES

Immunity.--In the period immediately following the war, important, work

was done on unsettled prob)lems hearing on prophvlaxis and treatment. Iln

studies conducted by Smadel and his associates at the Army Medical D)epartment Research and Graduate School, Washington. I).C.,'" it, was found, briefly

that in human volunteers immunity to the honologous strain of /1. ts1tsugamrushi persisted for at least 1 year, and in some for longer periods. In

contrast, resistance to heterologous strains of 1. tsutittsgamnish was of a

transient nature. Even within a month after inoculation with one strain, an

appreciable number of persons became ill following injection with a heterologous strain. By the end of a year, all were again susceptible to heterologous

56 See footnote 44 (2), p. 136.

57 Fulton, F. : Methods For the Study of Mite Typhus-A Progress Report. National Inst. Med.

Res.. Hampstead, London. 21 June 1944.

58 Smadel, J. E., Rights, F. L., and Jackson, E. B. : Scrub Typhus Vaccines Prepared Froin

Formalinized Suspensions of Tissues of White and Cotton Rats. Riq)ort dated 19 June 1945. headquarters, First Medical General Laboratory, 814th Hospital Center, U.S. Army.

59 Plotz, H., Bennett. B. L., and Reagan. R. L. : Preparation of an Inactivated rissue ('Ciltur.,

Scrub Typhus Vaccine. Proc. Soc. Exper. Biol. & Med. 61: 313-317, March 1946.

ro See footnotes 44 (3), p. 136; and 59.

"•1 (1) Smndel. J. E.. Ley. H. L., Jr., Diercks. F. If.. and Traub, R. : Immunity in Seruh Typhus:

Resistancce to Indutced Reinfection. Arch. Path. 50: 847-861, ecembher 19U541. (' Smairdei. .1. K., L,4y.

II. L.. Jr., Diercks, F. H.. Paterson, P. Y., Wisseruan, C. L., Jr., and Traub. R. : Immunization Against

Scrub Typhus: Duration of Immunity in Volunteers Following Combined i.ving Vaccine and Chemoprophylaxis. Am. J. Trop. Med. 1 : 87-99, January 1952.
SCRUB TYPHUS 139

infection. During the period of waning immunity, the disease which resulted

fronm the heterologous strain was modified from the classical picture. Indeed.

the illness observed in tests shortly after recovery was so mild that it would

l)robably not have been recognized as scrub typhus if rickettseniia had not

been denionstrated. O(n the other hiald. the disease which resulte(l when ihe

individuals were tested after 1 year generally presented the typical picture

of Scrub typhus.

Of further interest is the observation that only about 40 percent of the

subjects who developed illness following reinoculation with scrub typhus after

1 year disl)layed a significant (fourfold) rise in titer of I'rootei OX-K

agglutin ins.

Treatment.-In postwar studies, draumatic results in treatment of scrub

typhus and other rickettsial infections were achieved with broadl-spect ruin

antibiotics, such as (Chloromycetin (clihorailiphenicol), Aureomycin (chlortetracycline), and Terramycin (oxytetracycline).62 A program making use of

these for chemoprophylaxis under special circumnstances would not prevent infection but would prevent clinical illness. Field trials suggest that, if prophylactic medication is continued for 4 weeks or longer after exposure. it is

unlikely that signs of scrub typhus will appear after the drug is discontinued.6

Vaccines are still (1957) in the exp)erimental stage, but, in view of the

immunity factors discussed, it is not anticipated that effective protection will

be afforded in this manner.

SUMMARY

I)uring World War II, scrub typhus was found to be endemic in foci

distributed throughout a large triangular region of Asia and the Pacific which

lies between Japan, India. and Australia. Outbreaks are more common in

types of terrain that provide suitable cover for reservoir hosts as well as

moisture conditions favorable to the growth and activity of the vector mites.

Wild mice and rats and jungle tree squirrels are known to be naturally infected with R?. f.dtsupiianm h;. Larval mites of the genus 1'rombkcuha transmit

the disease from animal to animal or from animal to man. Since infection of

the mites can be transovarially acquired. the vector also serves as an important

natural reservoir of scrub typhus.

62 (1) Snmhdel, J. E.. Woodward. T. E.. Iey. 11. L.. Jr., and Lewthwaite, R.: Chloramlhlnicol

('hhoromyceptin) in the rreatnient of Tsutsugamushi Disease (Scrub Typhus). J. Clin. Investigation

28: 1196-1215, September (pt. 2) 1949. (2) Smadel, J. E., Jackson, E. B.. and Ley, 11. L., 3r.:

"l'Terramycin as a Rickettsiostatic Agt-nt and Its Usefulness in Patients With Scrub 'ryihus. Ann. New

York Acad. Sc. 53 : 375-384. 15 Sept. 1950. (3) l'rfezyna. A. I'.. roi'-Iing. C.. Tsu-lin. W., Dougherty.

W. J., and Bond. 11. B. : Treatment of Scruh Typhus in the Pesceador'•s Islands With Chioramphjenicol.

Aureomycin. and Terramycin. Am. J. Trop. 'Mod. 3: 608-614, July 1954.

wi Smadel. j. E., Traub. R.. Frick. L. 1'.. Diercks. F. II.. and Bailey, C. A. : Chlorampihenicol

(Chhiromypetin) in the Chemoprophyhaxis of Scrub Typhus (Tsutsugamushi I)isase). III. Suppression

of (Overt Di.senst by Prophylactic Regimens of Four-Week Duration. Am. J. Hyg. 51 : 216-228.

March 1950.

639,.243'°-C:'- -12
140 INFEC'fI( PUS D)ISEASES

'rie desert rodents, G7. )yrt,iulu~lhi and 67. qvrb;,/u.. wvere showii to be suiscelptilble to hinfeet ion with Iicrrib typ~hus andt were valuable experineiital aniinals ini studies onl this disease durilin' World War IL.

Clinical picture.- Af ter anti incubatiloll 1 eriodl of from (6 to 18 (lays. thle

Hitlless begins abruptly with chilly sensations or. ri(ors, followed by fever.

hleadIache. nmalaise. anld atnor-exia. Thie face is flushled, anld there is cnuc Vt

inject ioni. A p~riimafry lesioin or eschar is p~resenlt inii nearl v all cases at tile

t ime of oniset. It may nave beeii presentt for as long as .5 days earlier, and

uisually pers'ists throtughouit tile Iactive phlase of tile (lisease. rile eschar. relpreselits tile site of in fection 1) 'v the imite. ( ccasionial patients exhibit more thanl

oneP escIta r. 'l1li is lesion m~ay he 11p to 1 .0 cnm. lin diameter and consists of a1

centtral tough b~lack scabI suiIrouiiidP~ by a slight lY ellevated (11i11 redl areobht

f ig. 9). lit moist areas of thle bod(y. such as the axilla, groinl, amid scrot 11111,

lie scab is oftent lack intg, mnid the lesion apipea rs as a shallow lIMInched-olit

ulcer. It is neithuer painiful nior prurit ic. There is often regional or greneral -

ize(l l'mpi~aiphaen it is. Thle spleeni may become p~alpable. Tilhe fever ris-es ini

step)wise fash iou. reaclmihig 102' to 10.50 F. by the end of the first week. It

iistiall y remnainis elevatedl tint i the thirdl week at w-hich tinme it subsides by

lysis. As the( disease passes into its secomil week, the greneral symlptomus are

iuicreased excep~t in mld h cases.

Oni ab~out thle fiftlh to thle eighthI day, a dull red nuactilar er-ult io appears

first onl tile trunk (fig. 10)) and l.Ater spreads to the arms, legs. and face. It

varies lin intelusit v anmd exte'nt and lasts tronli I to 10 (days. Noll produc(ti ve

coughri is coinnionl. aild ini severe cases. lbromdllit is aiiid 1)iitimoiiOi a lmay appear~ I.

H1oemitgenl exalininat ion of the chest nuav reveal changes similar to those of

fprilima rv atyp~ical plellola Indked. 1 pit hological stutdies stuggest that these

fillii~tgs representl a vicket tsial pnleumlloiuit is. Ilivpoteiusionl, tad lcarldia. andl

evatiosis may occur at the height of t he (disease anid arme attributed more to

peri pheral vascullar colla pse thani to heart4 failure.

Thie cliniical feat ures presenited b~y thle scrub typhuts patienit reflect the

hiistop)athologry of tile disease. which is basically a dlissemniiated, focal vasculit is and~ lperivasculit is especially of the vessels of the skin, lun1gs, heart,

and brainl.

Leukocyte counts are usually wit hin niornial 1limiits, but a moderate leukoeyto~sis may (levelop (uhirig the second week of Hitlless.

Diagnosis.-The typ)ical case, of scrub tYphus is readi ly diagnosedl on time

cilinical finldinigs. Prior to the appearance of the cuttaneous ertiihtion, however, early- diagnosis depends upon finding ant eschlar, since lemnige, relapsing~

fever. malaria, infect ions hepatitis, typhoidl fever. epidemic ty)hulis, and

inunrinie typhus exhibit imay of the same cliniical1 featulres.

'ile (liag-iosis miay be conlfirimued by serological tests. A significant rise

ini titer ini the Weil-Felix IProfteii OX-K agglutiiiation test (lifreremitiates

scrub t vpllus from Other rickettsial inifect ions. H owever, patients withi relap)sing fever also dlevelopl)OX--K agltinn.(oiplenueit fixationl tests
44

I"1.1u1 .1 Th le rash (of tslitsiigaiiiiisbi hivl,4';I. is I faiint Ill:I(ular olie I fr4.11p1tly
142 INFEI'C1T US D)ISEASES

with purified suspensions of R. t.utmqamm.h may be useful ill the diagnosis,

but the sera imust be tested with antigeils prepared from several differelit

stralinlS Of the lklicro-organisui. 'hi'iS is nece&sSary becaiuse there are iimlportant

antigen ie differences between various strains. Although recovery and identification of the micro-organism proves the diagnosis, it is not feasible for

routine use.

Natural course.-After the fit-t week, the subsequent course of scrub

typhus may be relatively mild, with a total febrile period of 12 to 14 days.

or it may be moderately severe with signs of encephalitis and p1neumionitis

and fever up to 3 weeks. In severe cases. patients are febrile for about 3

weeks. have signs of 1lneumonitis. encephalitis, and often of circulatory collapse and myocarditis. Thromboses and cerebral or gastrointestinal hemorrhage may occur. I)eath is not infrequent in severe cases. However, the

mortality of untreated cases varies from 1 to 25 percent or more in different

series. Thlie death rate rises sharply after the age of 40. There is evidence

that the course of scrub typhus is likely to be more severe in men who have

been under the strains of combat or have lacked early treatment.

Recovery from scrub typhus is ultimately complete. Many p)atients, however, have a prolonged convalescence and present a picture of netirocirculatory

asthenia with sleeplessness, tremulousness, lack of ability to concenitrate, easy

fatigability. excessive sweating, palpitation. dysp1 nea. and sense 6f intrathoracic pressure.

RelaI)se is rare in cases that have run their natural course.

Foilowing an attack of scrub typhus, imuntmnity to the homologous strain

appears to persist for at least a year. Resistance to heterologous strains of

R. t.si/.hgamimih;, however, is transient.

Therapy.-The patient should be placed at bed rest, avoid overexertion.

and receive frequent small feedings and adequate fluid intake. Specific

therapy should be instituted as early as possible. Scrub typhus during World

War II was found responsive to high doses of PABA (best administered as a

10-percent chilled aqueous solution of the sodium or, preferably, the potassium

salt) :.4 since World War II, chemotherapy has been successful.

Prophylaxis.-Prevention of scrub typhus iin areas where it is enldemic is

difficult, at best, and may be impossible under combat conditions. When

feasible. preventive measures should include al)propriate clearing and oiling

of campsites to change the ecology of the area so that it is unfavorable to

rodents and mites. Impregnation of clothing with dimethyl phlthalate. or with

an emulsion of benzyl benzoate and dibutyl phthalate, affords considerable

individual protection as mites which come in contact with treated cloth are

killed. In view of the immunity factors that have been referred to. it is not

anticipated that effective protection will be afforded by the development of a

vaccine.

64 See footnote 52, p. 137.
CHAPTER VII

The Typhus Fevers

Chris 1. D. Zarafonetis, M.D.

Part I. Epidemic Typhus

Epidemic typhus fever is an acute febrile disease ,.tion with

?;ciR'etts;a prof'aze/h;. It is a louseborne infection and .-- a,,,ierized clinically by sustained high fever, headache, malaise. and later an exantheni. It

has been known under many names including exantheniatous typ)hus. jail

fever, ship fever, war fever, camlp fever, Old World typhus. Fieckfieber (German). tyl)lhus exanthematiqu6 (French), el tabardillo (Spanish). and hassin

chifusu (Jal)anese).

For centuries, epidemics of typhus fever have been associated with war,

revolution, and famine. and have indeed, in the past, been a factor affecting

the outcome of wars. The death toll exacted in some ei)idemics has been

estimated in millions of lives. An account of the historical role of typhus

fever has been written by Zinsser,' and Strong and his associates 2 have docuniented the great Serbian el)idemic of 1915.

Clinically. no differentiation was made between typhoid fever and louseb)orne typhus fever until 1837. In that year. Gerhard. in Philadelphia. noted

differences between the two. and was the first to call attention to the presence

of typhus in the New World. That typhus is transmitted by Pedhcidi

hunmnim. var. corporio was discovered by Nicolle, Comte. and Conseil in 1909.

'The causative agent, 1R. p/ow(azek;, was first described in 1916 by D)a RochaLima. For many years. it was believed that there was only one form of

typ)hus fever, but it is now known that the epidemic louseborne form and the

endemic fleaborne typhus are caused by different micro-organisms. It has

been further shown that ep)idemic typhus fever may be recrudescent in a

patient years after the original illness, in the disorder known as Brill's disease.

EPIDEMIOLOGY

Typhus fever exists in many parts of the world. with important foci in

the Balkans, North Africa. China, and Mexico. and it presumably occurs in

Poland. the U.S.S.R., and elsewhere. Maln is the reservoir of epidemic typhus

(p. 201). It is transmitted from man to man by body lice which become

infected by feeding upon typhus patients during the febrile period. The

rickettsiae multiply in the cells lining the intestinal tract of the louse. A week

1 Zlnsser. Hans - Rats, Lice and History. New York: Little. Brown and Co., 1934.

2 Stroing. Richard P.. Shattuck. George C., Sellards. A. W.. Zinsser, Hans. and Hopkins, .J. Gardner:

Typhus Fevwr With Particular Reference to the Serbian Epidemic. Cambridge, Mass. : Harvard University Press, 1920.

143
144 INFE(TIO4US DISEASES

or 10 days after the vector has become infected, the parasitized cells rupture

and large munbers of rickettsiae begin to appear in its feces. Lice prefer the

normal temperature of the body and usually remain close to their human

host. If the temperature is raised by fever or lowered by death, however,

they will migrate to a new host. Here, lice suck blood and defecate as they

feed, and when the site of the bite is scratched, the infected feces are rubbed

into the skin. This appears to be the principal means by which the infection

is p)assed from man to man. It is also possible to acquire it by crushing an

infected louse upon the skin. or by having dried infected feces come into

contact with the conjunctivae or the mucous membranes of the respiratory

tract. Infection with typhus rickettsiae is eventually fatal to the louse.

Conditions that predispose to louse infestation naturally p)redispose to

epidemics of typhus fever. The scene is set by crowding, inadequate housing.

lack of bathing facilities, lack of fuel, and such continued cold weather that

people wear their garments for long periods of time. Once louse infestation

is prevalent. introduction of the infection, either from a patient with typlhus

or frlom one with the recrudescent (Brill's) disease. may set off an epidemic.

The chaotic effects of war and famine, shifting populations, and the breakdown of orderly processes of government contribute conditions that favor

spread of the infection.

At the beginning of World War IL it was evident that American troops

would be exposed to typhus fever in most oversea theaters of operations. It

was recognized that few physicians in the Armed Forces would have had

experience with a disease conspicuous by its absence from the continental

I'nited States. Against this background, the United States of America

Typhus Commission was created by the Secretary of War on 22 October 1942

in response to a staff-approved recommendation of The Surgeon General,

initiated by Col. (later Brig. Gen.) James S. Simmons, MC, and established

by Executive order of President Roosevelt on 24 I)ecember 1942.3 The order

provided for a joint attack upon the problems of the disease by the Army,

the Navy, and the U.S. Public Health Service. As a result of the comprehensive mandates and authorizations of this broadly conceived Executive

order, and of the impetus given to t' .,, work by the director, field director.

and members of the Commission, typhus investigation was intensified, leading

to the development of specific diagnostic procedures, improved methods of

treatment, the large-scale production of a potent vaccine, and excellent lousecontrol measures. For detailed information regarding epidemiology and

preventive measures, and a history of the Typhus Commission, the reader is

referred to the brilliant account by Stanhope Bayne-Jones in another volume

in the history of the Medical Department in World War 11.4

3 Bayne-Jonem. S. : The United States of America Typhus Commission. Army M. Bull. No. 68.

pp. 4-15, July 1943.

4 Bayne-Jones. Stanhope: Typhus Fevers. In Medical Department, United States Army. Preventive Medicine in World War II. Volume VII. Communicable Diseases: Arthropodborne Diseases

Other Than Malaria. [It preparation.]
TYPHUS FEVERS 145

CLINICAL EXPERIENCE

Although epidemic typhus fever posed a constant threat to soldiers in

several oversea theaters (table 13). the remarkable fact remains, however.

that there were only 104 cases in U.S. forces and not a single death (table 14).

Bavne-Jones has described the extraordinarily effective measures that were

inilplemnenited for the protection of U.S. troops in areas where epidemics of

louseborne typhhus were prevalent among civilian populations. As one result

of this splendid record, there was no opportunity for medical officers in variotis station and general hospitals to accumulate extensive experience with

epidemic typhius in our troops. The clinical studies to be recorded here are.

therefore, largely those performed by members of the Typhus Commission.

and are generally concerned with the disease as observed in civilian pol)ulations. This is in contrast to the observations on scrub typhus in the several

excellent studies nmade by other medical officers and units in addition to the

contributtions of the U.S.A. Typhus C(ommission (pp. 116-138).

T.BLE 13.-Epidemic typhus in French North Africa, Egypt, and Iran, 1930-44

Number of reported cases

Year

French North Egypt Iran I

Africa

1930 --------------------------------------- 529 28s (2)

1931 ---------------------------------------- 930 265 1, 167

1932 ---------------------------------------- 965 2, 298 1, 544

1933 ---------------------------------------- 1, 671 7, 865 327

1934 ---------------------------------------- 1,456 7,536 1,212

1935 ---------------------------------------- 1, 977 3, 151 61(.

1936 ------------------------------------ 2, 1,2 2, 757 202

1937 .---------------------------------------- 1 ,921 2,083 116

1!3S ------------------------------------ 11,377 2,S67 16

1939 ---------------------------------------- 9, 353 4, 239 86

1940 ---------------------------------------- 3,547 4, 135 397

1941 ---------------------------------------- 21, 726 9, 324 245

1942 --------------------------------------- 77, 335 23, 941 1, 102

1943 ---------------------------------------- 27, 340 40,084 12,885

1944 ---------------------------------------- 6, 226 1S, 533 6, 436

I Data pertain to citics only.

2 ata are not available.

Sourre: (I) Stowman, K.: Typhus During the War. Epidemiol. Inform. Bull. 1 (7): 299-310, 30 Apr. 1945. (2)

Current Reports on the Prevalenwr of Certain l)iseases. Epidemiol. Inform. Bull. 1 (7): 311-326, 30 Apr. 1945.

The Disease in Nonvaccinated Individuals

The Typlhus ('ommission established special study facilities at the Cairo

Fever HIOsl)ital, Egypt, in March 194:3.- The Ministry of Health of the

- Minutes. Conferenep on Typhus, National Research Council, 22 June 1944.
146 INFECTIO USD IEASEN

Egyrptian Government provided the study ward and space for laboratories.

D)uring the 1943 and 1944 seasons, 15)9 patients with typhus fever were aduitted to this ward. and Ilulnerous other cases were observed in other wards

of the hospital. With three exceptions, all of the patients studied oil the

Commission ward were niales. Their ages ranged from I0 to 70 years, the

great majority falling in the 21- to 35-year age group. Ili general, tile patients were selected as early ill the disease as possible. The majority were

admiitted between the 5th and 10th day of illness. A few were admitted on

the first day of disease, while in four instances, patients were actually under

observation before the onset of illness.

TABLE 14.-Incidence of epidemic typhus fever (Iouseborne) in the U.S. Army, by area and

year, 1942 45

[P'reliminary iata hasd on Pflmplle tabulations of Individual mnedicat nveords]

[Rate expres.c•,d wS nunmbr of eamses ler annum Iwr 1.01) anverague strengthl

1942-45 11142 1943 1944_ 1-!45

Area Nunimhr Rate \Nunamhr Rate' Nunitber Rate Nmiubr of Cases of Case, of 'at. Number Rat of e s o Of .. WS

CoMItnntal United, .... -tte - , .. 0.0----------0 0.0.-----------I ------- i ----- . m

Ov,,rwas:.

Europe --------------------- -- 1 ()0 ) ---------- 0(.0•----------- .. ) ---------- 11. N I) 1" . W)

Mtetfiterruleami I - - 16 .01 ( . 4 12 .A3 3 ) -

Middle East ----------------- 14 .10 1 .17 ; .15 ---------- 0 5 .12

('hira-Burnia-India - --------. W .14 1 .11 25 1 .63 12 .07 25 . I1

houthwest 'acific ------------ ------ 0 . . . . ~~- - - - - 0 -- .. 0 -- -. --. -. --. -. ---.. . 0---- 0 ------------0

Central and South Iaeiflc -_. I 0 ------------- 0 1 0 -------- ---- 0------- - 0 

North•America- 2 ...................... - 0-......... : 0- 0-------- -- 0 - - 0 .------ - -)

Latin America ------------------------- 0 ----------- 0 ---------- --- - ---0 o------- -- 0

Total overseas ------------- 104 0U.01 3 0' 01 46 0.103 15 0.1K) 40 0.01

Total Army --------.-------- I-04 0.00 31P.00 46 0.01 15 0. kK 40 1101

Includes North Africa.

3 Ineludes Alaska and Iceland.

This section of the chapter will be restricted to a consideration of the

1muvaccinated subjects who received no special therapy beyond supportive

measures. There were 64 such "untreatedl" cases studied on the ( ommission

ward. The severity of tule clinical course of tile (lisease was estimated for

each patient after discharge from the hospital. The principal factors which

influenced the estinmtion of severity were tile intensity of subjective symp)toms

(headache. greneralized bodily aches and lpains, thinnitus, deafness). the degree

of prostration, the extent of neurological involvement (mental dullness,

stul)or. colla. inwontilnece of urine and feces, signs referable to tile central

nervous systell). the severity of cardliovascular involvenment (hypotension,

(achlyca rdl ila periplheral vascular failure. mllyo(ardial dalliage), and, filially.

occurrence of urinary retention, oliguria, nitrogen retention, bronchopleu-
TYPHUS FEVERS 147

monia, otitis media, parotitis, furunculosis, and gangrene.6 On the basis of

these criteria, these cases were grouped as follows:

B. Cases with minimal signs and siyniptoms, yet definitely diagnosed as

typ)hus on clinical evidence.

C. Cuses of moderate severity, slho'. ing slight prostration, involvement

of the central nervous system, cardiovascular changes, or mild complications.

D. Severe typhus cases with pronounced prostration, involvement of the

central nervous system, cardiovascular changes, or serious complications.

E. Cases of such severe illness that at some point in the clinical course

a fatal outcome was expected.

F. Fatal cases.

Of the 64 cases of "untreated" typhus fever, there were 2 in the B group,

14 in C, 26 in D, 7 in E, and 15 in F, the fatal cases, a mortality of 23 percent.

It was of particular interest that 33 (52 percent) of the patients developed

nitrogen retention (nonprotein nitrogen over 45 mg. percent) during the

disease. All 15 fatal cases were in this group, and no patient died who

throughout his illness had normal concentration of nonprotein nitrogen in

the blood.

The following case histories, taken from a Commission publication,7 will

serve to illustrate typhus fever classified as severe (E or F) :

Case I (classified as E; severe, with neurological involvement).-The patient, male, aged 25, was admitted on the sixth day of disease with headache as his chief complaint.

Temperature 40.70 C. p.r. Pulse 108. Respirations 36. Blood pressure 126 mm. Hg systolic and 66 mm. diastolic. Weight 121 pounds. The patient was moderately well developed and nourished. He appeared mentally clear and not acutely ill. There was no tinnitus or deafness. The skin was dark; no evidence of a typhus rash was seen. The

conjunctivae were negative. Th,. tongue was white coated and moist. The chest was

clear to percussion and auscultation. Examination of the heart showed nothing remarkable.

Laboratory data on admission.--Hemoglobin 83 percent (CuSO,); erythrocytes 4,500,000; leukocytes 7,550, with 81 percent polymorphonuclear cells. Urine was amber

in color, cloudy, reaction acid, and specific gravity 1.028. A few squamous epithelial cells,

1-2 granular casts per low-power field, 1-3 leukocytes per high-power field were seen in

the centrifugated sediment. The concentration of nonprotein nitrogen was 46 mg. per

100 cc. of blood. The plasma proteins were 6.8 gm. per 100 cc.

Hospital course (chart 4).--Throughout the firs•t N,•, of hospitalization the patient's

fever remained high r-id the rasa appeared, with ýntens*- 'onjunctival injection and the

development of petechiae in the left conjunctiva. .•a. -he patient, actively delirious,

became very talkative and attemPted to get out of r,, mntake by mouth continued satisfactorily until the 12th day of disease when subcutaneous injections of b percent dextrose

in saline and normal saline became nef'-, sary for the next 12 days.

On the 13th day he became more stuporous and then semicomatose. He lay with

half-opened eyes, breathing quietly. Facial grimaces and grinding of the teeth were noted.

Fluid intake by mouth practicall] ceased. He was put on constant bladder drainage on

this day because of urinary retention. His condition remained much the same to the

6 Yeomans, A., Snyder, J. C., Murray, E. S., Zarafonetis, C. J. D., and Ecke, R. S.: The Therapeutic Effect of Para-Aminobenzolc Acid in Louse Borne Typhus Fever. J.A.M.A. 126: 349-356, 7 Oct. 1944.

7 Yeomans, A., Snyder, J. C., Murray, E. S., Ecke, R. S., and Zarafonetis, C. J. D.: Azotemia In

Typhus Fever. Ann. int. Med. 23: 711-753, November 1945.

639243r---63--13
148 INFECTIOUS DISEASES

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+ +

. +

00 .z= C

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+ 9

----

00 0 0000Q

0 - 0 000 0 z-*" z o

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TYPHUS FEVERS 149

17th day of disease. The rash gradually faded out during this period and the conjunctival suffusion disappeared.

On the 17th day slight improvement was noted in his mental state. He stared about

the ward, his mouth open In a wide grimace. When spoken to he replied in a series of

unintelligible whining sounds. There was no indication that he recognized people. The

rash was no longer visible.

In the next 2 days he was able to obey simple commands. It was evident that he

was almost totally deaf. On the 20th day his temperature reached normal levels. Examination showed hyperactive knee jerks and ankle Jerks but normal plantar response. An

area of skin necrosis appeared over the coccyx.

On the 22d day the catheter was removed. When lie was spoken to it was obvious

that he was attempting to reply, but he could not articulate and the facial expressions

were similar to those of a crying baby.

The area of necrosis over the lower back continued to enlarge. The patient was

placed in a chair on the 24th day. A low-grade fever continued. He was by that time

able to eat solid food and the oral fluid intake gradually increased.

On the 27th day the patient was found to have not only hyperactive knee and ankle

jerks but a bilateral positive Babinski reaction. Voluntary motion of the extremities

was uncoordinated.

From this time onward improvement in his general condition was steady but slow.

The ability to stand and walk unassisted returned before the ability to form words. At

the time of discharge 68 days after the onset of the disease, the lesion over the coccyx

was healed. Spe.ch was slow, expressionless, and labored. Hyperactive reflexes were

still present in the lower extremities, but the positive Babinski phenomenon had disappeared.

On followup examinations during the next 4 months the patient showed progressive

improvement. Mentally he appeared alert. There was no residual deafness. The reflexes

in the lower extremities remained hyperactive, however, and speech was still slow,

labored, and monotonous in tone. Examination of the urine showed normal concentrating

powe~r, no albumin, and a negative urine sediment. The anemia that had developed

during the disease was no longer present.

Case 2 (classified as F; fatal, with post mortem).--The patient, male, aged 30, was

admittedl on the fourth day of disease complaining chiefly of headache. Temperature

40.00 C. p.r. Pulse 88. Respirations 36. Blood pressure 118 mm. Hg systolic and 64 mm.

diastolic. Weight 116 pounds. The patient appeared moderately ill, mentally clear, with

rapid respirations, and no cough. A few poorly defined maculopapular lesions were noted

over the chest, abdomen, anti arms. The conjunctivae appeared moderately injected.

The tongue was moist. A few crepitant rales were heard in the right midlung field

posteriorly. Examination of the heart showed nothing remarkable. The spleen was enlarged, but not tender; its tip was felt 7 cm. below the costal margin. The liver was not

palpable, but was found enlarged 3 cm. below the costal margin by percussion.

Laboratory data on, admission.-Hemoglobin 72 percent (CuSO4 ) ; red cells 4,110,000;

white cells 4,300, with 76 percent polymorphonuclear cells. Urine was amber in color,

reaction acid, specific gravity 1.023, albumin 2±, 8-10 white cells per high-power field,

and an occasional granular cast was seen in the centrifugated sediment. The concentration of nonprotein nitrogen was 30 mag. per 100 cc. of blood. The plasma proteins were

6.5 gin. per 100 cc.

Hospital course (chart 5).-In spite of frequent sponging, the patient continued to

run a high fever from the fourth to the ninth day of disease. On the fifth day, the

maculopapular rash Increased, but the macules were still scanty and poorly defined. On

the sixth day, the patient became disoriented. On the eighth day he was quite drowsy

and vomited twice. His general condition, however, appeared satisfactory. On the ninth

day he became semicomatose. The pulse rate had increased to between 130-140 beats per
150 INFECTIOUS DISEASES

CUART 5.-Clinical and laboratory findintgs in a futal case of epidemic typhus fever

DAY OF DISEASE 4 5 6 7 8 9 10 I,

40 -

39

TEMPERATURE 3-- ---

37

140

BLOOD :30 PULSE PRESSURE '20o o o ,110

*o 10---I oo

90 I a?

NORMAL0 TO I 

60

PLASMA 50 PROTEINS % NORMAL 4 0\

NONPROTE I N \ p

NITROGEN 1O0 0 MG. PER 100 Cc so I0 UREA soj/

CLEARANCE 60

"% NORMAL 40

20

'0

FLUID

eNTAKE 2

AND

OUTPUT

24-HF%. SPECIFIC GRAVITY 1.020 1 l011 10111.020 1021102010O6

ALBUMIN 4 + +44 4

RBOC ++ WBC + - = CASTS + I I I

minute. The blood pressure fell. The respirations were rapid. The neck was resistant

to passive flexion. Examination of the heart and lungs was negative. Spinal puncture

revealed an initial pressure of 90 mm., and the dynamics were normal. Seven cubic

centimeters of spinal fluid was withdrawn. The final pressure was 60 mm. The cell

count of the spinal fluid was 5 per cu. mm. The Pandy test was negative. An electrocardiogram showed low voltage of the QRS complexes. The patient was given 1,000 cc.

of 5 percent dextrose in saline subcutaneously.

On the morning of the 10th (lay, his general condition had become critical. There

was oliguria; the blood pressure was low; the heart rate still rapid. lie was given 100 cc.

of concentrated human albumin intravenously. Subcutaneous injections of 0.5 gm. of

caffeine with sodium benzoate were given every 2 hours. Slight improvement in his

general condition was noted throughout the day, with a decrease in heart rate and a rise

in blood pressure. The state of oliguria continued, however. There was no Increase in

the rash from the fifth day.

On the morning of the 11th day the patient had a generalized convulsive seizure

and died.

At post mortem examination 1 hour after death, the interesting findings were as

follows: The rash, which had been scanty throughout his illness, was not discernible.

No gross areas of pneumonitis were noted in the right lung; the left lung was crepitant

throughout; the bronchi appeared normal. The heart weighed 330 gin.; no gross abnormalities were seen on the epicardial or endocardial surfaces; the ventricular walls were
TYPHUS FEVERS 151

of normal thickness; the coronary arteries were patent. The liver weighed 2,430 gin. :

its was grayish in color, firm and rubbery in consistency; the surface was lobulated. with

numerous white fibrotic areas in the depressions between the lobules. On section the cut

surface was gray. Areas of dense fibrosis were present throughout the organ. Numerous

adult schistosomes were obtained from the blood in the portal vein. The spleen weighed

770 gin.; the surface was mottled with numerous white, bluish, and reddish areas, some

of which were firm in consistency. On section the pulp was firm and deep red in color.

The surface patches extended a few millimeters into the spleen substance and appeared

to be demarcated by a narrow zone of hemorrhage.

The right kidney weighed 210 gin.; there were a few pinpoint hemorrhagic spots on

its surface. On section the cortex appeared to be slightly pale. The kidney pelvis appeared normal. The left kidney weighed 190 gin., with findings similar to those seen in

the right kidney. The ureters appeared normal and patent. The mucosa of the bladder

was of light yellowish tint and was thickened. Small areas of hemorrhage were present

in the region of the trigone.

The mucosa of the large intestine and rectum showed mottled areas of bluish and

brownish discoloration. There were numerous elevated nodules of 0.5 to 0.7 em. in diameter with smooth surfaces. These were not pedunculated and were pale green to blue

black in color. The findings in the liver, bladder, and large bowel were secondary to an

extensive Schistosoma infection.

Pathological physiology.-The observation that there was a high incidence of nitrogen retention in their typhus cases led Yeomans and his associates to analyze the factors that might contribute to its development. They

reasoned that-

* * * a fundamental consideration * * * [is] that the caloric and protein Intake of

nearly all typhus patients is grossly insufficient. There is good reason to believe that the

destruction of the body tissues must be considerable * * * In order to prevent the accumulation of nitrogenous metabolites In the blood, the excretion of an adequate [amount]

of urine * * * is necessary. In the presence of a greatly increased protein catabolism

it is apparent that dehydration with a diminished output of urine will have considerable

effect upon the degree of azotemia observed.

Another factor * * * in the more critically ill patients * * * Is the onset of renal

insufficiency, most often associated with a rapid fall in blood pressure. [Thisl * * * is

of serious prognostic import. In our experience * * * the majority of these patients died

with evidences of overwhelming rickettsial infection or complicating conditions, such as

pneumonia, [but] a rapid diminution in kidney function was almost without exception the

first indication that the patient would probably succumb to the disease. The * * * renal

insufficiency itself was of more significance than a fall In blood pressure, since at times

such a fall was not observed or occurred in the absence of renal failure. At present we

have no evidence to indicate that the loss of renal function observed in these critically

ill patients was due to other than extrarenal factors.

In French Morocco, Maj. Theodore E. Woodward, MC. of the U.S.A.

Typhus Commission collaborated with Maj. (later Lt. Col.) Edward F.

Bland, MC, 6th General Hospital, in a study of 30 native patients with typhus

fever.8 They draw a composite picture of the pathological physiology of

severe typhus as follows:

The patient is acutely ill and very toxic, with a significantly low arterial tension and

a labile pulse. Usually, unless actively supported, the patient becomes dehydrated, the

8 Woodward. T. E.. and Bland. E. F.: Clinical Observations in Typhus Fever, With Special Reference to the Cardiovascular System. J.A.M.A. 126: 287-293, 30 Sept. 1944.
152 INFECTIOUS DISEASES

red cells decrease and plasina proteins fall with at considerable loss of the albumin fraction, indicating a reduced colloidal osmotic pressure. All factors indicate a drop of blood

volume with the pattern of hypoproteinemnia, hypoehioremia, and hemodilution without

blood destruction. The unstable circulation results in lowered glomerular filtration pressure, and hence oliguria amd anuria occur. The kidney, partially damaged by the specific

pathologic condition and called on to eliminate an increased amount of nitrogenous waste.

is unable to function normally unless adequately supported by fluids. Lowered blood

volume means less adequate filling of the heart during diastole and hence lowered cardiac

output. Each beat of the heart is less efficient. The use of cardiac stimulants under

these conditions is ineffectual, but when the volume of the blood is restored the organ

can operate more efficiently.

Woodward and Bland note that the typhus lesion had been demonstrated

by Wolback and his associates in heart muscle, in the kidney, and in almost

every other organ. However, the degree of both cardiac and renal changes

they observed was not disproportionate to the pathological changes occurring

elsewhere, and from their clinical studies it appears "unlikely that cardiac

failure as such is often a significant factor in the outcome of the fatal case."

In treatment, they advocate "general supportive measures to increase the

circulating blood volume."

Metabolic studies.-These observations focused attention on the azotenlia

and hypochloremia associated with a high proportion of typhus fever cases.

Since a better understanding of electrolytes and protein metabolism was

deemed essential for appropriate supportive treatment, Tierney and Yeomans '

undertook metabolic studies in cases of typhus fever on the Commission ward

in Cairo.

Tierney and Yeolnans determined the carbon dioxide content and the

chlorides of the serum in 34 cases. They found the serum chlorides to be

low in 62 percent of the patients during the first 2 weeks of disease, but the

serum carbon dioxide content was appreciably reduced in only four cases.

Explanation was sought for the low serum chlorides in the early stages of

typhus. The diets of these patients were probably poor in salt prior to

hospitalization, but this was not an important factor since there was no conspicuous chloride deficit in patients admitted to the Commission ward with

relapsing fever and typhoid fever. Perspiration was not a factor, as it was

rarely observed; indeed, failure to perspire was noted in typhus patients not

only in the dry climate of Egypt but also in moist climates. The salt was

not lost in the urine, for urinary excretion was in relation to the concentration of chlorides in the serum; when serum chlorides fell below normal levels,

the urinary chlorides diminished markedly. The fact that the serum chlorides

returned to normal spontaneously in spite of a poor salt intake was taken as evidence that the salt was not lost by the body and that the lowered chloride concentration was therefore due to expansion of the extracellular fluid volume.

During tile early stage of typhus, the patients frequently have nonpitting

9 Tierney, N. A., and Yeomans, A. : Metabolic Studies in Louse-Borne Typhus; Observations on

Serum Electrolyte Pattern, Serum Protein Partition, and Nitrogen Balance. J. Clin. Investigation 25:

822-837, November 1946.
TYPHUS FEVERS 153

edema; in the later stage, shortly before defervescence there is often a fairly

marked diuresis. These observations are in keeping with the suggestion that

early in the disease there is all increase in extracellular fluids, which would

lower the serum chlorides, and later in the disease there is a loss of extracellular fluid by diuresis with a resultant increase in serum chlorides. The

pt[ was normnal in all of the patients except one who had renal failure and

acidosis. The total base was also normal in all but one of the subjects studied.

In all instances, the quantity of undetermined acid anions was increased in

the majority of cases equaling that found in severe metabolic acidosis.

The total serum proteins were normal in approximately 75 percent of the

patients, but the majority showed a depression of the albumin fraction and a

very striking elevation of the globulin fraction to over 40 percent in the

average case. An electrophoretic analysis 10 of sera obtained from a severely

ill patient on the ward of the Cairo Unit of the Typhus Commission showed

that the relative proportion of albumin and the albumin to globulin ratio was

markedly reduced on the fourth day of fever and through convalescence. The

alpha and beta globulins were practically unaffected, but the gamma globulin

was strikingly increased on the fourth day and was even higher in convalescence.

Nitrogen balance studies were performed on 21 subjects. Eight of the

patients were given high-protein, high-caloric diets; ten, low-protein, lowcaloric diets; and three were given a combination of these. It was found

that there was no relationship between nitrogen output and intake or between

protein destruction and azotemia. A high-protein, high-caloric diet decreased

nitrogen wastage and loss of body weight during the acute phase of typhus.

Indeed, positive nitrogen balance was achieved in five of the patients studied.

Dietary management.--From these and other observations on the Commission ward, the following recommendations were made with regard to

management of diet, electrolytes, and fluids in the typhus patient:

1. A liquid diet high in protein and calories should be given. With

diligent nursing, the average patient will ingest at least 90 gm. of protein

and 2,500 calories a day. If the patient is too ill to take the diet, Amigen

may be given intravenously.

2. The routine administration of large amounts of sodium chloride

without determining the serum chlorides should be avoided. By including

in the diet or in the parenteral fluids 4 to 6 gin. of sodium chloride a day,

the serum chlorides should be kept within normal limits and good state of

hydration achieved. Usually, the fluid intake should be maintained between

3 and 4 liters daily.

3. The urine output should be at least 1 liter a day, and preferably 1.5

liters. As a marked drop in the urine output is an ominous sign, particularly

10 Dole, V. P., Yeomans, A., and Tierney, N. A. : Electrophoretic Changes in the Serum Protein

Pattern of a Patient With Typhus Fever. J. Clin. Investigation 26: 298-300, March 1947.
154 INFECIOi~US DISEASES

if assOCiate(I with a fall in the arterial blood- pressuixe, plasmia or blood

transfusions in siiwli cases are- urgently required.

4. In cases of shock or impending shock, plasmia or blood transfusions

are) indlicated1. The effect of plasina or blood tranisfusions onl hypoalbumninemnia. is transient. In order to produce ainy si gnificant change, very large

amiounts of I)Iasnia over a p)eriodl of days would he. required.

5.Acid sailts, such its animoniutin chl~oridle, are obviously coit rainidicated

b~ecauise of the increase in undeterinined ;icids Iin the blood.

Epidemic in Itally.-The clinical observations that have been described

were carried out under relatively idleal condlit ions. Ifowever, nmeibt'r1-41s of

the Typhus Comnmission and other phlysicianis of the tT.S. Armny Mtedieal

Service saw thousands of additional cases undi~er epidemic, and often chaotic,

con1ditions throughout Europe and the Far East. Ilii a few instances, efforts

were lmiade to glean clinical dlata even under the mnost adlverse of circumn111-

stances. Thiese rep~orts will be mnentioned1 briefly.

Tile elpideinic at Naples, Italy, during 194:3 aiidI 1944 involved somne 1,407

cases within the city itself and 492 cases outside Naples. Vigorous application of dlelousing mieasu res quickly b~rought. this epidemic under cont rol. This

historic accomplishment has been detailed by Bayne-~Jones.'' H ere. it wvillI

suffice to note that thle case fatality rate was about 22.6 p~ercent. WoodW~ard, 1 2

in his report. of the activities of the flying squadron group for typhus control

oiitside Naples, recorded brief observations onl 2.57 cases dliagnosed onl thle

b~asis of clinical findings, along wvith serological tests. Of interest was tile

relatively high incidence in chlIdren, many of whom showed a characteristic

rash and were moderately ill.

Observations in concentration camps.-MaIj. William A. 1)avis. MIC,

while serving as liaison officer fromt the UT.S.A. Typhus ('omninissiomi to tile

'21st Armny Cirotup, recorded the typhus fever ep~idemnic that occurredl at thle

Belsen C oncentration CIamlp, Belsenl, G-ermIanly. 3 This camlp wats takeni ly

ilie British Second Armny onl 15 April 1945. Amiong the 61,000) inhabitants,

there was widespread suffering fromt starvation, typlius, dlysentlery, tuberculosis, and other diseases. Typhus had beeni prevalenlt in the canil) for 4

miowtlis. and there were~ ap~proximlately 300cases at the timie of lib.erat ion.

PrIact ivally' all of the internees were heavily infested with lice.

D~avis statedl that thle appraisal andl diagnosis of caseis wit peculiarly

dlficiilt in this group. Prostration, semnistupor, dehydration, loss of weight,

weakiness, t reunors. andti a petecliial rash, whtich are considered characteristic

of typhus, were So commilon inl thle starving, louse-infected people that hie

ii BhlyllO-JoIIOM, Stanhope: Epidemic Typhus in the Mediterranean Area During World War It.

in Iticicettmial IDimeame4 of Mail. WVashington: American Association for the Advanicemienit of Scienep,

12 Woo~ward, T. R. :History of Flying Squadron Group for Typhus Control in Italy. To the

Fieldi Director, U.SA. Typhus Commiission, 21) Mar. 1944.

13 Davis, WV. A. :Typhus at Ielmien. 1. Control of the Typhus Epidemice. Ant. J. ilyg. 46: 66-83,

July 1947.
TYPHUS FEVERS 155

found these signs of little value. The rash was mild; very few had e'c'ihInloses, and the usual finding was a scattered lpetechial exanthelii best seen

after the patient had been washed. Gangrene was conmnon, particularly dry

gangrene of the toes. Pleuritic pain was a frequent complaint in the posttyphus period. About 30 cases of parotitis were observed that required

incision. Several patients had polyneuritic leg pains, which may have reflected vitamin B deficiency exacerbated l)y the increased metabolic demands

of fever. No statistics were available on the death rate from typhus fever

at, Belsen.

Epidemic typhus fever was also prevalent at the Dachau Concentration

Camp, Dachau, Germany, when it, was liberated by the Seventh U.S. Army

on 29 April 1945. Measoe.s were taken to control the disease, and special

clinical facilities were nade availal)le to the Typhus Commission '4 at the

116th Evacuation Hospital. On 16 May 1945. six nurses from thle 59th

Evacuation Hospital arrived and began their duties on the Typhus Commission Service, a special ward of 64 beds which admitted patients, 83 in all,

until 30 May 1945. The ward was closed 9 June 1945. Most of these

patients were treated with PABA (para-aminobenzoic acid) or serum thierapy as discussed in the section on treatmen÷ (p. 192). Here, the data on

121 untreated controls are of interest. These were male patients of various

nationalities in the wards of the 116th Evacuation Hospital, ranging in age

from 17 to 58 years, with an average age of 28 years. The duration of fever

averaged 16.2 days in this group.

Of particular interest is the observation that the typhus fever encountered at Dachau was clinically a mild disease. Fewer patients were seen

with full-blown rashes than in other epidemics. There appeared to be less

prostration and delirium, and a shorter convalescence. To be sure, there

were some severe cases, but not so many as had been expected. The coinparative mildness of the disease was surprising to Commission observers

who had seen patients in Cairo, Naples, and elsewhere, and had anticipatcd

that the general debility of the Dachau patients would predispose them to

a considerable mortality. The fatality rate from typhus for all Dachau

hospitals during 9 May to 9 June 1945, was, however, 9.1 percent.

Additional serious outbreaks of typhus fever were encountered among

civilian populations in other areas of the European Theater of Operations,

U.S. Army,1 5 and in Japan and Korea,16 but circumstances prevented the

ullndertaking of special clinical studies during these epidemics.

14 A Report on the Activities of the U.S.A. Typhus Commission at the DIaehau Concentration

Camp, I)achiu. Ge~rmnany, 10 May 1945-10 ,Juno 1945. prepared by Lt. Comdr. A. Yeomans, MC; Maj.

C. J. R. Zarafonetis. MC: Capt. D. 1I. Clement, MC% ILt. Comdr. R. A. Phillips, MC, USNR; and

Lt. Col. J. f'. Snyder, MC.

15t Gor ion, John E. : Louu..e-BornfI Typhus Fever in the European Theater of Operations. U.S. Army,

1945. In Rickettsial I)iseases of Man. Washington: American Association for the Advancement of

Science, 1948. pp. 16i 27.

6S,'oville, Addison B., Jr.: Epidemic Typhus Fever in Japan and Korea. In Rickettsial Diseases of Manl. Washlingtoll : Almerieal Associa tion for 1.ie Advancement of Science. 194S, pp. 28-35.

6392431- -6:- - -14
156 INFECTIOUS DISEASES

The Disease in Vaccinated Individuals

The remarkable record of low morbidity with no fatalities from epidemic typhus fever in the U.S. Army during the war years, 1942-45, was

achieved by taking adequate protective measures against the disease. One

of the most important was the compulsory immunization of all soldiers

going to areas where epidemic typhus was present or suspected. Accordingly, those few cases that did occur in troops, along with those encountered

in certain special studies, offer an unusual opportunity to analyze the modifications of clinical course resulting from vaccination. The value of serological tests in the diagnosis of typhus in vaccinated individuals is implicit

in the clinical material to be summarized, although particular consideration

of these tests will be left for the section on laboratory methods (p. 179).

The Cox (U.S. Army) vaccine.-Early work by Da Rocha-Lima (1918)

and Weigl (1920) suggested that killed suspensions of typhus-infected lice

or infected louse feces could endow some immunity as vaccines. However,

these and other methods advanced for vaccine preparation up to 1938 were

not practical for large-scale production. It was a highly significant discovery, therefore, when Cox 17 demonstrated in 1938 that rickettsiae could be

gTown in the yolk sac of the developing chick embryo. Cox and Bell 1I soon

prepared an epidemic typhus vaccine which consisted of a killed suspension

of micro-organisms grown in yolk sacs and purified by centrifugation. Subsequent modifications included an ether-extraction technique devised by

Craigie 19 and the incorporation of soluble antigen in the vaccine.20 The

resultant product, was not only satisfactory from the standpoint of potency

but was also feasible for commercial production. The final product used

by thle 17.S. Army consisted of a 10-percent yolk-sac s~ispension of the Breinl

strain of fl. prowrazeki, extracted with ether; it contained both killed microorganisms and soluble substances. Up through 1943, the initial vaccination

for U.S. Army personnel consisted of three injections of the vaccine. 1.0

cc. each. administered subcutaneously at intervals of 7 to 10 days, with

stimulating (loses given every 6 months in endemic areas. As the vaccine

was improved in potency through improvement in production, the initial

immunization series was reduced in mid-1944 to two doses of vaccine, with

17 Cox, H. R. : Use of Yolk Sac of Developing Chick Embryo as Medium for Growing Rickettsiae

of Rocky Mountain Spotted Fever and Typhus Groups. Pub. Health Rep. 53: 2241-2247, 23 Dec. 1938.

Is Cox, H. R., and Bell, E. J.: Epidemic and Endemic Typhus: Protective Value for Guinea Pigs

of Vaccines Prepared From Infected Tissues of Developing Chick Embryo. Pub. Health Rep. 55: 110-

115, 19 Jan. 1940.

19 Craigle, J. : Application and Control of Ethyl-Ether-Water Interface Effects to the Separation

of Rickettsiae From Yolk Sac Suspensions. Canad. J. Research, Sect. E. 23 : 104-114, June 1945.

20 (1) Plotz, H.: Report on the Testing of Four Different Typhus Vaccines in Guinea Pige, 20 Mar.

1942. to Col. George R. Callender, MC, Director, Army Medical School, Army Medical Center, Washington, D.C. (2) Topping. N. H., and Shear, M. J. : Studies of Antigens in Infected Yolk Sacs. Pub.

Health Rep. 59: 1671-1675, 29 Dec. 1944.
TYPHUS FEVERS 157

stimulating doses at the beginning and in the middle of the typhus season

(1 November and 1 February in the Northern Hemisphere).21

As might be expected, a satisfactory field trial of vaccine of the Cox

type was one of the principal objectives of the Typhus Commission when

it was formed in 1942.22 In January 1943, the field group of the Commission, with the cooperation of the Egyptian Ministry of Public Health, began

a study on the effect of the vaccine in a large number of persons intimately

exposed by their occupations to naturally acquired typhus fever. This study

was continued through the epidemics of 1943 and 1944. The subjects were

employees of the Cairo Fever Hospital at Abassia and the Embaba Hospital. Because of the exceptionally large numbers of patients with typhus

being admitted to these hospitals, the hospital staff was unusually exposed

to the infection, and in addition many of the employees lived in areas of the

city where attack rates were high. Before 1943, these workers had not been

vaccinated against typhus. During 1943 and 1944, vaccine of the Cox type

was, accordingly, administered to all employees who desired it. Careful records were kept on more than 800 employees at Abassia and over 500 at Embaba. Most of those who contracted febrile illnesses, whether vaccinated or

not, were seen by one or more of the Commission members. During the

course of these two typhus seasons, a group of 61 postvaccination cases were

observed.

Despite the mild course that distinguished many of these cases, Ecke

and his associates 23 usually found it possible to recognize the disease on

clinical grounds alone, and laboratory tests confirmed the diagnosis in almost every case. In some patients. however, the diagnosis of typhus was

made only by a rise in titer in the Weil-Felix and complement fixation tests

during illness or in early convalescence. The diagnostic significance of these

laboratory aids had been worked out by Zarafonetis in studies of 100 known

febrile illnesses other than typhus and 16 definite cases of postvaccination

typhus. In brief, he found that, on the one hand, nontyphus febrile illnesses

do not evoke high complement fixation titers in the sera of patients who have

had multiple doses of vaccine of the Cox type. On the other hand. typhus

infections regularly do stimulate high complement fixation titers in the sera

of vaccinated patients. Similar results were usually obtained with the WeilFelix test. So interpreted, these laboratory aids could be relied upon in

those cases where the clinical evidence alone was inadequate for diagnosis,

either becatuse of ill.olspicuolls syvll)tollis or insufficient, observation (p. 179).

"tA "a(hisk. J. F.. Jr.: Typhus Fever in the United States Army Following Immuntization : Ineldence, severity of tMe )isease. Modification of the (linical Comrse. and Serologie Diagnosit. J..A.MA.

133 : 1192-1199, 19 Apr. 1947.

22 See footnote 3, p. 144.

*- Eeke., It. S., Gilliam. A. G., Snyder. J'. C.. Yeomans. A.. Znrafonetis. C. J. R.. an(d Murray, E. S.

The Effect of Cox-Type Vaccine on Louse-Borne Typhus Fever: An Aecount of 61 ('Cses of Naturally

Occurring Typhus Fever In Patients Who Had Previously Reeived One or More Injection.s of ('Cox-Type

Vaccine. Am. J. Trop. Med. 25: 447-462, November 1945.
158 INFECTI( OUS DISEASES

These post vaccill 1ion cases Nwere arbitrarily classitied ill ile categories

devised for typhus in i(ot'acciliated persons (p. 145) with. in addition to

1,, C. 1). E. and F groups, an A group for cases "so mild that a detinite

diagnosis of typhus on clinical evidence alone was not possible, the lial

diagnosis being itiade oIlyv with the aid of laboratory data." The cases were

furlther groulped according to the amount of vaccine received and the interval

between the last inoculation and the onset of illness.

Thie course of typhus fever in vaccinated Egyptians was recorded by

the Typhus Commission observers. as follows:

Group I (three doses of vaccine at least 21 days prior to onset).-Clinical notes from the records of five patients who were thoroughly studied on

the Commission ward illustrate some of the features of postvaccination

typhus.

Case 1.-Three doses of vaccine, the last dose 39 days before onset. Male. aged 45

years. This pati ent had a severe chill the tirst day combined with frontal headache a l.

later, joint paills. Rash was moderate. lis mihl course was marked latterly by the

development of bilateral costovertebral pain and microscopic heinaturia. After 12 days

of moderate elevation of temperature he continued to maintain a low-grade fever until

the 21st day. (The importance of his hematuria in relation to typhus is not clear: Ililharzia infection is widespread in Egypt.) Clinical classification of severity: II.

Case 2.-Five doses of vaccine, the last dose 117 days before onset. Male, aged 26

years, Tryplms Commission field worker. He had rather severe headache and malaise.

The rassh was fleeting but definite. With the history and the rash no difliculty was Xlcxrienced in making the diagnosis, though the course was mild. Fever lasted 9 (lays. ('linical classification of severity: It.

Case 3.--Three doses of vaccine, the last dose 87 days before onset. The patient, male.

aged 45 years, appeared to be at least 55. lie was never especially ill during his course.

Ile developed a tremor of his limbs, almost parkinsonian in character. This disappeared

during convalescence. Fever lasted 12 days. Clinical classification of severity: B.

Case 4.-Three (loses of vaccine, the last dose 103 days before onset. Male. aged 1S

years. 'T'his ease was a prolblem in diagnosis. Moderately ill : said he felt "weak." but

had no specific complaint. There was nothing to be found but a very few tleeting macules

requiring ,'areful search. There was no conjunctival injection. Feve, lasoted 14) days.

Clinical classification of severity: I.

Case 5.-Five doses of vaccine, the last (lose 79 days before onset. An obese miiale.

aged 33 years. He complained of generalized body pains, especially in the knees,. and

said he felt "feverish." lie had severe headache. There was some thinnitus and slight

deafness. His course was mild. Fever lasted 8 days. Clinical classification of severity : B.

"The average duration of fever for all the patients in group 1 was 101,/2

days. The cases were classed as follows: I in A. 20 in B, 5 in C. none in

D, E, or F. Fifteen of the patients were females, average age 22.7 years;

11 patients were males, average age 31.8 years.

G'-rop 2 (two doses of vaccine it least 21 (lays prior to onset).-The

seven patiellts in group 2 had an average duration of fever of 12 days. The

cases were classed as follows: 4 in B, 3 il( C. Four patients were femnales,

average age 19) years. Three patients were males, average age 28 years.

Oro01 1 3 (one (lose of vaccine at least 21 (lays prior to omlset).-The 11

patients in group 3 had ant average duratioll of fever of 12.7 (lays. The cases
TYPIIt'S FI'EVERS 159

were classed as follows: 2 in B. 8 in C, and 1 in 1). Five patients were females, average age 21 years. Six patients were males, average age 34 years.

Group 4 (onset of typhus less than 12 days after first dose of vaccine).

-There were 17 patients in group 4. The average duration of fever in the

nonfatal eases was 15 days. The cases were classed as follows: 4 in B. 8 in

C, 4 in 1). and 1 in F. There were 12 females, average age 23.6, and 5 niales,

average age 27.8 years.

In discussing these results, Ecke and his coworkers pointed out that,

before the vaccination program was undertaken, typhus fever among the

employees of the Cairo Fever Hospital was characteristically severe. The

relatively few employees who remained unvaccinated and contracted tyl)hus

during the study period were likewise severely stricken. By contrast, among

those who had received two or more doses of Cox vaccine 21 days or more

before the onset of illness (groups 1 and 2), there were no severely ill patients, that is, D, E, or F cases, whereas two-thirds of the unvaccinated

patients in the same age groups fell into the severe groups, D, E. or F.

(Compare with the 64 nonvaccinated cases summarized on p. 147.) On the

basis of these observations, and insofar as attenuation of clinical course is

concerned, it was postulated that adequate vaccination against typhus could

be defined as two or more dloses of Cox-type vaccine of standard potency

administered more than 21 days before the onset of typhus.

On the basis of their observations during this study, Ecke and his coworkers recommended that vaccination be included in epidemic control programs.

Sadusk 24 consolidated much of the information regarding epidemic

tyl)hus fever that occurred in U.S. Army personnel subsequently to immunization. His report contains details of five cases, three in members of the

Typhus Commission. These case histories will illustrate the course of typhus fever in vaccinated Americans and, at the same time, will serve as a

reminder of the added health hazards to which medical officers are at times

exposed in line of duty.

Case 1.-A 41-year-old male officer, member of the U.S.A. Typhus Comnnission, for

almost a month before the onset of illness was engaged in typhus research work in Cairo,

Egypt, together with the officer described in case 2. They were both daily exposed to

infection with typhus by examining patients, picking infected lice off rabbits and patients,

and handling and grinding infected louse feces for injecting into experimental animals.

During the preceding 2 years, this officer had received a total of 22.0 cc. of vaccine in

single 1.0 cc. closes. Five cubic centimeters of this vaccine was of an experimental lot

and contained both epidemic and murine virus. The last dose of vaccih, was given on

1 March 1944.

On 21 May 1944, the patient had a mild headache, general malaise, and felt feverish.

Although the headache became more severe and the temperature ranged between 100.0°

and 101.00 F. during the next 3 clays, he continued his work. On the sixth day, 26 May.

'14 See footnote 21, p. 157.
160 INFECTIOUS DISEASES

lie took to his bed because of headache, fatigue, .111d m alaise. Backache was mamrked.

The next day hie reportedl to at inedicil MIMM:1ý iipis yWhere phyvsiCal eX~iIiIiit 14411 reveailed

afew pinlk papilleS Onl the left pamln and wriist. I t empjeratur U v f 9i.2* 1F., and atpls

raite dof 14M). 'he* raSh 11,141lisappqea red by thle fibliO ig nlrlii ino in. ad except foIr at miild

hefalie, anorex ia, and senlse or fatigule, thet patilent dild well on bed rest iii his quarters,

reporting daily to the dispeitsary. Ile was afebrile by 27 Ma 7th day) and was pernalt ted to raivW OI Ilt Otf IMi41 Ol 31 May (11th day)

P'riolr to the (Iliset of I yphis, Oil 21 Mar1Ch and0 4 kpril 19.44, the WVeil-Felix reaction

was negative with both Proteux OX-Ill and ()X--2 antigens and tile compillemlenlt fixation

titer wvas I1: 8 withI epidemic antigen aint I :4 with inurine antigen. fly the end( of tile

first week oif' diseaise ft(e Virol cu.x ( I-it titer rose to 1:20, and lit the second week it

ros1e to 4)1: So 1. It reverted toP liegat i e !it the fourth wveek. The complement fixaltionl titer

ro~se raipidly (o a1 highl oIf I1 1,024 in the second week. More than 2 years later, tile v'011-

jplefi44It fxtion Ii41 ( withI epidlemic auitigen ) was ,;till posi3tivye with af titer of 1: 10,

Case 2.-A :15-year-oldl miale officer, mnemiber of the U.S.A. Typhus Commzission, was

*'iigiged if) typ~hus researchi work in Cairo with the patient described in case 1, for a

iiioilith prio~r to onlset (If ilijiess. Althouigh exposed daily, 1ie recalledl that he was dangeroulsly exposedI on 11 .1 iie 11)44 w~henl he assisted1 with the handling andi grinding of

inlfectedl louse feces ill larg-e amo14untts. During- the period fronti 23 December 1941 to

lt) O ctober 19)43, lhe received a total of 12.0 cc. of' typhlus vac(cinle ill 1.0 (ce. increments.

Oti 22 Novemiber 1143 he receiv'ed 1.0 cc. epidemlic typhus vaccine and onl 10 April an additional. and final (lose 4)f 1.0 cc. (If vaccine. Atlthoug-h tile Weii-i-'elix reaIction was niegatiye with bot 11111)rotcus OI-It) and Proteug OX-2 a~ntigenl, tile compljlemenlt fixaltion titer

with epllelllic ant1 igeli was 1 :8. 3 days before and 11 days after the ]last dlose of vaccine.

Onl 23 .June 1144, the patient awalken~ed in the miorning- with a mild but troublesome

frontal headai1che which persisted Iliroug-il most of the day, and the following day recurred

together wvith 11ilal.lise and easy fatigability. HIis temperature was 101.00 F. lis these

sympltomlis persisted with an increase in bot h severity and1( extent of the headache, he was

adlmittedl to thle hospital late ill tile afternoon (If' thle next day, 25 June. T'he followimrg

flay his telliperat ure wa-:s 100.40 F., pulse rate was 80), respiratory rate 20, blood pressure

wvas 106 systolic and 60 dtiastolic. Altiloug-h lie (lid not appear acuitely ill. lie comlplained

of' iieiulahe. chilly sensaiotns11, and1 naulsea. Phlysical exainalilltionI revealed onily a markedt

inijectionl of' the scieral conjunctivae. Later in the afternoon him. te'mperaiture rose to

102-.00 1F. and1( a diffuse mal~cular eruiption appeared over tile anterior cliest, armns, shoulders,

and flanks with an ery thena tolls blusih that (disappeared uipon pressure. lie continued

1that a fternooni and1 night to have slight chlills. By the IlI'. t mon~tring the rash had1( deliliitely faded but his headache, whllichi waS flow g-eneral izeil, becamen exceptionall1y severe.

Chll s continued, and14 he( appearedl quite ill. There were initermiittenmt, drenchling sweats-,

aind hie 'omiplainled (If severe backache and1( genetral imaulaise. The temiperature r~ose to

1031.20 F. that nighit wi'th I ii 1)11 raite of onily W). The respiratory rate was, no(rmal~l.

Althbough t he temiperature fell toI 10)1.2* F. the fol lowvin.g mol4rning (28 little0) anld remained

belowv 100.60 F. throug.hout tile c~ours~e of the day, severe hleadache, imalaise, sweat ing, and

occa'Isionail chlills persisted. Hie voinited several tils an10 ~id onl one Occalsionl there wvas a

tranisient aminesia. During the course (If the next 2 days. these symlptom~ls lersistNil blit

thle temperature remiained relatively low and the ralsh becamle inlcreaisinlgly less evidenlt,

and dlisappeared comipletely by 1 Jluly. ()n '21) .)line0 the phmysician reported thait tile paltienlt

atppeared1 to be dlisoriented for a brief period but thiis was not confirmed andI w~as later

(lenlied by the patient. Fromt 30 June onl, tilere wvas raipidl and1 progressive improvemlenit,

ats illustrated in chart 6, wvith rapid fall in templerature by lysis, subsidence of headache,

malaise, nauisea, and vomniting. 1111(1 rapid inlcrease IIl serological titers for typhlus fever.

On 30 JTune, there was at left earache whlichl disappeaiN'd within 48 hours without specific
TYPHUS FEVERS 161

CuAwT 6.-Clinical course and early serological findings in a moderately severe case of

epidemic typhus in a vaccinated individual

PULSE TEMPERATURE

*F.

120 10S

110 ,02 9

t0o 101 all

"90 oo00 P 

s0 99

NORMAL - ~.--~ ~ ~ - -z

O 0

60 9?

DAY OF DISEASE I 2 3 4 5 6 7 a 9 10 II 12 13 14

BLOOD PRESSURE 106/60 106160 106/60 106W64 106170 104/66 110/60 114/60

RESPIRATORY RATE 20 2020 20 20 22 20 20 22 22 18 20 1I 2020 18 I8 20 20

HEADACHE + 1 4 + + +++ ++44 4++ + -. . . . .

CHILL + + +-

RASH - +4 - + + -

WBG X 1,000 6.3 5.6

PROTEUS OX-19 - - . . . .V-- 20 I180 1:160 I;640

COMPLEMENT I EPIDEMIC IS; 1.6 1:6 1:32 132 1!64 1.12 1A28 1:256 I;256

FIXATION MURINE -- 1 I-8 i:32 1:32 1:64

Source: Sadusk, 3. F., Jr.: Typhus Fever in the United States Army Following Immunization;

Incidence, Severity of the Disease, Modification of the Clinical Course, and Serologic Diagnosis.

J.A.M.A. 133: 1192-1199, 19 Apr. 1947.

therapy. Temperature was normal by 3 July. On 5 July he wrs permitted out of bed

and was discharged on the following day as an ambulatory patient.

During the course of the patient's stay in the hospital, there was no marked hypotension. On 25 June, the day of admission, the red cell count was 4,600,000, the hemoglobin was 95 percent, and the leukocyte count was said to be 6,300 with 45 percent stab

cells, 33 percent polymorphonuclear neutrophils, 20 percent lymphocytes, and 2 percent

monocytes. On 3 July the blood count was as follows: red cells 4,650,000, hemoglobin

9W percent, leukocytes 5,600 with 15 percent stab cells, 53 percent polymorphonuclear

neutrophils, 18 percent lymphocytes, and 14 percent monocytes. Urine examination on

26 June was negative. It was clear amber and specific gravity was 1.010. Tests for albumini and sugar were negative.

Serological tests were performed daily during the acute phase of the disease. The

Weil-Felix reaction with Proteus OX-19 antigen remained negative until the eighth day

when it became positive in a titer of 1: 20. It then rose rapidly reaching a top figure

of 1: 1,280 on the 19th day. It was still positive at 1: 80 on the 124th day but when next

checked, almost 2 years after the onset of the disease, it was found to be negative. Complement fixing antibodies began to rise by the end of the first week of disease, reaching

a peak with epidemic antigen of 1: 512 by the 19th day. The titer began to fall after the
162 INFECTIOUS DISEASES

31st day and wlhena last checked almo.st L' years later, the titer was still positive at 1:20.

Specific rickettsial agglutinations were negative at that timne. The temperature and pulse

record, along with other pertinent fildiligs durilig the acute phdase of this patient's disease, are showii ill chart 6.

Case 3.-A 36-year-old nmale officer, member of the U.S.A. Typhus Comimiission, was

engaged ill typhus control Ywork il ll)okkaid o, .Japan. (in 10 Novenilie, 19145, he was

heavily exposed in the room of a Japaiuese hospital to dust containing suspended louse

feces fronl the clothing of a patient with active tylvphus. Fromn 17 February to 28 July

1(.44 he ild received a total of 4.0) cc. of typhus vaccine iii IA) ('O . (loses. (O)n II May and

I ()ctober 1145, he received additional 1.0 cc. (loses of the Vac'ine. Oil ; Junue and

4 Aug.ust 1W45, serology was as follow.s: Weil-Felix negative, complement fixation I: 10

with epidemic antigen anmd negative with niurine antigen, and rickettsial aggilut i nation

1 :40 with epidemic antigen and negative with murine antigen.

On 22 November 1)45, the patient experience(d chilly sensations and generalized

malaise. The following day headache, apathy, anorexia, and irritability appeared. These

persisted during the next 2 days with chilliness, al1i although he felt feverish lie did not

take his temperature. (in the fifthl day, his temlperature wvais 101.80 F., pulse rate was

88, and respiratory rate was 20. Hleadache becamie niore severe and was predoominately

bitemporal. A persistent dry hacking cough set in and he vomited once. The next day,

sixth day of disease. lie refused hlotspital admission but finally took to bed in his quarters.

Headache became excruciating in severity, temperature rose to 102.20 F., and nausea and

coughl persisted. Although the temperature rose to 1413.80 F. the night of the seventh day

andi he became drowsy, there was suddenly a feeling (if relative well being the following

(lay with sudden resolution of fever by crisis and profuse sweats, lie wvas afebrile by the

9th (lay, and was out of bed on the 10th day, and back to work on the 13th day, although

he tired easily on exertion. The blood pressure remained normal throughout an(d there

was no rash. The lungs were clear.

The leukocyte count on the seventh day was 5,001. Oin the 13th (lay complete b)lod

count at an outpatient clinic showed 4,620.000 red cells, W0 percent hemoglobin, and 6,600

leukocytes with a differential of 64 percent segmented neutrophils, and 36 percent lymphocytes. On the 12th (lay, urine was negative except for a faiint trace of albumin with a

few leukocytes in the microscopic examination. These findings had disappeared by the

following day. (On the 21st day, electrocardiographic tracing was normal in all four

leads. The heart rate was 84, the PR interval was 0.16 second, sinus rhythni was present,

QRS complexes were 0.06 second, T waves were upright in all leads, and there were no

ST changes.

The serological changes are given in detail in table 15. Briefly, Weil-Felix reaction

became positive on the 7tlh (lay with a titer of 1 :40 and reached as high as 1: 80 by the

14th (lay. The complement fixation with epidemic antigen began to rise by the end of

the first week. reached its peak at 1: 1,280 at the end of the third week, and was still

positive by the ninth month. Rickettsial agglutination did not rise until the second week

but reached its peak at that tit~e with a titer of 1: 640 with epidemic antigen. It was

still positive by the ninth month.

The pertinent serological data on the three cases just mentioned are

given in table 15, and the essential clinical features of these and two other

vaccinated cases are summarized in table 16. Of particular interest, is the

method of infection. In each instance, there was evidence to indicate inhalation or conjunctival absorption of infected louse feces.
TYPHUS FEVERS 163

TABLE 15.-Serological findings and immunization record in three casei of epidemic typhus

fever incurred subsequent to immunization with typh us fever v(U'ine

Typhus vaccine I Sc4-roloviehal findings

D l)ate o.seruin l)i DeU-Felix of Complement Hickettsial

Ca•e ,pecimen lis±•ae flxation agglutination

D1)ate 'Amount

Ox X19 OX-2 OX-K Epidivn.ic .MurinvL Epi- _Mudemic line

I- 21 Feb. 1942-31 21.0 21 M ar._1944 -61 . ...I 1:8 1:4 ------- -

IMar. 1944 -A y 1944 47 1:-- 1 1:4 .....

J7 May 1944 7 1:80 -------------------------------- ------128-------- -----

6 June 1944 17 12----- 152 118--- -- --- 10 June 1944 21 1:0 - ---- 1:512 1:2568 -------

13 June 1944 24 1:20 - --- - 1:512 1:256

17 June 1944 28 - - 1:512 1:128 ..............

21 June 1944 32 - 1:512 1:128

24 June 1944 35 1:512 1:128

28 June 1944 39 - .---- 1:512 1:128 ..............

4 July 1944 45 - ------ 1:25 1:128 -

23 July 1944 64 - ----- 1:256 1:64-------------

3Aug. 1944 75 - .---- 1:256 1:32 ---------------

29 Aug. 1944 101 - ----- 1:64 1:16 ..............

10 Sept. 1944 119 - ---- 1:64 1:16 --------.-----

25 Sept. 1946 818 - - ---- 1:10 - - -------.......

2 -23 I....- Dee. 1941-10 12.0 7Apr. 1944 -77 -- 1:8- - - -

Oct. 1943.

22N•ov. 1943 ------- 1.0 21 Apr.1944 -63 - - - 1:8 -- -- ------

10 Apr. 1944 ------- 1.0 24 June 1944 2 - - 1:8 - -------.......

25 June 1944 3 - - - 18 -- ------

26 June 1944 4 - -- -- 1:8

30 June 1944 8 1:20 -------- 1:128 1:8 -----

2July 1944 10 1:80 ---- 1:128 1:32- -

4July 1944 12 1:160 1:40 ------- 1:256 1:32 -------- i ------

6July 1944 14 1:640 - - ------ 1:256 1:64 -------- -

11 July 1944 19 1:1,280 - - --- _ 1:512 1:64 -------- ------

23 July 1944 31 1:640 i 1:40-- ----- 1:512 1:64 -------- ------

29 Aug. 1944 68 1:160 - ---- 1:128 1:32 --------

24 Oct. 1944 1: ---- 1:128 1:16 .---------

7 Feb. 1946 595 - - ----. 1:20 -

3 ----- 17 Feb. -28 July 4.0 6June 1945 -169 - - - 1:10 - 1:40 -

1944.

9 May 1945 ---------- 1.0 4 Aug. 1945 -110 - - - 1:10 - 1:40 -

1 Oct. 1945 --------- 1.0 28'Nov. 1945 7 1:40 - 1:40 - 1:40 -

5 Dec. 1945 14 1:80 - 1:640 1:160 1:640 1:80

12 Dec. 1945 21 1:80 - 1:1,280 1:160 1:320 1:80

26 Dec. 1945 35 1:80 1:80 ------- 1:640 1:160 1:320 1:80

16 Jan. 1946 56 1:44) - 1:320 1:80 1:160 1:40

6 Feb. 1946 77 - - 1:320 1:40 1:160 -

1 27 Feb. 1946 98 - - .--- 1:320 1:40 1:160 -

26 Mar. 1946 125 - - ---.. 1:160 1:20 1:80 -

9 Nov. 1946 353 -- -------. 1:40 - 1:80 1:40

I Cox-type ether-extracted epidemic typhus vaccine.

2 Five cubic centimeters of this vaccine was of an experimental bivalent type containing epidemic and murine rickettsiae.

Source: Modified from Sadusk, 3. F., Jr.: Typhus Fever in the United States Army Following Immunization; Incidence, Severity of the Disease, Modification of the Clinical Course, and Serologic Diagnosis, J.A.M;A. 133: 1192-1199,

19 Apr. 1947.
164 INFECTIOUS DISEASES

L.~ ~ __ ._ .__ .

~ +

++ + I +- I

.- -92~

9z 0

06

'39 Eto m

or

E-4~
TYPHUS FEVERS 165

Sadusk's report was in keeping with other observations that the clinical

course of epidemic typhus is greatly modified when infection occurs subsequently to vaccination (chart 7). Fever is much lower and of shorter duration thi" in nonvaccinated cases, the extent and duration of rash are diminished, circulatory and nervous synmptoms are lesened, and the incidence of

complications is minimal. If hospitalization is necessary, the length of it is

reduced. The only symptom that is regularly present in vaccinated cases is

severe headache.

CHART 7.-Clinical counparison of raccipuited antd un raccinated groups

of typhus fever cases among employees of the Cairo Ferer Hospital,

El Abbasa, Egypt

UNIT

so

V'ACCINATED GROUP

50

UNVACCINATED GROUP

SEVERE

36

30 -

MILD

'26.4- 6...... ... MODERATELY

SEVERE

10 I"

NUMBER AVERAGE AGE DAYS OF SEVERITY OF DISEASE NUMBER

OF CASES FROM ONSET (NUMBER OF CASES) OF DEATHS

Source: Ecke, R. S., Gilliam, A. G., Snyder, J. C., Yeomans, A., Zarafonetis,

C. J. D., and Murray, E. S.: The Effect of Cox-Type Vaccine on Louse-Borne

Typhus Fever in Patients Who Had Previously Received One or More Injections

of Cox-Type Vaccine. Am. J. Trop. Med. 25: 447-462, November 1945.

Following is the only case known to have occurred in our troops in

Sicily.25 The patient, a private with the 77th Field Artillery, was admitted

to the 59th Evacuation Hospital, Palermo, Sicily, in the summer of 1943.

His history and clinical course were recorded by Lt. Col. (later Col.) William A. Reilly, MC, Chief of Medical Service, as follows:

A private claimed he was immunized against typhus in June 1941, and a recall dose

was given in June 1943. No record was obtainable. He left Africa on 13 July, after a

25 (1) Dr. Stanhope Bayne-Jones kindly brought this case report to the attention of the author

and made the records available for Inclusion here. (2) Letter, Lt. Col. William A. Reilly, MC, Chief

of Medical Service, 59th Evacuation Hospital, to Commanding Officer, 59th Evacuation Hospital, North

African Theater of Operations, U.S. Army, 21 Sept. 1943, subject: Resume of Typhus Patient's History, Photo, and Chart.
166 INFECTIOUS DISEASES

lon.g stay, and arrived in Sicily on 14 July 1943. lie does not know of having been bitten

by ticks, lice, or fleas.

lie was taken ill oil 23 August with headache, injected eyes, and fever. Fever disappeared by lysis oil 2 September (chart 8). On the third day of disease, 26 August.

a niaculopapular rash appeared on the trunk, thighs, and arnis, gradually increasing in

amount, intensity and distribut ion for tile next 5 days and being heaviest on the liits

(j1g. 11). In spots it was petechial and henujrrhlzgic and did not fade on pressure. No

tache noir or regii mal lyniphadeilitis wvas detected. There was a lniacular rash on huccal

inucosa. The pharynx was slightly reddenied. Between the fourth and eighth day. tile

eilar~ged spleen was palpable. (it the third and seventh day, bIe had 5,100 and 7,500 WIIC

norinally differentiated and uriiie specinenls were negative except for low specific gravity.

The boy was very ill, lost weight and stlrenigt h. There ,verv a few loose bowel nmovenments

between the seventh ald ninth days. A blood cultaure on tile liftlh day was negative.

Weil-Felix tests wvith the three I'ro'uus types were entirely negative oill tile a inthi day in

an Italian laboratory. ( )n the 11th day, the Proteus 0X-19 was positive 1:40, Proteus

OX-2 was positive 1: I(R). and P'rot'us OX-K was negative. A third Weil-Felix test, on

the 18th day of disease (10 September) showed a rising titer: ()X-19 was positive 1: 64"1,

OX-2 was positive 1: 1,280, and OX-K was negative. A guinea pig inoculated on tile

11th day, when temperature was normal for the first time, did not develop scrotal reaction. After fever subsided, tile patient gradually recovered strength, weight, and appetite.

No complications or sequelae were present 1 month after onset.

Only three confirmed cases of typhus occurredl aniong U.S. troops serving in the European theater, despite its prevalence aluong the civilian populations.26 Two infections were contracted in the Rhineland and one in the

Ironer Reich. All three patients had mild attacks of the disease, as indicated by the following brief case summaries : 27

Case 4.-A captain of the Medical Corps investigated a typhus outbreak at Fischbach,

Germany, on 23 March 1945. HIe was intimately exposed to tile disease while examining

and disinfecting patients but does not recall ever having found lice on his person. On

9 April, he developed a macular rash. He was never delirious, stuporous, or disoriented.

His convalescence was rapid and uneventful. A Weil-Felix test on 17 April was positive

in a serum dilution of 1: 640. The patient had not received a stimulating dose of typhus

vaccine since the original course in April 1944.

Case 5.-A lieutenant colonel, Medical Corps, accompanied the officer noted in case 4

(above) and both became ill on the same day. This patient's illness was even less severe,

with no rash at any time. He remained on quarters status, and returned to duty 15 April.

A stimulating dose of typhus vaccine had been administered on 23 March 1945, the day

previous to his exposure to the disease. The stimulation antedating that was in September 1944.

Case 6.-A sergeant of the 15th Infantry became ill 4 April 1945 complaining of pains

In the legs, headache, and fever of 102° F. He was admitted to hospital and observed

for several days. On 22 April he was transferred to a general hospital with the diagnosis

still undetermined. The patient had daily chills with fever up to 1040 F. for 11 (lays and

at one time developed a slight rash on the wrists, ankles, and abdomen. A Weil-Felix

test performed 5 May was positive in dilution of 1: 320. No likely source of infection

could be determined and there was clinical difference of opinion as to the identity of

the disease.

2r See footnote 15, p. 155.

27 Gordon, John E. : A History of Preventive Medicine in the European Theater of Operations,

T.S. Army. 1941-45, vol. 1. pt. III, p. 48. [Official record.]
TYPHUS FEVERS 167

CHAwr S.--Tempcruture chart •nid Pf'rtinent laboratory findinys of the only known caise

of typhus fevcir occurring among U.;. Army troops i Sictily, 1943

NAME- GRADE WARD 59TH EVACUATION HOSPITAL

AUGUST 1943 { SEPTEMBER 1943

PERIOD - --

26 27 28 29 30 31 I 2 3 4 5 6 4 DAYS 1

DAY OF 3 4 5 6 7 a 9 0 11 2 3 i4 LATER 1 DISEASE 2 3 4 __TER 8

TEMPERATURE ERF. TRANSFERRED TO WARD

105- .- ----------------

104 - _-

103 __

02 1 A_ -

100 -

99 --- -

N ORMUAL.

"--MALARIA SMEAR - IST WElL- FELIX '-GUINEA PIS INOCULATION

NEGATIVE NEGATIVE NO SCROTAL REACTION

BLOOD CULTURE GUINEA PIS SCROTAL REACTION-i RBC-4.76.NG.S5PRCN NEGATIVE 8 DAYS NEGATIVEWB-10

2D WEIL- FELIX- PROTEUS 0X-19* 1:40;-- 3D WEI L- FELIX -PROTEUS OX-i9+:64'0.

0X-2 + 1; 160; OX- K -NEGATIVE OX-2 *1;I 1,280, Ox-K-NEGATIVE

Fiouni 11.-Appearance of mnaculopaptilar rash on trunk, thighs, and arias on third dlay

of d1isease.
168 INFECTIOUS DISEASES

The Craigie (British Army) vaccine.--rhe cases of typhus fever acquired

after vaccination that have thus far been described occurred inl soldiers who

had received vaccine of the Cox type employed in all U.S. Armed Forces,

containing, as has been noted, soluble antigen and killed rickettsial microorganisms of epidemic typhus (R. prowazeki). British troops, on the other

hand, were inoculated with the Craigie vaccine, which consisted of two parts

of epidemic (R. prowa.zeki) and one part of murine typhus (la7'lkettsia

mwoseri) antigens. Soluble substances as well as killed micro-organisms were

included in the Craigie vaccine. In Germany, observing the tyvplus epidemic at Belsen, Davis 28 also had an opportunity to estimate the value of

this vaccine under epidemic conditions, collecting data on 14 cases of typhus

in British personnel who had been vaccinated more than 24 days before the

onset of their fever. Their clinical courses were milder and shorter than is

seen in typical epidemic typhus in nonvaccinated persons, with no deaths

and no serious complications. He noted as significant "the absence of serious

complications * * * Parotitis, gangrene, conjunctivitis, deafness due to

typhus, epistaxis, pulmonary consolidation, and pleuritic pains were never

observed in the British, although all were to be seen in the typhus patients

from the concentration camp. Their rash was never extensive, rarely developed into true petechiae which would not blanche on pressure. and never

formed ecchymoses. Delirium was observed in only 2 cases, and in these it

was brief. Roentgenograms of the chest were reported as normal or 'marked

increase in bronchovascular markings throughout both lungs.'" Determinations of blood nonprotein nitrogen were made on 10 patients about a week

after the onset of fever. Values ranged from 21 to 42 mg. percent in these

cases.

Davis also made observations on 16 cases of typhus in Hungarian soldiers who had only one or two doses of Craigie vaccine after exposure to

typhus at Belsen and 41 cases of typhus in well-nourished Germans who had

no vaccine. From a comparison of the three groups as shown in table 17,

and other data, it was concluded that Craigie vaccine was of definite value

in shortening the course and reducing the severity of epidemic typhus fever

when given in two or more doses from 24 to 100 days before the onset of

the disease.

The course of epidemic typhus fever was thus shown to be modified

favorably by prior vaccination with vaccine of either the Cox or the Craigie

type. The observations regarding the effectiveness of these two vaccines,

however, were not made under controlled or even similar conditions, and it

is not possible to draw conclusions as to their relative effectiveness from

these data.

28 Davis, W. A.: Typhus at Belsen. II. Clinical Course of Epidemic Typhus in Persons Who Had

Received Craigie Typhus Vaccine. Ann. Int. Med. 34: 448-465, February 1951.
TYPHUS FEVERS 169

TABLE 17.- Comparison of typhus in three groups at Belsen Concentration Camp, Belsen,

Germany

Average Age Average Duration dura- Deaths

Number Nationality Vaccination history (years) age of fever tion of (num-

(years) (days) fever ber)

(days)

14_____-British ------- Two to five doses Craigie 20-56 31.8 6-13 8.7 0

vaccine, all given more

than 24 days before

illness.

16_____-Hungarians___ One to two doses Craigie 18-38 28. 8 9-15 13. 6 0

vaccine, none given

more than 16 days

before illness.

41 ----- Germans----- No vaccine ------------ 20-52 25.9 13-24 14.9 2

Source: Modified from Davis, W. A.: Typhus at Belsen. II. Clinical Course of Epidemic Typhus in Persons Who

Had Received Craigie Typhus Vaccine. Ann. Int. Med. 34: 448-465, February 1951.

PATHOLOGY

Two important studies of the pathology of epidemic typhus fever were

undertaken during World War II. The first of these, 29 by Maj. Arthur C.

Allen, MC, and Dr. Sophie Spitz, at the Army Institute of Pathology (now

Armed Forces Institute of Pathology), Washington, D.C., entailed a comparison of the histological preparations and protocols of 78 cases of scrub

typhus (tsutsugamushi disease), 24 cases of epidemic (louseborne) typhus,

12 cases of Rocky Mountain spotted fever, and lung sections of 2 cases of

American Q fever. Since the principal emphasis of this study was placed

on the changes induced by scrub typhus, the main findings of the authors

are given in the chapter dealing with that infection (p. 132). However, a

number of other observations were made which are relevant here. The histology of the cutaneous lesion is described, as follows:

The macule of epidemic typhus histologically was essentially similar to that of scrub

typhus, although several differences were found. In the first place, although capillary

thrombi were present in all of the available sections of macules of scrub typhus as against

only 15, or 65 percent, of the macules in epidemic typhus, the thrombi were considerably

more conspicuous in the latter disease. They were more prominent not only because

more thrombi occurred in a single section, but because they were larger and were associated with more pronounced endothelial changes. In epidemic typhus, the affected endothelial cells tended to be larger, more hyperchromatic, and more often disintegrated into

chromatin dust, the last being a feature observed also In the capillaries of other organs,

Including the glomerular capillaries. Secondly, there was a tendency to the occurrence

In epidemic typhus of a necrotizing arteritis and thrombo-arteritis, not found in scrub

typhus. The necrosis might extend through the entire wall of the artery, unlike the lesser

degree of Involvement that is stated to occur in the experimental animal infected with

29 Allen, A. C., and Spitz, S.: A Comparative Study of the Pathology of Scrub Typhus (Tsutsugamushi Disease) and Other Rickettsial Diseases. Am. J. Path. 21 : 603-681, July 1945.
170 INFECTIOUS DISEASES

the rickettsiae of epidemic typhus. Indeed, in the human skill of cases of epidemic typhus

there may be infarct like hemorrhagic suppurative necrosis of the portions of corium in

association with severe arteritis. Thirdly, whereas no significant changes were noted in

the epidermis of the macule of scrub typllus, minor changes consisting of focal spongiosis,

patchy parakeratosis and focal "liquefaction degeneration" of the basal layers were infrequently observed in the skin of patients with louse-borne typhus.

The interstitial myocarditis and interstitial pneulnonitis of epidemic

typhus were intermediate in intensity between that produced by scrub typhus

and by spotted fever.

Changes in the adreial glands of patients with epidemic typhus were

similar to those of scrub typhus, except that there was a more conspicuous

focal mononuclear reaction. In addition, a few cases of epidemic typhus exhibited inflammatory and degenerative changes of capillaries and arterioles

of both parenchymal and adventitial tissues.

Similarly, lesions in the kidneys from patients with epidemic typhus

qualitatively resembled those of scrub typhus but were considerably more

pronounced. "Acute diffuse glomerulonephritis was found in 18, or 78 percent, of the cases; acute focal glomerulitis in 3, or 13 percent, and essentially normal glomeruli in 2, or 9 percent. The glomierular alterations were

basically those of scrub typhus, differing in more marked swelling and hyperchromasia of the endothelial cells, more frequent occurrence of thrombosis

of the glomerular capillaries and fragmentation of the endothelial cells.

Similarly, focal interstitial infiltrations, calcific bodies, hemoglobin casts of

the distal convolutions, and phlebitis, arteritis, and arteriolitis were more

conspicuous in epidemic typhus."

A comparison was made between reactions in the brain and meninges in

epidemic and scrub typhus. It was found that1. Although the meningitis of scrub typhus is slightly more frequent and extensive

than the qualitatively similar reaction in epidemic typhus, the involvement of the substance of the brain is considerably greater in the latter disease.

2. The distribution of lesions in the gray and white matter in the two diseases is the

same: In both the white matter is spared, in contrast with Rocky Mountain spotted fever.

3. In the current series the case incidence of involvement of the cortex in epidemic

typhus is much greater than in scrub typhus. The actual concentration of nodules in

the pons, medulla, and basal ganglia in epidemic typhus is more pronounced than in the

cortex. The pons and medulla are sites of predilection also in scrub typhus.

Several distinct histologic differences between scrub typhus and epidemic typhus are

noted :

4. The nodules tend to be larger in epidemic typhus, averaging 55 to 75 cells as

against 15 to 40 cells, and about 120 to 180 # as against 60 to 120 A.

5. There is somewhat greater cellular pleomorphism in the nodules of epidemic typhus,

especially In the larger. Karyorrhexis is common in the cells of the nodule of epidemic

typhus and rare In that of scrub typhus.

6. In epidemic typhus, the capillaries of the nodules show much more obvious evidence of damage in the form of markedly enlarged endothelial cells, karyorrhexis of

endothelial cells, and thrombosis of capillaries. Similar changes are found in arterioles

without associated nodules.
TYPHUS FEVERS 171

Thie. character of the, tissuie react ion ill these cases, suchl as fibritioid degenerat ion of collaggen. necrosis of lymph1)1 nodes and( spleen, thle predomliiiance of plasmna cells and basophilic macrophiages, and the acute glonierulonephrit is, led these observers to postulate that rickettsiae maY exert hyperer-gic

effects in addition to the better known diffuse vascular phIenlomneia caused by

them.

The second import ant invest igat ion of the pathology of epidemiic typhus

was initiated by the collection of material from 23 fatal cases studied b~y the,

U.S.A. Iyplmhls Commission in Cairo, Egypt, during 1943-45, which was reviewed by Spitz and Alleii. This, along wvith material from additional cases,

was subsequently studied by members of the Committee onl Pathology, D~ivision of Medical Sciences, National Research Council, in collaboration with

the Armed Forces Institute of P~athology. The splendid report 30 Of this

group) was not issued until 195-3 but lbecause of its broad scope and pertinence. to other work discussed in this chapter, the summary statement of this

studly is quoted, as follows:

This paper (lescribes the lesions elilc4(liltered in ant epidemic of typhus which occurred

lin Cairo during 11)43-1145. The tindiiigs have been compared to those ob)servedl by Wodbach, Todd, and P'alfrey in the Warsaw epidemic of 19)18 and by others since that time

lin order to lbriug together in one report all the knowmmi facts about the pathology of epidentic typhus.

The patients studied in the ('a iro epidemnic were Egyptians between the ages (of 10

kand 70 yeans. SRoni (if thent were bxlnoiihe.ht there was no clilnival or pa.thological evidence of avitaininosis, and1( some had clinically inactive qchistosomiasis. The

patients were adlmitted to the hospital (luring- the first 2 weeks of their (lisease, an(I the

clinical (liag-nosis of louse-borne typhus was confirined in many cases liy the WVeil-Felix

and complement tixation tests. lit some instances rickettsiae were recovered front blood

or from normal lice fed on the patientst. andl each st rain isolatedl showed the characteristics of louse-borne typhus. Two patienits wvere givena pa ra-am i nobenzoic acidl, without

clinical or pathological effects. The other patients. received no specific antityphus. treatment, andl none had been vaccinated against typhus. lin 14 paitients special efforts were

mnadle to reduce secondlary bacterial infection by using sulfonamnides and peniicillinl wuhen

necessary. This paper and the reports of the Unitedl States (of America Typhus ('ommaission on the clinical andl laboratory features. constitute one of the few comprehensive

account-% of an epidemic of typhus ini Egypt or, indeed,. in any tropical country. It seemis

likely, lin view of the (discovery of antibiotics that may be. effective in the treatment of

the disease and of the development of satisfactory vaccines, that there may nmever again

be at similar opportunity to study an epidemic of typhus which has not been significantly

modifihed either by treatment or by comnplicating infection.

The lesions discovered in the Cairo patients were essentially- the same as those

described in other epidemics in dlifferent parts of the world and in experimental animals.

The wide dissemination of vascular and other lesions lin the skeletal muscles, which was

well illustrated by the frequent involvement of the mutscles of the tongue, was more

apparent in Cairo cases thani in others, probably because abund~ant material was available

for miicroscopic examination. Evidence wvas obtainied by the demonstration of rickettsia30 Pathology of Epidenik, Typhus; Report of Fatal Cases Studied by the United States of America

Typhus Commission lin Cairo. Egypt, Duirinig 1943-1945. Prepared by the Committee on Pathology,

Division of Mledlial Sciences. Nationai Research Council W~ith Coliaboration of the Armed Forces

Institute of P'athology. Arch. Path. 56 : 397-435. October: 512-553, November 1953.
172 INFECTIOUS DISEASES

like bodies in sections of rags, which suggests, but does not prove, that a true

rickettsial pneumonia maily Interstitial ormhitis and prostatitis of a type not ordinarily seen in other infec., -eases was also' oblervid.

New information has been obtained concerning the topography of lesions in the central nervous system and the efft•t of the duration of the illness on the intensity of the

reaction. So-called inicroinfarets have been demonstrated for the first time in the brains

of patients who died from epidemic typhus.

(ilomerulonephritis did not occur in the Cairo patients, and a review of published

articles has led to the conclusion that its occurrence has not been proved. The bulk of

the evidence supports the idea that renal failure in epidemic typhus is probably due to

extrarenal factors, such as increased protein catabolism, dehydration, and reduction of

arterial blood pressure, rather than to primary renal damage brought about by direct

action of the rickettsiae. We have not beena able to convince ourselves that lower nephron

nephrosls occurs.

The pathological observations that have been briefly described here are

well illustrated in the Committee's report; selected prints are reproduced as

figures 12 through 32, through the courtesy of the Arcivyes of Pathology.
TYPbIItV FE~VER:S 1 73

Fiu;ujtF. 12.----(Top) Ca~pillary in derma slhowhiig swelling- and proliferation of endotheliumi to poinlt of occlusion. 'Slight perivaqcular accunmulation of mononuclear cells.

(X 430,

Fic~uui 13.- (Bottom) 1Finely ginmular capillary thrombuis, with pericapililary eollection or monomiuvitelo . cells in tleinniai ( x :112)
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TYPHUS FEVERS 179

DEVELOPMENT AND USE OF LABORATh PRY AIDS IN DIAGNOSIS

Along with the ad(vances in louse-control measures and immunization,

and extetlion of fundanmental kllowledge of the clinical and pathological

aspects of the disease, progress was also made during World War I in the

development of diagnostic laboratory procedures for epidemic typhus fever.

The most active work in this colinectioli was l)erfornlled at the Division of

Virus and Rickettsial Diseases. Medical Departmnent Professional Serice

Schools, Armyn Medical ('enter. Washington, 1).(., at. the Cairo Unit of the

U.S.A. Typhus Commission, and at the National Institutes of Health ill

Bethesda, Md.

Weil-Felix test.-In 1916, Felix 31 demlonstrated that sera from patients

with epidemic typhus fever would agglutinate suspensions of Proteus microor•anismns. Although it was soon recognized that these bacteria were not

etiologically related to typhus fever, the agglutination of Proteus organisms

was quickly developed into a diagnostic test for typhus. Further study revealed that Proteus vidgaris organismns could be dissociated into a motile

flagellated "H" type and a nonmnotile unflagellated "0" type. The diagnostic

agglutinin that appears in the blood of typhus fever patients is the somatic

"0" type. Additional experience prior to World War II indicated that suspensions of the Proteus OX-19 strain were agglutinated by sera from typhus

fever cases; that OX-19 and another strain, Proteus OX-2, were often agglutinated by Rocky Mountain spotted fever sera; and that suspensions of still

another variant, Proteis OX-K, were agglutinated by scrub typhus sera (p.

133). There remained, however, conflicting statements as to the time of appearance of the agglutinins during the course of illness, and concerning what

constituted a significant or diagnostic titer. Accordingly, early in 1943,

Plotz sought to determine the rise and fall of the various types of demonstrable antibodies in cases of epidemic typhus fever. Serial serum specimens

were obtained from 32 untreated and unvaccinated typhus fever cases studied

by members of the Typhus Commission in Cairo. Blood specimens were

obtained early in the disease, during the course of illness, and as long after

convalescence as possible. It was thus possible to establish patterns of antibody dynamics in cases confirmed, in 21 instances, as epidemic typhus by

isolation of the strain. The results of the various serological tests performed

on these sera were summarized in an important series of papers from the

Army Medical School.3 2

•31 Felix, A .: Die Serodlagnostik des Fleckfiebers. Wien. kiln. Wchnscbr. 29: 873-877, 13 July

1916.

32 (1) Piotz, H., Wertman, K., and Bennett, B. I. : The Serological Pattern in Epidemic Typhus

Fever. 1. The Development of Complement Fixing Antibodies. Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical Center, Washington, D.C., 1944. [Official record.] (2) Plotz,

I1., Wertman, K., and Bennett, T1. L.: The Serological Pattern in Epidemic Typhus Fever. II. The

Well-Felix Reaction. Division of Virus and Rickettsial Diseases, Army Medical School. Army Medical

Center, Washington, D.C., 1944. [Official record.] (3) Plotz, H., and Bennett, B. L. : The Serological

Pattern in Epidemic Typhus Fever. III. The Neutralizing Antibody. Division of Virus and Rickettsial

Diseases, Army Medical School, Army Medical Center, Washington, D.C., 1944. [Official record.]

6.19243V-63-- 15
180 INFECTIOUS DISEASES

In these cases, there was usually a high Proteu,8 OX-19 agglutination

titer, a low OX-2, and a negative OX-K reaction. A rise in titer was found

in all cases when early and late specimens were compared. A test was regarded a.z having diagnostic significance when the titer rose fourfold, occurring, in this group of cases, by the 5th to the 13th day of disease. Tests on

followup sera showed that the titer had fallen to insignificant levels within

about 3 months after the onset of illness. Table 18 shows the characteristic

pattern as observed in one of these patients.

TABLE 18.-Weil-Felix Proteus agglutination tests in epidemic typhus (case 1344)- strain

isolated

Serum titer with Proteus-- Day of disease _______ ______________

OX-19 OX-2 OX-K

4th ---------------------------------------- 0 0 0

5th ---------------------------------------- 0 0 0

6th ---------------------------------------- 0 0 0

8th -------------------- ------------------ 1:20 0 0

10th --------------------------------------- 1:320 1:20 0

12th --------------------------------------- 1:1,280 1:40 0

14th --------------------------------------- 1:640 1:40 0

19th --------------------------------------- 1:640 1:160 0

20t h --------------------------------------- 1:640 1:80 0

23d ---------------------------------------- 1:640 1:80 0

25th --------------------------------------- 1:320 1:80 0

27th --------------------------------------- 1:160 1:40 0

115th -------------------------------------- 1:20 1:20 0

286th -------------------------------------- 1:20 1:10 0

713th -------------------------------------- 1:40 0 0

Source: Wertman, Kenneth: The Well-FeliT Reaction. In Rickettsial Diseases of Man. Washington: American

Association for the AdvancemeL 'Science, 1948, pp. 184-189.

Using the identical macroscopic agglutination technique as employed in

the Division of Virus and Rickettsial Diseases, Zarafonetis 3 performed

WVeil-Felix tests on 1,002 sera from 203 eases of epidemic typhus fever. Two

or more serum samples were tested from each of the patients who had been

studied clinically in Egypt, Greece, Yugoslavia, and the Dachau Concentration Camp in Germany. All of these patients had survived their disease,

and sufficient time had elapsed for the development of antibodies if they

were to appear in amounts detectable by these tests. A summary of the

(4) I'lotz, H.. and Snyder. J. M.: The Serological Pattern in Epidemic Typhus Fever. TV. Rickettsial

Agglutination. Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical Center, Washington. D.C., 1944. [Official record.]

33 Zarafonetis, C. .. D. : The Serological Reactions in the Rickettsial Diseases of Man. In Rickettsial Diseases of Man. Washington: American Association for the Advancement of Science, 1948,

pp. 179-183.
TYPIIUS FEVERS 181

Proteus OX-19 agglutination results is given in table 19. An agglutination

titer of 1: 160 or more developed in 191 (or 94 percent) of these subjects.

Sera in five cases were entirely negative, serat in four others gave complete

agglutination only to a dilution of 1: 40, and in three more, to 1: 80. Of

interest was the finding that the complement fixation tests yielded diagnostic

titer changes in all of these patients. Thus were the WVeil-Felix and complemnent fixation reactions found to be dissociated phenomena. A similar

dissociation was also demonstrated for the Weil-Felix and rickettsial agglutination responses. (See p. 185.) Tlii:, significant observation is illustrated

in table 20.

TA3BLE 19.-Weil-Felix Proteus OX-19 agglutination results on 1,002 sera from 203 patients

with typh us fever

Maximum tier I Cases Cases Percent Percent

cumulative cumulative

Negative ------------------------------- 5 203 2.5 100.0

1:40 ----------------------------------- 4 198 2.0 97.5

1:80 ----------------------------------- 3 194 1.5 95. 5

1:160 ---------------------------------- 9 191 4.4 94.0

1:320 ---------------------------------- 13 182 6.4 89.6

1:640 ---------------------------------- 21 169 10.3 83.2

1:1,280 --------------------------- 24 148 11.8 72.9

1:2,560 --------------------------------- 30 124 14.8 61. 1

1: 5,120 and over ----------------------- 94 94 46.3 46.3

Total ---------------------- 203 100.0 ,

I Complete agglutination in dilution given.

Source: Zarafonetis, C. J. D.: The Serological Reactions in the Rickettsial Diseases of Man. In Rickettsial Diseases

of Man. Washington: American Association for the Advancement of Science. 1948. pp. 179-183.

Wertman 4 summarized the wartime experience with the Weil-Felix

reaction and constructed the following table to indicate the usual findings

in the various rickettsial diseases of man (table 21). He pointed out that,

despite the introduction of specific diagnostic reagents, the Weil-Felix reaction remained a valuable laboratory aid, as follows:

* * * The value of the Proteus agglutination test is that these antibodies appear

somewhat earlier than the specific ones. The antigen is easy to prepare and the technic

can be performed in any diagnostic laboratory. It should be emphasized, however, that

a significant test is one in which a rise in antibody titer can be demonstrated and no

single titer should be regarded as significant. Since one rickettsial disease cannot be

differentiated from another by means of this test, it must be regarded as only a diagnostic aid. The demonstration of the presence of specific antibodies, either complement fixing or rickettsial agglutinating, is necessary to establish a final serologic diagnosis.

34 Wertman, Kenneth: The Well-Felix Reaction. In Rickettsial Diseases of Man. Washington:

American Association for the Advancement of Science, 1948, pp. 184-189.
182 INFEC'TIOUS DISEASES

TABL. -E*.--,E4eroloyieal Iindingis in threc ttiphus rasesm tith mcgatirc VciI-Fcli.r OX-19

aglglutination results

Serologieal findings

D)ay of ("itse di.A. I ksComplement fixation Rickettsial agglutination

SWeil Felix

OX-19

Epidemic Mturine Epidemic Murine

'166 - 8 Negative- : 640 !: 40- : 6-10 I: 320

15 1:2 .: 2,564) - 1:320 1: 10,240 1:5,120

22 Negativ 1: 1.,280---- 1:164) 1 :5,120 .. !:2,56W)

30 - - do (:1,220S 1:80--- 1:2,5564) l:1,280 90 !-----do ----. 1:i160) _ 1: 10 - _. . 1:160- .. . 1:40

204S._ 5 do- 1: 2561 Negat 1: 1,281K 1:320

10 do--- 1:1,024 I : 1: 5,120 . 1:1,280

15 _do__ 1:512 ..... Negative 1:2,560). 1:640

112 - -do----- 1:32 ...... .... do.. 1:80- 1:80

3696__ 12 -- do_-- 1::64- -do 1: 320- 1: 160

17 -do-- 1:1,024 - ---- do--.. :1,2 0--__- 1:640

34 . -do__ 1:1,024 ___do-__- 1:640- -- 1:640

43 do- - 1:1,024 --------- do ------ l :640-.. 1:320

47 ----- do__ 1:512__ - ----- do-I 1:640- - 1:160

77 _____do_____-1:512 -- ----- ddo ....- Negative-_ Negative

117 ----- do. 1:128.-_-do... --- do- Do.

I End point titer was not reached.

Source: Zarafonetis, C. J. D.: The Serological Reactions in the Rickettsial Diseasei of Man. In Rickettsial Diseases

of Man. Washington: American Association for the Advancement of Science, 1948, pp. 179-183.

TABLE 21.-The usual Weil-Felix reactions in rickettsial diseases

Proteus

OX-19 OX-2 OX-K

Epidemic typhus- . + + + + 0

Murine typhus.. i + + ++ + 0

Scrub typhu .. 1..... 0 ++ + +

crbtphus ---------------------- :)I0±±+

Qfever ------------.------------------- - 0 0 0 .J+++± + 0

Rocky Mountain spotted fever --- ------- + + + 0

Source: Wertman, Kenneth: The Weil-Felix Reaction. In Rickettsial Diseases of Man. Washington: American

Association for the Advancement of Science, 1948, pp. 184-189.

Wertnian further describes the limitations of the Weil-Felix reaction:

In the first instance, it is impossible to differentiate epidemic typhus, murine typhus,

and Rocky Mountain spotted fever by this technic. * * * Secondly, positive reactions

have been reported with sera from eases other than those of rickettsial origin. * * *

Lastly, the Protcu8 agglutinins in rickettsial infections disappear In late convalescence:

therefore, the test cannot be employed as a survey tool to determine the qualitative or

quantitative degree of past Infection in a given area.
TYPHUS FEVERS 183

Tile next step was to (letermile what serological changes were induced

by vaccination as carried out in U.S. troops with vaccine of tile Cox type.

In a series of serological studies at the Cairo laboratory of the Typhus Commission,3 5 it was demionstrated, first, that a 1.0 nil. stimulating (lose of typhus

vaccine in 100 multivaccinated individuals resulted in no significant change

in Weil-Felix agglutination titers in tests with suspensions of Proteuw OX-19,

OX-2, and OX-K on sera taken before and 2 weeks after the injection. Secondly, no anamnestic reactions were detected when these tests were performed

on sera from 104 febrile patients who had previously been vaccinated.

Finally, serological tests were performed on serial serum specimens from! 29

cases of suspected epidemic typhus develop)ing subsequently to vaccination.

Here, it was found that the titer changes in Proteus OX-19 agglutination

tests were greater than those in the first and second groups and were. furthermore, of sufficient magnitude to have diagnostic significance. Examples

of results in typhus cases occurring after vaccination are, given in table 15.

Complement fixation tests with rickettsial antigens.-Nunlerous investigators were aware of the limitations of the Weil-Felix tests and strove to

develop specific rickettsial antigens for use in complement fixation and agglutination tests. The preparation of pure suspensions of rickettsiae in sufficient quantity was an obstacle until, in 1938, Cox introduced the yolk-sac

culture method. Using this method of rickettsial cultivation, Bengtson 36

prepared antigens and successfully performed complement fixation tests upon

sera from nlurine typhus cases. In 1942, Craigie:'7 demonstrated that rickettsiae could be separated from yolk-sac suspensions by ether extraction,

thereby eliminating most of the embryonic egg materials. This made available essentially pure suspensions of rickettsiae for use as antigens in serological tests and vaccines. Indeed, Wertman 38 later showed that this method

actually increased the specificity of the rickettsial suspensions by removing

about half of the syphilitic antigens normally present in tissues of the embryonic chick. Plotz and his associates39 soon noted that sera from both

epidemic and murine typhus patients gave complement fixation titers with

both epidemic and murine antigens. These investigators found that by repeated washing and centrifugation of the rickettsial suspensions a "soluble

substance" present in the supernatant fluid could be removed. This process

35 (1) Zarafonetis, C. J. D.: Serologic Studies in Typhus-Vaccinated Individuals. I. The Effect

of a Stimulating Dose of Typhus Vaccine on the Well-Felix and Complement-Fixing Antibodies.

J. Immunol. 51: 365-374, November 1945. (2) Zarafonetis, C. J. D.: Serologic Studies in TyphusVaccinated Individuals. II. The Effect of Non-Typhus Fevers on the Well-Felix and ComplementFixing Antibodies. J. Immunol. 51: 375-388, December 1945. (3) Zarafonetis, C. J. D., Ecke, R. S.,

Yeomans, A., Murray, E. S., and Snyder, J. C.: Serologic Studies in Typhus-Vaccinated Individuals.

I11. Well-Felix and Complement-Fixation Findings in Epidemic Typhus Fever Occurring in the Vaccinated. J. Immunol. 53: 15-30, May 1946.

36 Bengtson. I. A.: Complement Fixation in Endemic Typhus Fever. Pub. Health Rep. 56: 649--

653, 28 Mar. 1941.

37 See footnote 19, p. 156.

38 Wertman, K. : Nonspecific Complement-Fixing Antigen in Embryonic Egg Tissues. J. Lab. &

Clin. Med. 30: 112, February 1945.

39 See footnotes 32 (1), p. 179; and 20 (1), p. 156.
184 INFECTIOUS DISEASES

also served to eliminate the remainder of the syphilitic antiggen. The resuspended rickettsial suspensions were then shown to be essentially specific for

homologous sera. Thus was made possible the serological differentiation between epidemic and endemic typhus, with obvious epidemiological as well as

clinical significance.

This specific complement fixation test was used in several laboratories,

but comprehensive data for nonvaccinated cases were recorded primarily at

the Army Medical School and by the Cairo Unit of the Typhus Commission.

At the Army Medical School, Plotz and his coworkers performed systematic

complement fixation tests on the sera from the Cairo series of 32 unvaccinated patients with typhus fever (p. 179). All of these patients showed a

rise in titer in tests with epidemic antigen; 56 percent gave positive complement fixation by the 10th day, 78 percent by the 12th day, and 100 percent

by the 16th day of illness. Most of them gave fixation with epidemic antigen and no fixation with murine antigen (table 22). 11here cross-fixation

did occur, the titer with homologous (epidemic) antigen was always higher

than with murine antigen. All cases showed persistence of complement fixing antibodies, even when specimens taken many months after onset of the

disease were examined.

TABLE 22.-Complement fixation test results in case 1344, epidemic typhus-strain isolated

Day o disea Serum titer withEpidemic antigen Murine antigen

4th ------------------.----------------------------------- 0 0

5th ------- -------------------------------------------- 0 0

6th --------------------------- - -------- 0 0

8th ------ ----------------------------------------------- 0 0

10th ----------------------------------------------- 1:20 0

12th ---------------------------------------------------- 1:1,280 0

14th ---------------------------------------------------- 1:1,280 0

19th ---------------------------------------------------- 1:640 0

20t h ---------------------------------------------------- 1:640 0

23d ----------------------------------------------------- 1:640 0

25t h ---------------------------------------------------- 1:640 0

27t h ---------------------------------------------------- 1:640 0

115th --------------------------------------------------- 1:80 0

286t h --------------------------------------------------- 1:40 0

Source: Plotz, it., Wertman, K., and Bennett, B. L.: The Serological Pattern in Epidemic Typhus Fever. I. The

Development of Complement Fixing Antibodies. Division of Virus and Rickettsial Diseases, Army Medical School,

Army Medical Center, Washington, D.C., 1944. (Official record.]

Employing the same technique and antigens prepared by the Division of

Virus and Rickettsial Diseases, Zarafonetis 40 performed complement fixation tests on 1,002 sera from 203 cases of typhus fever, with results sum40 See footnote 33, p. 180.
TYPHUS FEVERS 1 S5

marized in table 23. Almost all of tile cases were epidemic typhus fever,

confirmed in many instances by isolation of the strain. In only two patients

did the complement fixation titer with murine antigen equal or exceed that

obtained with epidemic antigen. Sera from two of the cases failed to develop

titers in complement fixation tests with either epidemic or murine typhus

antigens, while both showed good responses in Weil-Felix OX-19 and rickettsial agglutination tests. From the serological findings in these two cases

(table 24), it appears that the rickettsial agglutination response. is dissociated from the antibody that gives rise to complement fixation. From this

and from similar observations with the WVeil-Felix test (p. 181), it is seen

that all three of the -serological reactionis occur independently of one aiotlher,

and one test may be negative while the other two give a positive finding for

typhus fever.

TABLE 23.---Complement firation results on 1,002 sera from 203 patients with typhus fever

Purified epidemic antigen Purified murine antigen

Maximum titer Cases Percent Cases Percent

Cases cumu- Percent cumu- Cases cumu- Percent cumulative lative lative lative

I Nit m- Nu m- Nu n- Nua m- ber Ur ber ber

Negative ---------------------- 3 203 1.5 100.0 124 203 61.1 100.0

1:8or 1:10 ------------------- 0 200 0 98.5 11 79 5.4 38.9

1:16or 1:20 ------------------ 2 200 1.0 98.5 16 68 7.9 33.5

1:40 ------------------- 3 198 1.5 97.5 21 52 10.3 25.6

1:64or 1:80 - 18 195 8.9 96.0 12 31 5.9 15.3

1:128or 1:160-_ 28 177 13.8 87.1 4 19 2.0 9.4

1:256 or 1:320 ------ 37 149 18.2 73.3 8 15 3.9 7.4

1:512or1:640_ o - 46 112 22.6 55.11 5 7 2.5 3.5

1:1,024 or over-----------------66 66 32.5 32.5 2 2 1.0 1.0

Total ------------------ 203 100.0 203 100.0

Source: Zarafonetis. C. J. D.: The Serological Reactions in the Rickettsial Diseases of Man. In Rickettsial Diseases

of Man. Washington: American Association for the Advancement of Science, 1948, pp. 179-183.

It now remained to determine the effect of vaccination per se on the

complement fixing antibodies. Tests were made on sera taken before and 2

weeks after a 1.0 ml. stimulating dose of typhus vaccine in 100 multivaccinated subjects (p. 183). Sera from 21 of these individuals gave epidemic

complement fixation titers ranging from 1: 4 to 1: 32 before the stimulating

dose, while 2 weeks later sera from 70 of the subjects were positive in dilutions ranging from 1:4 to 1: 128. Where there was an increase in complement fixation titer as a result of booster vaccination, there was a tendency

to return to the previous level within 8 weeks after the booster injection.

The question of anamnestic reactions was studied in 104 persons who

had been immunized with vaccine of the Cox type at some time before the
186 INFECTIOUS DISEASES

TABLE 24.--Serological findings in two cases of typhus fever with negative results in compleiment

fixation tests

Serological findings

Day of

Case disease Complement fixation Rickettsial agglutination

OX-19 Epidemic 'Murine Epidemic Murine

16261L_- 4 1: 160 -.. Negative Negative - -

6 1: 1,280- -do- -.- .do- - Negative 1 :160

8 1:5,120 - -......do..-- - do- 1:40- 1:1,280

10 1:5,120 - ----do- -do- 1:160 1:2,560

12 1:5,120 ------ do- -do-- 1:160_ 1:10,240

15 1:5,120_-----do_ -do- 1:320- 1:5.120

17 1:5,120 '---do -.do _ 1:320- - 1:5,120

1)-857__ 4 1:160 .... .. !t ._do_ - -- do- ... 1:160 . - 1:40

11 1:1,280- _do-. -do. 1:1,280- 1:320

18 1:1,280- -do -do ..... . 1:1,280 ---- 1:160

24 1:640 _..___ do --------. do 1:320 ------ 1:80

I End point titer was not reached.

Source: Zarafonetis, C. J. D.: The Serological Reactions in the Rickettsial Diseases of Man. In Rickettsial Diseases

of Man. Washington: American Association for the Advancement of Science, 1948, pp. 179-183.

febrile illness that led to their hospitalization (p. 183). No significant increase in complement fixing antibodies occurred in them as a result of the

nontyphus fevers.

With these studies as background, Zarafonetis and his coworkers,41

studying 29 vaccinated patients with proba/ble epidemic typhus fever, found

that the diagnosis could be made serologically provided the possible effects

of vaccination per se were evaluated as well. A higher degree of cross-fixation was encountered in these tests than had been found in nonvaccinated

patients with epidemic or inurine typhus fever. An example is shown in

table 25. This patient was proved to have epidemic typhus fever by isolation

of the strain. The high degree of cross-fixation present in the sera was not

due to a peculiarity of the strain itself, since sera from guinea pigs infected

with it gave high titers in complement fixation tests with epidemic antigen

but were negative in tests with murine antigen. Because of the observed

cross-fixation, it was deemed unjustifiable to attempt differentiation between

epidemic and murine typhus in vaccinated persons on the basis of the complement fixation test alone.

In seeking an explanation for the cross-fixation, it. was noted that the

same lots of antigen were used in both the vaccinated and the unvaccinated

groups and in the latter revealed no lack of specificity. Again, tests on

sera from guinea pigs infected with two strains isolated from the vaccinated

patients gave clear-cut identification of epidemic typhus fever. Accordingly,

41 See footnote 35 (3). p. 183.
TYP|II'S FEVERS 187

TABLE 25.--Serological findings in a patient with epidemic typhus fevers contracted after

receiving 5.0 cc. of Cox-type vaccine

Serological findings

Day of disease Weil-Feiix Complement fixation

OX-i_

Epidemic Murine

8th ------------------------- N egative . 1:4__ 'N egative

19th 1:160 ---- 1:512- - - 1:512

30th... . .. 1:160 ..... 1:512--- 1:512

40th._ .. 1:80 .... - 1:512-.-- 1:256

83d- ... ....... ........... ..... ... . N egative- 1:512 - 1:128

162d ----- do -- 1:256 1:16

I Verified by strain isolation.

Source: Zarafonetis, C. J. D.: The Serological Reactions in the Rickettsial Diseases of Man. In Rickettsial Diseases

of Man. Washington: American Association for theAdvancement of Science, 1948. pp. 179-183.

with the antigens known to be specific and the possibility of "intermediate"

strains ruled out, it appeared that the increased amount of cross-fixation

was the resui, of the vaccination itself. Furthermore, in vaccinated subjects without typhus there was a higher amount of cross-fixation than one

would expect. It appeared, therefore, that vaccination introduces some factor that gives rise to cross-fixation and that this is simply exaggerated by

subsequent infection. The following hypothesis was advanced:

Several workers have Ihoted the presence of a soluble substance in epidemic and

murine rickettsial suspensions derived from infected yolk sacs. This soluble substance

is common to both strains and if present in antigens used In complement fixation tests

is reslpnsible for cr(wss-fixation with heterologous sera. Plotz and his coworkers removed

this soluble antigen from rickettsial suspensions and these purified rickettsial antigens

gave little or no heterologous fixation. The antigens used in this laboratory are similarly

purified rickettsial suspensions and haw demonstrated their specificity in nonvaccinated

typhus cases.

While this soluble material is responsible for cross-fixation in complement fixation

tests, it also has immunogenic properties. Topping and his associates have found that

this material produced positive Weil-Felix reactions in rabbits, and that guinea pigs were

immunized as judged by the stimulation of immunity to challenge with guinea pig passage

material. They also found that it produced complement fixing antibodies when injected

into guinea pigs. These findings were considered sufficient to warrant the retention of

the soluble material In vaccine preparations such as are In use today.

Thus, antigens for complement fixation tests are purified by removing the soluble

sub-stance, while vaccines retain It for its Immunogenic properties. Therefore, an individual vaccinated with Cox-type epidemic typhus vaccine receives both epidemic rickettsiae

and soluble substance. It seems reasonable to assume that an immunogen'.c response will

be elicited by both of these components of the vaccine, though this may not necessarily

be detected In serologic tests. Subsequent infection with typhus rickettsiae stimulates a

further antibody response, including a soluble substance component which fixes complement in the presence of both epidemic and murine antigens. In other words, a complement fixing antibody against both epidemic and murine rickettsiae results from inocula639243v--6.3----16
188 INFElTrlI•S' D ISEASEX

tioll with vaccilne et.utailingg a soluhle substan'e. This anitiboly gives rise to eross-fixation,

thus tending to (ounteract the specificity tof altige•lis purified by removing the soluble

Substance.

Rickettsial agglutination.-ILiinited agglutination studies with rickettsial

suspensions had been perfornmed by a number of investigators prior to World

War II. Ini most of the early tests, a microscopic technique was used, but

with the development of mnethods for producing larger yields of rickettsiae,

mlacrloscopic tests offered pronmise of practical application. Stuart-Harris

and his ass'ociates' 42 using epidemic and mnlrine suspensions p)repared from

the hungs of mice infected by the intranasal route, detected agglutinins in

guiniea pig and humnan convalescent sera. They concluded that differences

between epidemic and inurine typhus could be (lemonst rated by rickettsial

agglutination. Van Rooyen and Bearcroft .3 were the first to employ suspensions of epidemic and murine typhus micro-organisms prepared from

yolk-sac cultures and purified by the ('raigie extraction technique. They

usedi a macroscopic agglutination technique with sera fronm patients with

typhus fever and concluded that a differential diagnosis between epidemic

and murine typhus was possible with this test.

Plotz and Synder " undertook an evaluation of rickettsial agglutination

with purified antigens similar to those employed in the complement fixation studies that have been described (p. 183). Again, the specimens tested

consisted of the sera obtained front the 32 unvaccinated patients in Cairo.

Agglutinins occurred in rising titer in all cases during the course of the

disease. Table 26 summarizes the results in one of the patients. It, may be

seen that the titer obtained with epidemic typhus antigen exceeds that found

with the niurine typhus antigen, but there is more cross-reaction here than

was noted in the complement fixation tests on the same specimens (table 22).

In extending the test to sera from patients with other diseases, it was found

that titers were obtained at times. These workers concluded, therefore:

"Since epidenmic and murine agglutinins may occur in convalescent specinmens

from cases of Rocky Mountain spotted fever, occasionally in high titer. caution

should be observed in evaluation of this test when used as a diagnostic

procedure."

Regrettably, routine rickettsial agglutination tests were not performed

in tile Cairo laboratory of the Typhus Commission partly because the procedure utilizes about. 10 times the amount of antigen employed in complement fixation. In the vaccinated patients with epidemic typhus fever, the

serological tests did not, therefore, include rickettsial agglutination. Data

obtained in tests on sera front one such patient, however, are given in

table 15 (case 3). In tile section (p. 204) dealing with murine typhus, it

42 Stmart-Ilarris. C. Hl.. Rittle. G. K. C.. and Oliver. J. 0. : Rickettsial Agglutination Studies in

Tyi•ihs Fever. Laneet 2 : 537-538, 34 Oet. 1943.

41 Van Rooyen. C. E., and Beareroft. W. c.. C. : Typhus RIekettsial Agglutination Tests in the

Middle East Forees and Egypt. Edinburgh M.J. 50 : 257-272. May 1943.

44 S•e footnote 32 (1) and %4). pp. 179--10.
TYPHUS FEVERS 189

TABLE 26.--Ricketlsial agglutination test restilts in case 13.# ý -strain isolated

Serum titer with1)ay of disease

Epidemic Endemic antigen antigen

4 th .. ~ . . .. . . . . . . . . . . . . . . . . .. . . . 0 0

5th ---.-----.-----.--.--------- -------------------- 0 0

6th ----------------.------------- 0 0

8th --------.--.--------------------------.---------- - 1:80 1:40

10th --------.--------.-----------.---.----------.--- 1:640 1:160

12th ----------------------------------------.------- 1 1:2,560 1:160

14th --------------- -------- ------------------------- 1:5,120 1:1,280

19th .------------------------------------- - - 1:10,240 1:1,280

20th -..--------- _-.---------------- ---------------- - 1:10,240 1:1,280

23d ------- -- -_ ---- ------ --- ..- ---- . .--- -- -- -- -- -- -- -- 1 :10 ,2 40 1 :1 ,2 80

25th -------------------------------------------------- 1:5,120 1:640

27th -----------------------------------.--------------.-- 1:5, 120 1:640

115th ----------------------.----------------------------- 1:160 1:40

286th ----------------.---------------------------------- 1:80 1:10

Source: Plots, II., and Snyder. J. M.: The Serological Pattern in Epidemic Typhus Fever. IV. Rickettsial Agglutination. Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical Center, Washington, D.C.,

1944. [Official record.]

has been suggested that the rickettsial agglutination test may be more specific

in vaccinated individuals than is the complement fixation test.4 5 Further

information on the antibody responses of patients acquiring epidemic typhus

fever after vaccination would be required to establish this point.

Neutralizing antibody test.-In 1940, Gildemeister and Haagen 48 described the association of a toxin with living murine typhus rickettsiae

grown in yolk sacs of developing chick embryos. These workers were interested in producing a vaccine and, among other questions to be answered,

wished to establish whether rickettsiae grown by this technique had kept

their pathogenicity for white mice. Accordiigly, they injected a suspension of yolk sac infected with R. rnooseri intraperitoneally into white mice

in 0.5 and 1.0 ml. amounts. To their surprise, all the mice died w:.thin 4 to

20 hours, some in convulsions. Further study oi this finding revealed that

this effect was due to the presence of a rickettsial toxin and that the toxin

was destroyed by heating to 60' C., or by treating with formalin; that is, it

was destroyed by procedures used to kill the rickettsiae. Finally, they

demonstrated that convalescent serum from either epidemic or murine

typhus would neutralize the toxin.

45 Plots. H.. and Wertman, K. : Modification of Serological Response to Infection With Murine

Typhus by Previous Immunization With Epidemic Typhus Vaccine. Proe. Soc. Exper. Biol. & Med. 59:

248-251, June 1945.

48 Gildemeister, E.. and Haagen, E.: Fleckfieberstudien. I. Mitteilung: Nachweis eine." Toxins In

Rickettelen-Eikulturen (Rickettsia mooseri). Deutsche Med. Wchnschr. 66: 878-880, 9 Aug. 1940.
119)0 INFEC'TIOUIS IDISEASES

Following tile report of Gildeineister and llaagen, Bengtson and her

coworkers " found that a toxic substance was present in yolk-sac cultures

infected with epidemic typhus rickettsiae. Henderson and Topping48 then

showed that this toxic substance could be neutralized by convalescent epideulic tyhlhus serilim, and devised a neutralization test. in mice which was

adopted by the National Institutes of Health as the standard potency test

for typhus vaccines. At about the saime time, hlamilton,4 demionstrated

that the toxins associated with suspensions of living epidemic and inlurine

typhus rickettsiae were imnmunologically separable as were the antibodies

that neutralized theni.

Plotz and Bennett 50 undertook an evaluation of the nouse neutralization test as a possible laboratory tool for use in the diagnosis of typhus

fever. Emnploying sonie 13,000 mnice, they carried out neutralization tests

on the serial serum specimens obtained from the 32 Cairo cases of epidemic

typhus fever. In recording the results of this study, complete protection

indicated that all mnice tested at a given serum dilution survived: partial

protection. that one or more but not all of the aninmals survived; and ?o

protectiopk, that all the mice in a group (lied. For uniformity in recording,

the 50 percent end point of each titration was determined by the method of

Reed and Muench. Table 27 illustrates tile neutralization titers obtained in

tests on sera from one of the Cairo cases. Actually, neutralizing antibody

appeared during the course of illness in all of the cases studied; 28 percent

developed neutralizing antibodies by the 6th day, 75 percent by the 8th day,

and 100 percent by the 11th day. The curve of neutralizing antibody response was quite similar to that obtained in Weil-Felix Proteus OX-19

agglutination tests on the same sera.

Of additional interest were the results obtained by the same authors

when epidemic typhus neutralization tests were performed with specimens

of serum from cases of Rocky Mountain spotted fever. The patients from

whom the specimens were obtained had not been given any typhus vaccine,

nor did they have a history of typhus fever. Neutralizing antibodies for

epidemic toxin were found, however, in 11 cases of Rocky Mountain spotted

fever studied. This finding indicated that the epidemic neutralizing antibody was not restricted to epidemic typhus fever, and hence, these workers

concluded that the mouse neutralization test is not reliable as an indication

of a past infection with typhus.

Isolation and identification of R. prowazeki strains.-Isolation of the

causative agent and identification of it through appropriate means is classically the only absolute method of diagnosis of an infectious disease. Strain

47 U.S. Public Health Service, Federal Security Agency: National Institute of Health Bulletin

No. 183. Studies of Typhus Fever. Washington: U.S. Government Printing Office, 1945, pp. 25-29.

4- U.S. Public Health Service, Federal Security Agency: National Institute of Health Bulletin

No. 1:3. Studies of Typhus Fever. Washington: U.S. Government Printing Office. 1945, pp. 41-56.

49 Hamilton, 1f. L. : Specificity of the Toxic Factors Associated With the Epidemic and Murine

Strains of Typhus Ricke*ttsiae. Am. J. Trop. Med. 25: 391-395, September 1945.

50 See footnote 22 (3). p. 179.
TYPHUS FEVERS 191

TABLE 27.-Epidemic neutralizing antibody findings in case 1344-strain isolated

50 percent end 50 percent end

Day of disease point titer final Day of disease point titer final

dilution dilution

4th--------------------------0 19th ---------------------- 2,580

5th -------------- 0 20th ---------------------- - 1,444

6th 0 23d ------------------------ 1,618

8th- 25 25th ----------------------- 1,618

10th ---------------------- 90 27th ---------------------- 722

12th- 645 115th --------------------- 161 14h2, 048 286th --- ---- 14th -------------------- ,4 8t--------------------51

Source: Plotz, ii., and Bennett, B. L.: The Serological Pattern in Epidemic Typhus Fever. IIl. The Neutralizing

Antibody. Division of Virus and RickettsalW Diseases, Army Medical School, Army Medical Center, Washington, D.C.,

1944. [Official record.]

isolation of R. prawazeli was, therefore, often performed in the field laboratories of the U.S.A. Typhus Commission in order to establish a firm basis

for the observations made in their various investigations. In addition to the

obvious importance of strain isolation for diagnostic purposes, it was also

desirable for laboratory comparison of immunity relationships between

strains that were isolated during epidemiological surveys in various parts

of the world. Strains of It. prowazeki were also available for special vaccine production if differences in immunogenic properties from the Breinl

strain (employed in the U.S. Army vaccine) had become manifest. Strains

were used further in the laboratory evaluation of chemotherapeutic agents

and in the preparation of antigens for serological tests.

Guinea pigs were, of course, invaluable in the initial isolation of typhus

fever organisms, either from the ground clot of blood drawn from the patient

early in the course of illness or from ground infected lice. The Cairo Unit

of the Typhus Commission maintained a colony of noninfected lice for use

in such studies.51 Pill boxes containing approximately 200 lice each, and

prepared with a. fine-mesh cloth screen through which the lice could feed,

were often carried by members of the Typhus Commission to distant points

of survey. The lice were fed on their persons until such time as an

appropriate case of suspected typhus fever was found. The pill box would

then be attached with adhesive tape to the patient's leg for about 10 days.

At the end of this feeding period, the louse box was carefully removed and

sealed in an envelope, not to be opened again until the worker had returned

to the laboratory, often hundreds of miles distant from the patient. At the

laboratory, the material was carefully ground and injected into guinea pigs

for the conventional isolation-of-strain procedure. In this manner, for

51 Snyder, J. C., and Wheeler. C. M. : The Experimental Infection of the Human Body Louse,

Pediculus humanun corporis, With Murine and Epidemic Louse-Borne Typhus Strains. J. Exper. Med.

82: 1-20, July 1945.
192 INFE~CTWUC 1)ISEASE8

exampjle, one officer 51 was ab~le to isolate in Cairo 1t) strains of le. protra-eki

fromt partisan soldiers ill -with typhlus in Yugoslavia during March 1945.

StipIlies of guiinea pigs were limiited so that field studies were often

hampered. F~or this reason, the obs-ervat ion of Snyder and his coworkers 53

that t wo desert rodlents, namely, 6erbilu8m gerbil/us and (Jerbillu.v pyraimhdum.. were susceptible to expewrimntel i typhus infection p~roved to be

valuiable for the studies of tile Typhus 1 ommimssion in Cairo.

The developing chick embryo was emphlloyedl for cuilt ivat ion of fl. pro wazeki in largeý quantities for vaccine lprodnctioii and for antigeins, as has been

noted. However, the emlbrvonated egg was not widely used for direct isolation of rickettsiae fromt the blood( of patients ill with typhus fever, and the

(iegree of successful stratin isolat ion that might be achieved throuigh this

technique renmains to be dletermined.

TREATMENT

The treatmnent. of epidemtic typhus fi'-ver miay be comnsidered in two broad

categrories. F'irst a re the general supplort ive mleasu~res ill-m~ichuimi goodI nursimorpn..

p~art icuilar at tent ion to (liet, flutids and electrolytes, and appropriate nianagremment of comnp1licat ions as they a rise. These nmeasurevs have been out iine(I

(1p. 1531) with the observations and reasoning onl which they were batsed, and

nceed little exposition here.

Supportive therapy-IDiligent nursing care is required throughout tile

febrile lperiodl anid also (luiring coiivalescence. The po~sit ion of sent istummporous

patients shoulid be changedl often to p~revenmt bo~th skini and pulmonary cornpl ications. The, oral cav'ity shouldl be cleansed frequently ini an effort to

p~revenit parotitis. Careful attention mlust be given to fluid intake aind outp)ut. As inuch as 4.000 cc. of fluids may be. requireti daily. preferably

admiin istered orally. Suippleniental intravenous ffluidls shouldl be gi veni whenever necessary to maintain fluiid balance. With resp-et. to diet, high hproteinl

and caloric intake is associatedl with less loss of weight and a shorter period

of convalescence. In severe cases, nonl rish ing, p~rotein andl carbohmydlrate nmixtumres may be given via anl indlwelling stomach tube. D elirium and extreme

restlessness may be controlled by chloral hydrate or parmldehyde, bit lbarhituiirates act lunIredietablyh.

Trhe present discussion is chiefly concerned with sp~ecific- treatmeneut. inchiding serotherapy,, the use of antibiotics, amid cpiemiot liera pv. and somne

consideration is griven to prop~hylaxis.

Serotherapy.-inunune seruim had beeni used by at nmimber of workers iii

the treatment of louseborne typhuts prior to World War 11. hlumnman conm52 Meniorandtim,n Msii. Chris J. 1). Zarafonetis. MIC. to BrIg. Geit. S. Bakyne-Jones. Di)reetor. U.S.A.

Typhiim Commission. 27 Apr. 1945. suibject : Typhus strains from Yugoslavia.

N .Sydr . C.. Zarafonetis, C. J. D).. andi In. W. T. :The Susceptibility of the Rodents.

Gc,?lu erbillum eblm anid Gc,-billua pyram idimn, to Experimental Typhus Infection. Prov. goe. Exmx-r.

Bliol. & 'ted. 59 : 110-112. June 1945.
TYPHUS FEVERS 193

valescent serum generally showed no noticeable effect on the course of the

disease, while there were conflicting rel)orts regarding the efficacy of sera

obtained from animals that had recovered from experimentally induced

typhus. With improved techniques for the growth of large quantities of

rickettsiae, however, the hyperhninunization of animals was facilitated. Refined, concentrated antityphus serum was prepared from rabbits hyperimmunized with suspensions of infected yolk sacs of developing chick emnbryos. 54

Serum prepared in this manner was shown to have a strikingly protective

effect in experimental typhus.'-

Knowledge of this laboratory experience prompted Yeomans, Snyder,

and Gilliam 56 to undertake a clinical trial of hyperimmune rabbit, serum in

patients admitted to the ward of the Typhus Commission at the Cairo Fever

Hospital. This study was begun in April 1943: 25 patients with typhus

were treated. All were skin tested for sensitivity to the serum, and, if negative, serum therapy was adlministered. The total amount of serum given to

each varied from 51 to 512 cc., with an average (lose of 186 cc. for this group

of patients.

Therapeutic effectiveness of hyperinmmune rabbit serum was found to

be related to the duration of illness at the time treatment was instituted.

The results in 10 patients treated on the second and third day of the disease

were almost uniformly good. The 15 patients who had been sick for 4, 5,

or 6 days before serum wal given did not show a striking difference in

clinical severity from the "untreated" controls, except that there were no

fatal cases. Of the 25) patients who received hyperimmune rabbit serum,

7 developed mild serum sickness.

Another opportunity to test the efficacy of serum therapy presented

itself to the U.S.A. Typhus Commission group working at the Dachau Concentration. Camp in May and June 1945.'17 Ten patients admitted to the Comnmission ward were given hyperimmune antityphus rabbit. serum on the

following dosage schedule: In the first 24 hours after admission, 0.5 cc.

per pound of body weight; on the second and third days, 0.25 cc. per pound

of body weight. All of the serum was injected intramuscularly in the

buttocks after appropriate skin testing. Owing to limited supply, the

average amount administered to these subjects was less than was given to

the patients in the Cairo series. This may be the explanation for results less

impressive than those obtained in the Cairo study. The illness in four

patients was mild, four were moderately ill: and one was severely ill. The

10th patient treated died of widely disseminated tuberculosis 4 weeks after the

54 Kurotchkmn, T. J., van der Scheer, J.. and Wyckoff. R. W. G. : Refined Hyperimmune Rickettsial

Sera. Proc. Soc. Exper. Biol. & Med. 45: 323, October-December 1940.

55 Wyckoff, R. W. G.. and Bobnel. E.: Therapeutic Effect in Guinea Pigs of Hyperimrnune Epldemic Typhus Antiserum. Proc. Soc. Exper. Blol. & Med. 49: 712-715, April 1942.

5• •eomans, A.. Snyder. J. C.. and Gilliam, A. G..: The Effects of Concentrated Hyperimmune

Rabbit Serum in Louse Borne Typhus. J.A.M.A. 129: 19-24, 1 Sept. 1945.

57 See footnote 14, p. 155.
194 INFE'TIOUS I)ISEASES

onset of typ)hus fever. The average duration of fever iIn the treated cases

was 15.2 days as opp)osed to 16.2 days in 121 "untreated" control cases.

Serum sickness appeared in 5 of the I0 patients treated.

It is of interest to observe that the hyperiiiliune serum did not have a

rickettsiocidal effect, for Plotz andi his coworkers as isolated rickettsiae from

11 of the Cairo patients after the serumn had been given. From the prolonged incul)ation periods noted in isolating these nicro-organiisms in guinea

pigs, it was postulated that the serum may have exerted a rickettsiostatic

effect. Finally, these workers suggested that the beneficial clinical effect

attributed to hyperiniiune rabbit serum --as due to its ability to neutralize

the toxic sul)stance elaborated by typhus rickettsiae.

Antibiotics.-IIn 1944, (-rude commercial penicillin was shown to inhibit the

growth of typhus rickettsiae in the yolk sac" and markedly to reduce, or

even comnp)letely p)revent, niortality from murine typ)hus infection in mice.60

Clinical trials of penicillin, however, wer-e limited in both the number of

cases treated and the dosages administered. For example, Col. William S.

Stone, M(C, Chief, Preventive Medicine, Medical Section, North African

Theater of Operations, U.S. Army, and Captain Woodward of the Typhus

Commission made availal)le to British workers in Italy "' 4 million Oxford

units of penicillin for trial in the treatment of epidemic typhus fever. Four

l)atients were treated, none before the sixth day of disease. The total amount

of penicillin dosage ranged from 509,000 units to 800,000 units. T'wo of the

four l)atients died.

Penicillin was giv'en to four additional cases of epidemic typhus fever

on the Typhus Conimission ward in ('ailo.6 2 Yeomans and his coworkers

could not determine on the basis of this limited experience whether penicillin given early, and in whit' were then considered "large amounts," did

or did not affect the course of typhus. The potential use'fulness of penicillin

for the treatment of secondary bacterial infections superimposed on typhus

fever, however, was recognized by them soon after this antibiotic became

available.

Postwar studies by Greiff and Pinkerton 63 with pure crystalline penicillin fractions revpu led important differences in the rickettsiostatic activity

of the different fractions. Penicillin X was about four times as effective en

a unit basis as pencillin G, and there were differences in the potency of other

fractions. From this, it would appear that the irregular results reported

58 Plotz, H.. Bennett, B. L., and Tabet. F. : Effect of Concentrated Hyperimmune Rabbit Serum

on Circulating Agent in Louse Borne Typhus. Proc. Soc. Exper,. Btol. & Med. 63 : 176-178. October 1946.

59 Greiff. D., and Pinkerton, H. : Inhibition of Growth of Typhus Rickettsiae iTt the Yolk Sac by

Penicillin. Proc. Soc. Exper. Bioi. & Med. 55 : 116-119. February 1944.

60 Moragues, V., Pinkerton. H., and Greiff. D. : Therapeutic Effectiveness of Penicillin in Experimental Murine Typhus Infection in dba Mice. J. Exper. Med. 79: 431-437, April 1944.

61 Medical Resareh Council, Special Report Series No. 255, Chemotherapeutic and Other Studies

of Typhus. London : His Majesty's Stationery Office. 1946. pp. 78-81.

62 See footnote 6. p. 147.

63 Greiff, D.. and Pinkerton, H. : The Rickettsiostatlc Action of Crystalline Penicillin Fractions In

Embryonate Eggs. Proc. Soc. Exper. Bio. & Med. 68: 228-232, June 1948.
TYPtlUtS FEVERS 195

could have been due to varying proportions of the penicillin fractions in

the preparations used. These workers concluded that. the clinical trials

referred to above were invalidated by the use of low (loses, started late in the

course of the disease, by the small number of cases, and by the fact that

fractions of p)roved potency against R,. proirazeki were not employed. The

effectiveness of penicillin inl human rickettsial infection, therefore, remained

undetermined.

The newer broad-sp)ectrum antibiotics were not discovered until after the

period under review and so are not included here, but their importance will

be indicated at the end of the discussion of therapy.

Chemotherapy.-A new chalpter in the treatment of epidemic typhus

fever and other rickettsial diseases was begun during World War II with

the observation that PABA exhibited antirickettsial activity in vivo. This

was discovered independently by Snyder, Maier, and Anderson in 194264

and by Greiff. Pinikerton, and Moragues in 1944.65 Its use was suggested

to the former group by the apparently deleterious effect of sulfonamides on

the course of experimental typhus infection and the knowledge that PABA

and sulfonamides are metabolic antagonists. The second group of workers

first tried PABA in an effort to enhance the action of p)enicillin. Still a

third discovery of the inhibitory effect of PABA on the growth of tyl)hus

rickettsiae was made in 1944 by Takemori, working at the Hygienic Institute

in Dairen, Manchuria."4

The letter report. of Snyder and his associates was circulated in laboratories known to be, concerned with rickettsial diseases. At the Army Me(lical

School, Hamilton, Plotz, and Smadel 67 undertook a systematic study of the

effect of PABA and related substances on the growth of rickettsiae. Inoculating the test. compound directly into the yolk sacs of infected chick

embryos, which were allowed to develop until death resulted from rickettsial

infection, they found a marked difference in survival time of the treated

eggs as compared with the controls (chart 9). In addition, it was shown

by direct count of rickettsiae in eggs, opened after an arbitrary period of

time, that their numbers had been greatly reduced in those treated w~th

PABA in comparison with the relatively rich growth in the controls.

The percentage of embryos protected with 2 mg. of PABA was, in

general, higher than when 4 lmg. (approximately 70 mcg/nml.) was used,

'4 Letter, J. C. Snyder. John Maier. and C. R. Anderson. International Health Division, The

Rockefellcr Foundation. to Division of Medical Sciences. National Research Council, 26 Dec. 1942,

subject: [Report on Chemotherapy of Typhus Fever].

65 Greiff. D.. Pinkerton. H.. anti Moragues, V. : Effect of Enzyme Inhibitors and Activators in the

Multiplication of Typhus Rickettsiae. I. Penicillin, Para-Aminobenzoic Acid, Sodium Fluoride, and

Vitamins of the B Group. J. Exper. Med. 80: 561-574. December 1944.

(W Takemort. N. : The Actions of Sulfonamide Compounds and p-Aminobenzoic Acid on the Virus

of Lymphogranulomna Ingulnale and Typhus Rickettsiae in Vitro. Japanese Med. J. 2: 1-,. February 1949.

(7 Hamilton. H. L.. Plotz. H.. and Smadel. J. E. : Effect of p-Aminobenzoic Acid on the Growth

of Typhus Rickettsiae in the Yolk Sac of the Infected Chick Embryo. Proc. Soc. Exper. Biol. & Med.

58: 255-262. March 1945.
196 INFECT'IOUS DISEA~SE

suggesting at toxic effect of excessive 1PABA. Eveni so, the niecessity for

using quantities of PAIIA upl to 2 m;g. to inhibit rickettsial growth ill anl

egg~ stuggested the possibility that a ntonspecific effect muight, be involved.

Accordingly, two isomers, ort ho- an~d mlet a-amiinobenzoic avid, ats well as

acet vl-p-aininobenzoic avid (bothl sierilized b)'y heat and sterilized by Seitz

filtrat ion), sulfanilanmide, sodium benzoate, anid benizoic acid were tested inl

concentrations eqluivalent to the miaxinmal (lose of IPABA (4 ing. p~er eggr).

With the exception of the heat-sterilized acetyl (derivat ive. none of these

substances had any apparent effect onl either thle time of (death or the number

ChARL~T 9.-Effect of 1j(1rU-fiftinoben~oie field (Ott time of deoith in

chiick emibryos inf ctled 01th Ric ket tsia prowalzek 1

[Cuniulati, percent of dead emibryos]

PERCENT

100

so CONTROL

- SURVIVORS

60

40 0" PARA - AIANODE NZOIC ACID

20

DAY OF DEATH AFTER INOCULATION

source Hlamiliton. 11. L.. 1'iotz. It.. and Smazdel. J. E. :Effect of j)- Ain~obenzoic Acid on the Growth of Typhtis Rickettsiae In the Yolk Site of the

Infected Chick Embryo. P~roc. Soc. Exper. Biol. & 'Med. 58: 255-2612,

March 1945.

of rickettsiae. Heating hyvdrolyzes a, certain portion of acetyl-P1ABA into

PABA, w-hich is the probab~le exp~lanation for the above observation. These

studies c'learly indicate that thle. inhibition of growth by PABA is (tie to a

specific action of the. drug.

Ani outstanding series of investigat ions by (4reiff ""and his colleagues

shedl further light onl the mechanismi of action of PABA inl rickettsial infections, as shown by Greiff inl tile discussion which follows.

The riekettsiostatlc action of para-aininobenzoic acidi, first observed by Snyder anld

his co-workers in mice, later confirmedI in the yolk sac by Ham&nilton and others and still

later (because of war-time secrecy) observed Independently in our laboratory, is a rather

68 (1) See footnote 65. p. 195. (2) Greliff, Donald: Biology of the Rickettslae. In Rickettmittl

Disenases of Man. Washington : American Association for the Advancement of Science, 1948, pp. 51-63.
TYPHUS FEVERS 197

striking example of the inhibition of an intracellular parasite by a compound usually

regarded as a vitamin. Pinkerton and Bessey showed that in riboflavin-deficient rats,

practically moribund from typhus, riboflavin had a striking "chemotherapeutic" action,

causing rapid recovery from what appeared to be overwhelming and certain fatal infection. With the sudden resumption of cellular respiration when the missing link is furnished, the normal resistance of the rat is restored. With this fact in mind we have

been interested in learning the mechanism of action of PABA, and particularly in determining whether or not this compound like other compounds and conditions found to

discourage rickettsial growth, causes an increase in the cellular metabolic rate.

In conjunction with our earlier work, we proved conclusively that cyanide had no

effect on the rickettsiostatic action of PABA. From this fact we concluded that 1PABA

e ,ther acted directly on the rickettsiae, in a manner similar to the action of sulfadrugs

on bacteria, or that PABA, like toluidine blue, increased cell respiration by short-circuiting

the cyanide sensitive system of respiratory enzymes.

Recently we have developed a reliable method for measuring the oxygen consumption

and carbon dioxide output of fertile eggs. In 3 separate experiments, we have found

that the injection of PABA into the yolk sac markedly increases the oxygen consumption.

The effect is noted after a delay of about 5 days, which is perhaps caused by slow

absorption of the precipitated compound from the yolk sac. From the 5th to the 10th

days after injection (almost exactly the period of active rickettsial multiplication) the

oxygen consumption continues to be 25-50 percent above that of the uninjected control

eggs. This of course does not prove that the rickettsiostatic action of PABA is due solely

to Uts indirect action in increasing cellular respiration, but in view of the facts previously

brought out, this seems to be a reasonable assumption.69

Greiff commented further in summarizing the work of his group:

Conditions such as low temperature and riboflavin deficiency, which decrease the rate

of cellular metabolism, favor the growth of rickettsiae. Higher temperatures and certain

dyes and other agents which increase cellular metabolism are unfavorable to rickettsial

growth. Our experiments indicate that the activity of the cyanide sensitive respiratory

enzyme (cytochrome oxidase) is one essential factor in the protection of cells against

rickettsial multiplication. In the case of toluidine blue and para-aminobenzoic acid, however, rickettsiostatic activity is correlated with increased cellular respiration brought

about by mechanisms which are cyanide-insensitive.

Clinical studies designed to determine the therapeutic effect of PABA

in epidemic tylphus fever were begun on the ward of the Cairo Unit of the

Typhus Coinlnission in 1943. Yeonmans, Snyder, Murray, Zarafonetis, and

Ecke 7o were able to report in 1944 that the drug had a favorable influence

on the clinical course of patients whose treatment was begun in the first

week of the disease. These studies were continued through 1945, both in

Cairo and at the D)achau Concentration Camnp, 71 and a summary of the

results of treatment of a cumulative total of 95 patients suffering from

typhus fever was later issued.72

6.) Recent observations indicate that PABA enhances monamine oxidase activity. This may represent the pathway through which increased oxygen uptake Is mediated by PABA.

70 See footnote 6, p. 147.

71 See footnote 14, p. 155.

72 Snyder. J. C.. Yeomans, A.. Clement, D. H., Murray, E. S., Zarafonetis. C. J. D., and Tierney,

N. A. : Further Observations on the Treatment of Typhus Fever With Para-Amino-Benzoic Acid.

Ann. Int. Med. 27: 1-27. July 1947.
198 INFECTIOUS DISEASES

The nmost carefully controlled observations were miade it Cairo. Here,

patients were. placed alternately in control and (PABA-treated groups. The

study groups were comnposed of 39 male Egyyptian patients, ages 18 to 48,

suffering from epidemic typhus fever. The diagnosis was based on the

clinical course, serological findings, and, in 19 instances, isolation of fl. prolvazek' from the blood or from normal lice fed on the patients during the febrile

period. None of the patients had been vaccinated against typhus fever or

gave a history of a previous attack of the disease. Most were somewhat

CHART lO.-('ouipurixon of temperatures of 20 para-aminobcnzoic acid treated patients and

19 alternate control patients. Cairo, Egypt. 1944 and 1945

(Mean daily rectal temperatures are plotted for each group, zero day being the day of admission of

4-ach patient to the study (the mean duration of illness at the time of admission for both groups was

4.4 days). The temlperatures of fatal cases are included up to the last reading before death qoiiirredI

TEMPERATURE

*.r

41.0

40.0

40 -CONTROL CASES ",/•

39C 01

380TREATED CGASES X, 38.( C

NORMAL ------------------ -

37.0 0 I 2 3 

'- 4 

4 ' S 'L 5 6 ; ? i 9 10 l) II 1 12 2 13 3 144

DAYS AFTER ADMISSION TO STUDY GROUPS

Source: Snyder, J. C., Yeomans, A., Clement, D. H., Murray, E. S., Zarafonetls. C. J. D., and

Tlerney, N. A. : Further Observations on the Treatment of Typhus With Para-Amino-Benzoic Acid.

Ann. Int. Med. 27: 1-27, July 1947.

underweight. but appeared to be in good physical condition otherwise. A

few of the patients were subsequently found to have subclinical schistosomiasis, but none was excluded because of this finding. One PABA-treated

patient developed an exacerbation of amebic dysentry( during convalescence

from typhus, but his case was included in the results. The patients were in

the first week of illness when they were placed in the control and PABAtreated groups in automatic rotation.

In the 19 control subjects, mean values were as follows: Age. 27.9 years;

duration of illness when admitted to the group, 4.4 days; duration of fever,
TYPHUS FEVERS 199

17.9 days (chart 10). The incidence of conmplications was higher in this

groul), and there were six fatal cases.

lit the 20 patients treated with PARA, nmean values were as follows:

Age, 28.5 years; duration of illness when treatment was started, 4.4 days;

duration of fever, 12.8 days. The incideence of complications was less than in

the control groulp, and there wits one death in this series.

The treatment regimen to be followed with PABA was evolved only

after considerable exl)erimentation. Yeonmans and his coworkers 73 outilined

the phul of therapy, as follows:

In all instances, PAIIA was adiniiiisteredl by mouth. The initial dose varlied from

4 to 8 gin. In the majority of cases, the initial dose was followed by 2 gin. every 2 hours

unless the concentration in the blood attained excessive values. Adjustments in dosage

were made in relation to fluid intake and urinary output. The fluid intake in nearly all

instances was adequate to maintain the output of urine between 1,500 and 3,000 cc. in

24 hours.

The effort was made to keep the concentration of PABA in the blood between 10 and

20 lug. per 100 cc. PABA is absorbed and exereted very rapidly, so that a 2-hourly

schedule of administration was decided on as that most likely to produce a relatively

constant blood level. l)eterminations nade at various times during treatment indicated

that the 2-hourly schedule was effective in maintaining a satisfactory concentration of

PABA throughout the period of therapy.

PABA was continued for varying lengths of time in the first cases. Subsequently,

it was decided that treatment should be continued until the Imtient's rectal temperature

was 37.5' C. (.99.5* F.) or less for 24 hours. The average amount of PABA for each case

was approxinately 127 gui. The patients who are the subject of discussion in this study

received PABA for at least 3 days.

Nausea and vomiting attributable to PABA occurred in the first few cases. Thereafter, in order to lessen gastric irritation, sufficient sodiunm licarboiate was given to neutralize the PABA. The acidity of the urine was determined at least once daily during

therapy. The amount of sodium bicarbonate was varied as required to keep the urine

apl)roximately neutral in reaction. After this plan was adopted, vomiting was encountered very infrequently.

PARA was available in tablets of 0.5 gin. each and in capsules of 0.3 gin. each.

Neither form was suitable for administration to typhus patients, who could not be persuaded to swallow the large numbers of tablets or capsules required for each dose, but

they took powdered PABA readily if it was suspended in water or partially dissolved in

a sufficient volume of 5 percent sodium bicarbonate solution to render the mixture slightly

alkaline. The usual amount was 2 gin. of powdered PABA with 25 cc. of sodium bicarbonate solution.74 After swallowing the mixture, the patient was quickly given water to

take away the slightly unpleasant taste of the drug. This method of administration was

entirely satisfactory in most instances.

Premature withdrawal of PABA therapy was followed by a mild febrile

period which probably represented a mild recrudescence of the disease. For

73 See footnote 6, p. 147.

74 Postwar experience in the treatment of hundreds of nontyphus patients has shown that a chilled, 10 percent aqueous solution of pure prescription-grade potassium para-aminobeuzoate (Potaba)

Is much more readily tolerated than the relatively crude mixtures employed during these typhus

studies. In retrospect, It would seem that even better results could be achieved in typhus with Potaba

if the need should ever arise again.
24 K) INFEtwIIOU?. I)ISEASES

this reason, it was found advisable to continue the initial course of PABA

for 48 hours after the patient's temperature had returned to normal.

At no tinme were crystals of PABA ever noted in the urine of the patients

treated. There was detected, however, a slight tendency to leukopenia during this forin of therapy. Snyder and his coworkers 15 found the mean of

the lowest counts was 5.200 per cubic millimeter for 19 control patients,

while the inean for the 20 patients treated with PABA was 4,100 per cubic

millimeter, but the difference was not statistically significant. Analysis of

the differential leukocyte counts did, however, reveal a slight but statistically

significant reduction in the percentage of segmented neutrophils (69.9 percent was the mean for the controls, and 55.1 percent was the mean for the

treated group) and all increase of a similar percentage in the lymphocytes.

The differences in percentages of monocytes, eosinophils, and basophils were

not significant. Although slight depression of the neutrohlhils was attributable to the adiliiii1stration of PABA, no instance of true agranulocytosis was

encountered in these studies.

PABA was thus discovered to have important antirickettsial activity

and, throng', -t udies as just dlescribed. was brought to the position of a safe

aid promising drug for clinical use during World War II. Its importance

in the managenment of epidemic typhus fever an(i other rickettsial diseases

was short lived as a result of the postwar development of broad-spectrum

antibiotics. 76 The wartime studies with PABA may vet be shown, however.

to have grieat significance both from the standpoint of rickettsial growth

factors and as a clue to certain intracellular metabolic processes.

75 See footnote 72, p. 197.

76 PABA has since been supplanted by the broad-spectrum antibiotics, which have greatly simplified

the treatment of epidemic typhus fever. Properly used, these will reduce the mortality of the disease

very nearly to zero. Chloramphenicol. Aureomycin (chlortetracycline). and Terramycin (oxyltetracycline) are all effective, and usually bring about dramatic Improvement within 24 to 72 hours after

institution of therapy. Woodward and Parker (Woodward. Theodore E.. and Parker, Robert T. :

Clinical Application and Mode of Action of Antibiotics in Rickettsial and Virus Diseascs. In The

Dynamics of Virus and Rickettsial Infections. New York: The Blakiston Company. Inc.. 1954, pp.

437-457.) consider the following dosage schedules to be optimal. For chloramphenicol. the initial

oral dose is 50 mg. per kilogram of body weight, and for Aureomycin and Terramycin, 25 mg. per kilogram of body weight is given. Maintenance doses are calculated on the basis of 50 mag. per kilogram

per day for chloramphenicol. and 25 mg. per kilogram per day for Aureomycin and Terramycin. The

total daily requirement is given in equally divided doses at 6- to 8-hour intervals. Administration of

the antibiotic employed is continued until the patient has improved and has been afobrile for about

24 hours. When oral medication Is not feasible, the Intravenous route may be used. The initial dose

of chloramphenlcol should be calculated on the basis of 20 mg. per kilogram of body weight, and Aurmomycin and Terramycin on the basis of 5 to 10 mg. per kilogram of body weight. Subsequent daily

requirements are calculated in the same manner. divided into four equal doses which are administered

at l-hour Intervals. Undesirable side effects such as nausea, vomiting. glossitis, diarrhea, anti proctitis are more commonly encountered with Aureomycin and Terramycin than with chloramphenicol.

The newer related antibiotic, terracycline. appears to be equally effective with less toxicity. There

have been no reports of hemopoietic depression from the short-term use of chloramphenicol in rickettsial diseases.

Cortisone has been combined with broad-spectrum antibiotic therapy in rickettsial diseases. Headache was promptly relieved, toxicity disappeared. the appetite returned, and the fever lasted less than

2 days on average. The addition of cortisone to the treatment regimen should especially be considered

in late, severely ill, extremely toxic patients.
TYPHUIS FEVERS~ 201

Prophylaxis.- Prevei t ioi i of ep~idemlic typ)hus fever was mtade practical ule

during W~orld W'ar 11 with the production of adequate (quanitities of a

p)otent vaccitie and1( by impijroved inethods of louse control.

Personnel ili the Armed Forces of the United States were vaccinatedi

with antiti'plius vaccine of the C'ox type. Although 104 caseAs of ep~idlemic

typ)hus were (detected inl U.S. troops, ilhere was not at single deathtI. Typhums

contracted after vaccination is, thierefore, relatively mild and rarelv if ever

causes dealli. Furthiermore, lice fed onl patijents whlo were vaccinateti before

acquiring typhus develop very few rickettsiae inl comparison to lice fed onl

unvaevinatedl patlients. rims, Vacciniat ion niot only alters the susceptibility

of tile individual but, when used onl a broad scwale, also serves to reduce the

ep~idlemic po)tenltial of the disease.

Ill thle complemlenltary effort Ito prevent the disease b etroving tile

vector, ai nmbelr of ilivents were developted, the muost effective being DD1T

diclordipenvtrciiorothae) A lo) percent I)I) powder dusted into

the clothing was found to p~rovidle almost complete prlotect ion against lice

for :i weeks or nmore.- l)l)T or other insecticiole lx)ow(ers are of grreatest

import ance whenl cond it ions ptreva il which are favorable for ani epidemic.

During World War 11. tile vigorous application of delousing mieasures inl

tile prevention or promplt control of typhuts epidemics was anl historic accomnplishmnlenlt inl tile' annals of preventivtle 1nedlivine.',

Part 1T. Brill's Disease

It is now recognized thiat liiill's disea-se is clinical recrudescence of a

prevousepitemnic.t.pu inifectiton. Tlievii' lsat ive minivro-orgranisit) R.pol

e4 may rentainl latent ill an individual for years followving Ilthe original

infection. As immunity wanes. andI possibly influenced by still undetermined

factors, the rickettsiaue are act ivatedi and give rise to illness which often

resembles that associated with thle primiary infect ion.

HISTORICAL NOTE

Nathan Brill first des.cribed the dlisordler ill l89S and again inl 1910 as

anl acuite infectious dlisease' of unuknown origin. Ilis reports were lhase(1 onl

the study of -221 cases occurring sporadically ill New York City during mtore

thanl a diecadle of obser-1vationi. Ili-ils clfinical descript ion is classic, Ilie also

notedi that Widal tests and blood cuiltures were negrative and( called attention

to thle s-inilarit y of fthe disease to typhlus fever.

Additional cases wvere soon reported by othiers. and inl 1910, Anderson

andl Goldbe'rger showed by cross-inmnunity tests that Brill's disease was

-7 Xonie stralins of live encouiitered during the recent Korean confllet. however, were T)PT resistant

tiHurlbut. It. X.. Altman. R. It_ and Nibley. C.. Jr. : DVT Remlmtann' In Korenji Hodiy Mee. Scienee

115 : 11- 12. 4 Jan. 1952). .It See footnote 4. p. 144.
2012 INFECTI US DISEASES

related to Mexican typ)hus. At that time, it was believed that there was only

one form of typhus fever, but during the next 30 years, it was clearly established that there were two distinct varieties; iamely, louseborne epidemic

typhus and fleaborne murine typhus. In the absence of epidemiological

evidence incriminating either lice or fleas, however, the position of Brill's

disease remained uncertain until Zinsser offered an explanation in 1934. On

epidemiological grounds, Zinsser postulated that Brill's disease resulted

from recrudescence of an old typhus infection which had been acquired in

Europe. This theory was further suplported by the fact that three strains of

rickettsiae which he and (Castaneda had recovered from patients with Brill's

disease gave biological reactions similar to those induced by 1. proiwazekd.

EPIDEMIOLOGY

Brill's disease occurs sporadically and infrequently among individuals

who have previously had epidemic typhus fever. The original infection

may have been acquired from a few years to as long as 50 years or more

in the past. Subjects who continue to live in typhus zones may serve as

the interepidemic reservoir of epidemic typhus fever.7 9 On the other hand,

Brill's disease in individuals who have migrated to nontyphus areas presents no epidemic problem. The incidence of Brill's disease is not known,

but it is very small in proportion to the total number of cases of epidemic

typhus fever.

CLINICAL PICTURE

The typical case resembles a mild to moderately severe attack of epidemic typhus fever as described in the p)receding section. All of Brill's

original cases exhibited a rash, as it was a required feature for diagnosis.

It is now recognized, however, that many mild cases occur without an eruption at any time during the course of illness.

The febrile course varies from a few days in mild cases to 2 weeks or

more in severe attacks. If an eruption is present, it may be sparse and

evanescent or it may be moderately extensive. Headache and malaise persist until the fever subsides. The mortality is low, possibly 1 or 2l percent.

The great majority of patients have a prompt convalescence and complications are rare.

DIAGNOSIS

The clinical diagnosis of Brill's disease may be made in a patient who

has lived at some previous time in an epidemic typhus area and whose illness

is characterized by fever, intense headache, and a maculopapular rash ap79 In this connection, it has been shown that lice fed upon patients during the first week of Brill's

disease become readily infected with R. prowazeki and, therefore, could initiate an epidemic under

.uitable conditions (Murray, E. S., and Snyder, J. C.: Brill's Disease. II. Etiology. Am. J. Hyg. 53:

22-32, January 1951).
TYPHUSX FEVERS

pearing on the fourth to sixth (Illy Of (liSease. In cases without at rash, thle

remaining criteria should lead to the consideration of Brill's disease in the

differential diagnosis.

From the foregoing, it is evident, that the specific diagnosis of Brill~s

dlisease must rest onl othter thani clinical findings alone. In this area, C7ol.

Harry Plotz, 11C. made it highly sigvnificant contribut ion (luring World

War 11,~ 80lemonstratinug that compIlement fixation tests with purified rickettsial antigens could be applied to the specific (diagnosis of epidemic typ~hus

and muirine typ~hus. The following serological evidence substantiates this

poinit of view:

III M cases of Jirill~s (disease examined aill showed at positive comuplement fixation with

an epidemic rickettsiail antigen. In1 10 case-; there wits fixation with an epidemic rickettsial antigen and( Ito fixation with an endemice riekettsial antigen. lit 13 (-ases there was

some cross-fixation but In all instanices where this occurred the titer obtained was higher

with epidemic antigen. The pattern of fixation inI this disease resemubles that tobtained

lin epidlemic typhus fever.

Absorption tests were performed onl speim-hens of seruin fromt Brill's disease where

cross-fixation had occurredl. An endemic rickettsia] antigen removed all the endlemic antibody with slight effect upon the titer of epidemic antib~ody. ()n the other hand], at similar

treatment of the serum with an epidemic rickettsial antigen resultedl in the removal of

both the epideminc and endemic antibody ; 114 selectivity of absorption wits observedi. These

results wouild indicate that the endemic rickett.sial antigen pattern was different from

that of the antigenie pattern of the epidlemic strain. The removal unselectively of both

endemic and epidemic antibodmies by the epidemiic antigen suggests that the latter may

be a more complete for complex antigen than the endenice antigen.

The results obtained lin Brill's disease are highly significant for time epidemiology of

typhus fever. They would indIicate that muild cases of epidemic typhus actually exist lit

the United States. The dilseaise is not transmnittedi from person to person lin this country

simply because the louse vector Is not present. Furthermore, these results Indicate that

one attack of typhus does not confer a lifelong immunity ats Is generally believed. The

virus is ptrobably harbored in the body and wvhent the resistance is lowered the virus

multiplies and induces at mild attack. If these cases should occur in it louse-infested

community the disease miight readlily spreadl from person to person. The observations on

Birill's disease strongly suggest that man serves as., the reservoir for epidemic typhus

between outbreaks Just as the rat does in endemic typhus.

Plotz further stated: "The complement fixation test now providles a

tool with which surveys of the prevailing types of typhus in a region call

be (determined."'8

Thus, recrudescence of rickettsial activity occurs unpredictably in a

small percentage of persons who have had epidemic typhus fever. Th~e factors which give rise to this phenomenon are not known, so that the specific

SO Plotz, 11: Complement Fixation In Rickettslal Dienses. Science 9T: 20-21, 1 Jain. 1943.

81 It should be noted that while aigglutinins for suspensions of Proteua OX-19) develop almost

uniformly during Iintial attacks of epidemic typhus fever, a sinillar response it; often lacking during

the recrudescent disease (Murray. E. S., M~orn, T., IMakovi(% P.. Sielski, S.. Itroz. V., Liupsa, F.,

Gaon. J.. Pavlevit, R., and Snyder. J. C.: Blrill's Disease. TV. Study or 26 CIse's in Yugoslavia.

Aju. J. Pub. Health 41: 1359-1369. November (P1t. 1) 1951). This is conipairsible to the Proteus

(tX-K findings In second attacks of scrub typhus.
O04 INFECTI( IU8 DISEASES

prevention of Brill's disease is not feasible at this time. Fortunately, other

measures kept the incidence of epidemic typhus fever in our troops to a

minimal level and, thereby, reduced the likelihood of Brill's disease in thent

to zero. The importance of Brill's disease, to the U.S. Army Medical Service.

therefore, lies in its epidemiological implications among civilians iin oversea

areas where our forces may be stationed.

Part III. Endemic (Murine) Typhus

Endemic or murine typhus is an acute febrile illness caused by infection

with R. wooxeri (syn. Rickettsii tfyph) transmitted to man by rat fleas.

Many of the terms applied to louseborne typlhus have also been used in the

past in referring to cases of endemic typhus. Clinically, the disease is sinilar to epidemic typhus, but it usually runs a milder course.

Prolbaly the finst clinical description was written in 1913 by Paullin

who recognized a iinild form of typhus fever occurring in Atlanta, Ga. The

recognition of murine or endemic typhus as a separate entity from epidemic

typhus fever and Brill's disease, however, wits not made until some years

later. An important advance was made by Neill in 1917. He noted that

scrotal swelling was produced in male guinea pigs by the intraperitoneal

injection of blood obtained from cases of typhus fever in Texas. Mooser

extended observations along this line in 1928 and emphasized that this

biological reaction was characteristic for a Mexican strain of typhus.8 2 In

contrast, scrotal swelling was not a feature in guinea pigs infected with

strains of classical or louseborne typhus rickettsiae. Meanwhile, Maxcy and

Havens conducted extensive epid(eliiological studies on tile ty vphus cases

which occurred in the Southern and Southeastern United States. On the

basis of these investigations. Maxcy. in 1926, postulated a rodent reservoir

for this form of typhus, and suggested that transmission of the disease to

man was accomplished by fleas.?" This theory was confirmed in 1931 by

Dyer and his associates who isolated the causative micro-organism from

rat fleas obtained at a typhus focus in Baltimore, Md.8 4

EPIDEMIOLOGY

Murine typhus occurs its a natural infection of rats and certain other

rodents in many parts of the world. The infection appears to be transmitted

N2 Moowr. 1. : lxperiments Relating to Pathology and Etiology of Mexican Typhus (Tabardillol.

1. Clinical Course and lPathologic Anatomy of Tabardillo in Guinea Pigs. J. Infect. Pis. 43: 241 260,

September 1928.

83 Maxey, K. F. : An Epidemiological Study of Endemic TyphuN (Brill's Disea•e) in thie Southeastern United States. Pub. Health Rep. 41 : 2967 2995. 24 Dec. 1926.

84 Dyer, R. E., Runmreleb. A.. and Badger. L. F. : Typhun Fever: A Virun of the Typhus Type

Derived From Fleas Collected From Wild Rats. Pub. Health Rep. 40: 334-338, 13 Feb. 1931.
TYPHUS FEVERS 205

among rodents by fleas, lice, and mites. The rat flea, Aenop8ylla eheopis,

is the principal vector involved in human infections. The causative microorganism, le. nwo8er;, may persist for long periods of time in the brain

tissues of reservoir hosts. Similarly, it has been shown that once fleas have

become infected, their feces may contain rickettsiae for at least 52 days and

presumably for the remainder of their lives. Rickettsiae present in dry flea

feces may remain infectious for long periods of time.

Human infections are acquired through the rubbing of infected feces

into the fleabite wound or into an abrasion from scratching. Infection may

also result from ingestion of food contaminated by infected flea feces or rat

urine and from contamination of the oral or nasal mnucosa with these

excreta.

Cases of murine typhus occur sporadically throughout the world. In

the United States, about 97 percent of the cases have been reported from

Alabama, Georgia, Florida. Louisiana, Mississippi, North Carolina, South

Carolina. Tennessee, and Texas (fig. 33).85 Other foci of importance are

the New York City area. N.Y., Los Angeles County, Calif., Norfolk area,

Va., and Pulaski County, Ark. Murine typhus is encountered in port cities

and in rural areas south of 330 N. latitude. Below this line, the long warm

season and field storage of crops permit rats to live and multiply outdoors

throughout most of the year, thereby enhancing the epidemiological potential for this disease. Although approximately 300 cases were reported in

the United States in 1931, the number later increased greatly and reached

a peak of 5%353 in 1944 (chart 11).

CLINICAL EXPERIENCE

Murine or endemic typhus was not an item of diagnosis in the U.S.

Army medical statistics until 1940; all forms of typhus were included in a

single figure prior to that time. From a practical standpoint, therefore, the

experience of the U.S. Army Medical Department with murine typhus did

not become meaningful until 1940 and thereafter.

During World War I, there were 787 cases of murine typhus in the

U.S. Army (table 28). Fifteen fatalities were attributed to this infection.

It is surprising that U.S. Army troops experienced a much greater incidence

of fleaborne typhus than of the louseborne disease. Bayne-Jones has discussed in detail the basis for the less effective control measures of murine

typhus during the period under review.8 6

85 Bradley. George H., and Wiley. John S.: 'The Control of 'Murine Typhus In the United States.

In Riclcettsial Diseases of Man. Washington: American Association for the Advancement of Science.

1948. pp. 229-240.

86 See footnote 4, p. 144.
24)6 NFECXTIOUS D)ISEASE'S

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::t:v

-,,1y .. W
TYPIIUS FEVERS 207

CHART 11.-Total reportcd cases of murinc (fleaborne) typhus

in the United States, 1931-45

NUMBER

6.000 A A

YEALY AVERAGE

1941-44

4.000 --

- YEARLY 1931-4o0/ AVERAGE

2,000

1931 1935 1940 1945

Source: Bradley, George H.. and Wiley, John S.: The Control of

Murine Typhus in the United States. In Rickettsial Diseases of Man.

Washington: American Association for the Advancement of Science.

1948. pp. 229-240.

TABLE 28.-Incidence of endemic typhus fevcr (fleaborne) in the U.S. Army, by area and year,

1942 -45

[Preliminary data based on sample tabulations of individual medical records]

IRate expressed as number of cases per annum per 1,000 average strength]

1942-45 1942 1943 1944 1945

Area

Number Rate Number Rate Number Rate Number Rate Number Rate

ot eases of cases of caes of cases of cases

Contine.ntal United States - 497 0.03 72 0.03 165 0.03 160 0.04 1 100 0.08

Overseas:

Europe ----------------------- 5 0.00 ---------- 0.00 ---------- 0.00 5 0.00 .---------- 0.00

Mediterranean --------------- 12 .01 --------- 0 8 .02 4 .01 ---------- 0

Middle East ----------------- 9 .06 ---------- 0 1 .02 8 .17 ---------- 0

China-Burma-India ---------- 34 .08 ---------- 0 7 .18 12 .07 15 .07

Southwest Pacific ------------ 87 .05 10 .14 39 .21 33 .06 5 0

Central and South Pacific .... 123 .10 13 .09 65 .22 35 .08 10 .03

North America 2 ------------- 1 0 ------------ 0 ---------- 0 1 .01 ---------- 0

Latin America ---------------- 18 .05 3 .03 1 .01 4 .05 10 .14

Totaloverseas2 - - - - - - - - - - - .. - 29 0.03 26 0.04 122 0.07 102 0.03 40 0.01

Total Army ---------------- 787 0.03 98 0.03 287 0.04 262 0.03 140 0.02

SIncludes North Africa.

SIncludes Alaska and Iceland.

SIncludes one almi5qsion aboard transport in 1943.
1208 iNXFE(TItiUS l)ISEAkSES

Despite tile heaivl igh invideuve of eiideinic typhus, thle sporadic

and unpredictable occurrence of cases generally p~revented clinical studies

by Mledical Department personnel. A few observations were mnade, however,

which mierit record. One of thiese wats ani iinvest igat ion in Jamaica, B.W.L.,

carried out by Plotz, Woodward, hi"flip. Bennett, and Evans."7 Since lJaitliica. bad becomiie at military base for U .S. forces as a re,,z'lt of the lenidlease agreenient of 1940, thle preselwe onl this island of typhuls illn ih formIl

wats a umatter of concern to the M1edicall D~epartment olf thle Aki r'hy. Tile

first case of typhuts to be recorded iin Jaminaca wits observed by Captainl

Woodardin D~eceimber 1941. The patient was a iiat ive laborer whio Cotmpblained of fever, Ileaudaehie, 2111d( generalized paiiis onl admiission to tlie Army

hosp)it al. Hle was nioderately toxic and. aside froma voij unticival i liject1ioll

and at few rales ait thle base of the. Imigs, thiere were nio oilier find~ings. Thle

teitplerilture ranged front 10)0' to 10.7') F. foi 14 days and fell by lysis. lit

sp~ite of careful searchi, no rashi was observed. HIis skini wits cafe au lait iii

color, and it sligh~t rashi may have heeii missed. Time Weil-Felix OX-19

agglutination titer wats 1:500) onl thle 8th day of illness. 1:1I,0(X) onl the 9t1

day, and 1: 2,.500 onl tile 12th daiy. Conipleniient fixationm tests indi~cated1 that

this patient hiad niumiine typhuis. Thtis case directed attention to thle likely

presence o! nmurine typhus on the island and led to the investigation. Although 68 cases of the disease were dliagnosedl, only 33 of these were seen

in the hospitals at Kingstoii. The cliniical and laboratory findings in this

group were sunimarized as- follows:

The onset Is usually sudden with severe headache, generalized pains, and temperature

which Is maintained for about 14 days when it falls by rapidi lysis. Rash was only seen

In 7 cases. In these cases thle rash was njaiilopapular in character. No rash was

observed in 26 cases but mnay have been i asked lin soini instances bY the (dark skini of

the natives. However, some patients, who were carefully observed, shiowed nto rash, andl

hence the possibility of typhus occurring without ant eruption miust be considered.

All of the cases had at Well-Felix (OX-IP) agglutination, ranging front 1: 500 to

1: 5,000; In most of themnia rising agglutination titer was obs-erved. Speciniens of serumn examined for complement fixing antibodies were positive ut least late inl all Cases. In the sera of

most patients, complement fixing antibodies wvere present wvhich reacted wvith all endemic

rickettsial antigen but not with anl epidemic rickettsial antigen. lin it fewv cases, Conlvalescent sera had relatively large aimounts of comnpleenitz fixing aiitibody against anl

endiemic antigen andl smnall anioutits against ant epidemic anitigen.

This study was particularly implortant in that it proved that endemic

typhus was ind~igrenous to .Jamnaica and l ad not. been nitroduice(I lby I.S.

Army engineer troops in 1941, as had b~een rumored in soitie quarters. A number of workers hia(1 voiced suspicion that imiriuie tvphu~s Was

present in the Philippine Islands. It remained for Woodward, Phiflip, anld

R7 Piotz. If., Woodward, T. E., Philip. C. B., Bt-nnett, B. L., and Frans, K. L,.: Endemic Tyidihus

Fe~ver In Jamaica, B.W.I. Am. J. Pvub. Health 33: 812-814. July 1943.
TYPHUS FEVERS 209

Loranger to establish its endemicity there during the latter part of World

War 11. The following case was recorded ilt their report: 8

On 23 April 1945, an American soldier became suddenly ill with a headache and chill

soon followed by fever, general malaise, nausea, and vomiting. At this time and for the

3 previous weeks he was billeted in a large warehouse in San Juan del Monte, a township

bordering the outskirts of Manila, Philippine Islande. Rats (Rattus norvegicus) had

been seen and subsequently trapped in this structure which is situated in close proximity

to native dwellings. Social contact in the latter was not denied.

Until 26 April when the patient was admitted to the 5th Field Hospital, the fever,

headache, and general malaise continued. These were the presenting symptoms with the

physical examination at this time essentially negative. The subsequent 2 weeks' febrile

course was of a remittent nature ranging from 99.40 to 104.4° F. On the 15th day the

temperature was normal and remained so except for minimal sporadic elevations to

99.40 F. Chills, headache, pains in the chest, abdomen, and lower back were the predominant symptoms during the first week of illness until the sixth day, when irregular, brownish-pink macular lesions appeared on the chest, shoulders, and abdomen. These lesions

became more intense and within 24 hours had spread to include the lower extremities and

feet at which time the individual macule was fixed on digital pressure. Remnants of the

petechial-like lesions were observed until the 15th day of Illness when a biopsy of one of

the fading macules was performed. Other than faint pigmented spots, there was no evidence of the skin manifestations after the 20th day.

During the early phases of the second week the temperature was high, the patient

was moderately toxic with moderate weakness and prostration. The severest phase lasted

4 days until the ninth day when he was symptomatically much improved. Moderate

lymphatic glandular enlargement was observed. There were no lesions whatever suggestive of a primary eschar. A slight cough with fleeting pulmonary rales was not remarkable. Delirium and severe central nervous system findings were not observed. By

the 13th to 15th day all outward signs of weakness and prostration had disappeared and

the patient became steadily stronger.

The treatment, entirely symptomatic, included parenteral physiological saline and

glucose solutions, small blood transfusions, supplemental iron, calcium, and vitamins.

Laboratory flndings.-Repeated examinations of blood smears for malaria parasites

were negative. Urinalyses were within normal limits. Numerous blood counts on 27, 28,

and 29 April, 3, 4, 6, and 19 May were normal with the white count ranging from 5,500

to 7,900, and normal differential counts. Red blood cells ranged from 3.8 to 4.5 millions.

Stool examinations were noncontributory. Agglutination with the 0 and H antigens of

typhoid and the A and B antigens of paratyphoid fever were negative and two spaced

blood cultures showed no growth. Diagnosis was established by the serial examinations

of repeated blood specimens as shown in table 29.

Comment.-The clinical features of continued pyrexia for 2 weeks with headaches,

absence of marked central nervous system manifestations, and the appearance of a macular

body rash on the sixth febrile day (without primary eschar) are strongly suggestive

findings of murine typhus fever. A biopsy of one of the late skin lesions demonstrates

the capillary changes and perivascular accumulation of cells so frequently observed in

rickettsial diseases collectively. The serological findings are unquestionably significant.

The patient developed increasing titers of Proteus OX-19 agglutinins, as shown by tests

performed employing suitable control serums. Agglutinins for Proteus OX-K did not

appear. More significantly, complement fixation on serial specimens of serums using

88 Woodward, T. E., Philip, C. B.. and Loranger, G. L.: Endemic Typhus in Manila, Philippine

Islands; Report of Cases and the Identification of Murine Rickettsial Agent in Domestic Rats by

Complement Fixation. J. Infect. Dis. 78: 167-172, March-April 1946.
210 INFECTIOUS DISEASES

purift*ie inurine (yolk-sac culture) rickettsiae as antigen clearly deinonstrated antibodies

of sulticient digllgtostic titer (table 20). The low titer of 1: 6 using an epideinic typhus

antigen is within tile norinal range of cross fixation frequently observed when these two

closely related antigens are employed to detect antibodies in the serumi of tile typhus

patient. Studies by Plotz and hIs collaborators. I)basel on the use of puritfed antigens,

have claritfed the serological patterns in epidemic and murine typhus fevers.

TABLE 29.--Seroloyical studies on an Amterican soldier with inurine typhus

iD ay of illness l'roteus O X -19 A gglutination ... .. .. .

0 X-K X-M urine Epidemic

7t h ----------- ----- ------------- 0 . .. ..

16th ---------------------------- - : 2.560 ---------- ------------

19th1 .. -------- ---- 1:2.560 (0 1: 34 1:6

24t-h ... -- ... -.. - - - I I : 2,560 0 I :96 1:6

31st__ - -------------------- I 1:1.2S0 0 1:96 0

Source: W\oodward. T. E., Philip, C. B., and toranger, (. L,.: Endemic Typhus in Manila, I'hilippine Islanuq,

Relort of Cassn IU( hlientificat ion of the Murine RickettsiaI Agent in I)omnestic Rats by Complement li xation. J. Infect.

Dis. 7s: 167-172. .Marcli-Apri! 1946.

Woodward and his coworkers noted two other cases which occurred in

Manila, and another which originated on Mindanao. In addition, they found

that. 18 percent of rats trapped in Manila gave evidence of endemic typhus

infection as detected by coinplement fixation tests with purified rickettsial

ant igens.

Woodward also observed inurine typhus in Morocco.89 There, Dr.

Georges Blanc of the Pasteur Institute undertook to determine the efficacy

of a living nmurine typhus vaccine in hulnan volunteers. This study gave

Woodward an opportunity to follow closely the incubation period and clinical course of endemic typhus. Although no clinical report was issued, the

pertinent observations made at that time were incorporated in his later

description of the disease.90

Murine typhus was encountered by other U.S. Army medical officers,

but no series of cases was reported as a clinical study. Scoville, Bennett,

Wertman, and Gauld, 91 for example, obtained data on 15 cases which occurred in Nashville, Tennr., during September 1944, focusing upon serological

aspects of the disease. Similarly, Plotz and Wertman 92 described 12 cases

Ml1 Letter. Capt. Theodore E. Woodward, MC. to Director, U.S.A. Typhus Commission, 14 Dec.

1943. subject : Report of Human Typhus Fever Vaccine Experiment.

90 Woodward, Theodore E.: Endemic (Murine) Typhus Fever: Symptornatology. In Rickettsial

Iliseases of Man. Washington: American Association for the Advancement of Science, 1948, pp.

1:14-138.

91 Scoville, A. J., Jr., Bennett. B. L.. Wertman. K.. and Gauld. R. L.: The Serological Pattern

in Typhus Fever. II. Murine. Am. J. Hyg. 47: 166-176, March 1948.

92 Plotz. H., and Wertman, K.: Modification of Serological Response to Infection With Murine

Typhus by Previous Immunization With Epidemic Typhus Vaccine. Proc. Soc. Exper. Biol. & Med.

59: 248-251, June 1945.
TYPHUS FEVERS 211

of murine typhus contracted after iuunutiization with epidemic typhus vaccine (table 30), again with the emphasis on the serological findings, which

are to be discussed.

TABLE 30.-Serological results found in individuals who were previously immunized with

epidemic typhus vaccine and who subsequently contracted murine typhus

Serological results

Day

of Typhus Complement Rickettsial Well-Felix Date of Where. Severity of

Case dis- vaccine fixation agglutination onset infected infection

ease

Epi- Mu- Epi- Mu- OX-1I OX-2

demic rine deiuic rilne

59 November J1,280 320 80 640 s0 so{1.~ ~~~icos I Mouderately A - -- £0 , 943. 1, 20 320 160 1, 20 0 1W severe.

21 S640 320 80 1,280 2.560 0

S.. 42 . 1942. 320 320 80 640 640 0 20 Nov. 1244 Fort Benning, Do.

58 1 . 160 160 80 320 640 0 Ga.

SI - 27 '27 May 1944_ A/C A/C 2,560 10,240 160 40 19 July 1944 Louisiana..---- Severe.

159 320 160 320 2,5W0 160 40

p ------ 22 September 1,280 640 320 640 160 0 17 Dec. 1944 CampGordon, Do.

50 1944. 1,280 640 320 320 0 0 1 Ga.

18 160 40 5,120 10.240 640 0

21 November 160 160 5, 120 10,240 320 0 23 Nov. 1944 Camp Shanks, Moderately B - 26 1941. 160 160 5,120 10,240 0 0 N.Y. severe.

31 160 160 5,120 10,240 0 0

Be 18 August1944 640 160 5,120 10,240 1,280 0 Birmingham, Do.

-do 701 320 160 160 1,280 160 0 Ala.

Ben- 38 October 80 80 1,280 5,120 640 40 24 Oct. 1944 Tampa, Fla.- Mild.

1944.

K- 30 September 160 80 5,120 10, 240 80 0 18 Sept. Camp Miles Do.

1944. :944. Standish,

Mass.

Ba _ 15 December 80 10 1.280 5,120 640 320 15 Dec. 1944 Robins Field, Do.

1944. Ga.

F.-- 44[January so80 80 640 5, 120 640 0 2 Jan. 1915 Austin, Tex._- Moderately

I5 1944.~ 80 40 160 2.560l 1.280 40 severe. T ------ 45 July 1944.... 1,280 640 1,280 5,120 1,280 160 14 Jan. 1945 San Antonio, Mild.

Tex.

14 32A 320 160 640 160 0

23 August 1943- A/C A/C 1,280 2,560 160 40

Com. 24 Recall dose.. 320 320 1,280 5,120 80 40 12 July 1944 lHunter Field, Do.

30 May 1944.. 320 160 320 2,560 40 0 Ga.

37 320 160 320 2.560 0 0

SCases S, P', B, Ba, and T showed a rise in OX-19 titer when serum specimens were examined during the febrile

period and early convalescence while the other cases showed high titers. These examinations were made in the hospitals

where the patients were treated. It should be observed that the specimens which were available for this study were

frequently obtained late in convalescence.

Source: Plotz, 11., and Wertman, K.: Modification of Serological Response to Infection With Murine Typhus by

Previous Immunization With Epidemic Typhus Vaccine. Proc. Soc. Exper. Biol. & Med. 59: 248-251, June 1945.

Zarafonetis 93 reported the epidemiological, clinical, and laboratory findings in two U.S. Army enlisted men who were stationed in Dakar, French

93 Letter, Capt. Chris Zarafonetis, MC, U.S.A. Typhus Commission, to Chief Surgeon, U.S. Army

Forces in the Middle East, through Brig. Gen. Leon A. Fox, Field Director, U.S.A. Typhus Commission, 10 Aug. 1944, subject: Report of Typhus Situation in Dakar.

6392437-63--17
212 INFECTIOUS DISE.AES

West Africa. at tile time of their illneiss. Brief sumnmaries of their ease histories follow.

A 27-year-ohl private (case I i was admitted on 5 .July 11.44 with the diagnosis obf

aciute tonsillitis. lie had a 1-day history of sore throat and diffitculty in swallowing, and

there were associated comlailts of Joint pains and aching. Physical examination was

essentially negative except for evidence of tonsillar involvenment. Temperature at that

time wits 99.6° F'. On the following day, the patient complained of a headache which was

not relieved by aspirin amid other analgesics and which persisted for several days thereafter. On 1) July the patient experienced a chill and complained of generalized aching.

Hlis temnperature reachetd 102.40 F., which was the maximum attained during his hospitalization. From 9 July until 24 July, he continuted to run a low-grade fever. At no

time wats there a rash evident. Serum taken on 12 July was tested at the Pasteur Institute at I takar and found to agglutinate Protcus OX-19 in dilution of I :2M. Serum wits

tested again on 18 July and this time agglutinated OX-19 to a titer of I : 1.0(0. Oni the

basis of the laboratory findings it a diagosis of typhus was imade.

The second case was that of a 23-year-old T/i3 (case 2) who wats admittted on 18 July

with complaint of severe headache and paiill i the chest for 24 hours prior to odnijisslon.

Ills physical examination at that time was essentially negative except for an admnission

temperature of 101.60 F. On 25 July. the 10th day of disease, a fine mnacular rash appeared over the chest and arms.

The rash had practically disappe-ared by 27 July. Fever had been present conthiinously for 13 days but wias falling toward normal oil .i. July. Ills courste had Ieen relatively mild for typhus.

These two patients were believed to have had mrouine typhus principally

on the basis of epidemiological evidence. I)urieux and other French workers

had concluded from extensive studies of typhus in French West Africa that

the louseborne form of this disease did not exist there. However, some 2(0

cages of relatively milh typhus had been diagnosed during tile preceding

decade. with only I death recorded. The strains of rickettsiae that had been

isolated from some of these cases were all identified as 11. moo.,er;. At the

time the American soldiers contracted their illness, two other cases. both

unrelated. occurred in the native population. Because of an outbreak of

plague in Dakar. both soldiers had remained within their military establishments for over a month prior to tile onset of their illness. An intensive

antirat campaign was underwav. and manlv rats were known to have been

present. in the areas where these soldiers contracted their typhus. Both patients were aware of frequent fleabites prior to their illness but recalled no

contact with lice.

On tihis evidence, Zarafonetis concluded that both patients had inurine

typluts and were of particular interest as instances ill which epidemic typhus

vaccination had been followed by illtirine typhus ilnfectioll. 4 The results of

serological studies in these two cases are presented in table 31.

Tile foregoing reports, some of which were fragmentary. contained tile

principal clinical references malde by U.S. Army personnel to miurine typhus

during Worhl War II. To be sure, many individual cases were observed in

94 See footnote 35 (31), p. 183.
TYPHUS FEVERS 213

Hawaii" and other areas to which U.S. Army troops were sent,"6 but these

were not the subject of clinical reports.

TABILE 31.-Serological findings in two cases of probable murine typhus fever occurring in

vaccinated individuals at Dakar, French West Africa

Days of Serological findings Amount serum of Cox- Last Onset of Days speci- Case type vaccinated illnes 01 men Weil-Felix Complement fixation vaccine fever from

onset -_____ ___ __

OX-19 I OX-2 1 Epidemic. Murine

9 1:200 .-----------... Not done ------ Not done Not done.

15 1:1,000 ------------.... do-- -- -----------. (10 o---- Do.

I14 June 1944 July 1944 24 22 1 1.280P 1:2,560 ... 1:40P1:80.... 1:512s .... 1:256(a)

4 725 1 :1,280 P :2,560 --. Negative ------ 1:512----.. 1:2E6

301 1.,280 P 1:2.5W0 0----.....do --------- 1:2560 _.. 1: 256 (a)

47 1: 32W -------- .... do ------- - 1------.. 1:256 1---- 1:128

12 1: 320 P 1: 640 ------- 1:40 P 1:80-- -. 1:512' .... 1:256 (b)

13 1:640P 11,280 .... Negative ------ 1:512 ..... 1:256

2 .... I 6 2 May1944 17July 1944 15 17 1:640 P: 1,280 -----.---- do -------- 1:1,024'3_ 1 :256(h)

34 1: 640 P 1:320 -------. ---- do --------- 1:512 -.. 1:256

71 1:40 P 1:80 --------- do --------- 1:256'3.... 1:64 (b)

I Well-Felix agglutination titers of less than 1 40 are arbitrarily considered negative. P =Partial

agglutination. Tests with OX-K suspensions were negative.

2 Performed at Pasteur Institute, French West Africa.

3 Tests on these specimens at the Army Medical Department Professional Service Schools, Army

Medical Center, Washington, D.C., gave titers of 1: 640 with epidemic antigen, while murine antigen

tests yielded titers of I : 320 for the specimens followed by (a) and 1 : 640 for those followed by (b).

Source: Modified from Zarafonetis, C. J. D., Ecke, R. S., Yeomans, A., Murray, E. S., and Snyder,

J. C. : Serologic Studies in Typhus-Vaccinated Individuals; Well-Felix and Complement-Fixation

Findings in Epidemic Typhus Fever Occurring In the Vaccinated. J. ImmunoL 53: 15-30, May 1946.

LABORATORY AIDS IN DIAGNOSIS

The same laboratory procedures that were employed as diagnostic aids

in epidemic typhus fever were also applied to murine typhus fever. The

Weil-Felix Proteus OX-19 agglutination test and complement fixation and

rickettsial agglutination tests with purified rickettsial antigens have the

same degree of specificity and diagnostic values here as they have for epidemic typhus fever. Table 32 gives the results of each of these tests on sera

from a nonvaccinated individual with mnurine typhus. The reader is referred

to the laboratory section under epidemic typhus for detailed discussion of

these and other diagnostic procedures which may be of value in murine

typhus, such as the inouse-toxin neutralization test and strain isolation.

It will be recalled that while the complement fixation test with purified

rickettsial antigens was specific for the homologous form of typhus, this

test lost its high degree of specificity in patients with epidemic typhus fever

who had been previously immunized with epidemic typhus vaccine of the

115 Essential Technical Medical Data, United States Army Forces, Pacific Ocean Areas, for July

1944.

96 See footnote 4, p. 144.
214 INFECTIOUS DISEASES

Cox type,97 and tile theory advanced by Zarafonetis to exphlin this finding

has been discussed (p. 186). ()n inspection of table 31 it will be seen that a

similar loss of specificity was found in tests on sera from murine typhus

patients who had been vaccinated against epidemic typhus fever. Plotz and

Wertman"9 independently made the same observations. They had performed tests on sera from 147 cases of imurine typhus in soldiers stationed

in the United States. Of these, 135 had the typical serological response for

murine typhus comparable to the pattern shown in table 32, but in 12 cases

an unusual response was noted, as can be seen in table 30. These workers

investigated these 12 patients with some care in an attempt to determine the

factors responsible for the atypical serological findings.

TAB LE 32.-Serological result.s in a nonvaccinated individual infected with inurine typhus

fever (case I)-8srain isolated

Serohogieal results

1 ) ay of ,.•,.•,e Well-Felix Complement fixation Hickettsial agglutination

OX-I9 OX-2 OX-K Epidemic Murine Epidemic Murine

5th-------------- 0 0 0 0 0 0

7th ---------------- :80 0 0 0 0 0 1:160

9th ----------------- 1:640 1:160 1:40 0 0 1:80 1:1,280

l1th ---------------- 1:640 1:160 1:80 0 0 1:160 1:2,560

13th ---------------- 1:640 1:160 1:40 0 0 1:320 1:5,120

14th ---------------- 1:640 1:80 1:40 0 0 1:320 1:5,120

16th ---------------- 1:40 1:80 0 0 0 1:320 1:5,120

18th--------------- :320 0 0 0 1:80 1:320 1:5,120

20th --------------- 1:160 0 0 0 1:160 1:640 1:10,240

22d ---------------- 1:160 0 0 0 1:320 1:640 1:10.240

31st ---------------- 1:160 0 0 0 1:320 1:320 1:5,120

75th --------------- 0 0 0 1:40 1:320 1:40 1:1,280

123d --------------- 0 0 0 1:40 1:320 0 1:160

Source: Plotz. H., and Wertman. K. : Modification of Serological Respon" to Infection With

Murlne Typhus by Previous Immunization With Epidemic Typhus Vaccine. Proc. Soc. Fxper. IBiol. &

Med. 59: 248-251, June 1945.

It was found that all of these patients had received typhus vaccine some time or

other within the preceding 2 years. The va(cine used consisted of formalinized epidemic

rickettsiae with no niurine rickettsiae whatsoever. All cases occurred in regions of the

United States where murine typhus alone is known to exist and in some instances other

cases of inurine typhus were present in the same camp at the time these cases were

admitted to the hospital. The clinical diagnosis of murine typhus seeems to have been

well substantiated. All cases developed a typical rash. A rise in OX-19 titers occurred

in the late febrile period and early convalescence in 6 cases, while most of the others

showed high titers. The febrile period varied from 8 to 23n days with an average of

about 14 days. Unfortunately, no attempt was made to isolate the agents.

97 See footnote 35 (3), p. 183.

98 See footnote 92, p. 210.
TYPHUS FEVERS 215

These investigators note further that, while many of the specimens in

these 12 vaccinated cases showed higher complement fixation titers to epidemic than to murine antigen, there was considerable cross-fixation and a

number of specimens were equally responsive to both antigens (table 30).

They contrast this with the nonvaccinated patients infected with epidemic

typhus, in whom there are high titers to epidemic antigens with, as a rule,

no considerable cross-fixation. Again, in nonvaccinated patients with nmurine

typhus, the complement fixation titer is higher with homologous than with

heterologous antigen, and there is little crossing (table 32). On the other

hand, rickettsial agglutination, in the 12 nonvaccinated cases, usually

showed a higher titer to the murine antigen, but in many instances there was

only a twofold difference in titer, and here again cross-agglutination is

marked. The same type of antibody response occurred whether the typhus

vaccine had been given 2 years or 1 week before the attack of murine typhus

and was not seen in patients vaccinated against typhus who subsequently

became infected with atypical pneumonia, measles, infectious hepatitis,

smallpox, meningitis, or other viral, bacterial, or protozoal infections. As

regards symptoms and clinical course, they note, the previous vaccination

against epidemic typhus had no apparent effect. upon the severity of the

subsequent attack of murine typhus.

Thus, the rickettsial agglutination test appeared to offer the most reliable means by which one might make the serological diagnosis of mnurine

typhus in a patient who had previously been immuiized with tile Cox type

of epidemic typhus vaccine.

part IV. Summary

EPIDEMIC TYPHUS

Our knowledge of typhus fever at the beginning of the war was so

incomplete, and during the war was so greatly expanded, that it seems appropriate to sketch here the composite picture of epidemic typhus that now

emerged.

Clinical picture.-The incubation period of louseborne typhus fever

varies from 7 to 20 days, with the usual onset about 10 to 12 days after

infection occurs. A prodromal stage of ill-defined malaise probably exists

for a few days. but is of no diagnostic value. In the majority of adult

patients, the clinical onset is abrupt, with malaise, chills or chilly sensations,

followed by severe headache and fever. There is anorexia, and sometimes

vomiting. The temperature rises rapidly during the first (lay or two to

1040 F., or higher, where it remains throughout the greater part of the acute

illness. The pulse rate usually exceeds 100 beats per minute and remains

full at least throughout the first days of illness. Severe aches and pains

appear early, and the thigh and calf muscles are sensitive to pressure. An
216 INi" F AI'TI ( bUS IfISEASES

early symptom is a roaring sound in the ears, which may be followed by

temporary deafness. Dyspnea and cough appear by the second or third

day. The tongue and mouth become dry and fissured, and thirst is a common symptom. The patient is tense and anxious from the beginning, but

mental disturbances do not usually appear until about the end of the first

week. These may be st upor or a period of excitement, even of delirium.

There are no diagnostic features prior to the characteristic eriiption.

appearing usually between the fifth and seventh day of disease. Initially,

it consists of faint rose-colored spots, 2 to 6 mim. in diameter, round to irregular in shape. The lesions first appear over the tipper anterior chest wall,

in the axillae and inner surfaces of the tipper arms, on the abdomen, lower

back, an(l buttocks. The rash usually develops rapidly and extends in a

few hours to cover the back, the lower arms and dorsal aspects of the hands.

and the legs to the knees. The face and scalp are spared; only rarely does

the eruption involve the palms and soles (fig. 34). The characteristic lesion

is miacular at first. but may become papular after a few hours. At the

beginning, the lesions will fade on pressure, but they usually become fixed

within 24 hours. Also, as the disease progresses, the lesions increase in

number and ,ize and may become confluent. Along with the appearance of

the rash, the conjunctivae become injected and the eyelids appear puffed.

The face may take oil a dusky, cyanotic hue. Typically, the eruption fades

rapidly at the time of defervescence.

By the end of the first week, the patient enters the critical stage. The

fever continues unabated, the delirium and cough are intensified. The heart.

rate is rapid and hypotension develops. The patient may be incontinent of

urine and feces and may be all but helpless. In the absence of complications, there may be gradual improvement as the fever begins to fall some 2

weeks or more after its onset. Some patients undergo a crisis with return

of the temperature to normal in 24 hours, while in others the decline may

be gradual over a period of 2 or 3 days. As the fever disappears, the headache vanishes, the mind clears, and the appetite returns. Recovery of

strength and nutrition is fairly rapid, but deafness and tinnitus may persist, for several weeks.

The clinical picture can vary widely, depending on what organs are predominantly involved or on complications. Pathological studies have shown

that the rickettsiae localize first in endothelial cells of the intima and then

enter large mononuclear cells which collect about blood vessels. Proliferation

of vascular endothelium and of mononuclear cells around blood vessels results in nodular accumulations. This focal. endothelial. proliferative, and

infiltrative response to the infection occurs in the skin, brain, heart, skeletal

muscles, spleen. adrenals, and other organs in varying degree. Clinically,

the characteristic rash and signs referable to the central nervous system reflect the underlying lesions. The myocardium is also commonly affected,

while the lungs may show a rickettsial pneumonitis.
TYPHUS FEVERS 217

The leukocyte count is frequently relduced during the first week, with

neutropenia and a relative lymphocytosis. Eosinophils are absent or reduced

during the febrile course. Mild normochromic anemia not uncommonly develops, but there is a return to normal values during convalesAence. Albuminuria is uniformly present during the period of fever. Granular casts

usually appear in large numbers in patients with azotemia. Elevation of the

blood urea nitrogen is often observed during the second week of illness, especially in severely ill patients. The total serum proteins may be normal or

slightly reduced, but reversal of the albumin-globulin ratio is commonly

noted. This is due to an increase in serum globulin, the values for which

usually range from 4 to 5 ing. percent. Reduction in the serum chlorides is

also common. Apparently, the chlorides are not lost through excretion during the disease, since the values spontaneously return to normal after defervescence.

Diagnoeis.-During an epidemic of typhus fever, the diagnosis may be

suspected before the appearance of the rash. A history of abrupt onset with

chills, fever, severe headache, louse infestation, or contact with lice or with

typhus patients leaves little doubt as to the nature of the illness. Certain

other coexistent diseases may, however, complicate early diagnosis. Smallpox, louseborne relapsing fever, typhoid, and meningococcal meningitis may

all be confused with early typhus. Once the characteristic rash has appeared

there is usually little difficulty in making a clinical diagnosis, although meningococcemia, measles, and relapsing fever with exanthem must also be considered. Murine typhus is not clinically distinguishable from louseborne

typhus in the individual case. Differentiation between these two forms of

typhus fever, as well as establishment of the final diagnosis, is dependent

upon certain laboratory studies. The diagnosis may be made by isolating

the micro-organism from the blood of the patient and identifying it through

biological and other tests. More practical, however, being less expensive and

time consuming, are the serological tests, which include complement fixation

with purified rickettsial antigens, rickettsial agglutination, and Weil-Felix

Proteus OX-19 agglutination. These should be performed on two or more

serum specimens obtained from the patient during the acute illness and convalescence in order to detect a significant change in antibody titer. Sera

from patients with lousebonie typhus fever, in complement fixation tests,

yield higher titers with epidemic typhus antigen than with murine antigen.

The same relationship obtains in rickettsial agglutination tests. With respect to the OX-19 test, a significant change in titer may be observed but is

relatively nonspecific, since it occurs in murine typhus and Rocky Mountain

spotted fever as well as in epidemic typhus fever. Usually, all three of these

tests reveal diagnostic (fourfold or more) changes in titer with their respective antigens. Rarely. however, there may be a dissociation of response, and

one of the tests may give completely negative results throughout. Sera from

patients who have contracted epidemic typhus fever after vaccination against
4P-4
~. T A 'lop
220 INFECFTIO)US DISEASES

it exhibit much more cross-reaction in the complement fixation tests than do

sera from unvaccinated patients, but the rickettsial agglutination test. appears to retain specificity in vaccinated as well as in nonvaccinated cases.

Natural course.-In the untreated case (that is, the -vaccinated patient

given no specific therapy), typhus fever runs its course in 14 to 20 days

unless terminated by death. The mortality varies in different epidemics and

is also greatly influenced by age. An overall death rate of 20 to 30 percent

was reached in Egypt and at Naples during World War II in patients 18 to

50 years old. At the Dachau Concentration Camp, however, the typhus death

rate was only 9.1 percent. In past epidemics, the fatality rate has been as

high as 70 percent. The disease is relatively mild in children, but it tends

to be severe with a high mortality in ohi people.

Deaths are rare in the first week of illness. In severely ill untreated

patients, evidence of increasing involvement of the central nervous system

often appears during the second week of disease. They may become deeply

stuporous, comatose, and die. Convulsions presage a fatal outcome. Other

patients develop signs of renal insufficiency, and still others present the picture of peripheral vascular collapse during the second week. There is a

striking correlation between clinical severity and the development of azotemia

with elevated blood urea nitrogen and creatinine levels. These changes appear to be caused primarily by extrarenal factors, such as greatly increased

protein breakdown, dehydration, and hypotension, rather than by a true diffuse renal lesion. Azotemia was detected in every fatal case of the Cairo

series, although not every patient who exhibits this change will die. Survivors showed no evidence of renal impairment when tested several months

after the acute episode.

The appearance of peripheral circulatory failure is usually indicative of

impending death. The extremities become cold and cyanotic, the blood pressure drops to low levels, and the pulse becomes rapid. The basis for this

peripheral vascular failure is unknown, but extensive involvement of the

capillaries, injury to the vasomotor centers of the brain, and severe myocarditis are probably important contributing factors. Electrocardiographic

findings in typhus fever are nonspecific and consist of low voltage, inverted T

waves, depression of ST segments, and an increase in PR interval.

The most important complications are bacterial pneumonia, multiple

skin abscesses, and parotitis. Although gangrenous involvement of the extremities has been associated with a number of typhus epidemics, it was rarely

observed in World War II outbreaks, except at Belsen.

Immunity and relapse.--Immunity is good in untreated subjects who recover from epidemic typhus fever. Delayed relapses do occur, however, and

constitute Brill's disease. Relapses are common in patients who receive rickettsiostatic therapy during the first few days of illness, but uncommon if

treatment is initiated after the eruption has appeared.
TYPHUS FEVERS 2221

Therapy.-During World War II, PABA was found to have antirickettsial properties and was effective in the treatment of epidemic typhus fever

in patients who had as well as in those who had not been vaccinated. Thoroughly studied, it was brought to the position of a safe and promising drug

for clinical use.

Prophylaxis.-Effective protection of the troops was accomplished by the

use of a potent vaccine and its production in adequate quantities, and by

improved methods of louse control.

ENDEMIC (MURINE) TYPHUS

Although the studies on murine typhus during World War II were relatively limited in comparison with those undertaken in connection with epidemic typhus fever and scrub typhus, there was accumulated nevertheless

sufficient information upon which to base the following summary description

of the disease.

Clinical picture.-The incubation period f rom actual exposure to the onset

of acute illness ranges from 8 to 16 days. Woodward noted that headache,

backache, and arthralgia are frequently experienced during the fourth to

sixth day after exposure. For a day or so prior to the onset of illness, prodromal symptoms such as nausea and general malaise are common. The disease then begins with chills or chilly sensations, headache, and fever. Nausea and vomiting frequently occur during this early period. Generalized

aches and muscular weakness may be pronounced.

The clinical features of murine typhus resemble those of epidemic typhus

except that. in the average case the disease is less severe than in the majority

of cases of epidemic typhus. In endemic typhus, the patient's temperature

increases in stepwise fashion for 3 or 4 days until it reaches its maximum

level, and then usually ranges between 103' and 1040 F. until defervescence

occurs. The total febrile course averages 12 days. but may be a few days

longer or shorter. Defervescence is by lysis over 2 or 3 days. A rash is

observed in about 80 percent of cases, typically appearing on the fifth day

of illness, but it may be seen several days earlier or later. When present,

its character and distribution are similar to that in epidemic typhus. Occurring in all degrees of intensity, it usually persists for about 5 days, but may

be ephemeral or may remain evident for 10 days.

In addition to intense headache, which is usually frontal, the average

patient with murine typhus exhibits mild stupor, prostration, and lethargy.

Transient partial deafness occurs at times. As in epidemic typhus, some involvement of the respiratory tract is common. A dry, hacking cough develops, usually in the second week, and crackling rales may be heard in the

base of the lungs. These are believed to be manifestations of interstitial

pneumonitis of rickettsial origin.
222 INFEC'TIOUS DISEASES

The pulse rate is increased and is usually regular. Minor elecrocardiographic changes of nonspecific nature ntay be detected for a brief period.

Persistent hypotension is not uncommon, especially during the second week

of acute illness, and is attributed to a coinbination of factors including extensive vasculitis of the capillaries of the skin and other organs and involveiiient of the brain with injury to vasoniotor centers. Clinical signs of inyo- cardial failure are usually lacking, but this does not rule out invocarditis,

which has been found in fatal cases of epidemic tylphus fever.

There are no characteristic changes in the formed blood elements. Moderate albuminuria is not uncommon. Azotenia may develop in severe cases

and is believed to be largely (te to extrarenal factors.

Diagnosis.-An illness characterized by an abrupt onset withi heada'l.e.

chills or chilly sensations, fever, malaise, prostration, nonproductive 0"ough.

and liter the appearance of a rash should suggest typhus fever amng)jlq the

diagniostic possibilities. Epikemiological considerit ions and characteristics

of the rash may aid in arrivirg at a tentative .linical diagnosis, but final

differentiation rests upon the use of appropriate laboratory tests. These inelude complement fixation with purified rickettsia! antigens. Weil-Felix Proteus OX-It) agglutination, rickettsial agglutination, and isolation of the

strain by animal inoculation. The last is not. practical for routine use, but

the serological tests are adequate and more practical. They should lk• performed on two or more sera obtained from the patient during the acute illness and convalescence to show a diagnostic change in antibody titer. In

endemic typhus, titers will be considerably higher with endemic than with

epidemic antigen in the complement fixation test. The same relationship

obtains in rickettsial agglutination. A significant rise in OX--19 agglutination titer may be helpful, but it( does not differentiate between endemic

typhus, epidemic typhus, and Rocky Mountain spotted fever. Sera from

patients who have previously received epidemic typhus vaccine, and later

contracted lnurine typhus, exhibit much more cross-reaction in complement

fixation tests than do sera from nonvaccinated persons. The complement

fixation test, therefore, (loes not differentiate the two forms of typhus in these

patients, but the rickettsial a-gglutination test, according to available evidence, retains specificity in such cases.

Natural course.--The usual course in adults is uncoml)licated, with subsidence of fever toward the end of the second week, followed by an uneventful convalescence. The disease is readily tolerated by children, but less well

by elderly persons. The mortality is 1 to 2 percent. Complications are infrequent and usually consist of secondary infections which give rise to parotitis, otitis media, or bacterial pneumonia.

Immunity.-After an attack of murine typhus, immunity is apparently

of long duration. Recrudescence, in a manner analogous to Brill's disease,

has not been reported.
TYPHUS FEVERS 223

Therapy.--Treatment is the same as for epidemic typhus fev-er. Smith -

and civilian workers 100 independently demonstrated the beneficial effect of

large doses of PABA in the management of murine typhus.

Prophylaxis.-Control measures are directed at reducing the rat populations that serve as the reservoir of the disease and the rat ectoparasites that

serve as the vectors. Rat control measures include general sanitation, rat

poisoning, and ratproofing of buildings. The principal method of ectoparasite control is by DDT dusting of ratruns and harborages. 10 '

Prophylactic vaccination, although possible, is not usually practical in

view of the sporadic occurrence of cases.

EPILOGUE

The preventive, clinical, and laboratory events concerned with the typhus

fevers during World War II represent a brilliant chapter in the history of

medicine. Many contributions were outside the scope of this review and are

detailed elsewhere. 101

2 No historical summary of typhus would be complete,

however, without acknowledgment of the keen stimulation and wise guidance

provided by Brig. Gen. Stanhope Bayne-Jones and Brig. Gen. Leon A. Fox,

Director and Field Director, respectively, of the United States of America

Typhus Commission. The U.S. Army Medical Department can be justly

proud of the contributions made by its members under the leadership of these

men.

99 Smitb. P. K.: The Use of Para-Aminobenzoic Acid in Endemic (Murine) Typhus Fever.

J.A.M.A. 131: 1114-1117. 3 Aug. 1946.

100 Levy, M. D)., and Arnold. W. T.: Para-Aminobenzoic Acid In the Treatment of Endemic

'Typhus Fever. Texas State J. Med. 42: 314-316, September 1946.

101 See footnote 85, p. 205.

102 See footnote 4, p. 144.
CHAPTER VIII

Rheumatic Fever

Lowell A. Rantz, M.D.

Rheumatic fever has been a problem to the U.S. Army ill all of its wars

for which historical data, are available, although it. attracted little attention

before World War 11. Enteric infection and malaria, in earlier wars, and

influenza and its complications in World War I, overshadowed all other acute

diseases. Inadequate diagnosis also prevented the recog'nition of the military importance of this disorder.

The recorded experience of the U.S. Army in the American Civil War 1

reveals that acute rheumatism occurred with remarkable frequency. In 5.2

years, 146,000 cases were reported among white troops at a rate of 61 per

1,000 per annum. Certainly, not. all of these were acute rheumatic fever,

but examination of the case records that have been preserved in the history

of that war indicates that a substantial number of them was certainly this

disease. This impression is confirmed by 642 deaths caused by rheumatism,

endocarditis, and pericarditis. Furthermore, the disease occurred principally in the winter among fresh levies of troops, an epidemiological pattern

which resembles that of rheumatic fever during World War II. In retrospect, it is impossible to define the magnitude of the problem of rheumatic

fever in the Civil War, but it. must have been great.

The situation during World War I was similar.2 There were 24,770

admissions for acute articular rheumatism reported, but the significance of

this disease was apparently overlooked even though it was occurring at the

rate of 6.00 per 1,000 per annum. The fact, that many of these cases were

rheumatic fever was not appreciated, and this disease is not mentioned by

name in the official history of the Medical Department in World War I. The

disease occurred with g'reatest, frequency in the same areas as it did during

World War II but at substantially higher rates.

In spite of this background and of the great advances that. had been

made in the period between the wars in knowledge of the pathogenesis and

natural history of the disease, the U.S. Army Medical I)epartment was poorly

equipped to cope with the probleml of rheumatic fever in the first years of

World War 1I. This was largely the result of several well-defined factors.

The first, and most important, was the failure of the Medical Department. to

realize the importance. of rheummatic fever as a military problem. Rheumatic

I Medical and Surgical History of the War of the Rebellion. Medical History. Washington:

Government Printing Office, 1970, pt. I, vol. I. pp. 637-639.

2 The Medical Department of the United States Army In the World War. Washington: Government Printing Office, 1925, vol. XV, pt. 2, p. 86.

225
226 INFECTIOUS DISEASES

fever was not required to be reported by all facilities on the weekly statistical

sumnmary until Decenmber 1941 :" and was often incorrectly diagnosed during

titt following 21/2 years.

Of equal iml)ortance was the failure to appreciate the intimate relationship between infection by group A heinolytic streptococci and rheumatic

fever. Medical officers in the field were not trained to (listinguish streptococcal from nonbacterial respiratory disease, so that the hemiolytic streptococcus was only recognized during the period 1940-43 as a common cause of

illness in those few camps where scarlet fever was occurring frequently. The

importance of the case without a rash was not realized. Lastly, the Army

and its consultants had not familiarized themselves with available civilian

and military data which would have made it possible to predict with considerable accuracy those geographic areas in which outbreaks of hemolytic

streptococcal infection and rheumatic fever might be expected.

Little information is available as to the situation during the prewar

expansion of the Armed Forces. During 1941, outbreaks of scarlet fever

followed l)v rheumatic fever occurred at Chanute Field, Ill., Scott Field,

Belleville. Ill., and Fort Knox, Ky. The incidence of these diseases elsewhere in the Army during 1941 was low. Drs. James 1). Trask, Francis F.

Schwenkter. and M. Henry Dawson, of the Commission on Hemolytic Streptococcal Infections, Army Epidemiological Board (Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army),

visited each of these camps in November 1941. They noted that medical

officers did not recognize the association of scarlet fever and streptococcal

disease occurring without a rash nor did they connect either of them with

rheumatic fever.4

The available records do not reveal that streptococcal disease was viewed

with alarm during the period 1941-42, although the incidence of scarlet

fever, in the total Army, during those years was comparable to that in 1943-

44 when interest in infection by these organisms was very great. This was

the result of the mildness of the acute streptococcal disease and of the failure

to report accurately the occurrence of rheumatic fever prior to 1943.

The first detailed information in regard to the problem of rheumatic

fever was obtained early in February 1943 when a survey of the continuing

scarlet fever epidemic at Fort Francis E. Warren, Wyo., revealed that more

than 100 patients ;with this disease had been hospitalized but neither correctly diagnosed nor reported to The Surgeon General. 5 Subsequently. the

rapid increase in size of installations in areas of high incidence of this dis3 Circular Letter No. 123, Office of the Surgeon General, U.S. Army, 16 Dec. 1941, subject:

Medical Department Form 86ab, Statistical Report (first section).

4 Report. M. Henry D)awson. M.D., Director. Commission on Hemolytic Streptococcal Infections,

Army Epidemiological Board. 24 Nov. 1941. subject: Report on Reconnaissance Trip to the Fifth

and Sixth Corps Areas by Dr. James D. Trask. Dr. Francis F. Schwenkter, and Dr. M. Henry Dawson. Members of the Commission on Hemolytic Streptococcal Infections. November 11-19, 1941.

5 Report, Lowell A. Rantz, M.D., Member, Commission on Hemolytic Streptococcal Infections,

Army Epidemiological Board, to Col. S. Bayne-Jones, Office of the Surgeon General. 23 Feb. 1943,

subject: Report of Epidemic of Scarlet Fever and Septic Sore Throat, at Fort Francis E. Warren.
RUEUMATIC FEVER U)

ease ii (C(lorado and(I Hali wats associated wit111 ellidlemcl(s of st reptococcal

infect ion aind rheutinat ic fever. Additional sur~veys Were miade which again

delCinetated the deficieniei&s in background and litnforinlat loll oil the pairt of

mnedical officers ill regard to streptococcal resp~iratory dlisease and~ its colilipI icat iois, althlough no control mneasures were reconinended. 6

1)uiring 1943, 6,7110 admissions for rheuimat ic fever were rep~orted front

the Army iii the Unitedl States. According to summaries of the statistical

health repo~rts, about 74 percent of these occurredl in the Seventh and Ninth

Service Commands. Ablout 43 percent of all cases occurred in the States of

Colorado, Utah, Idaho, Montana, an(1 Wyominhg. This largre nuimber of cases

of at serious disease requiring p)rolonged hospital care and resulting in miany

sep~arat ions fromt serivice attracted at very considerable interpst in the offices

of The Surgeon CGeneral of the Army and of the Air Surgeon. Three p~rogralins dlesignled to acquire new knowledge abou~tt leieolytic streptococcal (isease with special reference to its relatijonship to rhieumiaitic fever and to control methods were inst itutedl toward the end of 194:3. All were conducted

in the field with thle active assistance and1( cooperation of many command and

medlical officers.

One of these p)rogramls was undler the auspices of the Comumission oil

ileinolyt ic St relptococcal 1mmfect ions. Its purp~Iose wits the carefi l inivest iga -

tion of at large numbewr of cases of hiemolytic streptococ-cal respiratory infection for the purpose of deti-aing time natural history, b~acteriology', and jiniuninologvy of these dlisordlers. Associated with this group wats the Commission

onl Air-Borne Infections, Arniy Epidemiological Board. whose main interest

lay in the investigat ion of methods for control of airborne infection with

particular reference to the heinolyt ic strep~tococcuis. The results of these two

Commission p~rojects are describ~ed elsewhere.7 The ihird was the Army Air

Forces Rheuimaitic Fever C1ont rol Program. Office of the Air Surgeon, which

will be the sub~ject of at later section of this chapter. These three prograims

were in active operat ion throughout 1944. 'Much new knowledge was acquir-el. b~ut effectiv- nethiods m for the control of streptococcal disease and rhieumat ic fever were not forthicomning.

The Air Forces investigrated intensively the role of suilfonamide l~Nprlpylaxis (luring'( the early monthis of 1944. Streptococcal infection and rheumatic

fever were notably reduced, andl the use of this technique iii certaini defined

situnat ions. prila ri.ly for the prevent ion of these (disease-,, became established

Ariuly p~olicyv onl 1 November 1944 wvith the publdication of War Department

Technical Butlletin (TB MIED) 112. 1 Tofortuia tely, by this time, strains of

streptococci highly resistant to sulfonamides had emierged ando were causing

41 Report, Chemter 1%. Keefer. M.D., iDirector, a~nd 1,owell A. Rantz. M.D.. Mlember, Commtission on

llemolytic Streptococcal Infection%. Army Epbidemilological Board. April 1943, subject :Report of Investigation of Rheumatitc iFever at Fort Franisei H. Warren. Cheyenne. Wyo., Lowry Field, D~enver, Colo..

Buckley Field. D)enver. Ciolo., and Comp Carmon. Colorado Springs, Colo.

7 (1 ) Hhistory or tme Comnmimmion on Air-Bornie Infections, Army Epidemiological Board, 1941-45.

[Official record.] (2) CommimiMlon on Hlemolytic Strep~tococcal Infections~. Army Epidemiologicai

Board. [Vudated.] [Official record.]
228 INFECTIOUS DISEASES

disease among naval personnel where cheinoproplhylaxis had been widely used

on a, mass basis since December 1943.

Streptococcal infection continued to be epidemic throughout 1944, and

4,877 cases of rheumatic fever were reported in the United States. Tire highest incidence was again in the Sixth and Seventh Service Commands where

37 percent of the cases occurred. Twenty-four percent occurred in the States

of Colorado, Utah, Wyoming, and Nevada, where relativeia few troops were

stationed. Streptococcal infection and rheumatic fever became an important

problem among troops abroad for the first time in 1944 when 1,805 cases of

the latter disease were reported. This represented a rate of only 0.47 per

1,000 per annum or approximately 38 percent of that among troops in the

United States.

It became apparent, as the winter of 1945 began, that sulfonamide

lprol)hylaxis, the only method of proved value for the prevention of streptococcal infection and rheumatic fever, was no longer effective. Disease caused

by resistant streptococci was epidemic in the LT.S. Navy, and an outbreak of

infection caused by similar strains had occurred at an Army Air Forces

station. The entire problem was considered at a National Research Council

conference on 28 February 1945. The failure of sulfonamide prophylaxis

,%as detailed, and the hazards involved in its continued use were described.

As a result of these experiences in the Navy, this technique was applied only

selectively in the Army Air Forces and practically not at all in the Army

Ground Forces. The possible value of penicillin prophylaxis was explored at

another National Research Council conference on 20 March 1945, anti studies

for its evaluation under field conditions by the Army Air Forces were outlined but not undertaken.

The incidence of scarlet fever and rheumatic fever in the Army in the

United States decreased in 1945 in spite of the absence of effective control

measures. The incidence of streptococcal sore throat rose from 0.82 per 1,000

in 1944 to 3.64 in 1945. The effect was an increase in rate for the three

conditions combined, from 3.98 per 1,000 in 1944 to 5.21 in 1945. Only 1,675

cases of rheumatic fever were reported. Two thousand and fifty additional

cases occurred in the Army overseas. Another important National Research

Council conference on streptococcal disease was held on 7 July 1945. The

war ended in the autumn of that year, and information on the occurrence

of this disease and rheumatic fever during demobilization is not available.

EPIDEMIOLOGY AND STATISTICS

Statistical and epidemiological data in regard to rheumatic fever and

the causative hemolytic streptococcal infection has been presented in detail

in another volume in the history of the Medical Department in World War 11.8

8 Med.ial Department, United States Army. Preventive Medicine in World War II. Volume IV.

Communicable Diseases Transmitted Chiefly Through Respiratory and Alimentary Tracts. Washington : U.S. Government Printing Offlce, 1958.
RHEUMATIC FEVER 221)

This information will not be recapitulated, but a sununary is appropriate.

Of about 18,000 reported cases of rheumatic fever, 34 percent developed in

troops stationed in the Seventh Service Command at a rate about six times

the rate for the total Army. Leniolytic streptococcal respiratory disease was

epidemic in all of the high incidence areas for rheumatic fever, and a direct

relationship between infection by these organisms and the rheumatic state

was established by critical investigations.

Approximately 23 l)ercent of all rheumatic fever admissions occurred

in troops overseas. The rate was about two-fifths of that in the continental

United States. In terms of rates, the worst experiences were encountered

in the European, Mediterranean, and Middle East theaters. Three reports

describing the disease as it occurred in the North African, Mediterranean,

and European theaters have been published.9 The problem was much less

in the China-Burnma-India theater and in the Pacific and Latin American

areas.

Rheumatic fever was most common in the months of January through

June (77 percent of all cases) among men assembled for basic training, but

occurred frequently during all seasons and among all types of personnel,

particularly during the peak years of 1943 and 1944.

CLINICAL PICTURE

The clinical picture and natural history of rheumatic fever as it occurred

among troops has been well defined in a few publications,,' and in much

greater detail in reports of the activities of Army and Air Force rheumatic

fever centers."1 These three reports, describing the disease as it was seen

at Birmingham General Hospital, Van Nuys, Calif., Foster General Hospital,

Jackson, Miss., and Torney General Hospital, Palm Springs, Calif., are most

9 (1) Bland, E. F.: Rheumatic Fever and Rheumatic Heart Disease in the North African and

Mediterranean Theater of Operations, United States Army. Am. Heart J. 32: 545-559, November

1946. (2) Claiborne, T. S.: Rheumatic Fever and Rheumatic Heart Disease in a General Hospital

in North Africa. Med. Bull. North African Theat. Op. (No. 5) 1: 8, May 1944. (3) Foster, R. F.:

Rheumatic Fever Here and In the European Theater of Operations. Northwest Med. 45: 503-506,

July 1946.

10 (1) Wendkos, M. H., and Noll, J., Jr.: Symposium on Cardiovascular Diseases; A Survey of

Rheumatic Fever in a Large Station Hospital. M. Clin. North America 28: 124-147, January 1944.

(2) Wright, 1. S.: Experiences With Rheumatic Fever in the Army. Bull. New York Acad. Med. 21:

419-432, August 1945. (3) Connor, C. A. R.: Experiences With Rheumatic Fever in the Army Air

Forces. Am. J. Health 36: 236-243, March 1946. (4) Miller, J. H.: Rheumatic Fever at a Convalescent Center from March 1944 to March 1945. News Letter, Army Air Forces Rheumatic Fever

Control Program, vol. 2, No. 10, p. 30, October 1945.

11 (1) Report. Maj. Jules C. Welch, MC, Chief, Rheumatic Fever Section, Birmingham General

Hospital, to The Surgeon General, attention: Director, Medical Consultants Division, 30 Nov. 1945,

subject: Report on Studies on Rheumatic Fever. (2) Report. Capt. John F. McGinty, MC, Chief,

Rheumatic Fever Section. Foster General Hospital, to The Surgeon General, attention: Director,

Medical Consultants Division. 14 Dec. 1945, subject: Report on the Activities ond Findings of the

Rheumatic Fever Center, Foster General Hospital. Jackson. Mississippi. for the period from 2 Oct.

1944 to 1 Dec. 1945. (3) Report, Maj. E. P. Engleman, MC, Chief, Rheumatic Fever Center, Torney

General Hospital, to The Surgeon General. attention: Col. Arden Freer, MC, Director, Medical Consultants Division. 11 Mar. 1946. subject: Report of Activities of Torney General Hospital Rheumatic Fever Center. 1 Mar. 1946.
230l INFECI'(TIOU )1DI SiAMEI4

com1plele. I)ata derived tlherefronn aret lpresented in table 33. It. should be

rememnlbered t hat these were essenlitally convale.m'ent hospitals and that, the

aculte phases of the illness were not olserved by the officers preparing these

reports. The information about the early stages of the illness were compiled from abstracts of the station hospital records which iwtconmpanied the

patients. Tl'hese were usually quite complete. Examination of other reports,

mnd the extensive experience of the author in the tiehl during this period,

indicates that table 33 and the conunentary which is to follow presents an

accurate picture of rhieeumatic fever as it occurred during World War II in

the Army.

TAni,, 33. Clinical and historical information on rheumatic ferer an obser'ed in three U.S.

A rmy general hospitals

lllercmint expressed ms perfntages of easte In which the- respwetive "uanifrtations were observedj

llirninglnain Foster Torney

Cl inic data I(eal hmnnd hl'u ( eneral

I hwl)ital I Iospll I lospltol

(IM.ren t ) (IM'rmli;t ) (pe'r'enmt)

Past history of rheumnatic fever ... . .. 50.4 W... 41. 3 40. 6

History of preceding respiratory infection " 54. 9 40. 1 84. 5

Fx t racardiac inai) ifestat ions:

Arthritis ---------------------------- 100. 0 96. 7 98. 0

Chorea ----------------------.----------- -() .5 .2

Erythenma multiforue or inarginatumr . 5. 4 2. 2 2. 5

Erythena nodosum ... ... .. . . .. -2. 7 1.8 ()

Subcutaneous nodulehs-.... ......... .... . 1. 5 !. 1 .5

Pneumonia -----------------------.-------- - 3. 2 2. 5 3. 2

Cardiac manifestations:

Apical systolic murmur------------- if. 8 13. 0 45.0

Apical diastolic mur.mr . 2. 7 8. 4 2.5

Aortic insufficiency -----------------------.. I0. 3 7. 7 5.0

Pericarditis .------------------------------... 5. 6 3. 3 3. 7

Cardiac insuflicieney .----------------- 0 .6 1.0

Electrocardiographic manifestations:

Any abnormality ------------------------------- 53. 5 27. 7 47. 6

Prolonged AV conduction ------------------- 26. 8 24. 6 28. 2

Abnormal T waves ---------------.-------- 10. 1 3. 1 14.0

Total number of cases --------...-----.-- 262 807 401

I Not nrtvrded.

Striking differences between the rates of occurrence of various clinical

manifestations, notably those referable to the heart, reflect differences in

interpretation of physical and laboratory signs by medical officers in the

various hospitals. Rheumatic fever in the Army was an arthritic disease.

Almost lM) percent of cases exhibited subjective or objective evidence of

joint involvement. This simply means that. the nonarthritic form of the
RHEUMATIC FEVER 231

disorder was rarely recogmized. 1)etailed sttidies beginning with the initiating streptococcal infection revealed a considerable number of cases in this

category. 12

A past history of rheunmatic fever was obtained in 40 to 50 percent of

all cases. This demonstrates that persons who have hadt rheumatic fever

are much more likely to develop another attack after streptococcal infection

than are nonrheumatics. A preceding upper respiratory infection, sore

throat, or Scarlet fever had been recognized by about half of the patients.

Nearly all hospitalized patients had fever and malaise in addition to arthritis,

but many other clinical manifestations of rheumatic fever were uncommon.

Epistasis, erytheinatous skin lesions, pericarditis, pneumonia, and subcutaneous nodules occurred infrequently, although very often more than one of

these signs of severe rheumatic fever was demonstrated in the same patient.

Evidence of carditis was obtained frequently. During the acute phase

of the illness, the most. common sign was an alnormal electrocardiogram.

Prolonged AV (atrioventricular) conduction was demonstrated in about onequarter of all patients and unequivocal T-wave abnormalities in an additional :1 to 14 percent. The average percentage for all patients was approximnately 7 percent. Other abnormalities were reported by two of these

hospitals to bring the total presenting electrocardiographic evidence of

carditis to about 50 percent. The significance of many of these minor

changes in the tracings is questionable.

Arrhythmias of any kind were observed in less than 0.5 percent of cases.

Cardiac insufficiency developed in less than 1 percent and was almost always

of short duration. Only three deathis fo'om active rheumatic fever with

heart failure are recorded.

Cardiac murmurs were heard frequently, but the significance of many

is difficult to assess. Apical systolic murnmur- were discovered in 45 percent of cases in one hospital but in only abe-,t 12 percent in the other two.

Apical diastolic murnmurs were uncommon. Evidence of aortic insufficiency

was obtained in 5 to 10 percent of this group of patients. It. was often

inferred that. these lesions were the result of the episode of rheumatic fever

under study. This was undoubtedly so in some, but the author examined

a number of men in whom valvular disease. was present at the onset of the

attack and was a residuum of a previous rheumatic episode. The characteristic murmurs had been overlooked at the time of induction into the Army.

The available data, obtained at convalescent centers, do not permit ready

differentiation between these, two different situations.

(Carditis was present in 40 to 50 percent of all cases if only positive

elect rocardiographic abnormalities and clear-cut new murmurs are considered

to be indicative of its presence.

12 Rantz. L. A.. Bolxvert. 1P. J., and Spink. W. W.": lemolytic Streptococcic Sore Throat; The

Poststreptococcic State. Arch. Int. Med. 79: 401-435, April 1947.
232I NFECTIOU IMSDHEASES

EARLY TREATMENT AND COL'!?*E

D)ocumentary evidence in regaird to the usual early treatmlent of rheumaitic fever in the Armny is not available. Prior to the autumn of 1944,

these patiaents were treated in stattion hospitals until convalescence was sufficiently established to l1hrinit return to duty, s-elaration from service, or

transfer to at regional general hospital. D uring this early period, treatment

Was thle respimnsibllity of thle echief of medicine in eiticl stat ion hospital, and

%,aried greatlly front one to another.

('reat interest had been aroused ait abtout this time in the use of very

large amounits of satlicylates in the treatment of rheumattic fever. Regimens

were widely employed in which every effort wats mtade to adminitister lo) gnil.

per day of sodiunil liivat.Te drug15 was not often given intravenously

inl thle Army,. but significant toxicity wats frequiently encountered.

Thle otiier implort aint lpllate of thle treatment of rheumiat ic fever involved

rest. and this wits regularly utilized butt in widely differing degrees. Strict

bed rest over long periods of time and until aill clinical and hlaboratory signs

of activity had vanished was usual. Often, fantastic limitations of activity

Were imlpos~ed, and patients were forbidden to feed, wash, or shave themselves for numvit weeks. As late as 1944, WIar D)epartment Technical Bulletin

(TBt IEl)) 971, dated -29 September, warned that the head of the bled should

no', be raised (luring the p~eriod of active (disease, since absolute recumbency

wats believed to be ani inip()rant phlase of treatment. No chemtoprophylaxis

of streptoococcal infect ions wats undIertaken before 1944.

The responise to rest land the adlministration of salicylates in these

pat ients wats almost -tlwmmtvs excellent. F4ever and arthritis regularly melted

awity so that the patients ordinarily felt very well within 2 to :1 wveeks. and

restrictitons to bed'( becamme thificiult. More p)rolongned land difficult illneswse

d id ooMcli IX partivicularly ill thle p~resenc~e of peric-ardlitis, but such cases it(--

countedl for less than 5) pwerent. of the total. Heart failure was virtually

unknown and its mianagenment was not at significant p~roblleml. Only 1 (heathl

dume to rhileimitaitic fever Wvith heart failuire occurred in 1,470 cases admitted

to convalescent centers (table 33). Tile only (lata, in regvard1 to the duration

of labomratoryV evidlence of activity are front thle Tornev G~eneral H~osp~ital

experienice. Thle eryt hrocvte sedimentation rate ( Wtiltrobe) became normial

in tan averagre of 11.2 wveeks. It wats elevaLtedl for more than 4 weeks in

59 peve and~ for more than 9 weeks iii :14 pevn of 401 cases. Abnormal

rates persisted for muore thanl -5 months in only 12 percent.

Treatment of eatrly rleienuaiei fever wits doubt less mutch better standard1ized after Septembher 19)44 whein T'l AMEl 97 wats publlishedl. This

(direct ive recommtnendled abouit I ittonttl of bed rest at the stationl hospital

followed by transfer to a convalescent center by air. Sodium salicylate was

to be griven; inl a (lose' of 16 grin. dur11ing the(, first*24 hours, followed b~y 10 ginl.

per day. High bloodI levels of the drug11 Were doubtless attained, but toxicity
RHEUMATIC FEVER 233

must have been commonplace with this regimen. Continuous prophylaxis

with daily administration of a sulfonamide was directed.

The usual treatment of rheumatic fever with prolonged and often absolute bed rest until clinical and laboratory evidence of quiescence was obtained

produced results which were not entirely satisfactory because cardiac neurosis was a frequent complication. One group working at an Air Force

center 3 utilized early ambulation in the treatment of 100 patients, continuing the administration of salicylates. The results were impressive in

that the disease process subsided in the expected time without any increase

in the incidence of chronic valvular heart disease. The experience of the

author and his associates was similar in unpublished studies of a smaller

group of patients.

LATE TREATMENT AND RESULTS

It was not until the middle of 1944 that much information became available in regard to the course of rheunmatic fever in patients in the Army after

the first few weeks of illness. Prior to this time. patients were separated

from service, returned to duty after the disease had become quiescent, or

forwarded to a general hospital. In the experience of the author, the first

two events usually took place after about 6 months of treatment. Transfer

to a general hospital was reserved for the very few patients whose disease

was not ameliorated promptly or in whom the diagnosis was in doubt.

In Army Air Forces Letter 25-7, dated 29 April 1944, the Army Air

Forces designated seven regional hospitals as rheumatic fever convalescent

centers; namely, AAF Regional Station Hospital No. 1, Miami Area, Coral

Gables, Fla.; Orlando Army Air Base, Fla.; Keesler Field, near Biloxi,

Miss.; Davis-Monthan Field, Tucson, Ariz.; Las Vegas Army Air Field,

Nev.; Hammer Field, Calif., and Santa Ana Army Air Base, Calif. In September 1944. the Army Service Forces followed suit and Birmingham, Torney,

and Foster General Hospitals were so designated. All of these were in the

southern part of the United States. The directives stated that patients were

to be treated for about I month by bed rest and heavy salicylate therapy

at the station hospital. At this time, it was anticipated that the acute manifestations of the disease would have subsided, and the patient was to be

transferred by air to the center for additional rest and eventual rehabilitation. The number of available ambulance planes was not great, and it is

not, known how often this technique was employed. In the absence of air

transport, patients were to be kept at the station hospital until fully convalescent and able to travel by train.1 4

13 Robertson. H. F.. Schmidt. R. R.. and Feiring, W.: The Therapeutic Value of Early Physical

Activity In Rheumatic Fever. News Letter, Army Air Forces Rheumatic Fever Control Program.

vol. 2. No. 10. p. 17, October 1045.

14 Army Service Forces Circular No. 360, 1 Nov. 1944.
234 INXFFCTV')U& DIuEASES

Very coilillete st atemtenits atlh~lt tile ojientlotios of (lhe general hospital

ceniters have beeii preser-ved."5 and thle following1 im portant facts about the

late effeicts of rhelieunat ic fever ill troops have b~een obtained from them

ill adlditionl to t hose thlit were used earlier inl describing the nature of the

acute illness.

C omiplete. recover-Y without r-esidua %va~s the rule ill these cas-es of iiueumat ic fever inl y ugl adults. Chronic valvular heart disease was the most

ser110ios VOIiiiplicit ion. 3sosIhat t[al aort ic iufhevwas (demonsi rated ill froiti 5.0 to 10.3 percent, :niltral steniosis Ill 2.5 to 8.4 pverent : and

in itira I iisuticieuwvy Ill froml 11.8 to0 45.0) percenut (of all cases. Three diiflicul -

ties ar ist inl interpretinig thlese (lata. Onle per-tains to thle val-ving diagnostic

criteria that. were appl''ied. part icuilarlvin the r-ecotnit ion of mitral insufliciencv* %. It is evident that t hese criteria were (difficult to establdish. They were

less rigorous at Toruliev G eneral H ospital thatliat the other two centers. A

seCOmild stems fronm thle fNct thlit iniethical officers at thle centers at tribuuted all

of tile val vilar disease plreseilt at filie 1 tine of dlisimiissal fr-oil tilie lhospital

to the cumirra episode of rheumatic fever. There were many inist ances. as

already indicated, whlei sign! hicant mimurnus wer-e preseint at the onset of

lie ililness. 'l'liesit were certainly tilte result (of previous attacks. tilie signs

having beejin missed du1n uig1I lie in~duct ionl~l phsicalI exa Il i nat ionl. No sat isfactory (data perumitting detailed a lyiofthis import ant point are available.

A third difliculty arises f-oni th lieact that thle period of followup was short

since it is known that clinical evidence of rheutmat ic valvular hetart disease

appears slowly anid i rregularlv after anl acute rliemnnat ic episodle.

O ne excellent sItudy (if 1:35 pat ients il has pr-ovided valuable information

ais to tile outcomie after a per-iod of observat ion of 4 to 8 years. Followup

phyisical examnatuit ons revealed no0 abnormnalit ies inl 7-5.4 percent. An adldit ional W . or 11.8 per'cenit. had only anl apical systohlic iiumu.bel ievedl by

the alithlor to indlicate tilie ipreseiice of inlitral inufficiell&'iv. It is piobablel&

thlit few of t his latter groulp hadl signi lifcant vavlr(lisealse. NMitral stenlosus. or' non1t C stenosis. 01r iiisuffhciency Awere (discovered inl only 12.8 percent

of these pat ieints. It hais biecui suggested that niot all of t hese lesions wvere

lie result of thle rh eumnat ic fever whiich occurred dumnr im li1itary service.

Onlyv three of the entire group had( (definlite eila-rgenient oif the heart and

i~oule- shiowedl evidhence of rcaroliav insufficiency. The signs dlescribied above

hind be-en presenit ait thle terminiat ion (of thle rhleunmat ic at tack ili all but one

case. rlims. tihere hiad been anl extrnaordhinarily low incidence of progressioni

of hetart d~isease duini-lg thlis bulg perio(l of observation. Of tile group. 15.

or 11 Percent, 1had( expeienilcedl a rheumiat ic recili-relice since sep~arat ion fromi

the service. ('heniopnophivlaxis was not emiployed ill any eas.w

It is (list urlbing" to learn that definite heart consciousness. or neurovincvulatory astihenlia. as evidenced by precordial paili. (lyspl)ea. and( 1pal1pitat ion was

i.5 See footnote 11. p. 229.

14Eigiezman. E. 1'.. Holliister. L. E.. and Kolb. F. 0.: 5feqIelne of Rijemumtic Fever in Men:

Fmir tto Eight-Year 1Fdl4)w-Up Study. IJ.A.M.A. 155: 1 1.14 1144). 24 July 1954.
RHEUMATIC FEVER 235

present in one-third of these patients. Anxiety neurosis was a more common

complication of rheumatic fever in these individuals than valvular heart

disease. Only a few of the study group described were disabled and nearly

all were in school or were employed.

It is generally believed that clinical recovery from rheunlatic fever is

accompanied by complete disappearance of pain in the joints. It is of great

interest that this was not so in the. Army. Persistent arthralgia was comnlnonplace, having been noted in 50 to 60 percent of the cases and having continued for as long as 6 years.1 7 Physical and roentgen examination of the

joints never revealed any abnormalities after the first few weeks of the illness

during which time effective salicylate therapy was instituted. The residual

pain was often very disturbing to the affected individuals and interfered with

resumption of their normal activity.

RECONDITIONING

Formal l)rograms for the reconditioning of convalescent cases of rheumatic fever were not introduced in the Army until 1944 when treatment centers were established. Before this time, the station hospitals in areas where

the disease was common were completely lacking in facilities for this purlpose.

Neither space, personnel, nor a suitable climate were available. This serious

lack was an important contributing factor which led to the frequent appearance of cardiac neurosis. After the Army Service Forces and the Armny Air

Forces established centers, the situation improved greatly. Men were moved

to these establishments fairly early in the disease, usually during the second

or third month of illness.

Each of the centers located in general hospitals developed an elaborate

program of supervised, graded, and gradually increased activity for convalescent patients. The official reports speak in glowing terms of the efficiency of these techniques. Complete recovery was hastened and cardiac neurosis minimized.18 Reconditioning was also an important aspect. of the treatment at the Army Air Forces rheumatic fever centers,' 9 but information about

results was not preserved. A formal study of the problem which was conducted in the physical fitness laboratory at Randolph Field, Tex.. d(emonstrated that early activity proved to be safe and beneficial when accomplished

with careful guidance and under the control of fitness tests. 20

17 (1) See footnote 16, p. 234. (2) Starr, M. P., and Kimbro, R. W.: Residual Arthralgia in

Rheumatic Fevwr l'atients. News Letter, Army Air Forces Rheumatic Fev-'r Control Program. vol. 2,

No. 2. pp. 17-21. February 1945.

is See footnote 11, p. 22-9.

:1) Ershler. I. : Convalescent Program for Rheumatic Fever. News Letter, Army Air Forces

Rheumatic Fever Control Program, vol. 2, No. 1, p. 1, January 1945.

20 (1) Karpovich. P. V. : hysical Reconditioning of Rheumatic Fever Patients. News Letter,

Army Air Forces Rheumatic Fever Control Program, vol. 2. No. 4, p. 14, April 1945. (2) Karpovich. P. V.. Starr. M. P.. Kimbro, R. W., Stoll, C. G.. and Weiss. R. A. : Physical Conditioning

After Rheumatic Fever. [Official record.]
236 INFECTIOUS DISEASES

DISPOSITION

The problem of disposition of patients who had had rheumatic fever was

a knotty one during the early years of World War II, and formal gruidance

was not provided by The Surgeon General. Each hospital made its own

policy based on the experience of its medical officers. In general, men were

retained in service after recovery if there was no evident residual cardiac

damage. Often, the severity of initial illness was also considered. Some hospitals were separating all men in whom the diagnosis of rheumatic fever was

made because it was believed that the chance of recurrence was too great if

these individuals were retained in the service. An attempt was inade to

make the policy more uniform by the publication of Circular Letter No. 144

by the Office of the Surgeon General on 7 August 1943. Discharge was recomnmended for all men with residual cardiac damage and retention in service of

all others who had fully recovered. This policy, in the experience of the

author. was not closely followed by officers in the field who frequently tailored

it to fit individual cases.

Army Air Forces Letter 25-7 defined the disposition of rheumatic fever

lhatients in the Army Air Forces and stated that those who had made a coinplete recovery without residua should be returned to full duty. Those with

evidence of cardiac d(amage were to be discharged unless they possessed special

skills in which case they could be retained in the service and marked for limited duty. Various special situations were also considered in detail. Data

on disposition of 410 cases of rheumatic fever by an Army Air Forces center

show that 53 percent were returned to duty. Of those discharged, 67 l)ercent

had had a recurrent attack or activity continuing for more than 3 months.

Only 23 percent were separated from service because of residual cardiac

changes. This was less than 10 percent of the whole treatment, group. No

comparable directives from the Army Service Forces have come to the attention of the author, and it is of interest that the official publication on rlieuinatic fever, TB MED 97, does not discuss the important problem of disposition: this was to be the subject of a subsequent directive which was never

issued.

Uniforni disposition was not accomplished even by the three general

hospitals which served as rheumatic fever treatment. centers. 2I At Birmingham General Hospital. the advice given in Circular Letter No. 144 was followed until September of 1945. and approximately 50 percent of the patients

were discharged, the remainder being returned to limited duty. After that

(late, any evidence of carditis was accepted as grounds for separation. This

included more than 80 percent of all cases. The staff at Foster General Hospital formulated its own policy and discharged all patients with multiple

attacks of rheumatic fever in 1 year, those with any cardiac residua. and those

whose disease remained active for more than 3 months. Approximately 50

21 See footnote 11. p. 229.
RHEUMATIC FEVER 237

percent of cases assigned to this 'tospital received certificates of disability for

discharge. The medical officet in charge of the rheumatic fever cente,: at

Torney General Hospital believed that troops who had had rheumatic fever

were unsuitable for •Turther militarv service because of the great risk of iveurrence. Ile arbitrarily recomnmended So percent of them for discharge.

In retrospect, it is difficult to understand why a uniform policy for disposition of rheumatic fever patients was not established for the Army Service

Forces hospitals by The Surgeon General. The varying criteria for discharge from the service were unfair to the patients and created a sense of

frustration and insecurity among the responsible medical officers wh& were

constantly in doubt as to the proper course to follow.

CONTROL

Rheumatic fever control programs were not undertaken by the Army

Service Forces, although intensive research was carried out by the commissions working under the auspices of the Army Epidemiological Board, centers for care and rehabilitation were established.

The Army Air Forces. on the other hand, originated a full-scale rheumatic fever control program under direct authority from the Commanding

General, Army Air Forces, in the fall of 1943. its objectives-22 were (1)

recommendations for the use of sulfonamide prophylaxis for the control of

respiratory infections and rheumatic fever, (2) adoption of uniform standards for the diagnosis of rheumatic fever, (3) coordination and standardization of bacteriological techniques in the study of the hemolytic StreptoCO(8C, (4) establishment of a uniform convalescent program and followup

studies on positive and suspected c-ses of rheumatic fever, and (5) consideration of special projects and investigations at various Army Air Forces

posts.

All of these goals were accomplished with varying degrees of success.

The greatest activity was in the area of study and control of streptococcal

infection under objectives 1, 3, and 5. This work has been described in

detail elsewhere.2 Uniformity of diagnosis and treatment was accomplished

partly by educational activities directed toward the staffs of station hospitals, but more directly by the creation of centers for the care of patients

with rheumatic fever and the use of air transport permitting transfer to

these institutions at an early stage of the disease. Much was accomplished

by the wide distribution of a monthly newsletter published at the AAF Regional Hospital, Mitchel Field, Long Island, N.Y., with the support of the

Josiah Macy, Jr. Foundation of New York and edited by Capt. (later Maj.)

Charles A. R. Connor, MC.

22 The Denver Conferenee. News Letter, Army Air Forces Rheumatic Fever Control Program.

vol. 1, No. 1, p. 2, August 1914.

:3,14pe tfrnotet s. p). 22S.
238 INFECTIOUS DISEASES

Endless debate continued at various levels throughout war in regard to the advisability of refusing induction to individuals with a past

history of rheunnatic fever because the number of such persons who developed Irecurrence.• of the disease was high. Mobilization Regulations No. 1-9

was variously nmodified. Between August 1940 and April 1944, active acute

rheunmatic fever or verified recurrent attacks of the disease in the past placed

a man in the unacceptable group. The latter history was clearly not sought

adequate.y by examining physicians at induction stations. In April 1944,

the order was changed to include active acute rheumatic fever and verified

single or recurrent attacks within 2 years. This order was not well designed

since a. definite attack of rheumatic fever has the same significance at any

time in the life of the individual.-4

RESEARCH

Clinical investigation of nmany l)hases of rheumatic fever was undertaken at numerous hospitals. The large amount of clinical material available to miany Yhighly skilled investigators permitted the rapid accumulation

of information in regard to diagnosis, course, and treatment. Many reports

of these studies were l)lu)lished but will not be reviewed here. The lack of

special facilities in installations other than those specially supported by the

Army Air Forces Rheumatic Fever Control Program or by the commissions

of the Army Epidemiological Board prevented, for the most part, any fundamental work by these groups.

SUMMARY

Rheumatic fever was a coninon disease in the Army (luring World War

11. particularly in certain geographic areas. It was observed in all degrees

of severity, but the disease responded well to rest and the administration of

salicylic acid and its derivatives. The course was usually monocyclic, and

recovery in all but a few cases was complete within a few months. Valvular

heart disease was a gratifyingly uncommon complication. The major problems encountered were those concerned with development of cardiac neurosis

which was caused by overly severe restriction of activity, apprehension on

the part of the medical officers in charge, and inadequate programs for convalescent rehabilitation. This situation was greatly improved during the

last 2 years of the war by the creation of treatment centers.

Investigation of many aspects of the prevention and management of

rheunmatic fever was carried out. Much pertained to the study of thet close

relationship between infection by group A hemolytic streptococci and the

rheumatic state and to measures for the control of strep)tococcal infection.

24 It is certain that young adults who have had rheumatic fever are more likely to experience

recurrences when exposed to streptococcus infection during military service than are nonrheumatics.

They should be identified with car(, at the time of induction and a chemoprophylactic regimen instituted at once. This should permit them to contribute fully to the military effort.
CHAPTER IX

Meningococcal Infections

Worth B. Daniels, M.D.

HISTORICAL NOTE

Outbreaks of meningococcal infection are known to have occurred during all wars since the illness was first described by Vieusseux I in 1805. Important milestones in the development of knowledge of this disease can be

briefly summarized. The isolation of the causative agent by Weichselbaum 2

in 1887 led to a search for a specific cure. Flexner and Joblinga thought

that the antiserum prepared by them at the Rockefeller Institute in 1908

favorably modified the course of the disease.

Within 1 month of mobilization in World War I, the annual rate of

admission to hospital for white enlisted men in the United States reached

1.71 per 1,000 troops, and within 7 months an explosive outbreak of meningococcal meningitis had begun (chart 12). In January 1918, the rate had

risen to a peak of 4.48 per 1,000.4 This epidemic afforded Herrick 5 an

opportunity to study the use of antiserum under controlled conditions and

to make observations on pathogenesis. His studies indicated that antiserum

given intravenously reduced the mortality in patients with bacteremia and

in those with meningitis. In spite of the use of meningococcal antiserum,

however, there were 1.836 deaths among approximately 5,900 cases (31 percent case fatality ratio) among troops throughout the U.S. Army in a period

of 33 months during and immediately following World War 1.6 Herrick's

studies clearly showed that meningitis does not develop as the result of

extension from the nasopharynx but begins as bacteremia with later localization in the meninges, joints, and other tissues. This concept has greatly

influenced treatment and, together with the development of the sulfonamides,

has been a factor in lowering the death rate.

I Vieusseux, M.: Msmoire sur la Maladie qui a r~gne A Gfneve au printemps dle 1805. J. de

med., chir. et pharmacoi. 11: 163-182, 1805.

2 Welchselbaium, A.: Ueber die Aetlologie der akuten Meningitis cerebro-spinalls. Fortschr. d.

Med. Berlin 5: (No. 18). 573-583, 15 Sept. 1887; ibid., 5: (No. 19). 620-626, 1 Oct. 1887.

3 Flexner, S., and Jobling. J. W. : Serum Treatment of Epidemic Cerebrospinal Meningitis.

J. Exper. M. 10: 141-203, January 1908.

4 The Medical Department of the United States Army in the World War. Washington: U.S.

Government Printing Office, 1928, vol. IX, pp. 203-221.

5 (1) Herrick, W. W.: The Epidemic of Meningitis at Camp Jackson. Preliminary report.

J.A.M.A. 70: 227, 26 Jan. 1918. (2) Herrick, W. W.: Early Diagnosis and Intravenous Serum

Treatment of Epidemic Cerebrospinal Meningitis. J.A.M.A. 71: 612-617, 24 Aug. 1918. (3) Herrick, W. W. : The Intravenous Serum Treatment of Epidemic Cerebrospinal Meningitis. Arch. Int.

Med. 21: 541-563, April 1918.

6 See footnote 4.

239
240 INFECTIOUS DISEASES

CHART 12.-Admissions to UT.S. Army hospitals for mcningocvoceal infewtions among troops

in the continental United Statcs, by month, World War 1 1 and World War 11 2

(Rate exprewsed as numbe'r of cases pwr annum Iper 1,000 average strength]

RATE

5

WORLO WAR I

4

2

A J 0O A J O 0 A J 0

1917 1911 1919

RATE

3

PLOR WAR 11

MOBILIZATION

Jo J A J 0 4A J 0 J A J 0 JA J 0 J A J

1940 1941 1942 1943 1944 1945

1 The World War I rates represent primary admissions only and are limited to white enlisted

men. These rates are from individual medical records as published in the official history of World

War I.

2 The World War II rates comprise secondary cases as well as admissions and are preliminary,

based on the statistical health reports.

Sulfanilamide early proved to be a highly effective agent, in the therapy

of these infections. 7 In 1940-41, during the outbreak in Halifax, Nova

Scotia, Dingle and his coworkers 8 showed the effectiveness of sulfadiazine

in a small group of patients.

7 gchwentker. F. F., Gelman, S., and Long. P. H. : The Treatment of Meningococlcl Meningitis

With Sulfanilamide; Preliminary Report. J.A.M.A. 108: 1407-1408. 24 Apr. 1937.

s I)ingle. J. H.. Thomas. L., and Morton, A. R.: Treatment of Meningococclc Meningitis and

Mq-ningococcaemia With Sulfadiazine. J.A.M.A. 116: 2666-2068. 14 June 1941.
MUNINGOCOCCAL INFECTIONS 241

INCIDENCE DURING WORLD WAR II

In World War 11, imobilization began with the federalization of the

National Guard in September 1940, and the induction of large numbers of

selectees followed shortly. For over 2 years, only sporadic cases of meningitis occurred in troops. In December 1942, closely following an increase

of respiratory disease in the late fall, the incidence of meningococcal infections rose sharply throughout Army installations in the United States. By

March 1943, the outbreak had assumed severe proportions, and the incidence

rate had reached 2.9 per 1,000 troops (chart 12). The rate amnong newly

inducted soldiers was from 5 to 10 times greater than among soldiers with

a year or more of Army service. At one post, where crowding among new

inductees was excessive, the weekly rate rose to 42.2 per 1,000 per annum. 9

Throughout 1943, the year of most numerous casev, data based on individual medical records show that 7,083 patients were adlmitted to hospitals

with meningococcal infections; 6,370 of these developed the illness in the

United States. The incidence rate per 1,000 per annum was 1.0 for the total

U.S. Army, 1.2 for troops in the United States, and 0.4 for troops overseas.

For the year 1943, in the United States, the statistical health report

rates per 1,000 per anmun by service command are as follows:

Service Command Rate

First ------------------------------------ -------- 1.2

Second --------------------------------------------------- 1.6

Third ---------------------------------------------------- 1.4

Fourth --------------------------------------------------- 1.5

Fifth ---------------------------------------------------- 1.3

Sixth ---------------------------------------------------- 1.5

Seventh -------------------------------------------------- 1.3

Eighth ----------------------------------------------------. 8

Ninth ---------------------------------------------------- 1.0

The incidence of meningitis (0.8 per 1,000 per annum) in the European

Theater of Operations, U.S. Army, during 1942 was greater than among

troops in the United States. During 1943, the rate in the European theater

remained about the same (0.9). In other oversea theaters, the rates in general rose somewhat, but no significant outbreaks occurred.

During September and October 1943, the incidence of meningococcal

infections among Army troops in the ITnited States fell nearly to the preepidemic level. A rise to a second, less elevated, peak began in the winter

of 1943-44, with return to the preepidemic rate by summer. It is of some

interest that the peak of the second rise (1.1 per 1,000 in February 1944)

came 11 months after the height of the epidemic (2.9 in March 1943). table

34. In World War I, the second peak (1.2 admissions per 1,000 for white

enlisted men in October 1918) occurred 9 months after the first peak (4.5

9 Sartwell, P. E., and Smith, W. M.: Epidemiological Notes on Meningococcal Meningitis in the

Army. Am. J. Pub. Health 34: 40-49, January 1944.
,24.2 INF.EC'TIt M'S DISI"EASES

in Januarv 191St)*' The second rise in incidence aiiong troops in the United

States during World War 11 was as intense as that which (ccurred during

Worhl War 1. and was miore sustained. Attention is called1 to this becaus

sulfonamides were widely used proplhyactically in tile fall and winter of

1943-44. following distribution of ('ircular Letter No. 170, Office of the

Surgeon (Ceiteral.S .8. Army, dated 30 September 1943. This letter established as .AryiV policy the administration of sulfadiazine to all newly inducted soldiers during tihe seasons when respiratory diseases were prevalent

(chart 12).

Again, duriming the winter montlis of 1944-45. the admissions to hospital

rose. but to a iuch less (legree than during the previous winters.

TrABLE :1-4. Inridrncr and deaths duc to ,saeninflococrall infections. I '.S. A r.t!, World War I

and World War !1

('I.ine I'eak of intvident in the i' United Nunilmr Nunlwer fati dity States I

P'eriod of ca.ses of deatihs r-itio

(pervent )Period Rate I

World War I (April 1917- D)t-eeinher

1919): I World War I:

('ontitiettA I 'llited States . 2, 878 986( January 1918- 4. 48

Total Army 4 5, 839 1, 836 31. 4 Octolhr 1918- 1.21

World Wa r I1 (January 1942-

I1)eiember 1945): World War I1:

Cot inental United States - - 10, 619 410 :3. 9 March 1943__I 2. 89

Total Army . .13, 922 559 4. 0 March 1944... I. 14

I The Worhl War I daita pertain to itm.issions for white enlisted men in the United States, whereas the World War II

data represent incidence for all Army pwersonnel in the United States.

irate expres•,ed as number per annum per I.(XWJ averaive strength.

Admissions only. ID)ta on secondary caeas are available only for enlisted men in the U nited State~s andl Europe

combined. Baised on the distribution of admis•ions in the two areas, the incidence in the United States is estimated at

3,,50K) case4s.

4 ('onsists of admiissions in the entire Army and ,econdary cases among enlisted .. ien in the United States and Europe.

St,,condary eaises among o|licers and among enliste:l men outside the United States and Europe are not available, but thle

Incidence is estimated to tb, 5,9(m) eases for the entire Army.

N-NoTE.-(I) l)ata for World War I were obtained from "Tlhe Medical D)epartment of the United States Army in the

World War." Washington: (Government Printing Oflice, 1925, vol. XV, pt. 2. (2) D)ata for World War 11 ar, preliminary. (3) The number of deaths are from complete flies of individual medical records, and incidence is basel on sample

tabulations of individual medical records, except for data on Iwak incidence which are from the statistical health report.

Dluring the years 1942-45. in spite of the availability of highly effective

treatment, meningocO(c('al infections caused more deaths (559) th an any

other infectious disease, except. tuberculosis. Table 35 shows the number of

deaths in the U.S. Army during this period resulting from the more serious

infectious diseases and the death rates from these diseases per 100.000 average strength.

ito See footnote 4, p. 239.
311NING0)C)C'AIL INl'ECTMiNS 243

Of 13,922 patients attacked by meningococcal infections during 1942-45.

only 559 deaths were reported-a case fatality ratio of 4 percent During

World War I, the ratio was nearly eight times as great, 31 percent. Chart

13 indicates the case fatality ratios in the continental United States by

month during the two wars. The ratios for World War I are based on white

enlisted patients in the continental United States.

RATE

100 - _____ ____ ___

CHAir 13.-Case fatality ratios for meningoeoecal infcrtioes, by months, in the cim- so_

tinental United States during World War a V ( and World War I1 '

I The World War I ratios are presented in 6O0

terms of numbers of deaths per 100 primary ad- WORLD WAR I

missions for menlngocoecal infections among / /

white enlisted men in the United States. I)uring ,oil, 

World War I for all enlisted men in the United 40

States. the rate was 34 deaths per 100 admis- 4 -; ;

sbuns. or about 28 (deaths per 100 cases in the is % ::

United States. V1 ,

2The World War II rQtios are presented in I

terms of numbers of deaths per 100 cases (pri- 20 " • f",l 'I " I,

mary plus secondary cases) among all Army per- WORLD WAR II 1 iI

sonnel in the United States.

JM J S D M J S D M J S VJ

191? 1910 1919

1942 1943 1944 1945

TABLF 35.-Comparative mortality of certain infectimos diseases in the U.S. Army, 1942-45

[Preliminary data, pending publication of final statistics]

[Rate expressed as number of deaths per annum per 100,000 average strength]

Number of deaths

Cause of death Rate

1942-45

1942-45 1942 1943 1944 1945

Tuberculosis ------------------------------ 3. 16 806 107 192 201 306

Meningococcal infections -------------------- 2. 19 559 73 269 139 78

Bacterial pneumonia ----------------------- 1.59 404 51 121 117 115

Lobar pneumococcal pneumonia-. 1.41 358 51 121 91 95

Malaria -------------------------------- -- 1. 19 302 25 113 89 75

Scrub typhus ----------------------------- 1. 1 283 ------ 49 180 54

Poliomyelitis ----------------------------- 1.05 267 5 49 66 147

Infectious hepatitis ------------------------- () (1) (I) (1) 68 191

Primary atypical pneumonia -----------------. 67 170 38 48 42 42

Diphtheria --------------------------------. 48 123 1 10 22 90

Amebiasis I -------------------------------. 15 39 6 4 7 22

Bacillary dysentery I ------ -------------- .06 16 3 6 3 4

SOther infectious diseases causing more deaths than amebiasis were scarlet fever (61) and syphilis (70). Several

other infectious diseases ranked higher than hacillary dysentery asa cause of death. Even though amebiasis and bacillary

dysentery had low death rates, both were feared disases.

639243°--63-19
244 INFECTIOUS DUSEASES

The organization of medical care in the Army permitted the observation of early cases. resulting iii better recognition of the various forlits of

the disease. It is, therefore. proposed in this chapter to describe the different forms that meningo(*ock-al infection assumed in soldiers during World

War II. indicating how studies of the early stages contributed to knowledge

of its pathogenesis, and to review the methods and results of treatment

varried out in Army installatieis.

PATHOGENESIS

During nonepidentic periods, the rate for meningococcal carriers in

troops ranged from 2 to 1() percent." In periods of epidemic. carrier rates

among troops rose and in studies made (luring the epidemic were reported

as ranging from 23 12 to 80 percent.13 The carrier rate was lowest anlong

newly inducted soldiers.

The micro-organism probably invades the body from the nasopharynx.

and infection in this region may or may not be accompanied by evidences of

respiratory infection. The subsequent manifestations are those of bacteremia

and localization. Observations during World War II supported conclusions

similar to Herrick's in World War I, since they clearly indicated that the

course of events consisted of invasion of the bloodstream followed by localization in the mneninges. skin, or other tissues of the body if not prevented

by natural resistance or by therapy. The experience of all observers emiplhasized the necessity of viewing this disease as a bacteremia, which was sometimes overshadowed by the advent of the more dranlatic symptoms of meningitis. By early recognition of the bacteremic stage and prompt institution

of treatment, the infection might be terminated before its localization in the

meninges or before it had become fulminating. If meningitis or other severe manifestation did, notwithstanding. supervene, the chance of recovery

still was better than in cases that had not had prompt treatment. Whlen

medical officers became familiar with the disease, through experience in the

epidemic, they recognized it in the bacteremic stage and prior to the advent

of meningitis in as high as 30 to 40 percent of the patients. 1 4

MENINGOCOCCAL BACTEREMIA

Prodromal symptoms.--The ii dlts began, as a rule, with prodromal

symptom: of disease of the upper n-spir'c 'dry tract. After an indefinite period

1I Dingle., J. H.. and Finland. M. : Diagn. -'iArment and Prevention of Meningoeocceic Meningitis. With R~num4 of Practical Aspects of Trituient of Other Acpte Bacterial Meningitides. War

Med. 2: 1-58, January 1942.

12 Personal communication, C. T. Nelson, Fourth Service Command Laboratory. to the author.

13 Cheevrer. F. S., Breese. B. B., and Upham. H. C.: The Treatment of Meningococcus Carriers

With Sulfadiazine. Ann. Int. Med. 19: 602-608, October 1943. 14 (1) Daniels. W. B.. Solomon. S.. and Jaquette, W. A., Jr.: Meningococcie Infection in Soldiers. ,T.A.M.A. 123: 1-9, 4 Sept. 1943. (2) Thomas, H. 3.. Jr.: Meningococcic Meningitis and

Septicaemia : Report of Outbreak in the Fourth Service Command During the Winter and Spring of

1942-1943. J.A.M.A. 123: 264-272, 2 Oct. 1943.
of from til 41.1iv to a week or iliore. lith ai etatiisIt~ue llorle alrllte.

Thlere wa-;I uialv a1 sudtltli chillI with ii i.I P-e iii tern peratllt ile tilt 1 lilt,

(IIIM't inii-Ii b e .M : ie x e i-t N.i;tia v:1ktie4. acingti~ of iiniisdets. Iiiloelt it'adatle. 1iai-e. o4iit:1i. painl ill joilills. orl avilte iiili:iiiiiii1it loll of

Rash. -lit' Iisll Iliyulit 1)( se~ sI):l-se 111:at ca iefiil I :11 't'11'itl1i't;i t

st'a itvl a It'et'ssiv to hiitl it. or It ~ri bi e oblviousP andli( oted l)iv It lit

pI l t ieflit .It a t'pp', IIv illa id \Varlt't d I fotrms-. andit kalowvvltle of Hts Van11-

\\i:Ii Ws Ilt't'-siVV to thle reco-llit loll oh, t liew sa

The rwlilmllolit'slv It'1ioii wS pete'tetiiia or* pliipiiiitc anid variled fromi I to 1:,

dleIlildI l~ilt Iililk Iiiiauilt' Si111ii:1i. to thle roste spo0ts ol' t * phlltit Ie vere

\V1111-11:111Y pnvlt'tii. a lit II ol a'lie tame I htvY hado a cewrll ta Ia'tt'l ik. iThe
4)11 tile ext remiities. these iioduleq bo~re it st rikinig iresemitdative to Illw sillaller

lesionls of ervi eleiia iiotos.iiiii. (h)c.1sioiial I. t here were pe ec lat. IIiI tlie (-oltjillictivat, auid til oral Ilii(coii iteiilibraiies.

Vrious coiibilt at iollt oIf tilie c~t :ialcolts 111111 ill fta ti 'Ii 41414,111,114: I ildeeul.

iliost p)2it eut s Showed miore t hanl oiie type of lesionl. Th'le rash app ea red allywhere oil lie bodly hilt usually Spa red t he face anld wits less coitiiioii on tilie

pajiiuis andt Soiles. It wits oft en evident ill crops. TFile Itizueular lesionls siolietimles receded with fall ill telilperatuire. oni' to reappear as IStle telliperailuire

ag I I rose. Thle raphidity' wit il which tilte raishi oftenl apit-pared iiia1de it tiecesSarv to examntie crflye ryslispected patienit at hiourly v ut ervals: inl a

few lholurs,, it couldl advaiice fronil a few vagu'le Spots to a1 widlespireadl erl-liption.

In fulni miat mug hactereutila, a widespread exteunsivye evehlyivutiotc rashl

developed. involvitig. in1 SOMP1utie p lttS s, Ien as nineh 110 aSo I peret Of thle hod1.

Ill a1 few Pat melits. la rge aryeas of lienullrrilagge dlevelopJed l Ieuleatlx thle couip ijict ivae and ill tilie oral oni1conls membd ranies. Somie of tdhe evehlioniot. mc esmoiis

biecamie vesicular, and Ilicerait i4)i oct-asiouiahl (W-curre(l. rile rapi jdIisapll~~ieraite(e Oif tile Illactihlopipijlztr coilitfOlmmeiit of tihe rashi within 12 to IS hititrs after

tile h~egijIiIIi mgof tl(I IteraV withl suilfadiazine was almiost diaguiost ic of menii ~gmotc(al hact eremtia.

Other symptoms,- I terpes simp l)ex was ctiiiiinoii. usnaliav 4 iccu r-iig, azioitit

the second dayV of illniess. Herpes ZoSter. inIVo]lvn tlie 01)]Ill.tllaluiii .111d uIaI.Xilbury brzinclies of the fift h craniial nerve. was observed inl one Ipat jeutt

At adinission. thle temtperature Of paint vitli mieliiuinrk041Pcccl Ill nuu111i'ved

fromt 970 to hNM0 F. It was greiierahlv betweeni 10l' mid 1O0-2 F'.

I'Amkotcvt osis (1.5.O04JO to 501))per cuibic inill imteter) , wit hi a1t uiwreaste

illi iolyniorpi~domiilear cells. w~as thle rule, but inii few patients the uilliliber

of leukoct pes wats normal.

Variations in Menitgococceenia

There wits a Simplje acutle formi of ieni) ngoVoccenilla with fever. malaise.

pa in fuil oi ots. rashl, aut(I lelikmyosy )is. The progress of this type could lie

arrested at this Stage by therapy with sillf adiazinle. as illust rated ill case, 1.

Case 1.-A soldier. aged .34. hald hiad at slight cold4 for aboumt 2 weeks be-fore admtission.

D urinig it* II' 1fteriaoitm of the flaiy IN-fort i1ei4111ti55hi41 he. sttIidct-i I y hgaii to 64.1 1i1t1isuaiIly

ti rEt and)to 141 tvlje 2111 o~ver. DI iiring" thle 1nýIght thc had1( (liily seisatit 141 alteriiu It ii withI

feverisliiiess, and11 miI the imolrtnitw, of tilt, 4lay af a1411inissi1 hie 112111 21 11140414-r2Itt-ly SPVPere

1ieatilztee. lHe was5 m1(ittt'y. butt no~t seriu'ilsly. ill. Hi s falce was filushedl 24iul hiis telliperal-a

ture wvas M41 30P.. There was SliIght hillit~l~tliltio)II of tile iuise 211141 t1 roztt. 21114 a1 m iitieit'-

pazputlar rash ( fig. 35) was mcat teredl 41VeI. hilt t runk and14 all extremities .Neurolmlgical

e'xaminationii ;:11. Iv. elitiirely mtlrmlai results1. The Iceukocytes iitiiilmi-t're U010 tI. N't per cl)1E

mtillimieter. with 81 INt-e~lt ImIlyllt1hIollucltt4ealr cells. 11,0041 ('1 clt~ltre0 011 21E1411111k1fl y'ieI-eltl

I yjelit. I t 1g11415 Lilltlt pttl lre was iS ltdoie 14. A, mimia 441 tith- blood1 for ct111 tre

had l Iit-e raikeii. siilfadiaziiie WI giVenlb 1114111l~thl. 're tlll$'ralturtr was 114)1r1t1111 w~ith1111

2 fla1ys. Thei paien i'It .evehbxljtI Ill, sihs fir hilt.en iitilis.
MENlN(G4WOCC V(AI IN"ECT"IO NS4 247

The disease at times wvits relatively miild and stibactite, so that the fever.

malaise. p~ainlful jolints. and rash suiggested rheunmatic fever or erythlemia

imiiutiformne. The following case is illuistrat ive:

Case 2.-A soldier, aged 21, hadt been well uintil 3 da ' s before u~admissiona. whet lie

sud~denlly hadii a Shaking chill with the dlevelopmiient oIf fever. tatalaise. sald sore throat.

Thle oillly maga) tticiiitt fillili tgs were a few eryttenautouis blo tches oat the chest antd the legs

alitl at palpable Spleen. There witas a contimiottoS fluctuati tag fever dualn ra the suaceeditiig

11 dayts. A rash clonsist lug. of inactilar, papuilar. anad nodula r lesionas. with a few petechialu,

apliwarei I i at crops. These titadin.gs su-ggested erythemja titalt iforaine andu ery theita n toilos5Uii.

S4ho rt ly after admaission. rednes.s, tetadernes." anad swellIintg iof the ri~ght anakle ulevelo'pedt.

The leuik iytes numtaibered 16,34K) per cubici maillimaeter. with 73 p~ercenttp tuIrhtier

cells. Mauay erythroieytes were tDoted ill Several NIMecimaens Ot urine. The Spinal fluid wvas

tnormaal. (Culitures of thle blood~l yieldled typie IIaaae! ai c l1S After the first dlose of

%itlfaahiaazine by mouth, tile temperature becamae tiormaal anad rentiaitied SO. The rash fadedl

prom lt ptlyS.

The extraordlinarily mildl character thlat nlienlingoc-occal infection occasionally aissumned is illustrated in case 3.15

Case 3.-The 10-year-old son of all officer was adnmitted to anl Armjy hospital with

haitli Iaut headache tand fever ( 111W F.). Admnissiota was gratated ontly (iii thle itnsistetnce

of his iapprehetnsivye muother, who fearedl pol ihlhyel itis-. Btecaluse of praessurae fti ma the

moiithter. examinaitiontlt (if the cerphrolspllai~l tillid~ antdt ('la1tti i-e (Of tilie blo od was tutahile. Th'le

Sptinal tiuihl was aariinal. Two dhays later'. cultures oIf both blood atad spinal fluid that

were miagle o n admiaassiont g-rewv meineiagroocci. No sped tiic t reattaeWi had beena gi vean. At

this t imea. oni (carefual scrutinly. one skini les-ion thotighlt to bie a Smiall pieteclalal hemiorrhiage

was foaild: a Secontd exitinlt la tion of the spinial thlnu Showed a1 normala tfatu and~ was

Sterile. Aniother culture oIf blood drawn onl the third dJay agrain yieldedl enetitgrocolcct.

As. the platienat had liec-line afrebrile land aSyluptolnati(' no suilfonamides wvere givetl. 'Stabsequtetat cultures Eof the blood were st( rile. For 10 (days the patienat was wVatcleiel closely

and developed tait recuarrence (If symptonis and no nmanifestat ions (if illness. At this thiiae

a comn se of therapy wi th stillfadiazine wats adminti stered. The patient was di scha rgetI

well after approim tately 3 weeks of Observation.

It is probable that, during the p~eriodls of increased p~rev~alen~ce of menin ifococcal infection. some cases of mld ( character with spontaneous recovery

were not dletected. We know that recovery from ineningococcal lbacterelnil

has occurred after minlimal amlounits of sullfonlailide, ill somne cases wvitit a total

dlose of as little as 2 grams. These patients usually had a mild illness with

fever and1 were given a single (lose of sulfadiazinle by the ward] officer. after

which no drug, was adlministeredl. Later, the original cultures of blood( taken

before therapy were shown to contain Ineningococci. but the patients hadl by~

then b)ecomne apparently well.

In other patients, the course was chronic andl Irodtlcedl a p~ersistent. lowgyradle, febrile illness. which inl case 4 was not severe enough to prevent thle

perform'anlce of muil itary duty.

Case 4.-A soldier, aged 23, was admitted to t-he oIrthopiedic- se-rice liecause oIf an !injuredl anakle. It wits learnied that for about 3 wee-ks lie hada beena sufferhing fronm maala ise.

evening- fever ish iiess, and iln intermtittent eruiption (If red nioduales oitt his leg~s. While ilt

1.51 erswial111 commui I eat 1(11, Ri. 11. Turner, to the a uthor.
248 JxFt~mr14u 115I ':A.I*:5

tilh' 114444j41t11 IlkS U-111114-1101111 1it'i111gtt1 'i'41 4111 118.4V to 1012" F.. M~igi'at i l ii- irt la ýii l %%IIua ts

pries4t-II iilI li it sc 4111. tt I''4 red eylit'iiijitiis j41ij4111 rash l'11 li 11t'Iii'e4. Thais m-as mos44t apij41relit

on thlt extremitites. 'IThe Ieliktovyes iiIiIt'ere 121.0II10 ' 4'ill( viihicilllimeter'. withi Sl im-rm'iit

U1441311111 lit1) lliigal 41 1('4'1 i' t I. ot 11%' ('4IIt- I ig l's 1 my tlit' and411gI4 th spna flu'I Iid was4 normal (( . All t'~t

11't're1144 StlIteIIigll '111-M31114441 Mit 11 'l withZiiS 24I hours' 111'.1114 it ltrie jazim.I1114 wa a 1s iiiiiiterI ii .il

TIransitioni Fromi Bacterem ja To Meningitis

'lie r'ecogniit ion of nieicitigoloccal infect ion before any evidence of inlvasionl of tile mienliug~es wats relatively eaksy dutring the ep~idemlic, whten the

index of suispicion was high ; it Was inl the sporadic case that delays ill diagnosis and treatmIlent were likely.

Case 5.-A p~rivate, atgt41 20, Wits ailhtitted withi at histo~ry of1 sore' thrtot whIich4 hadt

144't'I 1411*(tit fr41 I wt'4k. )tin tit (lly b11'Iefore'( adin(1o1511 t here' wj1Is it Sudden4'I olset' io

slhakil^-g chil~ls, fetve'r. mid it 411fi~ll tSS41'illies fJits. it few Si1111ll 4'r3'thlintolust~l4 iioflilillr

leions f ortm 1(24 Ow sk 4in d vlo'4li(4- 4'Nd. 1 1 tit :1 41113'S.11 1 Ii 14'11 Mi li Sd Iti hill41113ti~ Both I kn*444 

midboth rIelbow andl~r~tli4 the H.-l40 it wristh und'r ank'le11were4' ienlleIr' mid14 vIk'ilt 1141t 1141 ii1'

swoIltlen.iThe 1,(Im1'4kocy'tes nu4itii-e (11,514 pillieercib. milmeeWith 11 448eei J4431IN-14i44i1i4't poll't'ino

pI''t'ic t iir'it cellsi '11ative teti d4$in~~oite Ii i'ec44vei' f 1.11444441 '1IS to ke~t4 WHS l ('lit I111 '' flier

410S'i119P of S' iV4 I~kt'gii 1111-41 t114i')4' WIlls 114 pt g'4 thsIi. fiitoktl't-111411 V 12194 l0

delarse hi llstrat res the05 K whliothnseveof ('Ualale. nllso 10 voaufe talt ion. Wiowilg

3howr thet pitietlct ofs a pi'rosisten 1wash (luring(o thle Sgreate(r paere o t ef 'itiswtl'1huit tlogel orlSolinkis (I.il~gleo rseiis.^,rs soso h rn. esii ii

Cnasled 6-1,2 0 e 11 lt'iiocte IN-v cibiimillime tOther wvith 9 pe4rcIIleniS~'ti414415t thel.

WriIS 4t 14'44'4 1' witi It' iail hurm 411134,14~1 Ilt 1-441144 tloo -Y 100w. 154(its tnicei w ot culur arter~iI14141

('eI'lly i' 141k4''44 It 1 1.1141 there4'wits W14 114 growth. 11 114'I (h1gi414 44 s .o' te 41(e'Il

Casei14414l 6 l hit' t4'iiil t'IIIies tile timp rt1 10 ".11111 of lit' at ieiit 11144'I el W4i '444'il). Sho4l''wing

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MENING )OVOCCAT INFECTIO NS 249

The speed with which meningitis couldl (levelop) hi a patienit with nieningococceinia was ext reimely variable. The next pattieiit rep~orted1 (case 7)

wits o1e in whoim early meningitis wits p)resent oin admliission. as indicated by

recovery of ineningococci Onl culture fronm an otherwise normal spinal fluidi.

The history. however, gave clear-cut evidence thiat bacteremnia hiad existed1 for

about -24 bours before adhmission. This case also illustrates how rapidly meniingitis call advance in spite of promplt and adequate tlleralpy with sulfadiazine.

Case 7.-A private, aged 37, was well until the miorning of the day before adm~issionI.

when he suddenly hadl a shaking chill and began ito feel ext remnely weak. I leadache was

modlerately severe but suibsidedl during the evening. Oti thle morning- of thle day (if adimission the patient's headache was gone, but he nmoticedi that he wats covered with tiny dark

purplish spots. His right knee wats moderately painful onl walking. Severe fronltal headache again developed onl his admission to thle Wvard. lie wits obviouisly acute and seriously

ill, although alert anid well oriented. Scatteredi over the trunk aind all extremities were

umyriads of dark petechiae, all less than 2 mmi. lin dimmeter. There was no stiffness of

the neck, and Kerimig's and llrutlzinski's signs wvere not present. A specimen 41f spinal

Iltili coitai medl 3 lymphocytes per cuibicl11 milmeter, at no~rmal concentration of suigar, and

at smeiar of it wats negative for inicro-4)rganismns. By the following (lay, however. type I

meningococcus grew lin the culture of this fluid. Inmmediately after time initial luimbar

puncltuire, 5 gill. of sodiliiiii Stlfadliain~fe (lin 1.5M~ cc. oif saline and dlextrose solution) was

given intravenously.

Four ho4urs after adnmission the patient dleveloped projective vomniting and rapidly

became stuporouls. All tile signs of meningitis were present. Five and one-quarters hours

after the first lumbhar puncture another specimen of spinal fhlud was obtainedl. The fluidf

wats un1(ler greatly increased pressure andl containmed 17.7M0 leukocytes per cubic millimeter,

wvith 99 percent polymnorphonuclear cells. Thle concentrat ion of suigar hald fallen to a

level too low to) read with accuracy and time level of sulfadiatzinle had reached 8.2 mu~g. per

140) cub~ic centimeters. Snmear and culture of this second speciimen w~ere negative for

Inenlngococci lin spite of the add~ition of1 para-aminobienzoic acid to the culture mnedia. After

an ext remely stormmy course, the patient recovered.

Although thie culture of blood onl adlmission was contaminiated andl no

meningococci were found, the history of a shaking chill, the presence of a

lplrplurie rash extensive enough to be noticed iby the patient. and~ a p~ainlful

knee joint-all at a time when the p~atienlt was entirely free of headachle--

were believedl to lbe evidence. that invasionl of the bloodistream occurredI severa] hours before admlissi~on. That miening~itis was in the earliest p)lase at

the timle of adniission wats shown by the fact that the spinal flulid was nornial

in every respect excep~t thiat lnennimgoocci were growni onl culture. There

were no mieniivveal signs excep~t severe headache.

FULMINANT MENINGOCOCCAL BACTEREMIA

Without adrenal hemorrhage.-A form of fulminant, rapidly fatal

meningococcal infection occurred, with little or no evidence of meningitis

either during life or at necropsy, and without the clinical manifestations of

the Waterhiouse-Fi'iderichisen syndrome, whiile the adrenals, at necropsy,
250 INFECTIOUS I :ASEX

showedl no abnormality. The rash was wvidesprIeadj and( frequentl as exten

sive as that seen inl patients who hadl massive b~ilateral Itelirorritagge inito thle

adlrenals. Thle following is ai case in poinit

Case 8.-A 20-year-ohl soldier wits admitted ait 4 :30) a.mi. after ant illiness of at few

hou rs. with (.hills, fever. hleadatche, aiid Nveakiiess. ()n admiiss ion tithe temiperature was

1i7T* F. stupor wats manrkea. rh'le pulse was st i* nw. poundin g. aind rapid. TII~ it( blood

p~ressl- was 1201 systolic andl 70 diastolic. There wats not stiffnless of tile necqk (ir other

evidenve ..f mceliii iigal i rritat ion. WVidely scattered over* the skini weire iiyriads- 'f petechia I

and puipurvic lesions, soiiie oif which coalescedM to form areas of evchymo sis. Tile cerehirospinal tluid wats no~rmial. A culture of the blood14 ],lateýr gem type I iiieliiiiigoc cclls. Sodium

sulfadiazine, 4.0 g w.,~ as promipt ly griveu initra venously. Stupor dleepenesl. aind only

terminilally dlid cyililosis develop. D eath occurlred 8 hrsafter adniliss-ioii.

At autopsy iieither tilie adrenials nor- the( leptoitil nliigesO shi iwed alliormial ities . There

w-ere small I scattered hemuorrhnages thrin ug-hlout mo. st of the orgaunns.

Instances of a fatal form of fulminating bacteremia associatedl with

so-calledl tubular (legelerut ion of the adrenal vortex, as describ~ed by Ricki,"

occulrred1 amiong Army personnel. The adrenials in these patients were not

the site of hemorrhage. These cases occurredl with andl without mlenlingitis.

The following case, reported by Kinsman, D'Alonzo, and IIuSSi. 17 is illustrative:

Case 9.-A 20-year-old white soldier was adliiitted tol the hospital at 3:30 pall. oil

22 JTamnuary 1!)44. about 2 hours after sudldeni onset of wveakiness, shaking chills. fever.

hueadachile, pa in in tile back. and exhadust ion. The temuperature oil admiiissionu was 104.(P F.

The leuikocytes uiunuh1ered 11.9t54). with 84 perceint iieutrolphils. Physical examiniiationi revealedl nuchual ri~gidity of niliniiiial (legree. but Kerniig's signI was absent. Thle pharyinx

was mo4 dera tely injec-ted. Type i nien ii~ ngce ccu~s wats later reco vered front the spinal fluid.

Early the next morning- (23 .January ) the patient developed aii inicreasingly widespread.

miottled purpuric alnl e(('lytuotic rash over' the entire body, including- the face 1111( nec-k.

About 80 percent of the surface (of the body evenitually wea~mue involved. There wvere

scattered hlemorrhag~ic spots. most of theiii large, anl in('h or miore in (diamieter. These

wer'e also oIbservedl in the coinjuinctivae 1111d mouth : the uivula wits comipletely black front

hemiorrhage. In spite of treatment, the eruption contimiiue to spreadl. The patient becamie

restless, coiiplainiiig, of chilliness, aiid oIf the burniing and~ soreness of the eruption. His

lips, fin~gernails, tmid( entire skin became cyanotic, the pulse was 110. and blood pressure

wvas 130 systo~lic art(] 100 diastolic. Nuei('ll r'igidity had( niot incr'3easedC andl Kei'nig-'s sign

was still absent. The leukocytes; nunmbered 27,200, with 87 percent neutrophils%. The

temiperature wats 1050 F. At 1 :10 p.m. he hecamite comiatose and markedly cyaniotic, with

raupidl respirations. The temtperature cl imbed to 107.80 F.. arid] the respirationls dIropped

tol 8 per minute. A (direct smear of his blood showved diplococci lying within the cytoplasm (If the neutrophils. The culture of the blood was later reported positive for type I

mienlng(Icoc('ls. The patient expir'ed at 3 :10 p.m.. 261 hours after oInset. A seeondl spinal

puncture wats (lone at the timiie of the necropsy anid showed 2,200) cells..

Nec'ropsy revealed wvidespread1 focal henmorrhiages tin the pulmioinary par'enc'hymia and

pete('hial hemiorrhages in the pleur'a, pericardium, andl eiidoeardillil. Examination oIf the

adlrenials showedi no g-ross hemor'rhages. M icioscopically, there wats marked congest ionu

If' Rich, A. R.: A Peculiar Typie of Adrenial Cortical Damage Associa ted With Acute Infections.

andl~ Its l'ossible Relation to) ('lrcilaitory Collnmlse. Bull. Johns Hopkins Ilosp. 74: 1-15, .lmauiur 1944.

17 Kiusnimmn,. 31. .. 1)'Alonzo. C. A., and Rusmi. S. :Fulminating 'Meningocuccic Septicemila Associate(I With Adronal [A'sio~ls ; An Analysis and Dlvscisioni of Sev'en Cases. Arch. lnt. Aled. 78:

139-169, August 1946.
\IENIN(0&'ECIAI IN'ECTVIONS 2-) 1

of the shinusoid. iburt 11i0 o xt flivatii5 IeIIIf n bloodi. Thie veiI ill tilte gleeriieru1lir zo ble d.-

phlyet-1 a ~'VIR11oilae V.Vtuillansili. andl appema red tef avt-ragre siz~e, while t hose ill t he I inner

part of thle faiseicilarl anid ret icillar zonles had14 shrunk. t heir cyte qilasri le I-ng~h rl gnees

dairk. arnd sprinrkleul With Ii WOII pigr'iienit. Ill this caste thle tulliuilar (halalges ill the e eater

half of thlt fasciruiri11 r layer were jireerinienit. Th'le lesion %vas-- si ml hir to that dsr s

b~y l100). The ('(cr41 ilk teeit' ler thlrr of thle tZiitiIa wei WAelie coverte,1lte 0 i0 halesll

linicil h\y vactriolated cells. r1u21y Of whiich had14 1111414-inne Me eira iaWith fraying Oitfthe

cytoeplasm arid( pykrrotiv chaig-ites ec thIle rnurdei. Ill soime iristanices. the adr-enal cells had

41 sa ppea reel enit irely fromii tilit, inn er la1yer. o f thIit e vrtex. lea vil- ointily a ret iv(illa r st rtema

hetW~eei thle ceerige~te4l caineis.'1 meitiecuawa riot aitiornial.

The inieniiiges were iot otspuolulis-ly~lS itkViveclvl 1)11 g-riss examiiitiatoni. Microscoili4tallY. there was :I fair anlieuint Of actute inflillarirnatory 4cellular1 eXuldate ill thle S1ilearacliiFulmuinatinge mieningeroccal lbactereniiuu Without mlenlingtitis. 0ccuihrred

Wvithi the cfi ivial mninaifest at ions of tilie Wtlu seFiercsI Syndtromte,

and vet nto hemrorritage or ot her 'Ibnl-IIoIuiait v of tile adr-eitals Was founid at

Ileeropsy. iFourt suchi cwvss were fotiid amionig 30h) fattal cases niat lv1zed (table

:3(')).'8 In a litniher of others. the huistory stiggestedl this Syildroinie. but thle

case abstracts were Jim full enough to allow reliable deduc'tions. nlomnas ~

has rep~orted 3* such cases inl a series of 49 fatal cases.

TABLE. :I6.-Cause of dcath I in *iOf) cascs of mnefi'ayorc)(aI inhfedion rrveircwd at I/ic A rnie'

Forr's I us!it alf of Patohology~

(tifis INundwihe of tat I 'tI -'f( en

Furnhmiiat hin haet ereinia :

W~ithuoutt adlrenal hemorrhage 2 .10 ............ 3

Weith adrenal hemorrhlage 3------------------------------------------.I. . 26 42

Total--------------------------------------------- 156 52

Menlingitis---------------------------------------------------- 144 4S

Total----------------------------------------- :300 100

I Waitt renal ('omlipiititiolP4Ie'stiiil~Ited, va.e' fCltIity ini the total V.S. A rmtytI 0.1 l'rvent) Il the vases 10'.civ dtW to sill.

fonamihle mierapjy.

2 Four of these'( paltient.is showeds UItl (' ilii etbi lltiiiif(eSttliiouis of the' W *ite-rlioU'ie- riett'ric-iiseii synd roiae.

3 Five of theme- ptbtivnlts did noift exhibiit the (.iflivn l Iall l1111fe'stationa of the ietor'-ri rhsasyndrome.

Case 10.-A soldier, aged 21, suddenly became ill 24 hours before admuission with severe headwa he. stiftfness, gellr'ieni i ci a chli i. 1 nalisen. air14I voi uiiiti rig. Oil examiat ioitjn. aside14

fronti fever. dnluskv cyniluisi s, and14 petecliiae sca tteredl over thle skin, nro oither Iev'at 14)1

from nrn~rial wats focund. About 18 hours a fter audmissionr. inl spite of at concent rat iont O f

9) ril-g. Percent of Sill fnldiaxirue inu the bloodl. tilt Ipatienit hlecainn rapidhly worse. The skin

erupjtioni spread a nid Pallor, with cyaoiifu~s, becamre extreime. The extremriities were clammyii

1*4 D1)131VIeS. W. It. :TllP CMIi reOf 11100i 1 ill Men liglOMCewe h Inifect ion : Ani Anraolys is of 3001 Filital

Cames. Am. J1. Med. 8: 40i8 47:1, Aprirl 1950i.

19 Thotims 1.1I. N.... J..:''lii' Tre tlills lit oif Fut 1111110t lag MiellI gieeigeel C Ill efeetr lurs. IIIll. U.S.

.trmly '%. D~ept. No. 7:3, lip. 78 84. Februrary 1944.
2 52 INFECTI( D'1 l)ISEASES

and there was eviden'ce •iif ainked shlocik. A 'nilt( e of llood was positive for mllenitlgi letiCI'i Stained tillis t)hfblood I froimi the fingertip showed diph ciicci within tihe lenko- 'lvtes rs -iIeP fro'mtll punctu'red pn rpri(c skiil lesions revealedi gratiil-niegati vC( diliICIIcci.

The ltient died in shock 30 iL IrIIs after a hlni ssiiil.

Necropsy s(i•.wel lit)iidi'ial hetii'rriaage ol" evidence of ellnllilgitis. Petchilne were

scatteredl over all Se'ous srllifaces. Tlh ieitertitill tissues of the llyoca'ldillillm s.howedt4i

a difflise infiltration witIh pl llyoluillI 'm h lentlI r leulkoicytes.

The records of 300) of the soldiers who died as the result of meningococcal

infection bet\ween September 1940 (imobiilization) and 31 D)eceimber 1945 were

reviewed at the Ariliy Institute of Pathiology (now the Arlned Forces institute of Pathology), Washington. ).DC. (table 36). Ten percent were cases

of ftilhinatiirg hacterenmia without adrenal hemorrhage. Of these. 13 had no

enienhgitis. 16 had slight meningitis. and the autopsy record of I was inconiplete. The average duration of life after admission to hoslpital was 33 hours,

iraliiging from 2 to 101 hours. Four of these patients satisfied all the clinical

criteria of tile l'iiterhoise-Firilericiisen s•nidr(mle, hut at autopsy, the aldrenals were not abnilornmli|. Tihe average hiuratlion of life in these 4 cases was 40

hours from time of aidmnission to hosp)ital.

With adrenai t emorrhage.-Fulminiiiting ienli ingococcal bacterenlia with

perilpheral vascilar failure and hemorrhage into the adrenals evident at

iecroipsy-t-he so-called WVaterhouse-Fri (lericlisen syn(lromne-was described

first in 1894 Iby Voelcker.-> Additional cases were later reported by the

autilhors whose niamne the svndrome bearS.•. 1 o more (iraiatic or catastrophic

situation requiriing imnme(liate therapy can face the physician.

Froni the beginning of the epidemic, patients with this syndlrome were

admiitted to Armyii hospitals. Some died before specific treatmient was histitlte(l. In the analysis of 300 fatal cases, it was found that in 121 cases (40

lpercent) death was (lit to this form of infection. (Five additional cases in

this series had aldrenial hemorrhage without the clinical synmdromne (p. 2.54).)

In view of tile rarity of this disease. it is not sirprising that, of the whole

series of 126 fatal cases with adrenal hlemorrhage. 14 (11 percent) caine to

iecroisy lackinhg correct diagniosis. Ante mortem. these were classifie(d as

follows: Rocky M[ouintain sp otted fever. 3: heat stroke, 2: purpura heinorrhiagica, i: endemic tvphius 1; aculte leukemia, 1: pachymeningitis. 1: and no

d(iagnosis, 4. A few more than '00 instances of this form of mnelningococcal

infection had been reported in the world literature before World War II.

In two IUblished series of 214 and 182 patients with meningoc()ccal infection, the W1aterhouse-Fri (lerihhsen syvl(lroime occurre(l in 3.3 and 2.2 percent. reSIpectively. 22 As noted, the records of the 300 cases studied at the

20 Voelhki'r. A. F. : Pathologieall Report. Abstract. Middlesex HIopital Reports. 1894. p. 279.

• 11 W_ terhiousi,. I.: A Casie of suprareinii koi• -xlihxy. Lianicet 1: 577 579. 4 Matr. 1911.

{2) Fridi.ri.h sen. C. Neben nheriin 11111ltlxi e i k einei n Kindhrn. J.alhrh. f. Kinihrhi. 87: 109-125,

1818.

-- (1) See foltnotte 1,. p. 250. (2) BTirnhaixd. AN. G... n .1 Jorda n. A. C. : Bilateiral Adr'enal

IlinIlrrhalm !, (Waiherho ui l,-1' riilhrhl lil' Sylid romeni) \Associatie' W ith Menlingoiel•ecaIl Se htiveendi : Re port

of F'olilr ('Casis tnAdults Il With i Revii'w of tile Literaiture. J. Lab. & Clin. Mi'ii. 29): 357-365,

April 1944.
A rined Forces Inlst it ute of Pat hology- showed that 126 (42 percent ) of the

soldIiers with adlrenlal hemlorrhag1'e died ( tablle 36') 'More thani 50 instances of

this sy-ndromle Were reported iii the literature lby ][T.S. Armny Medlical Corps

officers. 'Flis is an incomplete list as mnany cases were (described only because of un musual features, lollig sutrv ival period. or recovervy.2

Mening~it is was usually absent or extremiely slighlt ini these p~atients. Ini

amialvsis of the 1,26 cases of fuilminiating haictereimiia with adrenal lienorrhage.

no post inorteni evidlence of nieningit is was found in 61 , in 48, the mieningit is

was early and~ minimal,: in 7. it was 1Iodleratelv Severe; in another T. severe;

in 3 cases. time gra(Ie of meningitis was not clear front the recordls. Early

dleath imay have b)een responsible for the slight degree or absence of mneningeal

inflanmmat ion.

Clinical course.-As with other mnen ingococeal infect iois. p)lodl3)lt al resp~iratory svmt ptoms usually preceded the onset. These were followed by general itch igil. painful joints, headache, weakness. nausea, vomniting, chills, and

fever. Within a few hiours there was a dramatic, suddlen changre, with the

dIevelopmnent of apprehiension. restlessness. and often an initial deliriumii. At

a later stage, there were frequent lucid intervals. A previously insigrnihicant

rash suddenly becaine wvidespread. purpuric, and ecchymotic. and often covered two-thirds of time body. The colmjitnctivas and~ butccal inucoims llteelltlranles

showed hiemnorrhages. As a rule, there were no signs of involvement of the

immeminges, bitt mieningitis, usually of mild degriee, mnight be present. Cyatiosis, low blood pressure, rapid, thready or imperceptible pulse, cold, wet.

extremities, and all evidences of extreme shock supervened. Anuria with

retention of nitrogen was usual. Within a few hours to a day or more. pitllmnonary edenia usually supervened, and death generally occurred in spite of

heroic therapy. Ini fatal cases, the average duration of life from admission

to dleath wvas 24 hour1Is. 2 4

A classical instance of this clinical course follows.

Case 11.-A 21-year-old soldier developed headache, weakniess. general aching, and

voifltili 11/, iours befor'e atdmUission to hospital at 5 p.m. on 17 April 1943. 111 ni iight,

23 (1,i Wright. 1). 0.. lndt Rejpert, L. B. :Fulminating Mleningococcenila With Vascuilar Collapse

~V~er~oue-rilerchenSyndronme) Report oin Four Adult Patients Who Ret 4vered. Arch. lilt.

Med. 77: 143-150. Februairy 1946. (2) Kasich. M., andl Disick, S. : Meningococceinia With Bilateral

Adrenal Hemorrhage iVtromeFheihe Syndrome) :Report of Two Cases. J. T1ennessee MI.A.

36: 464 -467, December 1943. (3) Marangoni. B4.A.and l)Agati. V. C.: Iepatorenal Fa iluire in

the Wit terlhouxR.-Fridericlisen Syndronie : Cl jaico-'a thologic obs~ervations In Two Cases WVith Prolonged Survival P'eriods~. Ani. J.M%. 9c. 207: 385-393. March 1944. (4) D'Agmmti. V. C., and Maranlgoni, B. A.: The WVate~rlmommiS4,-IrilderlchIsten Syndrome. New England J1. Med. 2:12: 1-7, 4 .Jain. 1945.

15) Park. F. R.. and Tlaplin. G. V. :Meningococelc Meningitisi With WVaterhouse-IPriderielisen 'Syndtrome. Report of a Cast, Wi'th Recovery. [Official record.] (6) Felder, S. L.. and Stacy. A., .Jr.:

N!eningococ('emia, With WVate-rhiouis-Frilderielnisen Syndrome. [Official record.] (7) LIchll11ter. J1. W..

andi Fish, C. E. : The Waite-rhotuse-Fride(ricelini syndrome : A Repoort of at Case in a Soldier. M1it.

Suirgeon 93: 77-81, Jumly 1943. (8) Bus~h. F. W., and Bailey, F. R. : Tlhe Treatment of Meningocovens~ Infections With Especial Reference to the Witterhouse-Frlderilch~en Syndrome. Ann. lilt.

Mled. 20: 619-631. April 1944. (9) P'otter, H. W., andt Bronstein, L. H. :The WVaterhoume-Friderichsen Syndrome; Report of a Cas~e Terminating in Recovery. J. Lab. & Clin. Med. 29: 703-708,

JTuly 1944.

24 See footnote 18, p. 251.
It 1~i~,, f 111 1it vsir1 il.- u i ric l e(rl 11iti ilmi I ;I II i II e I- z Ia It wit fIhI I I; ItIz I I l uer d II I ,N4'1it~ :

Ille 'if l 411 ie l ' lvi' I I Il II il I ;.It I itI c * ihie r 11 iel; i l~le I, .I t ý111 u I'; I icn Iz i-' r I it I IS Wl %4(

%% g e~t .1 1 llIýe r I le of gI .;~ 111Il oIIa :14 tI I w siUJ 14 4 1('Ihlita s 4 1sit. an 37 Ili;Ihle t I' I ll spI)~ ill 14

4IihIt, 14)-1 of 1- i f sp l I-I' rea . 4,11dO, uv n h ulottl' occ(h '1U lvihpll ~l( IiL.3f;I .( irI4Ih1144IV%

:1111i 1dtugelli. luiis 0111: Sa f . 1ed T heuiia pjugIl difed. ill pivlll ilwl xto evidetit:1 :14; u~

:tbuinctruill Titoo))S V :1 (l ('5 il :1j41s 0:iti )I(II;if- I w4' (lilt :1c14 pitt -Ivii'' lett teal

1FIotoIio [.I:II 3G. 4)1 ltei. ora.r ish l .1 pal i~ it'- t wi1th 4)Xe : ia tllý vine rvIlhe al andu~u

o~h'ltt~~4. ie~fl~iI lv '4vi It ti~ ile oelth il-uu uuila t ic.t 1)1. f Ile tI4Wt'll~t
MI.NINGOCOCCAIL INFECTIONS 255

might well be the sole cause of death. Marangoloi and )'Agati, 25 following

observation of two patients with long survival periods (80 and 88 hours),

have expressed the opinion that there are two distinct stages in the Waterhouse-Friderichsen syndrome: First, the phase of profound shock and circulatory collapse; if this is survived, the second, or hepatorenal, phase begins.

Clinically, it is characterized by marked oliguria with azotemia, and pathologically, by severe central necrosis of the liver associated with changes in

the glonieruli and tubules of the kidney. A number of observers-6 believe

that circulatory collapse in the Waterhouse-Friderichsen syndrome is primarily the result of widespread hemorrhages and changes in tissue, rather than

of adrenal insufficiency secondary to hemorrhage into these glands. It is

pointed out that (1) in this condition death requires but a few hours, whereas

adrenalectomized animals live for several days; (2) classical clinical manifestations of the Waterhouse-Friderichsen syndrome can occur in patients with

fulminating bacteremia without abnormality of the adrenals at necropsy;

(3) conversely, among the 126 patients found to have had adrenal hemorrhage

at necropsy, in 5 the clinical manifestations were not those of the WaterhouseFriderichsen syndrome 27 (table 36); (4) some recovered patients had been

given no adrenocortical hormone; and (5) in patients who recovered, the

discontinuation of adrenocortical hormone after a few days di~i not lead to a

recurrence of symptoms. If there were adrenal insufficiency secondary to

hemorrhagic destruction of the adrenals in these cases, such temporary therapy would scarcely have been curative.

Accordingly, although the severity of adrenal hemorrhage appears in

direct correlation with the length of life in the series of fatal cases shown in

table 37, it cannot be assumed that there is a direct causal relation between

them. The severity of the adrenal lesion may be regarded rather as an index

of the severity of the whole pathological process, in which it occurs as an

end result.

The Waterhouse-Friderichsen syndrome before the development of sulfonamides was invariably fatal. In 1945, Weinberg and McGavack collected

from the literature 11 instances of recovery and reported an additional case

with recovery. 28 Thirteen other patients who recovered have been either

Army personnel or cases observed by the author.29 Undoubtedly, a number

"25 See footnote 23 (3), p. 253.

"2c (1) See footnotes 17, p. 250 ; 19, p. 251 ; and 23 (1)and (3), p. 253. (2) Thomas, H. B., and

Leiphart, C. D.: Septicemia and Purpura With Adrenal Hemorrhage in Adult (Waterhouse-Fridericti- sen Syndrome) : A Discussion of the Role Played by the Adrenal Gland In the Production of the

Syndrome: Report of Two Adult Cases. J.A.M.A. 125: 884-890, 29 July 1944.

27 See footnote 18, p. 251.

28 Weinberg, L. D., and McGavack, T. H.: Waterhouse-Frlderichsen Syndrome; Report of Case

With Recovery. New England J. Med. 232: 95-101, 25 Jan. 1945.

29 (1) See footnotes 17, p. 250; and 23 (1), (4), (5), (6), (8), and (9), p. 253. (2) Wechsler,

H. F.. and Rosenblum, A. Ii. : Meningococcic Meningitis. MiU. Surgeon 95: 132-135, August 1944.

(3) Meyer, R. R. : Meningococcal Meningitis: A Report of Thirty-Three Cases With No Deaths.

New England J. Med. 230: 452-455, 13 Apr. 1944.

C19243"--63- 20
256 INFECTIOUS DISEASES

of additional cases were not reported. Probably some of the recovered patients, although clinically examples of the Waterhouse-Friderichsen syndrome, actually had fulminating bacteremia without adrenal hemorrhage, but

when a patient has recovered, there is no way to ascertain the nature or location or extent of tissue damage that was associated with the clinical syndrome.

"rTABLU 37. - -Severity of adrenal hemorrhage and duration of life in 126 of 300 fatal case.1 of

meningococcal infection

Number of Number of hours from wbui.hion to

Number of aues with death

Grade of hemorrhage castes Percent rehvant

data

Average Maximum NMinimum

Mild ------ 21 16. 7 20 48 120 I3"

Moderate-- _ -- 47 37.3 44 22 60 1 •

Massive ---.------------------- 56 44. 4 53 16 49 1

Not recorded ------------------ 2 1.6 1 53 53 53

Total_ ------------------ 126 100.0 118 24 120 ! •

MENINGOCOCCAL MENINGITIS

Although it was clearly demonstrated in many patients that meningococcemia preceded the onset of meningitis, the commonest. type of meningococcal

infection in all Army installations was that exemplified by case 12. Here,

the results of meningeal involvement were so dramatic as to overshadow completely those of bacteremia. Bacteremia and meningitis set in almost simultaneously.

Case 12.--A soldier, aged 20, was admitted in violent delirium. The history obtained

after the patient had improved indicated that he had been perfectly well until the evening

of the day before admission, when severe occipital headache suddenly developed, with a

feeling of great fatigue. I)uring the night, pain In the left elbow and ankle began. Early

oil the day of admission the lost consciousness and regained It only after 12 hours of

treatmnent in the hospital. Examination revealed a gravely ilI patient, who had many

sinall erythetnatous mnacules scattered over the trunk and extremities. Several of the

lesions were hemorrhagic. There was prontitn'ed rigidity of the neck, positive Kernig's

and Brudzinski's signs, and slight weakness of the right side of the face. The leukocytes

numbered 18,800 per cubic millimeter with 80 per(ent polymnorphonuelear cells. Culture

of the blood was later reported as sterile the spinal Iluld showed 9,MK') leukocytes per

cubic centimeter, of which fly) percent were pl lyInorlhouiclear cells. Gram-negative Intracellular diplococci were seen on) sinear, [l(] type I nieningoco((cus was present on culture

of the spinal fluid. Imnediate therapy with sulfadiazine resulted in complete recovery.

The review of 300 of the fatal cases of meningoccccal infection showed

that 144 (48 percent) were classified as dying of meningitis (table 36). Only
Mk2NINGOCOCCAL INFECTIONS 25 7

6 of these patients came to necropsy without correct diagnosis, as follows:

No diagnosis, 2; endemic typhus, 1; malaria, 1: pachymeningitis, 1; and psychosis, 1. It is of interest that only 26 of the 144 patients lived 96 hours or

longer after admission to hospital. The average duration of life of the 118

patients who lived less than 96 hours was 36 hours, the range being from 1 to

95 hours (table 38). Since meningococcal meningitis itself, before the use

of sulfonamides, rarely killed in so short a period, one might reasonably

expect other lesions due to the meningococcal infection to play some role.

Of the 118 patients who died within 96 hours after admission, evidence of

lesions other than thtose in the meninges was rel)orted in 62. Certain lesions

associated with the death of those patients are listed, as follows:

Number of

Lesions patien ta

Pneumonia ---------------------------------------------------- 2Ce

Encephalitis -----------------------------------------------------. 1

Myocarditis ----------------------------------------------- 11

Pressure cone ---------------------------------------------- 4

Purulent pericarditis ---------------------------------------- 4

Periadrenal hemorrhage -------------------------------------- 1

Tubular degeneration of adrenals ------------------------------ 1

Meningococcal peritonitis -------------------------------- I

Purulent arthritis ------------------------------------------- I

Subarachnoid hemorrhage ------------------------------------ 1

Bleeding peptic ulcer ---------------------------------------- 1

Total ------------------------------------------------- 62

A pressure cone was noted 4 times, myocarditis 11 times, and pneumonia 26

times. Encephalitis was found in 11 cases, its occurrence indicating an organic basis for the changes in personality occasionally reported in patients

who recover from meningitis. It seems probable that th,- majority died of

the concomitant bacteremia with toxemia or some complication.

TABLE 38.-Duration of life in relation to severity of illness in 118 of 144 cases of meningitis

studied at the Armed Forces Institute of Pathology

Number of Number of hours from admission to

Number of cases of death

Severity of lesion cases Percent known

duration

Average Maximum Minimum

Moderate- 10 8 10 23 62 1

Severe _ ------------ 93 79 93 38 95 1

Not recorded ..--- 15 13 10 30 90 2

Total --.---.----------- 118 100 113 36 95 1

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _
258 INFECTIOUS DISEASES

The duration of life in relation to severity of meningitis in the patients

who lived less than 96 hours after admission to hospital is shown in table 38.

Those patients with a moderately severe grade of meningitis died on the

average of 15 hours earlier than those classified as severe on the basis of spinal

fluid and autopsy findings. This is additional evidence that these patients

died from bacteremia before the meningitis had reached severe proportions.

Among the 144 cases of meningitis studied at the Armed Forces Institute

of Pathology, the cause of death of the 2(i patients who lived longer than 96

hours is shown, as follows:

Meningitis -.-...-.-.-.-.-.-.-.-- .-.----- ----- __..-- - - - - 9

MenlngoencephalItis .. .. 3

Pneumonia nd( meningitis. 4

Sulfonamide nephrosls .. 3

Adrenal infarction 1

Myocarditis---------------------------------------.-1

Brain nbsce•ss due to N.cis.cria intracellularis--------------... 1

Ilemoglobinuric nephrosis after transfusion -- 1

Pulmonary Infarction----------------------------------------1

Multiple lung abscesses---------------1

Recr'rrent fulminating ineningococcal sepsis -------------------- 1

The duration of life ranged from 4 days to 4 months: 10 died on the 5th

(lay of illness, 3 on the 7th, 2 on the 8th, 3 on the 9th, 2 on the 10th, 1 on the

l1th, 1 on the 13th, 1 on the 15th, and the other 3 lived 1, 1, and 4 months,

respectively. It is seen that only 9 of these 26 patients died of meningitis

alone (1 patient was treated inadequately beginning on the 7th day of disease,

and sulfonamides were stopped in 1 after good response because of assumed

drug fever). Three patients died of myocarditis, brain abscess due to Neisseria intraeelularis, and pulmonary infarction after recovery from meningitis.

It will be noted that there was no instance of chronic basilar meningitis or of

hydrocephalus, the common sequelae of meningococcal meningitis in the past.

COMPLICATIONS

In the various series of cases of meningococcal meningitis reported (luring World War II, complications of the disease occurred in approximately

10 percent. The most coninion were transient paralyses of the fourth, sixth,

seventh, and eighth cranial nerves. Herpes zoster involving the trigeminal

nerve appeared in one patient. Aside from occasional residual nerve deafness

and a rare instance of persistent diplopia, these lesions (C~ared completely

with recovery. Paralysis of the serratus anterior was reported.8 0

In fulminating bacteremia, electrocardiograms were rarely made because

of the critical condition of the patient and the emphasis placed on needed

therapy. However, two instances of changing electrocardiograms with

T-wave inversions and abnormalities in the S-T segment have been de3o See footnote 14, p. 244.
MENINGW•, WiVAL INFECTIONS 259

scribed.' 1 Both patients recovered. Sudden and unexpected death from

myocarditis occurred in one patient after apparent recovery from meningitis.

In this case, H~olman reported marked degenerative changes throughout onethird of the myocardiunm at necropsy. Myocarditis of significant grade was

present at necropsy in 28 of 126 fatal cases with adrenal hemorrhage. Bronchopneumonia terminally was not uncommon. Optic atrophy, corneal ulceration, conjunctivitis due to N. intracellidaris, pericardit is, and osteoperiostit is

have each been noted in published reports.

Spontaneous glycosuria at onset was reported as occurring in one-third

of 26 patients with meningococcal meningitis,3 2 but rarely among Army personnel during the Second World War.33 It may be accompanied by ketosis,

hyperglycemia, and diminished sugar tolerance. Coma with glycosuria and

ketosis at the onset of meningitis might lead to the erroneous diagnosis of

diabetic acidosis.

In meningococcemia, inflammatory joint affections occurred in from

one-third to one-half of the cases. These were usually simple inflammatory

reactions but occasionally effusion into the joint, and rarely pyarthrosis

developed. The latter required aspiration, but, surgical drainage was not

necessary in any reported case during the Second World War. Residual

joint stiffness, persisting for some weeks after recovery, was noted.3 4

Some of the ecchymotic skin lesions ulcerated, but sloughing of large

ecchymotic lesions rarely occurred. These were slow to heal. In almost all

fatal cases of bacteremia and many of meningitis, pulmonary edema and

effusion into the pleural sacs were terminal complications of the illness.

Renal complications of meningitis are discussed in the section on treatrient.

OTHER MENINGOCOCCAL INFECTIONS

Only one instance of meningococcal pneumonia was reported during

World War 11.5 This followed 5 weeks after a classical attack of primary

atypical pneumonia. The patient developed severe, diffuse pneumonia with

high fever. The sputum on two occasions contained about 75 percent meningocoxc(ci (proved bacteriologically and serologically) and 25 1)ercent henmolytic streptococci, group A. The course of the disease, ending in recovery,

was apparently not influenced by the adequate doses of sulfadiazine given.

The patient gave no evidence of bacteremia or meningitis.

".1 (1) Rappaport, J. N., and Zuckerbrod, M. : Recovery From Fulminating Meningococcic Infection With Myoca-ditis Proved by Electroca-diograpby. J. Lab. & Clin. Med. 30: 307-316, April 1945.

(2) Holman, D. V.. and Angevine. D. M.: Meningococcus Myocarditis; Report of Two Cases With

Anatomical and Clinical Characteristics. Am. J.M. Sc. 211: 129-137. Februar3 1946.

Z Ferguson, F. C., and Barr, D. P.: Glycosuria in Meningitis. Ann. Int. Med. 21: 173-186,

August 1944. u (1) See footnote 17, p. 250. (2) Federer, J. J.: Glycosuria and Hyperglycemia Associated With

Acute Meningitis: Report of a Case. New England J. Med. 233: 342-343, 20 Sept. 1945.

34 See footnote 15, p. 247.

35 Roberg. N. B.: Meningococcic Pneumonia. Bull. U.S. Army M. Dept. 4: 97-99. July 1945.
260 INFECTIOUS DISEASES

Thirteen cases of proved meningococcal conjunctivitis were described

among U.S. Army personnel during World War II.36 All occurred during

the period of increased incidence of mneningococcal infection, and only one

was associated with bacteremia or meningitis. The response of all these

patients to therapy with sulfadiazine was excellent.

LABORATORY DIAGNOSIS

In nieningococcal infections. the assistance of the laboratory in arriving

at the correct etiology and confirming the clinical diagnosis was directly proportional to the adequacy of methods of culture, the care with which studies

were carried out, and the cooperation between the wards and the laboratory.

At the beginning of the epidemic. laboratory officers in the Army hospital,

like the clinicians, had had relatively little experience in the study of this

disease. The standard operating procedure consisted of directing the ward

nurse or attendant. to send the tubes of cerebrospinal fluid obtained from

the patient to the laboratory for examination. The laboratory, as a rule,

made no great speed in examining this fluid or inoculating media. Under

these conditions, the percentage of positive cultures and of bacteriologically

confirmed diagnoses was not enviable. As the number of cases rose, however,

there was rapid improvement in this situation in most hospitals, with better

coordination between the clinician and the laboratory. In some hospitals,

a representative of the laboratory camne immediately to the bedside when a

lumbar puncture was to be done. Inoculations with blood and cerebrospinal

fluid were made directly into previously warmed culture media, and these

were promptly incubated in proper atmnosphere. The improvement in results

was striking. With this method, it was possible to achieve bacteriological

confirmation in 95 percent of the patients who had not received treatment

with sulfonamides prior to obtaining material for smear or culture.8 7

The micro-organismns isolated from patients during the outbreak have,

as is usual in these infections, been predominantly type I. The distribution

of types of meningococci recovered by the Fourth Service Command Laboratory from 1,436 known cases of meningococcal infections from August 1942

to D)ecember 1945 38 is shown in table 39.

In the majority of patients ill with the Waterhouse-Friderichsen syndrome or with fulminating sepsis, careful examination of films of blood

taken from the fingers for differential counts revealed diplococci within the

leukocytes. Smears and cultures made from petechial, purpuric, or even

36 (1) Baner, C. E.. Gall. E. A.. and Cox. C. 1). : Meningococcal Conjunctivitis; Report of Three

Cases. MIl. Surgeon 95: 24-27. July 1944. (2) Theodore. F. 11., and Kost, P. F.: Meningococclc

Conjunctivitis. Arch. Ophth. 31: 245-247, March 1944. (3) Reid, R. D., and Bronstein, L. H.:

Meningococcic Conjunctivitis. J.A.M.A. 124: 703, 11 Mar. 1944. (4) Thygeson, P.: Primary Meningoeoccei Conjunctivitis Treated by Sulfatdlazine. Ant. J. Ophth. 27: 400-401, April 1944.

37 See footnote 14 (1). p. 244.

3s See footnote 12, p. 244.
MIENINGOCOCCAL INFIECTIONS 261

macular skin lesions showed nieningococci in many instances. Tompkins 3

obtained positive cutaneous smears in 39 of 48 cases. In soime patients,

smears showed bacteria at a time when culture of the blood was sterile.

Bernhard and Jordan 40 compared the results of concomitant examination

of smears and cultures of material from purpuric lesions with cultures of

the blood and of the spinal fluid in 40 patients. The smears from the purpuric lesions were positive in 68 percent and the cultures in 8S percent,

while the cultures of the blood and cerebrospinal fluid were positive in 75

and 82 percent, respectively.

TAnLE 39.-Distribution of types of meningococci in 1,436 cases of tneningococcal infection,

Fourth Service Command Laboratory, August 1942-December 1945

Types of meningococci Number Percent

Group I ------------------------------------------------- 1,288 89 7

Group II -----------------------.------------------------- 27 1.9

Group Ila ------------------------------------------------- 108 7.5

Polyvalent .--------------------------------------------- 13 .9

Total --------------------------------------------- 1,436 100.0

' Includes micro-organisms with the biological characteristics of meningococci that agglutinate in polyvalent antimningococcal serum but not in group-specific .,rum.

The importance of careful bacteriological studies should not be underestimated. However, during an outbreak of meningococcal infection, the

diagnosis of bacteremia can and must be made on clinical grounds long before there is any report of culture of the blood if one hopes to prevent

meningitis or fulminant infection. The finding of diplococci in leukocytes

in smears of blood or smears from purpuric lesions is of importance, but in

patients with rash the clinical impression of a trained observer should be

relied upon in instituting treatment. Since, during the epidemic, 92 percent

of the patients with meningococcal meningitis showed a characteristic rash,'

a high degree of diagnostic accuracy could be attained on purely clinical

grounds. In neither meningitis nor bacteremia should initiation of treatment be delayed by waiting for laboratory reports.

TREATMENT

At the beginning of the epidemic, although Circular Letter No. 170 had

been issued, there was little standardization of treatment in U.S. Army hospitals. To a great extent, this was due to the dearth of published reports

39 Tompkins, V. N..: The Diagnostic Value of Smears From Purpuric Lesions of the Skin in

Mentngococcic Disease. J.A.M.A. 123: 31-32, 4 Sept. 1943.

40 Bernhard, W. G., and Jordan, A. C.: Diagnosis of Meningococcic Infections, Use of Material

From Skin Lesions. Mil. Surgeon 95: 405-409, November 1944.

41 See footnote 14 (1), p. 244.
262 INFECTIOUS DISEASES

on the use of sulfadiazine in large groups of patients with meningitis, to

difficulties in obtaining the( drug, and to the inability of some installations

to acquire the sodium salt of sulfadiazine. Early cases were treated with

sulfanilamide, sulfapyridine, sulfathiazole, or sulfadiazine alone or in conjunct;on with antisera or antitoxin. Thomas,'42 of the Fourth Service Command, reported a mortality of 20 percent in 40 cases treated during the

first week of the epidemic (the week ending 1 January 1943) and 8.8 percent

in 317 cases early in the epidemic. However. during February and March

1943, this was lowered to 2.1 percent in 761 cases. The fall in mortality was

not the result of a decrease in virulence of the mnicro-organismn. While 108

soldiers were being treated in one Army hospital in the Fourth Service Command with a mortality of less than 3 percent, there were 4 deaths among 8

civilians in the same county. The early high mortality was probably due

to inexperience of the medical officers with the disease and delay in instituting treatment. Correction of these conditions was prompt, with dramatic

reduction in mortality.

Meningococcemia.-The treatment of soldiers with simple meningococcemia became relatively standardized in Army installations and was highly

effective. Under clinical observation, it became obvious that those with uncomplicated meningococcemia who were treated early did not require large

doses of sulfadiazine. An initial dose of 4 gin. was given followed by 1 gin.

every 4 hours until the temperature had been normal for at least 2 days.

Parenteral administration was resorted to in patients who were vomiting.

Renal complications.-Treatment of patients with meningitis varied

somewhat at different Army hospitals. Massive dosage of sulfadiazine

reaching more than 20 gin. in the first 24 hours 43 was used, vith the achievement of concentrations in the blood of 18 to 24 mg. percent. Among 134

patients so treated, complications of therapy (86 percent of which were

renal) occurred in 28 percent. At another hospital, a loading dose (of sodium sulfadiazirte) of 0.1 gm. per kilogram of body weight was given intravenously in 1,000 cc. of isotonic sodium chloride solution. Following this,

one-half the initial dose was given parenterally every 8 hours until the patient could retain the drug by mouth. Concentrations in the blood and cerebrospinal fluid of 13 and 11 mg. percent, respectively, were obtained with

excellent therapeutic results. However, gross hematuria occurred in 15 percent and anuria in 6.6 percent of the patients. When dosage was reduced

to 0.05 gm., followed by 0.025 gm. per kilogram of body weight 4 hours later,

and the latter dose repeated every 8 hours thereafter, no renal complications

were noted.4 4 With this dosage, the average concentrations of sulfadiazine

in the blood and spinal fluid were 8.5 and 6.5 mg. percent, respectively. In

42 See footnote 14 (2), p. 244.

43 (1) Oehs. L.. Jr.. and Peters, M. :Management of Meningococcic Infections at the Station

Hospital, Fort Benning. Ga. War Med. 4: 599-605, December 1943. (2) Kaplan. G. : Massive-Dose

Sulfadiazine Therapy in Meningococcus Meningitis. New York State J. Med. 43: 2210-2212, 15

Nov. 1943.

44 See footnote 13, p. 244.
MENINGOCOCCAIL INFECTIONS 263

this connection, it is of interest that Dowling and Lepper 45 reported that no

urinary calculi appeared in their patients with pneumonia when the concentration in the blood did not exceed 9.2 mg. percent.

Ochs and Peters,4 6 while treating patients with all initial intravenous

dose of 10 gin. of sodium sulfadiazine in 5 percent solution, encountered renal

complications in 5 of 23 patients. Later, 2,000 cc. of 1/6 molar sodium lactate

was given intravenously before administering the sulfadiazine with the complete elimination of renal complications.

Drug of choice.-Sulfanilalmide, sulfathiazole, and sulfapyrid ine were

used early in the epidemic because of the scarcity of sulfadiazine. The latter became the standard drug for treatment because of its efficiency and relatively low toxicity. Sulfanilamide retained an important place in therapy

until penicillin became available. When gross hematuria, renal colic, oliguria, or anuria developed during sulfadiazine therapy, sulfanilamide was

an effective substitute, since its use was not associated with the deposition of

acetylated material in the urinary tract.

In analyzing the records of 300 of the patients who died of meningococcal infection, 47 only 3 instances of death as a result of sulfonamide medication were found. All of these were due to renal complications caused by

therapy. Since it can be assumed that virtually all patients who received

any specific treatment were given sulfonamides, the case fatality ratio from

complications of therapy with sulfonamides in the 13,922 cases treated during the Second World War was estimated to be about 0.04 percent (the total

mortality from renal complications). This is astounding when one considers that massive dosage was administered to very ill, and often seriously

dehydrated, patients. No death from hemolytic anemia or agranulocytosis

was encountered.

Since the close of World War I1, other sulfonamides have proved curative. Gantrisin has been shown to be effective in two small series of cases

of meningococcal infection. 48 It has the virtue of greater solubility and,

in consequence, rarely causes renal complications. If extensive trials justify

the promise of this drug, it may be preferred to sulfadiazine. Its dosage

is similar to that of sulfadiazine.

Fulminating infections.-The treatment of soldiers with fulminating

bacteremia and with the Waterhouse-Friderichsen syndrome may be considered together as, in general, their treatment was identical. Among the 300

deaths analyzed, 156 patients died of fulminating meningococcal bacteremia,

126 with and 30 without adrenal hemorrhage (table 36). Of these, 30 had

45 Dowling, H. F., and Lepper, M. 1I.: Toxic Reactions Following Therapy With Sulfapyridine,

Sulfathiazole and Sulfadiazine. J.A.M.A. 121 : 1190-1194, 10 Apr. 1943.

46 See footnote 43 (1). p. 262.

47 See footnote 18, p. 251.

48 (1) Brickhouse, R. L., Lepper. M. H., Stone, T. E., and Dowling, H. F.: The Treatment of

Pneumonia and Other Infections With a Soluble Sulfonamide, Gantrosan (NU-445; 3,4-dimethyl-5-

sulfanilamido-lsoxazole). Am. J.M. Sc. 218: 133-137. August 1949. (2) Rhoads, P. S.. Svec, F. A.,

and Rohr, J. H.: Bacterial Meningitis: Results of Treatment in Seventeen Cases With a New

Sulfonamide (Gantrisin). Arch. Int. Med. 85: 259-264, February 1950.

639243--63--21
264 INFECTIOUS DISEASES

had no specific therapy, 98 were treated with sulfadiazine, 14 with other

sulfonamides, and in 14 there was no record of treatment. Penicillin was

given concurrently with sulfadiazine to at least 16 patients. The records

concerning antiserum, antitoxin, and extracts of adrenal cortex were not

adequate for analysis.

Thomas, 49 early in the epidemic, stated that the three major objectives

of treatment were to combat bacteremia, toxemia, and shock. He advocated

3 to 5 gin. of sodium sulfadiazine intravenously with 1,000 cc. of 1/ molar

sodium lactate and the maintenance of a concentration of sulfadiazine in the

blood of 10 to 15 rag. percent. Intravenous administration of 20,)(1" units of

meningococcal antitoxin was advised as an initial dose, followed by the

same amount every 4 hours until 100,000 units had been given. Plasma,

isotonic sodium chloride, and aqueous extract of adrenal cortex in large doses

(30 cc.) at frequent intervals was advocated. In instances where pulmonary

edema supervened, it was suggested that 500 cc. of 1.5 percent solution of

sodium chloride containing 25 gin. of dextrose be given. A goodly number

of patients were treated by a regimen of this type with certain variations.

Many received no antitoxin and others either insignificant amounts of

adrenocortical extract or none. In the treatment of 13 recovered cases of the

Waterhouse-Friderichsen syndrome, the only constant and recurrent features of therapy were the administration of sulfadiazine in adequate

amounts, intravenous isotonic sodium chloride and dextrose, and oxygen.

Penicillin, adrenocortical extract, desoxycorticosterone acetate, plasma,

adrenalin, adrenalin in oil, meningococcal antitoxin, or antimeningococcal

serum were given in some. It would appear from the description of treatment that recovery occurred in any case where early adequate antibacterial

therapy and proper antishock measures were carefully carried out. The

major objective was very early recognition of bacteremia with prompt treatment before the infection became fulminating.

Cortisone. which has become available since World War II, offers an

additional potent agent in combating the adrenal insufficiency incident to

adrenal hemorrhage. Too few instances of its use have been recorded

clearly to evaluate its place in therapy. However, its use in the WaterhouseFriderichsen syndrome with adrenal hemorrhage is rational, in view of its

proved value in critical episodes occurring in Addison's disease with complicating infection. The number of circulating eosinophils should be determnined to assist in differentiating this syndrome from fulminating bacteremia

without adrenal hemorrhage; the former may show more, and the latter less,

than 50 cells per cubic millimeter. Therapy with cortisone should consist

of an additional dose of 200 mg. divided into four 50 mig. doses injected intramuscularly into four separate sites to hasten absorption.50 Subsequent

49 See footnote 19, p. 251.

50 (1) Personal communication. P. HI. Forsham, to the author. (2) Forsham, P. H., and Thorn,

G. W.: The Diagnosis and Treatment of Adrenal Cortical Insufficiency. Veterarns Admin. Tech.

Bull. TB 10-62. pp. 1-23, 30 Mar. 1950.
MENINGOCOCCAL INWECTIONS 265

dosage may be guided by following the level of circulating eosinophils.

These should be kept at 15 per cubic millimeter or below.5' This will probably require 50 mg. or more every 6 hours for the first 2 days and 25 mrg. at

the same interval for the next 3 days. Thereafter, the dose should be gradually reduced and discontinued over the period of 1 week.

Potent new pressor agents have become available since the Second

World War. Norepinephrine by continuous intravenous infusion has

proved helpful in maintaining blood pressure and combating shock in two

instances of the Waterhouse-Friderichsen syndrome.52

Serum

In meningitis, antimeningococcal serum in conjunction with sulfadiazine

was employed intravenously and occasionally intrathecally in some hospitals.3 Serum was often given to patients who had not shown an adequate

response to therapy with sulfonamide 36 to 48 hours after the initiation of

treatment. It became rapidly apparent, however, that patients treated with

sulfonamides alone fared as well as those to whom serum was given in

addition.54

Antitoxin

Meningococcal antitoxin, originally advocated by Ferry 5 and used

extensively by Hoyne,56 was given to a few patients with meningitis, especially those with fulminating infections. In the early period of the epidemic, antitoxin was employed in some installations, particularly those in

the Fourth Service Command, in patients ill with fulminating bacteremia.

At 10 station hospitals, 134 patients were treated with this material. It was

thought by Thomas 57 that benefit was observed in 56 of these patients. In

retrospect, it. appears that mortality in cases of fulminating bacteremia

treated with antitoxin is not lower than in cases treated with sulfadiazine

alone. The excellent therapeutic results with sulfadiazine alone led the

Council on Pharmacy and Chemistry of the American Medical Association

51 Faloon, W. W., Reynolds, R. W., and Beebe, R. T. : The Use of the Direct Eosinophll Count

in the Diagnosis and Treatment of Waterhouse-Friderichsen Syndrome. New England J. Med. 242:

441-445. 23 Mar. 1950.

52 (1) Personal communication, P. B. Beeson, to the author. (2) Unpublished observatlons of

the author.

53 (1) See footnote 43 (1), p. 262. (2) Borden, W. B., and Strong, P. S.: Epidemic Meningitis;

A Report of 15 Cases at Fort Eustis, Virginia. Mil. Surgeon 91: 517-522, November 1942.

(3) Kasich, M., and Shulman, B. : Thirteen Cases of Meningitis Treated With Serum and Sulfonamides at Station Hospital, Fort Dix, New Jersey. Mu1. Surgeon 90: 419-424, April 1942.

54 See footnote 14 (2), p. 244.

55 Ferry, N. S.: Meningococcus Antitoxin; Prophylactic anti Therapeutic Tests on Guinea Pigs.

J. Immunol. 23: 315--324, October 1932.

56 Hoyne, A. L. : Intravenous Treatment of Meningococclc 'Meningitis With Meningococcus Antitoxin. J.A.M.A. 107: 478-481, 15 Aug. 1936.

57 See footnote 19. p. 251.
266 INFECTIOUS DISEASES

to remove antinteningococcal serum and ineningococcal antitoxin from the

accepted preparations listed in "New and Nollofticial Remedies."*

Penicillin

During the early period of the war, penicillin was in its experimental

stage and not in sufficient production for use in treatment of meningococcal

infections. Beginning late in 1943, small amounts first became available at

some Army hospitals for the treatment of patients with this infection. TB

MED (War Department Technical Bulletin) 9, dated 12 February 1944,

first advocated the use of penicillin in conjunction with sulfadiazine in patients with fulminating infection and in those who failed to respond to, or

should not receive, sulfadiazine. Therapy both intrathecally and by the

usual parenteral routes was advised in meningitis.

There were relatively few published reports on the use of penicillin in

meningococcal infections. Kolmer 59 reported that in 96 collected cases

treated by intravenous, intramuscular, and intrathecal injections, the mortalitv was about 8.5 percent. Of these 96 cases, 76 were described by Drs.

D. H. Rosenberg and P. A. Arling, who stated that 75 recovered, a death

rate of 1.3 percent. This is comparable to the mortality in similar series of

patients treated with sulfadiazine.6° Although the reports from the Army 61

do not represent studies of the use of this antibiotic in large numbers of

patients, they quite clearly indicate its place in therapy.

Rammelkamp and Keefer 62 found no penicillin in the cerebrospinal

fluid after constant intravenous administration over a 24-hour period, and

as a result of their observations, the intrathecal together with other parenteral routes have been used in patients with meningitis. Rosenberg and

Sylvester 63 reported the finding of penicillin in the spinal fluid in patients

with meningitis, and Price and Hodges reported the cure of four patients,

following intramuscular and intravenous administrations alone.

58 Status of Antimeningococcic Serum and Meningococcus Antitoxin; Report of the Council on

Pharmacy and Chemistry. J.A.M.A. 124: 95, 8 Jan. 1944.

59 Kolmer, John A.: Penicillin Therapy. New York: D. Appleton-Century Co., Inc., 1945, p. 202.

60 (1) See footnote 14 (1), p. 244. (2) Hill, L. W., and Lever, H. S.: Meningococcic Infection

in an Army Camp. J.A.M.A. 123: 9-13, 4 Sept. 1943.

61 (1) Kinsman, J. M., and D'Alonzo, C. A. : Meningoeoccemia; A Description of the Clinical

Picture and a Comparison of the Efficacy of Sulfadiazine and Penicillin in the Treatment of Thirty

Cases. Ann. Int. Med. 24: 606-617, April 1946. (2) Kinsman, J. M., and D'Alonzo, C. A.: The

Penetration of Penicillin Through Normal and Inflamed Meninges. New England J. Med. 234:

459-463, 4 Apr. 1946. (3) Letter, Lt. Col. T. Murray Kinsman, MC, Chief, Medical Service, Regional

Hospital, Fort Bragg, N.C., to The Surgeon General, 27 Mar. 1945, subject: Transmittal of Report

[Penicillin Studies]. (4) Rammelkamp, C. H., and Kirby, W. M. M.: Factors Determining the

Dosage of Penicillin in the Treatment of Infections. Bull. New York Acad. Med. 21: 656-672.

December 1945. (5) Dotterer, J. E.: A Fatal Case of Meningococcal Meningitis Treated With

Sulfadlazine and Penicillin. ETO Med. Bull. 31: :36-38. May-June 145. (6) Lo Vetere, A. A.:

Penicillin's Application to Meningitis, Meningococcemia and Septicemia. Kentucky M.J. 43: 24-27,

January 1945. (7) Price, A. H., and Hodges, J. J.: Treatment of Meningitis With Penicillin

Injected Intravenously and Intramuscularly, New York State J. Med. 44: 2012-2014. 15 Sept. 1944.

62 Rammelkamp. C. H., and Keefer, C. S.: The Absorption, Excretion, and Dist•i'bution of

Penicillin. J. Clin. Investigation 22: 425-437, May 1943.

4IRosenberg, D. H., and Sylvester, J. C..: The Excretion of l'Penicillin in the Spinal Fluid In

Meningitis. Science 100: 132-133, 11 Aug. 1944.
MENINGOCOCCAI. INFECTI )NS 2617

Studies were undertaken at the Regional Hospital at. Fort Bragg, N.C.,

to obtain further information on the most efficient mode of therapy. In 20

patients with primary or secondary syphilis given 20,0N) to 40,000 units of

penicillin every :1 hours from 1 to 8 (lays, no penicillin appeared in the

spinal fluid. In six patients with lneningeooccenlla uncomplicated by

meningitis, 25,0(X) to 40,00( units of pencillin were given at the same interval.

Twelve specimens of spinal fluid obtained 8 and 24 hours after institution of

therapy and on the fifth and ninth days of treatment. showed no penicillin.

One patient with tuberculous meningitis showed a trace of penicillin at the

11th hour after 200,000 units of penicillin. and none at the 23d hour. Another patient with the same disease was given comparable amounts and

showed no penicillin in the spinal fluid at 18 hours, and only a trace at 23

hours when the blood level was 0.4 units per cubic centimeter. Two patients

with meningococ(cal meningitis were treated intramuscularly only. One

showedl a measurable amount of penicillin in the spinal fluid only at 24

hours, and in the other assays revealed none at 11/2, 21/., 10, and 16 hours

after treatment was begun. Both l)atients showed initial improvement but

relapsed after 24 hours. In one, culture of the spinal fluid remained positive

for meningococci. Both patients recovered promptly when sulfadiazine was

administered. In seven other patients with meningococcal meningitis, penicillin was administered (intramuscularly) in large (loses in the early part of

their illness prior to beginning the usual therapy with sulfadiazine. The

range of penicillin in the spinal fluid was from 0 to 0.5 units per cubic centimeter. 11/2 to 27 hours after treatment was started. It is clear that, without

intrathecal adminiist ration, penicillin may penetrate into the spinal fluid, but

irregularly and in low concentrations. This work did not invalidate reported

recoveries, but it indicated the hazards of modes of therapy that exclude

the intrathecal route.

It was demonstrated 64 that, following the administration of 10.000 units

of penicillin intrathecally, from 4 to 20 units per cubic centimeter were still

present in the spinal fluid 8 hours later and from 0.08 to 0.31 units after 24

hours.

In a study65 of comparable cases of mncomplicated meningococcal bacteremia, 18 were treated with penicillin and 12 with sulfadiazine. All patients recovered and were free of symptoms within 24 hours. Those treated

with penicillin had normal temperatures at 12 hours while, in the sufadiazine

group, the temn)eratures remained elevated for 24 hours. The rash faded in

both groups in 2 days. Penicillin was apparently more effective than sulfadiazine in rapidly controlling symptoms in this group. However, its inconstant appearance in the spinal fluid after intramuscular injection made it

a less desirable mode of therapy, since bacteriostatic levels of penicillin inl

C,4 See footnote 61 (2), p. 266.

65See footnote 61 (1), p. 266.
268 INFECTIOUS DISEASES

the spinal fluid could not be depended upon to prevent meningitis, or to

control early meningitis if it occurred in these cases.

In eight patients with nieningococcal meningitis, alternate cases were

treated either with sulfadiazine in the usual dosage, or with 25,000 to 40,000

units of penicillin every: 3 hours intramuscularly and 10,000 units intrathecallv daily for 3 days.66 All patients recovered. Those treated with

sulfadiazine (leveloped normal temperatures more rapidly, became free of

headache and mieningeal manifestations sooner, and were out of bed earlier

than those who received penicillin. One patient who received intrathecally

10,000 units of a dark-colored penicillin in 10 cc. of normal saline promptly

developed extreme headache, stiffness of the neck, opisthotonos, and increasing fever associated with a rise of leukocytes in the spinal fluid from a few

hundred to 50,000 within a few hours. It became necessary to stop the intrathecal penicillin and resort to sulfadiazine therapy. One other patient given

the saime dark-colored penicillin developed meningeal irritation of less

marked grade.

In reviewing 300 fatalities due to nieningococcal infection (table 36),

instances of the administration of 20,000 to 25,000 units of penicillin intratlhecallv were noted. In one, following a large cisternal dose, hemorrhage in

the inedulla was found at necropsy. 67 Several instances of pleocytosis and

actual hlemorrhage have attended doses in excess of 10,000 units.6 8

Meningitis developed in two patients 9 while on intramuscular penicillin. One was being treated for meningococcemia and one for abdominal

wounds. From the history of the first patient it is possible that meningitis

already existed in spite of a normal spinal fluid.

In rare instances, penicillin was effective when sulfadiazine failed. A

native of New Guinea (at Aitape) was seen at the 30th Evacuation Hospital

by the author and Col. Vernon J. Erkenbeck, MC, in a moribund condition

with meningococcal meningitis. He had been under treatment with massive

doses of sulfadiazine for 5 days, and concentrations of sulfadiazine in blood

and spinal fluid were high. In spite of this, there was extreme opisthotonos

and hyperpnea, and death seemed imminent. Penicillin intrathecally and

intravenously produced rapid improvement and ultimate recovery.

Since World War II, it has been shown that satisfactory cerebrospinal

fluid levels of penicillin call be attained by the intramuscular route alone if

enough penicillin is given. Dowling and his coworkers T0 found that 1 million units of aqueous penicillin intramuscularly every 2 hours resulted in

adequate concentrations in the cerebrospinal fluid.

66 See footnote 52 (2), p. 265.

67 See footnote 18, p. 251.

68 Annual Report, Professional Service Division. Medical Consultation Service, Office of the Chief

Surgeon, Headquarters. European Theater of Operations, U.S. Army, 30 Dec. 1944, p. 13.

69 (1) See footnote 61 (5), p. 266. (2) Personal communication, W. M. M. Kirby, to the author.

70 Dowllng, H. F., Sweet, L. K.. Hirsh, H. L.. and Iepper, M. H.: Specific Therapy of Bacterial

Infections of the Central Nervous System. J.A.M.A. 139: 755-758, 19 Mar. 1949.
MXININGOCOCCAL INFECTIONS 269

It becomes clear that sulfadiazine has proved to be the drug of choice

in the mild or average instance of mueningococcal infection. Penicillin should

not be used as a routine measure. It should be given in massive dosage in

conjunction with sulfadiazine in fulminating bacteremia or meningitis, and

to replace it when intolerance to, or complications from, sulfadiazine develop. When improvement is not noted after 36 hours of treatment with

sulfadiazine, massive parenteral penicillin therapy should be instituted without discontinuing sulfadiazine.

Therapy With Other Drugs

Certain new antibiotics that have become available since World War II

are highly effective in the treatment of both bacteremia and meningitis.

Aureomycin (chlortetracycline),71 chioramphenicol,12 and Terramycin (oxytetracycline)7 3 have been used successfully in the treatment of small groups

of patients. Should a patient demonstrate clear-cut evidence of sensitivity

to the sulfonamides and penicillin, one of these other drugs can be used

with confidence.

Adjuvant Therapy

Fluid balance.-Patients admitted with meningitis, or severely ill with

bacteremia, are almost invariably dehydrated, so that careful attention to

fluid balance is necessary for its own sake as well as to prevent the renal

complications of sulfonamide therapy. Urine flow should not be less than

1,200 cc. per day. Attention to this detail of therapy was often painfully

learned by medical officers when gross hematuria or oliguria developed during administration of sulfadiazine. It was soon found that the use of sodium

sulfadiazine in 5 percent solution, as suggested in Circular Letter No. 170,

was fraught with danger unless a large amount of fluid had preceded treatment. When the patient's condition permits slight delay, Ochs' recommendation 74 of 2,000 cc. of 1/6 molar sodium lactate prior to sulfadiazine may be

wise. He also advocated using the same quantity of this solution following

the drug and the maintenance of an alkaline urine. However, renal complications were rare when the initial dose of sodium sulfadiazine was administered in 1,000 cc. of isotonic sodium chloride or the same volume of 1/6 molar

sodium lactate. In some hospitals, the major portion of the intake of fluid

was administered to comatose patients by Levin tube and in others by a

parenteral route. The latter is preferable when there is vomiting.

71 Conn, Howard F. (editor) : Current Therapy. Philadelphia: W. B. Saunders Co., 1951, p. 19. 7 2 McCrumb, F. R., Jr., Hall, H. E., Merldeth, A. M., Deane, 0. E., Minor. J. V., and Woodward. T. E.: Chloramphenleol in the Treatment of Meningoeoccal Meningitis. Am. J. Med. 10:

696-703, June 1951.

7S Hoyne, A. L., and Riff, E. R.: Terramycin Therapy for Meningitis; A Report of Fourteen

Recoveries Without Other Medication. J. Pediat. 39: 151-154, August 1951.

74 See footnote 43 (1), p. 262.
270 INFECTIOUS DISEASES

Sedation.-Restlessness is common and when mild can be disregarded or

allayed by simple sedatives, such as the barbiturates. Great restlessness and

almost maniacal delirium occur frequently with meningitis, often making

lumbar puncture or intravenous treatments difficult or impossible. Paraldehyde, 16 cc., proved the most effective sedative. Intravenous barbiturates

are occasionally necessary, though undesirable. Morphine, though considered hazardous by some because of its depressant effect on respiration, is at

times essential. Extreme restlessness and even delirium can often be relieved

by lumbar puncture with the reduction of pressure of the spinal fluid.

Catheterization with relief of bladder distention often quiets a restless,

thrashing patient who is hard to keep in bed. It has been noted that the

delirium is frequently a resistive one, so that attempts to restrain the patients movements result in a heightening of delirium. Freedom to thrash

about in bed for a few minutes without restraint is often followed by quiet

and relaxation. In fulminating bacteremia, morphine appears to be the

most effective drug for restlessness and is indicated if shock supervenes.

Lumbar puncture.-Initial diagnosis may be the only occasion for the

use of this procedure in patients who show prompt and continued improvement following treatment. As a therapeutic procedure for reduction of

intracranial pressure, lumbar puncture is of great importance when headache

is excessive, restlessness intractable, coma deepening, and hyperpnea, Biot's

breathing, or other respiratory abnormalities are marked. Striking improvement has been noted in patients following reduction in intracranial

pressure.

Complete recovery with return to full duty after an average hospitalization for 1 month and a similar period on sick furlough or reconditioning

has been usual. Data as to actual days lost are not available. In mild and

uncomplicated bacteremia, many soldiers have been returned to full duty

within 2 weeks from onset.

Preliminary tabulations of individual medical records, during 1942-45,

indicate that 105 U.S. Army personnel were separated for disability due to

meningococcal infection.

PATHOLOGICAL FINDINGS

The vast amount of pathological material available at the Armed Forces

Institute of Pathology is being carefully studied by the medical officers assigned there. The major lesions disclosed at autopsy in those patients who

died of meningitis were inflammatory changes in the leptomeninges of the

brain and cord, usually without evidence of organization of exudate. True

encephalitis was present in relatively few cases (p. 257). The pathological

findings in patients with meningitis who died early were comparable with

those who died of bacteremia.

Of the 156 patients who died from fulminating bacteremia (table 36),

126 showed hemorrhage in the adrenal glands ranging from mild extravasa-
Mk]NING)OCOCCAIL INFI'X'TIONS 271

tions to the conversion of both glands into sacs of blood. There was no

evidence of meningitis in 74 of these 156 patients and in 64 others the

meningeal inflammation was minimal. Pulmonary edema was striking in

almost all and gross hemorrhage into the lung was not unusual. There were

small effusions into one or both pleural cavities in about half of the patients.

Widespread focal hemorrhages were scattered over the serous surfaces in

most cases and sometimes involved the myocardium. Interstitial myocarditis, occasionally severe but usually of mild focal character, occurred in

28 of the 126 patients with adrenal hemorrhage. Renal changes indicative

of shock were observed in 6 of 26 patients analyzed by Thomas.7

5 As has

been noted (p. 263), in only 3 of the 300 patients who died of meningococcal

infection was death the result of renal lesions due to sulfonamides.

TREATMENT OF MENINGOCOCCAL INFECTIONS

It seems worthwhile to outline briefly recommendations for treatment

based on the published reports and the experience of many medical officers

with about 14,000 patients ill with meningococcal infection during World

War II, and on advances in therapy since the war ended.

Acute or chronic bacteremia.-Sulfadiazine, 4.0 grn., should be given by

mouth and be followed by 1 gin. every 4 hours until fever, symptoms, and

other manifestations of infection have been absent for at least 48 hours.

When there is vomiting, comparable amounts of sodium sulfadiazine dissolved in a liter of normal saline solution should be administered intravenously. These dosages are usually sufficient to maintain a concentration

in blood from 5 to 11 mg. per 100 cc. of plasma, and as a rule prevent the

development of fulminating bacteremia or meningitis.

Fulminating bacteremia with peripheral circulatory failure.-This is

a major medical emergency requiring immediate action and continued, constant observation by resourceful physicians and nurses. Even though meningitis is present or suspected, it is of quite secondary importance, and the

patient should not be subjected to the strain of lumbar puncture.

An hourly chart of pulse, respiration, temperature, and blood pressure

is begun. The patient is placed in the shock position. Oxygen is administered continuously to combat cyanosis. External warmth is applied. An

infusion of sodium sulfadiazine, 0.1 gm. per kilogram of body weight dissolved in 1,000 cc. of normal saline solution, is begun in an antecubital vein

of one arm; in the other arm, an infusion of 500 cc. of 10 percent dextrose

in water is begun; 500,000 units of penicillin dissolved in 20 cc. of normal

saline solution are injected into the tubing and then 100 cc. of aqueous

adrenocortical extract. This is followed by 500 cc. of plasma or blood, if it

appears necessary. Meanwhile, the following intramuscular injections are

given: (1) Cortisone, 200 mg. divided into four 50 mg. doses injected into

73 See footnote 14 (2). p. 244.
272 INFECTIOUS DISEASES

four separate sites, and (2) penicillin, 1 million units divided into two

500,000-unit doses injected into two separate sites. If the systolic blood

pressure is 80 amm. of mercury or less, a 4-cc. ampule of l-norepinephrine

(levofed bitartrate, each cubic centimeter containing 1 mg. of levofed base)

should be added to the flask of 10 percent glucose and given at a rate necessary to maintain adequate blood pressure. This is usually about 2 to 4 Jsg.

per minute.

Further therapy may include: (1) Plasma, or 25 gan. of concentrated

human albumin administered in 5 percent solution, if indicated for shock;

(2) sodium --ulfadiazine, 0.05 gm. per kilogram of body weight every 4 hours

intravenously until the drug (approximately 1 to 1.5 gin. every 4 hours) is

tolerated by the oral route; (3) penicillin, 1 million units every 2 hours

intramuscularly; (4) cortisone, 50 nig. intramuscularly every 6 hours for

the first. 2 days and 25 mg. every 6 hours for the next 3 days; thereafter, the

dose should be gradually discontinued over the course of a week; and (5)

small quantities of ginger ale or sweetened fruit juice, orally, as soon as

possible amounting to 3,000 cc. of fluids or more daily.

The dosage of sulfadiazine should be guided by frequent determinations

of drug level in the blood, 15 to 20 mg. per 100 cc. being the optimum range

Full chemotherapy should be continued for at least 4 days after the patient

has recovered from the acute phase of his disease, counted from the first

day of normal temperature.

After the first day, no more than 1,000 cc. of normal saline need be

given daily intravenously. Should pulmonary, sacral, or peripheral edema

appear, however, the quantity of normal saline solution should be markedly

reduced. If marked pulmonary edema develops, 1 to 3 units of plasma or

25 to 50 gm. of concentrated human albumin may be administered slowly.

Positive preisure oxygen may be helpful.

If the patient is failing, hypoglycemia and hypopotassemia should be

considered. The appropriate blood determinations should be made, and their

abnormalities corrected. An electrocardiogram might show evidence of

potassium deficiency.

In those patients with fulminating bacteremia whose manifestations are

not those of shock, the use of plasma, norepinephrine, oxygen, and adrenocortical compounds should be omitted.

A count of circulating eosinophils should be performed to assist in differentiation of the Waterhouse-Friderichsen syndrome from fulminating

sepsis without adrenal insufficiency; the former may show more, and the

latter less, than 50 cells per cubic millimeter. Cortisone dosage should be

adequate to maintain the number of eosinophils at 15 per cubic millimeter

or less.

Meningitis.-The potential seriousness of this condition is such that, regardless of its severity, all patients should receive a liter of saline containing sodium sulfadiazine intravenously-6 gin. for a heavyweight, 5 gm. for
MJENINGOCOCCA L I NFECTIONS 273

a mediumweight, and 4 gin. for a lightweight adult. It is wise to administer

half the criginal dose parenterally 4 hours later, but, in conscious and cooperative patiei',s who are not vomiting, the oral route may be used at this

time. If, following this, continued parenteral therapy is needed, 2 gin. of

sulfadiazine dissolved in saline should be injected intravenously or subcutaneously every 8 hours. In comatose patients, the drug may be adininistered by stomach tube. Sulfadiazine, in doses of 1 to 1.5 gm. orally every

4 hours, will usually maintain the concentration in blood around 8 mg. and

concentration in the spinal fluid around 6 mg. per 100 cc. A concentration

in blood of 6 to 10 mag. is adequate. In fulminating cases, the dosage should

be adjusted to maintain the concentration in the blood between 15 and 20

mg. per 100 milliliter. In the gravely sick cases, penicillin should also be

used, in the doses just mentioned. If the patient is known to be sensitive to,

or develops complications of, sulfonamide treatment, penicillin in massive

dosage (1 million units every 2 hours) should replace it. If sensitivity to

both of these agents should be present, chloramphenicol, Aureomycin, and

Terramycin are effective drugs.

DISCUSSION

The experiences of medical officers who have treated meningococcal infection during the Second World War have clarified and extended knowledge

of the various forms which this infection may assume. These observations

amply confirmed the opinion of Herrick and others in the World War I

epidemic that the disease begins as a bacteremia and, if not prevented by

spontaneous resistance or therapy, involves the meninges, skin, and other

organs, or it may be fatal in the bacteremic form.

The major contribution has been the development of a tried therapeutic

plan, which has reduced the case fatality to 4 percent in contrast to about

31 percent in World War I (table 34). In the Zone of Interior, where no

problem of evacuation existed, the case fatality was 3.9 percent compared

to 4.5 percent for oversea areas. The ratios for the continental United States

in 1944 and 1945 were, respectively, 2.9 and 4.9 percent, based on 2,577 and

815 cases. It is not probable that with our present therapeutic tools mortality can be further significantly reduced, unless some means can be found

which will enable the physician to recognize incipient meningococcal bacteremia during the phase of prodromal respiratory symptoms.
CHAPTER X

Cutaneous and Other Aspects of Diphtheria

Averill A. Liebow, M.D., and John H. Bumstead, M.D.

Diphtheria was a new and serious problem to the U.S. Army during the

Second World War. Combat in the tropics again proved to be particularly

favorable for the spread of this disease, especially the cutaneous form.

During the First World War, the British recognized the diphtheritic nature

of the desert sores that were so prevalent among the troops in Egypt and

Palestine. In World War II, lesions of the same nature were common during the North African campaign over similar terrain. During 1943 and

1944, cutaneous diphtheria on a large scale became apparent among troops

in the Pacific. Hitherto, it had not been reported from that area, and it

was not until Corynebacteriuna diphtheriae was found in such lesions known

as tropical ulcer, ecthyma, and jungle rot that their etiology was determined.

These lesions were of epidemiological importance because they were a prolific source of pharyngeal and nasal diphtheria among the soldiers and to

those with whom they came in contact. It was found that an enormous

reservoir of diphtheria-in the cutaneous form resembling that seen in soldiers-existed among natives in the Pacific, particularly among the children.

The lesions of childhood probably accounted for the immunization of the

natives early in life. It seemed that the conditions of combat reduced American soldiers to the epidemiological conditions prevailing among the natives.

Studies of the lesions of soldiers and of natives in the tropics revealed

the presence of a hitherto unknown hemolytic corynebacterium, which could

easily be confused either with C. diphtheriae on Jiiffler's medium or with the

beta hemolytic streptococcus on blood-agar plates.

Several groups of investigators seized the opportunity to study the

effectiveness of penicillin in the treatment of the numerous carriers and

clinical cases of diphtheria that were available in some hospitals.

Part I. General Aspects of the Military Problem

INCIDENCE

Preliminary statistical data on the incidence (total cases) of diphtheria

in the U.S. Army for the years 1942-45 by area, based on sample tabulations

of individual medical records, are presented in table 40. During 1942

through 1945, 619 cases of diphtheria were reported in the Army in the

continental United States and 5,105 additional cases from the Army overseas.

Among the oversea theaters in 1945, the year of highest number of cases, the

European Theater of Operations, U.S. Army, had the highest rate, with the

275
276 INFECTIOUS DISEASES

North African and Mediterranean Theater of Operations, V.S. Army,

second, and the combined Pacific areas, third.

Deaths due to diphtheria, during WVorld War I1, totaled 125 (table 41).

Of the total, 115 occurred in the Army overseas. Mortality was greater in

1945 for the Army as a whole, with 67 deaths occurring in the European

theater alone.

TABLE 40.-Incidence of diphtheria in the U.S. Army, by area and year, 194--45

[Preliminary data based on sample tabulations of individual medical records]

[Rate exprtssed as number of cases per annum per 1.000 average strength]

1942-45 1942 1943 1944 1m

Area I -

Number Rate I Numberate Number Rate Number Rate

of casets of eases of ecases of a•s

Continent~d United States ------ 619 0. 04 67 003 0.04 I 152 0.04 195 0.07

Overseas: . 557 0. 58 _

Europe --------------------- 2.5, 0.58 0.33 45 0.17 245 0.15 2.240 0.94

NMediterranean i --------------. , 087 .73 2 .09 197 .43 6'1 .97 "260 .73

NMiddle East - --------------- 45 .31 1 .17 23 .43 11 .24 10 .24

China-Burma-India ------------ : .47 8 .91 15 .38 155 .9"2 30 .14

Southwest Pacific ---------- 615 .33 3 .04 7 04 100 .19 505 .49

Central anid South l'acific. - - 519 .41 4 .03 69 .24 266 .61 180 .4'S

North America 2 .------------ 19 .4 2 .02 3 .02 14 .11 Latin America ------------ - 23 .0o 5 .05 2 .02 1 .01 ....15 .21

Total overseas-............ -5.105 0.48 55 0.09 364 0.22 1.426 0.37 3

,:Of0 . 7 0

"Total Army --------.------- 5.7"24 0.22 U2 0.04 569 0. 0 1 0 , 4 0. 46

' Include% North Africa.

SIncludes Alaska and Iceland.

3 Includes admissions on transports.

Evidence is presented (p. 315) that cutaneous diphtheria probably played

an important role in the dissemination of all forms of the disease, although

relatively few cases were diagnosed and reported officially. For example,

the incidence of cutaneous diphtheria in the total Army in 1944 and 1945,

based on sample tabulations of individual medical records, totaled 485 (table

42). The majority of cases occurred in the combined Pacific areas and in

the China-Burma-India theater.

Among the British in the African desert, the rate for all forms of

diphtheria was 4 to 5 per 1,000 per annum.1 A comparison of British and

American incidence of diphtheria in the Mediterranean theater during December 1943 and January and February 1944 follows:

British American

December 1943 -------------------------------------- 558 64

January 1944 --------------------------------------- 490 42

February 1944 -------------------------------------- 302 33

1 Proceedings of the Conference of Army Physicians. Central Mediterranean Forces. Held at the

Institute Superlore di Sanita, Viale Regina Marguerita. Rome. 29 Jan. to 3 Feb. 1945, pp. 101-118.
DIPHTHERIA 277

TABLE 41.-IDeaths due to diphtheria in the U.S. Army, by area of admission and year of death,

1942-15

[Preliminary data based on tabulations of individual medical records]

[Rate expressed as number of deatlhs per annum per 100,000 average strength]

1942-45 1942 1943 1944 1945

Area - _ -

Number Rate Number Rate Number Rate Number IRate Number Rate

Continental United States - 10 0.07..........00 2 0. 04 2 0.05 .

Overseas:

Europe ----------------------- 72 1.64 ---------- 0 ---------- 0 5 0.30 67; 2.82

North Africa ------------------ 1 .74 ---.------ 0 4 .88 3 .46 4 13.1

Middle East ----------------- 3 2.05 ---------- 0 2 3.77 1 2.16..... . 0

China-Burma-India ---------- 3 .68 1 11.43 ---------- 0 2 1.19- - - 0

Pacific I ---------------------- 21 .68 ---------- 0 2 .42 8 .82 - l1 .78

North America --------------- 2 .41 ---------- 0 ---------- 0 1 .77 t 1.47

Latin America. - -------- 0-- ---------- 0 - --------- 0 0 .......... ------..0 - --------- 0

Total overseas 2 - - - - - - - - . - - - 115 1.07 1 0.17 8 0.47 210 0.52 86 1.85

Total Army---------------- 1 0.49 1 0.03 10 0.15 22 0.28 92 1.21

1 Total Pacific Area (Southwest, Central, and South Pacific).

2 Includes 3 deaths on transports in 1945.

TABLE 42.-Incidence of cutaneous diphtheria in the U.S. Army, by area and year, 1944-45

[ Preliminary data based on sample talbulations of individual medical records]

[Rate expressed as number of cases per annum per 1,000 average strength]

1944-45 1944 1945

Area

Numberof Rate Numberof Rate Numberof Rate eases cases cases

Continent.l United States -------------- ------------ 15 0. 00 5 0.00

Overseas:

Europe ------------------------------------------ 45 0.01 ------------- 0 45 0.02

Mediterranean --------------------------------- 6 .01 1 0 00 5 .01

Middle East ---------------------- --------------------- 0-o -------------- 0 - - 0

China-Burnia-India ----------------------------- 120 .31 110 .65 to .05

Southwest Pacific -------.---.---------- -------- 2'5 .13 3 0 .U6 175 .17

Central and South Pacific ----------------.------ 89 .11 54 .12 35 .09

North America 2 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 0 ------------ 0 1 0

Latin America ---------------------------------------------- o 00--- -- - 0

Total overseas I .............................. 470 0.06 191 0.05 2751 0.06

Total Army ----------------------------------- 485 0.03 200 0.03 285 0.04

I Includes North Africa.

2 Includes Alaska and Iceland.

3 Includes admissions on transports.

NOTE.-Ahsolute zero is indicated by zero in the units column; 0.00 indicates a rate of more than zero but less than

0.005.
278 INFE:"I'll'S I)ISEASE'•S

It, must be stated, however, that the Americans required laboratory confirmation of diaguosis, whereas the British did not. The rate among German prisoners of war was far iii excess of that of American soldiers. Local

epidemics were reported in German prisoner-of-war camps in the United

States.- In some cases, cutaneous diphtheria was described, and tropical

ulcers were reported to be numerous among the prisoners. At the same time,

diphtheria increased steadily among Army troop)s in the continental I nited

States.

After the oc(cupation of Germany, the incidence of nasopharyngeal

diphtheria increased tremendously, probably through association of soldiers

with the civilian population among whom, during the war years, diplhtheria

had become a major problem. Circular Letter No. 69, Office of the Theater

Chief Surgeon, IHeadquarters, Theater Service Forces, European Theater,

issued on 28 September 1945, summarized for medical officers the general

principles to be followed in the diagnosis, treatment, and control of diphtheria. In addition, the December 1945 and January 1946 issues of the

Medical Bidletin from the Office of the Theater Chief Surgeon contained a

series of articles on diphtheria written by medical officers in the theater.

During the calendar year 1945, 2.240 cases of di)litheria occurred among

American troops in Europe with 67 deaths (tables 40 and 41). The incidence in December 1945 was approximately 2.8 per 1,000. During the early

months of 1946, from 3:0 to 50 cases were. being diagnosed each week with

1 or inore deaths.

IMMUNIZATION

The policy at first was not to immunize young adults routinely against

diplhltheria because moderate to severe reactions would occur in an appreciable number of cases. al,''mgh studies were made of the incidence of Schickpositive reactors anong U.S. Army troops and small diil)lhtheria-iimnmuli zation programs were conducted.3 Late in 1945, as the incidence of diplhtheria

increased among U.S. troops in the European theater, only immune personnel were assigned to the army of occupation on the Continent. U.S.

Army civilian employees, their dependents, and dependents of military personnel destined to join the occulpation army in the European theater were

immunized.

2 (1) Fleck. S., Keilam. J. W., and Klippen, A. J.: I)iphtheria Among German Primoners of War.

Bull. 17.S. Army M. Dept. No. 74, pp. 80-89. March 1944. (2) Monthly Progress Report. Army

Service Forces, War Department, 30 Nov. 1943. Section 7: Health. p. 22.

3 For a more detailed discussion of the diphtheria-immunization program during World War II.

the reader is referred to the following two sources: (1) Long. Arthur P. : The Army Immunization

Program. In Medical Department, United States Army. Preventive Medicine in World War 11.

Volume 111. Personal Health Measures and Immunization. Washington : U.S. Government Printing

Offic,. 1955, pp. 271-341. (2) MeGuinness. Aims C. : Diphtheria. In Medical D-partment, United

States Army. Preventive Medicine in World War II. Volume IV. Communicable Diseatse Transmitted Chiefly Through Respiratory and Alimentary Tracts. Washington: U.S. Government Printing Office, 1958. pp. 167-189.- J. B. C., Jr.
DIPIHTHERIIIA 279

Accordingly, on 12 January 1946, the Office of the Theater Chief Surgeon, European Theater,4 directed all major commands to institute an immunization program for (1) all medical department, hospital, and dispensary personnel, (2) all personnel whose duties brought them into frequent and intinmate contact in camps or enclosures with prisoners of war,

displaced persons, internees, or German civilians, and (3) all units of battalion strength or smaller showing two cases in any one week. It was decided to dispense with Schick testing at that time.

In May 1946, the rule was changed, and all military l)ersolnel going

overseas who were shown to be susceptible to diphtheria by the Schick test

were ordered to be immunized.

Part II. Tropical Ulcers and Diphtheria

SOURCES AND DISSEMINATION OF INFORMATION

The presence of C. d;phtheriae in skin lesions, particularly ulcers, was

reported by widely separated groups of observers in the South and Southwest Pacific Areas and in Burma during World War I1. However, in

Saffron's 1944 review of the literature on cutaneous diphtheria no mention

was made of the incidence in these areas.5

Cutaneous diphtheria was recognized among American forces in the

Mediterranean theater but was the subject of only one brief general report.8

More interest was displayed by the British, among whom the incidence of

diphtheria was generally higher.7

South Pacific.8-The observations in the South Pacific Area were made

chiefly on members of the 25th and 43d Infantry Divisions, as they were

evacuated fronm combat in the Solomon Islands, and on troops of the 27th

Infantry Division, following their evacuation to Espiritu Santo in the New

Hebrides after the Battle of Saipan. The first of a series of reports from

the 39th General Hospital, Auckland, New Zealand, appeared in September

1943. The information was soon disseminated throughout the area in Medical Circular Letters Nos. 5 and 14, dated 20 October 1943 and 5 January

1944, respectively, Headquarters, U.S. Army Forces, South Pacific Area.

4 Medical Bulletin No. 2. Office of the Theater Chief Surgeon, Headquarters, Theater Service

Forces., European Theater, January 1946, pp. 1-7.

5 Saffron, M. H.: Cutaneous Diphtheria as a Military Problem; A Review of the Literature,

With Report of a Case. Arch. Dermat. & Syph. 51: 337-340, May 1945.

6 Medical Bulletin No. 19, Office of the Chief Surgeon, Headquarters, European Theater of Operations, I May 1944, pp. 27-29.

7 (1) See footnote 1. p. 276. (2) Hunt, T. C.: Medical Experiences in North Africa. 1943-44.

Brit. M.J. 2: 495-498, 14 Oct. 1944. (3) Diphtheria In Campaigns. British M. Bull. No. 36,

pp. 1-2, June 1944. (4) MaeGibbon, T. A. : Diphtheria In the Middle East; Some Observations on

71 Cases. Edinburgh M.J. 50: 617-625, October 1943. (5) Williams, H. C. M.: Cutaneous and

Conjunctival Diphtheria; Series of Cases. Brit. M.J. 2: 416-417. 2 Oct. 1943.

8 Unless otherwise Indicated, the material presented in this chapter on tropical ulcers and cuta.

neous diphtheria In the South Pacific is taken from Llebow, A. A., MacLean, P. D., Bumstead,

J. H., and Welt, L. G.: Tropical Ulcers and Cutaneous Diphtheria. Arch. Int. Med. 78: 255-295,

September 1946.
28t) INFECTIOUS DISEASES

Similar material oil diphtheria was made available in February 1944 by

newsletter from U.S. Navy headquarters for malarial and epidemic control

in the South Pacific Alea. In addition, there were the evangelical efforts

of the medical consultani, Col. Benjamin M. Baker, MC. who did much to

make the staffs of the various hospitals conscious of the diphtheria problem.

The final report totaled 174 cases of cutaneous diphtheria and 94 cases of

noncutaneous diphtheria, in all of which C. diphtheriae had been demonstrated.

The following tabulation is based on a study of patients from the Solomon Islands campaign at the 39th General Hospital from 7 February 1943

to 1 July 1944, inclusive, and on cases of diphtheria from the 27th Infantry

Division during their stay at the rest area on Espiritu Santo:

Proportion

Number of strains

Type of cases of cases torigenic

Cutaneous dlptheria ------------------------------- 174 145: 173

Throat cases -------------------------------------- 64 60:62

Nose cases ----------------------------------------- 5 5: 5

Nose and throat cases ------------------------------ 1 1: 1

Carriers ------------------------------------------ 4 12:23

The clinical observations on cases in the Saipan group admitted to the

122d Station Hospital on Espiritu Santo were also reported separately from

this hospital." On Fiji, 35 cases of nasopharyngeal diptheria were found

in the 164th Infantry of the Americal Division following the Guadalcanal

campaign. Diphtheria among marines in process of evacuation from

Guadalcanal has been described by Norris and his coworkers.'0 The laboratory work on diphtheria in the various hospitals in the South Pacific has

been reviewed by Murray."

During the early phases of the South Pacific study, from March to September 1943, intensive parasitological and bacteriological studies were made,

including anaerobic cultures, dark-field examinations, potassium hydroxide

smears, cultures for fungi, and Giemsa stains for Leishmania. Cutaneous

lesions were searched with care for Leishmania in cases from the Solomon

Islands and Saipan, but neither protozoa nor spirochetes were found, and

such fungi as Monilia and Epidernwphyton were rarely encountered. When

the frequency of C. diphtheriae became apparent, a special procedure was

employed to investigate the epidemiology and pathogenesis of lesions associated with this micro-organism, and bacteriological methods were simplified

to facilitate its detection. A standard clinical record form was designed,

which emphasized such factors as previous diphtheria, immunization, former

Schick tests, history of sore throat, and evidences of neurological damage.

9 Stern, R. L., and Grynkewich, S. E.: Diphtheria Epidemic In Adults In the Tropics. Bull.

U.S. Army M. Dept. 5(5): 562-569, May 1946.

10 Norris, R. F., Kern, R. A., Schenck, H. P., and Silcox, L. E.: Diphtheria in the Tropics;

A Report of 18 Cases on a United States Naval Hospital Ship. U.S. Nay. M. Bull. 42: 518-524,

March 1944.

11 Murray, R. : Laboratory Service--South Pacific Area. [Official record.]
DIPITHERIA 281

Routine nose and throat cultures were taken, and Schick tests were made

in all instances where nasal or pharyngeal diphtheria did not make imnlnediate treatment imperative. Before a patient was discharged from a hospital, another physical examination with emphasis on the neurological aspects was performed.

Burma.-In the Burina portion of the India-Buurnma theater, 141 cutaneous

lesions were found, chiefly in soldiers from the Myitkyina combat area.

They were reported from the 20th General Hospital, Ledo, Assam, in Septenmber 1944, by Livingood and his coworkers, who had given them careful

stu(dy.12 In 21 percent of these 141 patients, it was possible to demonstrate

toxigenic C. diphtheriae. There was, however, a high incidence of complications among those lesions from which C. diphitheriae was not isolated, but

since they were morphologically identical with those harboring the microorganisms, the diagnosis of cutaneous diphtheria seemed reasonable. Only

eight cases of nasopharyngeal diphtheria were diagnosed in the interval

during which most of these cutaneous cases were observed-September to

December 1944. Particular attention was paid to the complications of the

disease as well as to morphology of the characteristic lesions and their treatment, and a valuable followup study was made, which furnished an estimate

of the cost to the Army in man-days.1 3

Reports from the 69th General Hospital, Ledo, Assam, in October 1944

and January 1945 14 referred to 70 p)atients. All throat cultures in this series

were negative, and no clinical cases of nasopharyngeal diphtheria were

diagnosed.

It is interesting to note that the British in the India-Burnia theater at

the same time were seeing a number of cases of cutaneous diphtheria, some

with neurological complications.1

12 (1) Cutaneous Diphtheria, 20th General Hospital, 20 April 1945. In blunigart, Herrman L.,

and Pike. George M.: History of Internal Medicine in India-Burma Theater, inclosure 11 thereto.

[Official record.] (2) Letter, Maj. Clarence S. Livingood, MC, Office of Chief of Dermatology and

Syphilology, 20th General Hospital, to Commanding Officer, 20th General Hospital, 15 Sept. 1944,

subject: Cutaneous Diphtheria. (3) Letter, Maj. Clarence S. Livingood, MC, Office of Chief of

Section of Dermatology and Syphilology, 20th General Hospital, to Commanding Officer, 20th General Hospital, 9 Oct. 1944, subject: Cutaneous Diphtheria. (4) Letter, Maj. Clarence S. Livingood,

MC, Chief, Section of Dermatology and Syphilology, 20th General Hospital, India-Burma Theater,

to Commanding Officer, 20th General Hospital, 25 Jan. 1945, subject: Cutaneous Diphtheria.

(5) Letter. Lt. Col. Francis C. Wood, MC, Chief of Medical Service, 20th General Hospital, to

Commanding Officer, 20th General Hospital, 15 Sept. 1944, subject: Cutaneous Diphtheria. (6) Letter, Maj. Herbert S. Gaskill, MC. Chief. Neuropsychiatric Section, 20th General Hospital, IndiaBurma Theater, to Commanding Officer, 20th General Hospital, 18 Mar. 1945, subject: Preliminary

Report on the Neuritis Complicating Cutaneous Diphtheria.

1.1 Letter, Capt. Daniel J. Perry, MC, Assistant Chief, Dermatology and Syphilology Section,

20th General Hospital, to Consultant in Dermatology, Office of the Surgeon General, 28 Aug. 1945,

subject: Follow-Up Studies of a Group of 140 Cases of Cutaneous Diphtheria.

14 (1) Letter, Capt. Harvey Blank, MC, Chief, Section of Dermatology and Syphilology, 69th

General Hospital, India-Burma Theater, to Commanding Officer, 69th General Hospital, 31 Jan. 1945,

subject: Analysis of 40 Additional Cases of Cutaneous Diphtheria. (2) Letter, Capt. Harvey Blank,

MC, Chief, Section of Dermatology and Syphilology, 69th General Hospital, Advance Section 3,

India-Burma Theater, to Commanding Officer, 69th General Hospital, 1 Apr. 1945, subject: Report

of Cutaneous Diphtheria Among the Detachment of a General Hospital.

15 Blumgart, Herrman L., and Pike, George M.: History of Internal Medicine in India-Burma

Theater. [Official record.]
282 IN EC'rioT1 ! ISEA•IES

Southwest Pacific.-'The group at the 9th General lHospital on Biak 16

observed a total of 210 cases of diphtheria between 1 November 1944 and

1 March 1945. There were 102 case- of dernmatitis from which C. dihtherim,

was isolated. Of the 31 recovered strains tested, 19 were virulent. There

were also 60 other cases with wounds, burns, otitis media, otitis externa,

and other such lesions, and 48 nasopharyngeal infectious from which the

C. diphtherite was isolated. The patients in this group were froni nine

widely scattered bases in the Southwest Pacific Area, New Guinea, the

Netherlands East Indies, and the Philippine Islands. On Biak, where the

studies were conducted. 112 patients were from 22 different. organizations.

Quarterly reports front several hospitals in the Southwest Pacific Area,

among them the 54th General Hospital on Biak and the 105th General Hospital in lHollandia, New Guinea. indicated early in 1945 that diphtheria was

under surveillance. D)uring a 3-month period at the 13th General Hospital,

Finschhafen, northeast New Ghuinea, 26 cases of na•opharyngeal dilihtheria

were seen together with 25 individuals who had cutaneous lesions from

which (C. dfpltheriac was cultured. They were usually virulent nlicroorganisms of the nieitis type. Technical Bulletin No. 17, (ffice of the Chief

Surgeon, lHeadquarters. U.S. Army Forces in the Far East, dated 23 October 1944, called to the attention of all mledical officers the increase. in the

number of reported cases of clinical diphtheria in the area and directed that

measures be instituted to prevent the spread of the disease.

Zone of Interior.-After prevalence of the condition was recognized, the

patients with cutaneous lesions received thorough study in several large

centers in the United States. At the Moore General Hospital, Swannanoa,

N.C.,1 7 a skin isolation ward was established to which there were 228 admissions between 1 March and 3 October 1945. Cultures of ulcerated lesions

in the skin were positive for corynebacteria in 107, 18 of which proved to be

toxigenic. At the Harmon General Hospital. Longview, Tex.."' a survey

was made of 385 admissions: most, of the patients in the survey were from

the Pacific areas. Seventy persons were p)roved to have C. dipht/h'riae either

in the nose or throat or in cutaneous lesions. Fifty-eight of these strains

of the micro-organism were virulent, but 12 were toxigenic C. diphtheriae.

This represented an incidence of 3.1 percent in the population of the hospital at the time of admission. Fifty-six of these patients had tropical

ulcers or ulcerated dermatitides. In 8 of these, C. diphtheri(e was found

to be toxigenic and in 30, atoxic. At the Baxter General Hospital, Spokane,

Ill Oppel. T. W., Smith. J. J., Montanaro. A., and Tompsett. R. R. : Clinical Features of Diphtheria in the Tropics. [Official record.]

17 Bronson. L. M. : Memorandum on Cutaneous Diphtheria at Moore General Hospital. (Official

record.]

Is (1) Denhoff. E., and Kolodny. M. II. : Studies on Cutaneous Diphtheria and Tropical Ulcers.

Arch. Dermat. & Syph. 55: 360-368, March 1947. (2) Denhoff, E.. Kolodny, M. H.. Daniels. W. B..

and Mitchell. L. P. : Plan to Control Diphtheria in an Army General Hospital. Bull. U.S. Army

M. Dept. 6: 59-60. July 1946.
iI)IPTHERIA 283

Wash.,' 9 between 1 Decenmber 1944 and 15 February 1945, there were 62

healed or active cases of cutaneous diphtheria, of which polyneuritis developed in 11. At the Letterman General Hospital, San Francisco, Calif.,20

diphtheria in medical p)ersonnel attending patients on the dermatology wards

again proved a problem, until the diphtheritic nature of many of the lesions

encountered on these wards was recognized. The localized outbreak was

studied in this hospital and will be discussed later.

Diphtheria, particularly of the cutaneous variety, was discussed in

detail at the Ninth Service Command Conference on Internal Medicine

held at Letterman General Hospital on 7 and 8 November 1945.

Policies-In recognition of the increasing importance of the problem of

diphtheria during World War II, information, as it became available, was

disseminated by the highest echelon. The diphtheritic nature of certain

types of tropical ulcers in the Pacific was first given wide publicity in the

May 1944 issue of the Bulletin of the U.S. Army Medical Department. Following a tour of inspection of the Pacific area in October 1944 by Col. Francis R. Dieuaide, MC, Chief, Tropical Disease Treatment Branch, Medical

Consultants Division, Office of the Surgeon General, War Department Technical Bulletin (TB MED) 143, entitled "Cutaneous Diphtheria" was issued

in February 1945. This bulletin summarized the reports from various tropical areas, gave directions concerning diagnosis and treatment, and emphasized the epidemiological significance of the disease. Similar material on

the recognition and treatment of cutaneous diphtheria was published in the

March 1945 issue of the Bulletin. A special circular on management of

patients with cutaneous diphtheria was prepared by the Medical Consultants Division, Office of the Surgeon General, and was issued to service

command medical consultants on 3 August 1945.

The many cases of polyneuritis that had been reported from the Mediterranean theater,21 the South Pacific, Burma,22 and elsewhere, attracted the

interest of the Army Epidemiological Board (Board for the Investigation

and Control of Influenza and Other Epidemic Diseases in the Army), which

established an investigative commission composed of Dr. George D. Gammon and Maj. (later Lt. Col.) Emanuel B. Schoenbach, MC. The commission arrived in Merano, Italy, on 31 May 1945 and devoted its attention to

the many cases among the German prisoners of war, since cases among U.S.

soldiers were no longer available in large numbers. A preliminary report

of 42 cases considered diphtheritic polyneuritis and of 28 others was submitted in August 1945.23

19 Sampson, J. J.: Late Neuronitis Following Proved and Suspected Cutaneous, Faucial and

Wound Diphtheria. Am. J.M. Sc. 212: 432-448, October 1946.

20 Letter, Maj. Frank R. Day, PhC, Adjutant, Letterman General Hospital, San Francisco, Calif.,

to Office of the Surgeon General, 20 Oct. 1944, subject: Reported Cases of Diphtheria at Letterman

General Hospital.

21 See footnote 1. p. 276.

22 See footnote 12 (6), p. 281.

23 Gammon, G. D., and Schoenbach, E. B. : Preliminary Report on Investigation of Polyneuritis

In the Mediterranean Theater of Operations, U.S. Army, 20 Aug. 1945. (Official record.]
2•84 INFECTIOUS DISEASES

MORPHOLOGY

Typical lesions.-Tlie characteristic lesion from which C. d;phtheriice

was demonstrated in highest incidence was rounded with angular irregularities, deep and punched out, but did not as a rule extend far into the subcutaneous tissue. In the South Pacific. 84.1 percent of lesions harboring

C. diphther had this appearance. They were sinilar to lesions of cutaneous diphtheria seen in temperate zones, to the desert or veldt sores of North

Africa and. Palestine, to the "Garigha" of northern India, and to the lesions

seen among the Melanesianis and Tonkinese in the New ]lebrides, and the

Claamorros in the Marianas Islands. A typical lesion could develo) in as

short a time as a month.

The margins of the diplitheritic ulcers were declivitous, indurated. and

often rolled (figs. 37A and B. and 38). Occasionally, they were sligrhtly undermined but not to the same extent as the trop)ical l)hagedenic ulcers described,

for exaniple, by Janmes in the Melanesians.21 U-sually, there was a cone of

induration, erythema, and bronze-violet pigmentation about the sharply defined

Sore (fig. 3S).

In the India-Bturma theater, a dry, black eschar was often noted similar- to that of phenol burns or decuhitus ulcers. In other instances, there

was a fibrinous crust which when removed after the application of soaks

revealed the lesion described. The esehar could usually be loosened at the

edges but adhered firmly at. the center as if it were a part of the subcutaneous tissue.

Usually, the base was relatively clean, with a moderate serous or serosanguineous discharge. but sometimes there was adherent fibrinopurulent

material. The exudate beneath the crust. was gray or gray green rather

than yellow. Occasionally, there was a gray-green fibrinous memlbrane,

which ordinarily was difficult to scrape from the surface but could be peeled

off in some instances. It was present chiefly in lesions of short duration.

This membrane was often fitted to the irregularities of the ulcer (fig. 39).

Under advantageous conditions, healing occurred by granulation from

below and ingrowth of epithelium from the sides in such a manner that the

scar was on a level with, or slightly below, the surrounding skin and only

slightly less in diameter than the original lesion (fig. 37B, C, and D). At.

the center was a covering of thin white skin surrounded by a border of persistent bronze-violet pigmentation (fig. 37D). The latter tended to persist

for months or years. Persistent hyposthenia or anesthesia in the scars was

emi)hasized by some observers;25 however, a degree of anesthesia in newly

formed scar tissue is not surprising in any lesion.

24 .hneeop. C. S. : Tropical Plingaedenhe Ulcer In the. Pacific. Tr. Roy. so,.. Trop. MNed. & llyg.

:11 : 647 666. April 1938.

25 See footnotes 12 (4 1, p. 281" and 19, p. 243.
404

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2S83 INFECTIOUS DISEAxSES

destruct ion of the nail. and it, onle of tilie Ijlt-Ima, vases tihis seelits to have

MORPHOLOGY IN RELATION TO THE BACTERIOLOGY OF THE

LESIONS

The observers ini Hiii'ia2 were of the opinion that thle. appearance of

the punchied-out ulcers wvas sufficient ly chiaracteristic to) enable t he diagnosis

of cutaneous diphitheria to be muade or ruled out, purely oil clinical grounds,

in a high percent age of cases. Evidlence for t Iiis view was that, although

toxigeniei C. d'/'ltherhc wais cultured in only 21 ptieiiet of their cases. a,

AFiGuim 4w).-- INtille ui~c'rs. A. Ariitt' membranoulhtis d iplihterifl of vortb!1& su kis I*--

g011innii 4 dlays Post ft~lftione-11. It. D iphthteri tic Wt eer or penis resenhiling- ('Jmllt4rt it) its

lirinuiess but has adherent green mettbraite fromt whiehci tox igenite Corpinhcbtl~cil ait di,,Iitlicirim, was culturedI. The patienit had11 just returnedl fromt the soiqititoti Islandqs aun14 110141

not ind~ulIgedi in sexual intercourse for' MOre 1 han 1 year1.

very hi gil percent age dleveloped suich comlliicationls as neuritis and cardit is

even whenl thle Cultures wvere negative. lin thle group of cases from Saipan.

anI at~ternlpt was made to predict froim the Clinical appearance of the lesions,

before thle results of cuilture became available, whlet her it ivould Contain

C. (N1'hthcr'b. A. correct predict ion was miade in WU. percent, of the attemplts at. judlging 191 ulcerated lesions. This suggests that, in the age

group concerned and ini time territory u~nder consideration, it was C.(~h

t/u'rhi,e that played the import ant role in giving the lesions their characteristic m~orphiologrical stamlp, although~ no11 clzuiim is made that the lesion is

pathiognomnon ic. Thie observers in the Southwest. Pacific Area (lid not. support this view and stated that there was no characteristic lesion.

Amiong the factors that may determine whether a, culture p)ositive for

C. diphifhc1hWe is obtainedl is the interval between the onset of thle lesion and

2s see footnote 12 (4). 1). 281.
DIPIITIIERI A 289

Fu;u~ttI 41.-Epidermophytosis superinfected with ('orync'bac- tcriu~m diphithcriaec. Tile indurated. rolled ed'ge '1nd dt•qlb cavity

was ihac' (teristic of diphtheritic Iih'ers in this region. The lesion

wNas ac'q(uir ed 4I hrilig tilt, Battle of Saipan.

the timle of culture. Thus. in tile South Pacilic series. there was an incidence of 26.3 anid 23.4 percent of toxigenic ijero-organ11 Isjs in ulcerative

lesions of two groups of soldiers. totaling 556 men, who were evacuated

some 6 to S weeks after comblat (wlen itmost of the ulcers were acquired),

comlpared to an incidence of 6.2 percent in a group of 224 soldiers evacuated

some 20 weeks after combat. In this study, all ulcerative derniatitides were

cultured, althougli the lesion had the typical punlched-out al)pearance. The

observers il the Idiiia-Burnia theater also stated that the clhances of a positive culture decreased with the age of the lesion.

Another factor that may prevent finding C. diphtheiae in typical

lesions is the al)l)lication of various forms of treatment, especially penicillin,

to which C. diphtherwie is sensitive. The analogy may be that the shovel

that made the ditch is no longer there. In the Saipan group of the South

Pacific series, 84.1 percent of lesions containing C. diphtheriae were grossly

typical. but only 98 (53 percent) having ulcers thought clinically typical

yielded C. d;phtheriae on culture some 8 weeks after combat.

The duration of the. lesions yielding a positive culture seems also to be

a (leterminant of the toxigenicity of the strains recovere(d. Thus. in the

South Pacific series, 40 of 43 (93 percent) diphtheritic ulcers of less than

12 weeks' duration yielded toxigenic micro-organisms, whereas of 25 older

ulcers only 17 (68 percent) contained toxigenic bacilli. In one ulcer, a strain

recovered on 18 November 1943 was toxigenic in contrast with one morphologically and biochemically identical obtained on 28 January 1944 from the
FIcuizr: 42.- Aloist. desql h,1iV iatii e. l uh1llerali'e 4lerinallilis. VirIulenit Uvw•ctc't 'iltmin

dipihtlhcriv•c from scalp anl lhcer''s of" leg. iA's.itoil acqutlired ill IIle Solollloll Islaids.

FIGURE 4 .- Cull '(1os diplllthe'rii as . seeni ill fit hIlilida -Buarama t heatPer. The resemiblance' to the lesions shown ill figuirte, :17 42 ill lth Soulth Pacific Are:a is striking. A. A

recent lesion. The ulher is still shallow and a1 thin layer of filbritious nmaterial adheleres

to the hase. The sitlrr4 'lmiding, fisstic is cryt1heIwi lolls mllid moduhrately edemnatous. It. t

blahck atilierent eslhar forms the 1' center of tilt' well-definedl lesion. 4'. In another instminiiie

tilt, esclh:" has, Ivii ehivacl, Idu IVitlill g thi- ti IiMiICh'hl-uOit cl'rallicter of the lesicon anud its

relatively clean Iase. 1). A more eliroiit dipilitheritic ull<cer retakininigf lie punlheti-out

character with relatively clean graltmations at its Imse. The margin is inulurated. The

surrounlin. tissue is sliýhtlyv ehnu:ulltous +and lltas a bronze-violet color. E. A healehl

lesionl. The slight ly depresseed thinl H sc.l l has Well, covered by epithelium. A nairrow

Zone of brlolnze pigmientation is seen.
'I I I IT I IVR 1A

44P

7z,

Al

12 1:: C
2042 INFE"'Tt rous IISA:s

recurrent lesions. Similar observations were made ill a case at the Moore

( -eneral llos;)ital.2 91 anid the same general observation was recorded by the

Southwest Pacific groupi as follows: -In solie instances, a (ulture earlyv in

the lisease shiow. virulent organismns. Later, organismls with tile samle

nlorphology and fermientation reactioniS were isolated, but were non-virulenit

by guimea-pig tests.'"" These observat ions indicate that tile longer C.

d;Xihtlhr;,t' persist ill at cuitanleouis lesion the less likely is the recovered strain

to be toxigenic. This probably aecolnlts loto the relatively high incidence of

atoxic strains ill cutaineouis lesions when seen iin the United States.:" Neuritis

il inlividuals darryling avirulent C. d(phther;a' suggests that they may at

one timle have harbored toxigenie inicro-organ isins. Carriers in general have

.a relatively high proportion of atoxic strains. The mnechanismn of this is not

clear but mIay be based on tile formation of atoxic variants.•32

Ill the Saiplan group. to deteriiliie whether both toxigenic and atoxic

strains might Coexist in the same lesion, two or three colonies from tie primlary plates were tested in each of five instances, but tile Various strains

were all toxigenic. roxigenicity was not lost ill vitro when a series of mieroorganisms, which had been stored oil blood-agar slants in frigor for as long

as 14 nmonths with only one intervening transplantation, was retested.

There is a possibility that C. diphther;u'. which is not toxigenic for the

rabbit or gutinea pig, may have a destructive activity on the humnan skini.

This is suggested by the work of 1usric.ha and Ilanja.:a who injected microolrganismls. obtained from the "Garighuma sores of Assaml, imitracutaneously

into other men. Ulcers resemblling those of the donor patients resulted.

while diph lieroids sinmiahrly inoculated prodluced no effect. These experimnentlS require confirination.

Other bacteria were usually associated with C. diphtheri, e in the elltaneous lesions. Considering only tile 145 ulcers from which toxigeniv

V. d;phtherlie was obtained inl the South Pacific group), 6 yielded pure cIIItures of C. aOphtheriae on blood-agar plates, and in 84 others this wias tfle

predomiinant nliero-orgaiismn. The associ-ated bacteria iin this group were

almost invariably st.phylococci (65 percent), beta hemolytic streptococci

(47 percent), a new hemolytic corynebacterium (9.6 percent) belonging to

the conmnion group) that. includes tile animal patlhogens (Corynebacterium.

pyoge'e.n and Corynebacterihm, orh.,(, and other dilphtheroids (4 percenut).

The new heniolytic corynebacterium was made the subject of a special study

and is discussed on pages 293 and 31.). The presence of beta hemolytic strepto-occi in such high incidence, both in the soldiers and ill the natives, contrary to sonie opinions cooncerninlg the rarity of this micro-organism ill trop29 See footnote 17, p. 282.

M, See footnote 12 (1). p. 281.

31 See footntotes 17. p. 282: and 18 01), p. 282.

T2! Dudley, S. F.: Critical Retview. Schick's Teat and Its Applications. Quart. J. Med. 22:

321-379. January 1929.

33i Paaricha. C. L.. and Panja. G. : )iphitheritie Ulcors of the Skin. The "Garigha- of Chittagong Hill Tracts. Indian J.M. Research 27 : 64"3 650. January 1941).
DIPHTHERIA 293

ical environments, is of interest. At Harmon General Hospital , almost all

of the 56 ulcerated dermatitides under study had cultures positive for hemolytic Staphylococcuw, aureuv. but less than 10 percent were positive for beta

hemolytic streptococci.

METHODS OF DIAGNOSIS

Early difficulties.--Until educative efforts emanating from higher medical

echelons became effective, or until suspicion was raised by the development

of suggestive complications or nasoplharyngeal infection in contacts, there

was great delay in accepting any of the cutaneous lesions of the tropics as

diphtheritic. In the words of Col. William S. Middleton, MC,8 5 Chief Consultant in Medicine, Office of the Chief Surgeon, European theater, "a new

generation in medicine has grown up without clinical awareness of the disease [diphtherial." Part of the difficulty resulted from burying reason in

the shroud of obscurant nomenclature, such as tropical ulcer, ecthyma, or

"Garigha," and veldt or "Naga" sores. These exotic local names for a condition general in the tropics fostered the expectation of an exotic etiology.

Part of the difficulty, however, resulted from inadequate bacteriological

diagnosis, for few laboratory officers had had extensive experience with

C. diphtheriae in the United States. In one general hospital, where an alert

clinical staff had correlated expert dermatological knowledge with the observation of a large number of cardiac and neurological complications suggestive of diphtheria, there were no positive reports of skin cultures for

C. diphtheriae during the first 6 weeks of observation of a large number of

patients. Subsequently, positive bacteriological diagnosis of C. diphtheriae

was made in approximately 60 percent of the cases.36

Technique of cultures.-In experienced hands, the simplest methods of

culture were effective. It was found best to bring the media to the bedside

and to remove a small quantity of material from the base of the ulcer with

a platinum loop filled with saline or broth, if necessary. It was not important to get beneath overhanging margins or to scrape deeply. The bacteria

were everywhere over the surface of the granulations at the base. If the

ulcer was relatively clean and not crushed, direct culture of the base was

successful without further p)reparation, and it was not necessary to apply

alcohol or other agents. It was far more satisfactory as a routine procedure

in hospital cases to apply a warni saline pack to the lesion from 3 to 24

hours, which helped to remove any excessive exudate, fibrinous crust, or

ointment that may previously have been applied. Saprophytic bacteria

were relatively abundant in the protein material of the external parts of the

exudate.

Corynebacterium diphtheriae in smears.-In smears from the lesions,

34 See footnote 18 (1), p. 282.

35 Semiannual Report, Chief Consultant in Medicine, Office of the Chief Surgeon, Headquarters,

European Theater of Operations, U.S. Army, 1 Jan.-30 June 1945.

36 See footnote 12 (1), p. 281.
294 INFECTIOUS DISEASES

C. dilphther;ae was often found witlhiii olymorphonuclear leukocytes of the

exudate (fig. 43(C). Somnetimes, the nicro-orgaiismis were Iimeirous. and

the predoniniant element of the bacterial l)ol)latioit, but usually there was

an admixture of grant-positive cocci inl chaiais and clumnips. In exudates,

the nticro-organismns were observed frequently to be stouter than in the classicai descriptions, which are based on the appearance of the bacteria on

Liiller's mnediuni (fig. 4:11)). The bacteria from cutaneous lesions assumed

the classical forms when growin on this material. NI the tropics, great difficulty was encountered in distinguisuhig C. d;jiPhthe'atU from the new heniolytic corynebalcteriuim that wits so frequently found ill these lesions as well

its in infections of the throat. C. d;ldhth/r;,n coulh usually be differentiated

from ordinary diphiheroids, since the former were longer. more lfleomorpIlic.

with slender and chlb-shaped forms, more gralhu'hi, anmd less iltensely grami

p)osit ive.

With the Saipain groulp, an attemilpt was made to determline how well

purely mnorp)hological criteria would bear the test of subsequent bacteriological investigaltion. ]it smears of exudate from 150 ulcers, the presence

or aliseli'e of C. diplhtheriae wits correctly predicted in 83.3 percenm. In 10

instaiinces, 6.7 perceiit. the characteristic bacilli were not seen ini direct

smears but were fouid in the cultures. In 15 iistances, 10 lpercent, gramipositive pleomiorllhic bacilli were incorrectly diagnosed as C. diphlheh•ae

from the simeiars. This denioistrates that, with experience, a reasonably

accurate guess cain be iiiade, which may apply under field conditions where

facilities for (clilture are not, available.

Bacteriological media.,-With tihe propler use of blood-agar pliies, isolated colonies could be studied aid picked for subculture, usually within 24

hours. it was found importanit1. To adjust the p11 of the agar to 7.6I before sterilizing, since C. diph1hU'r'te grows better oni slightly alkali ine iedia.

2. To cool the niedium to 450 C. or less before adding fresh blood. If

the blood is overheated, the niiarrow ring of hemolysis characteristic of

C. d/;phtheru,, tyl)~.I*e mits av ybe obscured amid the coloniies ae less readily

distihguished front those of staphylococci iin( d iphtheroids.

3. To emnlploy good streakiig teclnique, so that the colonies on the plate

were well isolated and dhid not plreemi the creami cheese conffluemlce too often

characteristic of rouithi laltes in badly comiducted laboratories. On this

miediinm. the dif'ereithiation from the umusual corv'nebacternim is silnple, for

the latter produces intensely hemolytic coloniies resembling those of the beta

henmolytic Streptococcdu.

Liffler's serum was found useful when examined 8 to 12 hours after

incubatiomn, for then C. diphlherifte appears in long slender pleomorjphic

form, permitting a tentative differemiiation from the generally much shorter

and thicker diphmthR'roids. It was extreimelyv difficult, however, to di(tinigiuisli

C. diphtkeriae froi,m the new heinolyvtic corl'ebiacteriumn.
DIPHTHERIA 295

Tellurite medium, pmarticularly Miiller's modificat ion,37 was very successful in some hands. The difficulty with this medium was that some batches

of crystalline potassium tellurite supplied early in World War II seemed

to have become partly decomposed during the vicissitudes of transportation

through the Tropics and were more toxic for C. diphtheriae. On this medium, there was often a delay of up to 48 hours before typical colonies of

C. diphtherhie made their appearance. The advantages under ideal circumstances are the selectivity of tellurite aiding differentiation of the type

of C. diphtheriae. The new hemolytic corynebacterium generally was markedly inhibited on this material.

In the India-Burma theater. contrary to experience elsewhere where

mitis was found, the micro-organisms were described as being of the intermedius variety.38 In the same theater, at the 20th General Hospital, 90

percent, of micro-organisms described as virulent C. diphtheriae were said

to ferment sucrose but not( dextrose or levulose. In the South and Southwest Pacific39 experiences, all of the virulent C. diphtheriae were sucrose

nonfermenters.

ASSOCIATED CLINICAL FINDINGS

It was noted by all observers that, aside from the complications of neuritis and myocarditis, there were usually no general symptoms of intoxication when the ulcers alone were the seat of C. diphtheriae. The patients

usually complained of nothing more than local discomfort, if that.

In rare instances in the South Pacific group, there was an unexplained

tachycardia. One had a persistent elevation of the pulse rate to as high as

120 per minute on complete bed rest, without fever or changes in the electrocardiogram. The tachycardia disappeared as the ulcers healed.

It. was noted by the observers in Burma that the general feeling of wellbeing may have contributed to the psychoneurotic state observed in some

patient" whose. hospitalization was prolonged because the ulcers failed to

heal or because there was a recurrence during attempts at reconditioning.40

Suppurative adenitis or lymphangitis were remarkably rare despite the

presence not only of virulent C. diphtheriae but frequently of hemolytic

Staph. aureus or beta hemolytic streptococci. Moderate local swelling of

the lymph nodes without heat, however, was frequent.

In two Schick-positive individuals, a striking erythema and edema

occurred about the ulcers following administration of diphtheria antitoxin.

This may be analogous to the Francis reaction as observed in pneumococcal

infections.

Hyperhidrosis of the hands and feet in association with cutaneous diphtheria was noted by the Burma group in 13 percent of the patients.

37 Medical Bulletin No. 2, Office of the Theater Chief Surgeon, Headquarters, Theater Service

Forces. European Theater, January 1946, pp. 21-24.

38 See footnote 12 (1), p. 281.

39 See footnote 16, p. 282.

40 See footnotes 12 (4), p. 281; and 13, p. 281.
296 INFFCTIOUS I)1SEASES

RELATION TO THE SCHICK REACTION

The relation of the incidence of the lesions to tihe Schick reaction of the

individnal is of considerable interest, as it has both etiological and prophylactic connotations. It. was found in the South lPacific experielnce that individuals with diphtheritic ulcers are much more frequently Schick positive

than the general population of which the patients are a part (table 43).

This indicates that tile Schick-negative stage is in large measure l)rotective.

At the Moore General Hospital, 13 of the 1 patietws with virulevt C. diphthre'ri in their cutaneous lesiois had positive Schick reactions. These

lesions had been present for as lmog as 4 mionths. All of those at the hlarmon

General H1ospital, however, had negative Schick reactions. In another large

group in the India-Burma theater (69th (Teneral Hospital), 40 percent of

infected individuals were Schick positive. while 20 percent of uninfected

individuals in a ranldoln salnpling of admissions wvere Schick positive. It is

notable that the divisions, after combat service inl tile Tropics, have a lower

incidence of Schick-positive individuals than the 315 to 45 percent before

going overseas. On the dermatology ward at a large hospital in the United

States, :14 percent of patients front the Pacific admitted with this disease

were Schick positive in contrast with the T7- general medical adiliissionis

from the Pacific areas, of whoin oinly 13.3 percent were Schick positive.

Thirty-two percent of the ind(lividuals harboring avirulent C. dipht heriw

were Schick positive. This suggests a general, largely subclinical. diphtherization anologous to that which Dudley found in his school studies. Bensted,41 during an outbreak of diphtheria among British troops in northwest

India. performed Schick tests on his battalion anid observed that all of

those subsequently developing diphtheritic ulcers were Schick positive.

TABLF 43.-Schick reactions of individuals wivh diphtheritic tropical ulcers in three infantry

divisions in the South Pacific Area

I'cers containinig Ulcers tomtainiiig

toxigenic atoxh, ('. diphtAeriae Rem-fltonq C'. diphtheriaa

Infantry division

Number Percent Number Percent Number Percent

tested positive tested postIve tested positive

251h and 43d conibined 57 42. I 14 28. 5 - -..

25th- 9, 000 21.0

43d- 11, 968 27.8

27th- 74 20.3 12 8.5 12, 135 11.0

Source: liehow. A. A., MarcLafl, P. I).. Iturnstead, J. II., anl Wel t, I,. o.: 'I'ropial ri'ers and ('ut:aneous diph,-

theria. Arch. hit. Nlcd. 7m: :..m5 ihiri, ':4etem1,er Ilmoi.

41 Bensted, II. J. : A Limited Outbreak of Diphtheria Exhibiting Both Cutaneous 1nd Fluclial

I,4alotis. J. Roy. Army M. Corps 67: 295-307, Novembtr 1936.
DIPIITHERIA 297

Several instances, however, have been recorded of the development of

diphtheritic ulcers in Schick-negative individuals. One patient in the 27th

Division had been found Schick negative 1 month before admission for a

diphtheritic ulcer of 2 weeks' duration. In the India-Burma theater, one

patient, a medical officer, who was known to have had a negative Schick

test before he acquired the infection, later developed postdiphtheritic neuritis and myocarditis. In the same group, there was another man, previously

Schick negative, from whose ulcers toxigenic C. diphtheriae was cultivated.

Two Schick-negative individuals in whom cutaneous diphtheria appeared

are mentioned in the April 1945 report from the 69th General Hospital in

the India-Burma theater. One had been Schick negrative 41/2 months before

the cutaneous lesion developed at the site where lie had been scratched by a

psychotic Chinese soldier patient. The other was a cook who had been

found Schick negative 3 weeks previously; lie had suffered a laceration from

tripping over a crate. These cases, as well as others in which the Schick

reaction was negative within 1 to 5 days after apparent onset, indicate that

a negative Schick reaction does not necessarily imply immunity to cutaneous

diphtheria and its complications.

The interpretation of a Schick-negative reaction in an individual with

established ulcers is difficult. The Schick-negative state may either have

existed at the time the skin became infected or it may have been induced by

the micro-organismns resident in the skin.

Certain patients have positive Schick reactions despite the fact that

ulcers containing toxigenic C. diphtheriae have existed for many months.

This suggests that the skin is not a good absorbing surface for the toxin.

It has long been known that a single attack of pharyngeal diphtheria fails

to reverse the Schick reaction in about 60 percent of persons retested 3 to 4

months after recovery. Further evidence that the skin does not absorb toxin

as efficiently as the pharynx is the long latent period before neuritis develops

in the purely cutaneous cases (p. 301).

CUTANEOUS AND EXTRACUTANEOUS DIPHTHERIA

Incidence.-The concomitance of cutaneous and extracutaneous diphtheria has been noted previously, especially by Bensted, and Cameron and

Muir 42 in the Middle East. In the South Pacific studies, routine cultures

of the nose and throat of 174 patients with diphtheritic ulcers revealed C.

d;phtherkae in 19 (11 percent) of them. This is a much higher carrier rate

than in the general military population of which these patients were a part.

Ten of the nineteen individuals had clinical pharyngeal diphtheria, and two

had fibrinous rhinitis. There were also six pharyngeal carriers and one nasal

carrier. In the India-Burma series, only 1 of the 119 patients with ulcers

had virulent C. diphtheriae in the throat, but 8 others had diphtheroids re42 Cameron, J. D. S., and Muir, E. G. : Cutaneous Diphtheria In Northern Palestine. Lancet 2:

720-723, 19 Dec. 1942.

6:39243--63---23
298 INF:rI'i- :T I .)I' -:AI.

sembling C. dlphthlerhw. There was another patient with both faucial and

cutaneous lesions who was not included in the series.

Autoinfection of nasopharynx from the skin.-lin the India-lurnia

series, two questionable faucial involvements occurred more than 6 weeks

after the onset of postdiphtheritic neuritis, which apparently resulted from

cutaneous diphtheria.

In 3 of the 12 clinical cases of the South Pacific group mentioned previously, the patients had been sent to the hospital for the treatinwent of tIheers'

and were found to be Schick positive. Acute pharyngitis developed while

the patients were in strict isolation for periods varying from 21 ., to 5 weeks.

All three had had ne-ative throat cultures and were not. given antitoxin until

the pharyngitis bNcc-aie manifest. These cases demonstrate that in all probability autoinfection of the nasopharynx from the skin can occur. The other

clinical cases were admitted primarily for pharyngitis or rhinitis, although

in five of them vilcers antedated the diphtheria of the throat for periods

varying from 3 to 7 weeks.

In 27 pharyngeal cases observed at the 122d Station Hospital in the

New Hebrides, 14 (52 percent) had had skin ulcers that antedated the nasopharyngitis from 1 week to 3 months. In the newly described British series

of 76 cases of cutaneous diphtheria, 12 were coincident infections of the skin

and throat. In nine of these, the skin infection definitely preceded that of

the throat or nose.

COMPLICATIONS

Incidence.-The incidence may be described as actual and apparent.

1. The actual incidence of complications, as well as the severity of the

disease, is determined by the toxigenicity of the micro-organisms and by

the level of susceptibility of the population. Dudley in particular has

pointed out how susceptibility, by a process of latent immunization, tends

to fall in an environment where C. diphtheriae is widely disseminated. Evidence that this has occurred in the Tropics is the Schick reaction of veterans

of the Pacific campaigns as compared with those of trainees.

2. Tile apparent. incidence, given constant factors of toxigenicity and

susceptibility, is determined by the accuracy with which all cases of diphtheria. complicated and uncomplicated. are diagnosed. This has been especially true in the Tropics, where the clinical manifestations frequently have

been very mild (as described by Norris and his coauthors) and where, as a

consequence, skillful bacteriological technique is particular necessary. Many

cases of diphitheria have been dismissed as ordinary nasopharyngitis when

routine cultures are not taken. Brigadier Dorland of the British Army has

expressed this point in remarking about the apparent high incidence of comiplications. In 48 cases of faucial diphtheria at the 9th General Hospital on

Biak, Oppel found only 5 with typical membrane. In this hospital, in February 1945, C. diphtheriae were found in the throat of 12 of 24 cases of acute
DI)IHTHERIA 299

pharyngitis or tonsillitis; common colds were not included in this series. So

mild had the diphtheria been that it was actually the presence of typical

complications that first drew attention to the existence of the infection, which

previously had escaped bacteriological detection. This mildness is probably

the result of latent immunization. Obviously, the apparent incidence of

complications will be high if, because of inferior bacteriological technique,

few diagnoses of diphtheria are made.

In alny particular series, it is difficult, to state whether this factor or

toxigenicity and susceptibility have determined the stated incidence of complications, but all of these possibilities should be kept in mind.

Diphtheritic neuritis.-Di phtheri tic neuritis was reported from many

parts of the world, especially from tropical regions, during World War I1.

Such factors as have been mentioned in the preceding section probably account for the following variations in the stated incidence of the postcutaneous form: South Pacific Area, 3 of 85 patients (4 percent); Southwest Pacific Area, 6 of 102 patients (6 percent) ; India-Burma theater, 61 of 141 patients (43 percent) at the 20th General Hospital and 19 of 40 patients (48

percent) at the 69th General Hospital.

Since the differential diagnosis and detailed clinical description are presented in another volume in the history of the Medical Department in World

War 11,43 no more than a few general remarks will be made here. Caution

must be exercised in accepting neuritis as a complication of cutaneous diphtheria. The minimal evidence that neuritis is of cutaneous rather than nasopharyngeal origin is the demonstration of C. diphtheriae in the skin and its

absence in the nose and throat. Gathering this evidence has been neglected

in many series of cases, including the earliest ones of Walshe."

Cultures of all known foci of diphtheritic infections are especially important in view of the mildness of the nose or throat symptoms in some cases,

especially of anterior nasal diphtheria, where crusting and nasal discharge

may be minimal. It must be remembered, however, that even if the microorganisms are found only in the skin they may at one time have been present in the nasopharynx where they may no longer be demonstrable. This is

emphasized by the fact that in some series it has been specifically stated that

the patients spontaneously mentioned neither the sore throats nor the skin

lesions in giving an account of the symptoms antecedent to the first neurological illness.45 Thus, in some series of cases it is not possible to state to

which variety of diphtheria the neurological complications are related.

In contrast to the nature of the complication following pharyngeal

diphtheria, the cranial nerves, particularly the ninth, were rarely involved

in cases proved to be purely cutaneous. It was generally true also in Samp43 3Medical Department, United States Army. Internal Medicine in World War ii. Volume IIl.

Infectious Diseases and General Medicine. [In preparation.]

44 Walshe. F. M. R. : Post-Diphtheritic Paralysis. Note on a Form Following Cutaneous Diphtheria. Lancet 2: 232-233. 24 Aug. 1918.

45 Perkins, R. F., and Laufer. M. W. : Clinical Study of Postdiphtheritie Polyneuritls. 3. Nerv.

& Ment. Dis. 104: 59-65. July 1946.
300 INFECTIM'S DISEASES

son's series of 20 cases, and a sintilar impression was held by Quilliulnn,4

although no detailed evidence was presented. This may be less true of paralysis of accommodation, which is transient, and in which especially skillful

observation is necessary, than of pharyngeal paralysis. There is no doubt

that diphtheritic neuritis can occur in individuals with positive Schick reactions. Apparently, in sonme instances, the toxin is absorbed upon the nervous

tissues sufficiently to result in neuritis, while not. enough antitoxin is stimulated to reverse the Schick reaction. Generally speaking, a single clinical

attack of nasopharyngeal diphtheria fails to reverse the Schick reaction in

approximately 60 percent of cases. Low antibody levels do not preclude

previous, even relatively recent, diphtheritic infections, as Bronson 47 would

imply. This is pointed out by the observations of tialninon and Schoenbach.

In Bronson's series, it is mentioned that S0 percent of proved cutaneous

diphtheria, even of long duration, had positive Schick reactions. Also,

Bronson nientioned a patient with nitsopharyngeal diphtlheria who was

Schick positive :1 months after the infection an(d who had had antitoxin for

treatment in the meantime. Three in Sampson's series had positive Schick

reactions at the time the neuritis was diagnosed, but in these cases C. diphtheriae. was not demonstrated. In the 20th General HIospital group, all

patients with definite complications had negative Schick tests.

In most cases of undoubted diphtheritic neuritis, there is an elevation

of spinal fluid protein, sometimes with changes in the colloidal gold curve,

but almost always without pleocytosis. 4 1 In D)elp, Sutherland, and Hashinger's 4 cases, the spinal fluid protein levels varied between 157 and 230 mg.

percent. The average in Perkins and Laufer's I' Series of 21 cases was 114

mg. percent, but some were as high as 200 nig. percent. In Sampson's group

of 20 instances, most of which were postcutaneous, approximately one-third

were below 40 lug. percent, the others were higher, and the maximuin was

134 Ing. percent. In the India-Burma series, the proteins were described as

elevated in nearly every case and in general "proljrt ional to the severity of

the neurological disease." 51 This so-called albuminocytological dissociation

has caused a great. deal of confusion, and much neuritis of diphtheritic origin

has been classified under the Guillain-Barre syndrome, rather than under

the etiological diagnosis. Often, this has been in flagrant, disregard of the

principle that eponyms should be applied only to the syndrome as originally

described. A part of the confusion has arisen from lack of knowledge of

401 Medical Bulletin No. 2. Oftfice of the Theater Chief Surgeon, Heahdquarters. Theater Service

Forces, European Theater, January 1946, pp. 19-20.

47 Bronson, L. 11. : On the Etiology of Neurological Disease Following Infections of the Throat

and Skin and the Incidence of Diphtheritic Infections. Arch. Neurol. & PIychlat. 56: 558-566,

November 1946.

4s (1) See footnote 8. p. 279. (2) Rankin, J. n. : Diphtheritic Polyneuropathy. WTO M. Bull.

32: 32-35. July-August 1945.

49 Delp, M. II., Sutherland. G. F., and Ilashinger. E. M. : Post-Diphtheritic Polyneuritin: A Report of Five Cases With Albumlnocytologlc Plonowlation Simulating Gulllain-Barrt's Syndrome.

Ann. Int. Med. 24: 618-628, April 1946.

5o See footnote 45, p. 299.

51 See footnote 12 (4) and (6), p. 281.
DIPNITHIERIA 301

cutaneous diphtheria and its scars. Also, there has been ignorance of the

fact that a positive Schick reaction is not incompatible with diphtheritic

neuritis. The greatest cause of the difficulty, however, has been inadequate

bacteriological diagnosis of cutaneous and mild nasopharyngeal diphtheria.

These remarks must not be construed to imply that there were no other

causes of neuritis among U.S. soldiers: some had all of the features of the

syndrome as originally described by Guillain, Barre, and Strohl.52 It is

desired to emphasize here, however, that the vast majority of cases of neuritis seen in the tropics were diphtheritic in origin.

In the South Pacific series, it was considered desirable to subdivide the

cases of neuritis, as follows:

Group A.-Neuritis complicating proved cutaneous diphtheria without

evidence of C. diphtheriae elsewhere.

Group B.-Neurh.is associated with ulcers of the skin unhealed at the

time of admission but not demonstrated to contain C. diphtheriae.

Group C.-Neuritis in individuals with scars of tropical ulcers.

Group D.-Neuritis in individuals with scars of tropical ulcers and history of sore throat.

Group E.-Neuritis in individuals proved to have diphtheritic pharyngitis.

Group F.-Other cases of neuritis clinically indistinguishable from

diphtheritic neuritis.

After the diphtheritic nature of certain tropical ulcers became apparent, there was no instance of neuritis of the type discussed that could not be

related either to the ulcers, sore throat, or to proved diphtheritic pharyngitis

or dermatitis.

Notable in cutaneous diphtheria is the long incubation period of neuritis. In the three cases in group A of the South Pacific series, the symptoms began between 3 and 7 months after the lesion was first noted by the

patient. In two of the patients, the lesion occurred 2 and 4 months, respectively, from the time that the toxigenic C. diphtheriae was first cultured

from the lesion. In pharyngeal diphtheria, neuritis most commonly begins

within 6 weeks after onset of sore throat. In a series of 21 cases of neuritis

observed at a neurological center in the United States, the average time of

appearance of the neurological symptoms after onset of the nasopharyngeal

disease was 26 days, whereas it was 21/2 months after the onset of the cutaneous lesion.5 There is some variation in this, since in another group at the

Baxter General Hospital 54 the incubation period of the cutaneous cases

varied between 30 and 77 days, and of the pharyngeal cases between 30 and

72 days. The interval between the onset of the ulcers and the onset of the

52 Guillaln, G.. Barr#, J. A., and Strohl, A.: Sur un syndrome de radiculo-ndvrlte avec hyperalbuminose du liquide cephalo-rachidlen sans rsactlon cellulaire. Remarques our les caractcres clintques et grapblques des r~flexes tendineux. Bull. et mrm. Soc. mdd. d. h6p. de Paris 40: 1462-1470,

13 Oct. 1916.

m3 See footnote 45. p. 299.

54 See footnote 19, p. 283.
302 INFECTIOUS D)ISEASES

neuritis in the lndia-JBurnia, series was 68 days in the 20th General Hlospital

group and 7:3 days inl the referred p~atients. It was of the samne order of

magnitude atit the 69th General hlosp~ital inl the samne theater.55 InI a rep~orted

Britishi experience inl North Ai a a u~ initerval of 6 to 10 weeks elapsed

in huost cases after the skin lesions were niote(1 and before the neurological

symptoms aippea redl.

'Fhe durat ion of the iieurohgiceal syinltoliis is considerable. InI Samupson's

series, it varied bet ween 50 and 155 dayvs. lit thie India-Burmla group, thle

averag'e case lastedl 100 days.

Among the interesting clinical manifestations is thle, fact thiat, contrary

to other varieties of nerintis, persistent, muscle weakniess was rare. One

inst ance. however, is reported by Sampson inl which there waIs residlual

pnaralysis of tilie serrat ms anterior and deltoid muscles. The group at Baxter

General H osp~ital observed a, partial electrical reaction of degenerat ion inl

all of thiesevere case-s. Patiinwats a most unutsuial sviln)tolin.

Carditis in cutaneous diphtheria.-Myocardlit is has come to be the

muost important cause of (death in diphtheria. D)uring World W~ar 11, tissues

froin 221 cases of diphitheria were sent to the Army Institute of Pathology

(now the Armed Forces Institute of 1Pathology), Washington, D.C., for

St ud . ThIere was evidence of inyocarditis inl 143 or 65 1)ercellt of these

cases. By 1945, postdiplitheritic inyocarditis had become anl important cause

of deathI aniong troop~s inl the -army of occupation in Germany. At the

7th Medhical Laboratory,"8 Griifelting, Germany, it was the cause of death

inl 12 of tite 28.5 post mortem examinations reviewed, and at the 4th Medical

Laboratory,3 9 Paris. France, in 15 of 1.021 autopsies. In all b~ut, 1 of these

27 fatal cases of myvocarditis, antitoxin had been admninisteredl 5 or more

dlays after thle onlset of dliphtheria, if at. all. ('iltanleous (ilitlhitIria also was,

complicated by inyocarditis, as seen inl eight of the deaths inl thle Army Institute of Pathology series with such a pathogenesis.

Inl thle Indlia-Burnia group of 14160~ cases of cutaneous diphtheria,

indlubitable evidence of carditis existed inl four instances, one of which came

to autopsy, andI( of probable mnyocarditis inl three, a total incidence of .5 percent. Inl seven others, thiere were suggvestive findings inl the electrocardiografphic tracings, but. the dliagnosis cotild not be definitely established. All

individuals with (defin ite inyocardit is had extensive skin lesions. A program

of case finding was instituted which included a careful physical exanimna-

:aSee footnote 14 (1), p. 281.

A' Rep footnote 7 (2). p). 279.

57 Gore. 1. : 'Myocardial Changes In Fatal D~iphthieria : Summary of Observations in 221 Cases.

Amn. J.M. Sc. 215 : 257-266. 'March 1948.

58 Medical Bulletin No. 2. Office of the Theater Chief Surgeon, Hleadquarters, Theater Service

Forces. European Theater. January 1940, pp. 14-18.

59 Mepdical Bulletin No. 1. Office of the Thenter Chief 'surgeon. Ileadquartem, Theater Service

Forces. European Theater. D~ecemiber 1945. pp. 19-23.

60 (1) Kay. C. F.:, Myocardiai Comnplications of Cutaneous Diphtheria. [Official record.] (2)

Kay. C. F.. and Livingood. C. S.: M1yocardlial Com~plications of Cutaneous Diphtheria. Bull. U.S.

Army X. Dept. 4 : 462 -464. October 1945.
DIPHTHERIA 303

tion, as well as electrocardiographic tracings, as soon as possible after the

diagnosis of cutaneous diphtheria was made, and at intervals of 15 to 30 days

thereafter until well after the lesions had become inactive. In the same

group) of 141 individuals, the incidence of neurological complications was

43.5 percent. All four of those with definite myocarditis had neuritis. Neuritis usually preceded inyocarditis except in the one fatal case. The earliest

appearance of the electrocardiographic changes was on the 20th day of the

existence of the cutaneous lesion; in the fatal case, the severe symptoms

appeared on the 38th day, followed by death 3 days later; and in another

case, mnvocarditis appeared on the 60th day. The duration of electrocardiograplhic changes was from 60 to 90 days among those in whom the diagnosis

was certain and approximately 30 days in those in whom the diagnosis was

considered probable. The incubation period was shorter in the postpharyngeal cases.6'

The clinical findings were usually minor. Four patients in the IndiaBurma group were asymptomatic, two complained of dyspnea and faintness

on slight exertion, and the one who died first suffered abdominal pain with

nausea and dyspnea on exertion. Eighteen hours before death, discomfort

extended upward into the chest, then there was vomiting, collapse, fall in

blood pressure, gallop rhythm, and leukocytosis. The electrocardiographic

tracings usually did not show a P-R interval in excess of 0.20 second, nor

were abnormalities in the QRS segment striking. The most consistent abnormalities were depression or frank inve' io, of T-waves in the C-R3 lead.

These occurred in all but the fatal case of the India-Burma group. This

was also the experience of Ball'who enihasized depression of the S-T interval. Conduction defects apparent in the two cases of myocarditis that

followed nasopharyngeal diphitheria were not observed among the postcutaneous cases in the India-Burma group, but they were described in other

instances that apparently followed diphtheria of the skin.-2

Several writers have stressed the importance of serial electrocardiographic tracings to diagnosis.6 3 Careful observations of pulse and blood

p)ressure must, however, not. be forgotten.

Delp and Dimond, who were successful in treating two severe cases of

myocarditis. emphasized the importance of putting the patients at absolute

rest, elevating the foot of the bed, applying external heat, and slowly administering glucose solution by vein.

61 (1) Ball, D.: Diphtherit!c M1yocarditis; With Report of 2 cases. Am. Heart J. 29: 704-

707, June 1.945. (2) Craig. C. McK., and Manch, M. D.: A Study of the Aetiology of the "Desert,"

Septic, or Veldt Sore Amongst European Troops; And Its Association With Faucial Diphtheria.

Lancet 2: 478-479, 13 Sept. 1919. (3) Delp, M. H., and Dimond, E. G. : Diphtheria and the Heart.

J. Kansas M. Soc. 47: 254-259, June 1946. (4) See footnote 00 (1), p. 302.

62 (1) Greene, R. C. : Combined Sulfonamide and Diphtheritic Myocarditis in Cutaneous Diphtheria.

Am. Heart J. 32: 250-256, August 1946. (2) Solomon, S., and Irwin, C. W.: Cutaneous Diphtheria

With T'oxic Myocarditis; Report of Fatal Case With Necropsy Findings. Ann. Int. Med. 26: 116-120,

January 1947.

., See footnotes 61 (3), above; and 60 (1), p. 302.
304 INFECTIOUS 1)ISEASES

TREATMENT OF CUTANEOUS DIPHTHERIA

Case finding and methods of study.-After the high incidence of

cutaneous diphtheria in tropically ac'quired cutaneous :nfections was recognized, and particularly after the dangers of contact cases were realized, relatively efficient methods of case finding were instituted. The.-. c'onsisted in

temporarily isolating all patients with ulcerative dermatitis and making

cultures designled to detect C. diphtherhie. In some institutions, new patients

were held on a special admission ward. Routine cultures were made from

material from the cutaneous lesions and from the nose and throat. If the

culture was positive for 0. diphtherie. the patient was treated specifically

in isolation until virulent organisms were no longer recovered. The other

patients were released for treatment in a general dermatological ward. Such

a method was found valuable in the South Pacific study in handling the

heavily infected 27th Division in the New Hebrides rest area. After a series

of talks designed to acquaint the battalion surgeons with diphtheria of the

skin, a centrally located clinic was established to which all patients with

tropical ulcers were referred for culture. Those found positive were hospitalized. In this way, many patients were put under treatment, and the

dissemination of the organisms was checked. This procedure was especially

effective in curbing contact cases. Oppel and his coworkers reported that a

similar method was adopted in the Southwest Pacific Area. Individuals

who were found to have cutaneous lesions infected with C. dlphth-eriae and

were Schick positive were treated with antitoxin. The procedure at Moore

General Hospital and at Harmion General Hospital was similar. The

desirability of making nose and throat cultures in such cases was stressed in

these institutions, as was also the use of Schick-negative attendants in caring

for them.

Antitoxin.-During the Second World War, serum therapy was not productive of remarkable results in the local lesions so far as could be determined by observers of wide experience. Certainly, serum was not lethal

to the organisms, which may persist for many days after treatment. At

Moore General Hospital, it was necessary to keep patients isolated for an

average of 61 days, whether or not antitoxin had been administered. Antitoxin, however, may act as a prophylactic in preventing the serious consequences of autoinfection of the nose and throat. Also, experience in the

India-Burma theater indicated that antitoxin, even when given late in the

course of a cutaneous infection, seemed to be valuable in preventing complications (table 44). On the other band, the healing time in the India-Burma

group was not reduced; in 69 individuals given antitoxin, the average was

48 days in contrast with 41 days among 28 individuals who did not receive

antitoxin. It was also the impression in the India-Burma theater that

better scars resulted in those treated with antitoxin, provided it was administered within 30, or better, within 12 days of onset. It is significant

to note that of the 14 patients in the India-Burma group who were reclas-
DIPUTHERIA 305

sified or transferred to the Zone of Interior, none had had diphtheria antitoxin within 32 days after onset of the lesions. These statements are to be

regarded as suggestive, rather than final, statistically proved conclusions.

According to Livingood,64 the most important factors in preventing complications, loss of man-days, and loss of life from cutaneous diphtheria are

early diagnosis of the disease, prompt hospitalization, and administration of

diphtheria antitoxin as soon as possible.

TABLE 44.-Study of influence of antitoxin on incidence of complications in 103 patients with

diphtheria, 20th General Hospital, India-Burma theater

Antitoxin given Antitoxin given No antitoxin

Complication within 32 days 32 days after given after onset onset (31 patients) (36 patients) (36 patients)

Neuritis ------------------------------------- 6 10 17

Neuritis and probable myocarditis ------------- 1-----------------1

Neuritis and myocarditis --------------------- ------------------------ 2

Myocarditis, probable ----------------------------- 1 ---

Myocarditis, acute, severe -------------------- ------------ ------------- I

Percent patients with complications ------------ 19. 4 30. 6 64. 5

NoTE.-Most of the men who received no antitoxin, or who received it late in the course of the disease, had the more

severe lesions. Thererore, the results recorded in the table must be viewed with caution.

Local treatment.-The most important principles in healing the ulcers

seen in the South and Southwest Pacific and in Burma seem to have been

bed rest and the application of moist dressings. Outpatient treatment results

in the lesions remaining unhealed for many weeks and continuing as a

prolific source of diphtheria bacilli. Although C. diphtheriae is sensitive in

vitro to sulfonamides, in ulcers it seemed to be almost unaffected by these

drugs. In many instances in the South Pacific, the organisms were cultured

directly from lesions packed with crystals or covered with sulfonamide ointment. Application of sulfonamides, however, gave the lesions a cleaner

appearance.

Penicillin, locally applied in concentration of 250 units per cubic centimeter in physiological saline, has certain very definite indications that became evident during the course of a series of controlled observations in the

South Pacific Area on Schick-negative individuals whose lesions contained

toxigenic bacilli. The actual healing time of the ulcers was not significantly

reduced. Results of treatment of lesions containing toxigenic C. diphtheriae

in Schick-negative individuals are shown, as follows:

Mean

Number healing

Of time

Type of treatment patientm (daye)

Local, exclusive of penicillin -------------------------- 27 18.6

Penicillin soaks ------------------------------------- 43 16.5

54See footnote 12 (4). p. 281.
300 IxNFECTIOnUS DISEASES

III the l1idia-llLurina experience., penlicillinl seeined to give more lititial iml~oveinelilft aind affoirdled move relief fromt pnainm, bift a fter 2 weeks its effect

wats not sliperior. to t hose of othier measures. Nevertheless, i-i thle South

l'ac-i ic, iii eachi of six inist aiwes where al uilcer treated lca-,lly wit Itl penlicilliii was coinpared bacteriologically withI a, ,aline-treated control inl lie same

hiidiviluial, It was found thtat the toxigremei bacilli imivariabi.; disappeared

fromi tdie former wvit hu 4S hoturs aft-tr lie applicatioii of jpeincihhin, whereas,

inl the hit icr, tie%, persisted until the lesion w-as almiost htealedl. TIike observat ions at I larinoni (Xviteral H ospit al were similiar, pat iogeiic orgralujsnis,

beint, elin itti ted III cases treated pitvritterally withi penicillin inl an average

of 4 lavs. in t]lose treated with salinie alonev, only 2.5 percelit wvere cleared

oft ile organiiismls ill all average period of S dayis. Penlicillinl iredhitle ]lot

oilv tilie hiazardl of long colitact wit Ii C. db/)/lflrioac to the patient hiniself

hult to thle voimlnuit vIIIN at large.

Th'lere seemls to he Sonme varnat ion inl resist ance of dipjlitiierizi 1 acill i to

pllmicilhill. as ecir~liasizedl by 'McI anmiels.0 5 Hi s results itidlicat ing- peniciillini

resistancve of a1 miajority of'strainls, however, are not inl harmiony ?_with those

of othier observers, nlor withil thle reiteral clinical exp~erience as samnmmarized inl

thle precediniz, sectionl. 'McIDa-iiels (lid not state the mnuber of bacilli

employed inl his, test, anl important factor inl (eterininiing resistanice to inl11 ibit orY agents.

Surgical measures.-The experienice of flie India- Buimarn gr~oup ind(1icaited

that operattioul Should be couisideredl if thle ulcer fails to heal inl 6O to 70 (lays.

Il ip li~ttheritic ulceers a1 Contracthig sear was not formed: also, thle thini new

skiii broke down once inl every th ree patien-ts. Tule mtost successful methiods

in a small grotip treated by Royster 11 seemedl to be excisioni of the ulcer

an1d a smiall margin of normal skin, followed by applicationl of a Sp)litthickitess skinl graft, rat her than of the slidling, flap, or extensive unideriniining and simple closuire. The skitn adljacenit to tihe graft becamne more lpliab~le.

Skinl grafts simply applied to large, ulcers, even after they had begunll to

(rranulat e cleanily, failed to take.

Factors in healing time.-If anl atoxic organismn was ptresenit, the healing

time seemed to be si (nilitcvalit lv reduced. The following tabulationi shows, the

relationl of toxigrenicity of C. d;1h flu rhu to Itealiiig t ime inl hospital:

Jt Ca i

lien Ii pigi

Paticn ti tint

C. diplitlariae (nturiher) (days),

Organisms toxigenic-------------------------------- 107 19.2

Organisms atoxic ---------------------------------- 21 11.4

aa .mcDanIelq, 1I. E. : Penileiiin Resitdance of Diphtheria Bacelili. Mit. Surgeon 96: 95-96,

JIanuary 1945.

66 ioyster. H. P. : Surgical Mlanagonment of Cutaneous Postdiplitherltic Ulcers. Plast. & flecon-

,triic. Surg. .3: 294-302, 'May 1948.
DIPHTHERIA 307

Conclusions.-These observations suggest that the most efficient way of

handling the patients is to put them at rest in bed and to apply penicillin

locally in continuous soaks of 250 units per cubic centimeter. Most clinicians

recommend the administration of antitoxin, at least if the individual is

Schick positive. In retrospect, it would probably have been best to send

only Schick-negative individuals into combat in the Tropics.

COST OF CUTANEOUS DIPHTHERIA TO THE ARMY

A substantial amount of disability was caused by cutaneous diphtheria

during World War II. The lesions were present in all tropical areas, but

the exact incidence is difficult to estimate. In the 35th Infantry, 25th Division, 6 weeks after evacuation from the New Georgia campaign, 19.4 percent

of 200 men who were carefully questioned and examined had either active

lesions or scars suggestive of previous infection with C. diphtheriae. Two

of these were actually proved to have the organisms in their lesions. At

the 54th General Hospital on Biak, 29 percent of admissions to the medical

service were because of skin disease. It can be assumed that a considerable

proportion of this was of diphtheritic etiology. In the South Pacific Base

Command between 1 January and 30 June 1944, skin disease was the primary

diagnosis of 9 percent of all medical evacuations to the United States. Many

of these skin cases that had been studied at the 39th General Hospital were

proved to be diphtheritic.

Much of the disability was the result of the location of the lesions on

the feet and other places likely to be injured, an obvious consequence of the

fact that trauma was a factor in their causation.

In a followup study of 140 patients in the India-Burma series, a total

of 18,783 man-days were lost, an average of 41⁄2 months per man, not

including the days lost by 30 patients after their return to the Zone of

Interior.6 7 The total duration of skin lesions from appearance to healing

averaged 91 days in another series in the India-Burma theater.68

The chief causes of prolonged hospitalization were breakdown of the

thin scars when activity was resumed, or the neuritic or cardiac complications of the disease. In 53 of the 140 case., in the India-Burma group, the

scars broke down upon resumption of activity and 13 of these showed no

tendency to heal. This was the final result reported in August 1945. At

the end of January 1945, in that group,6 9 the causes of hospitalization in

excess of 70 days in a. total of 96 patients (69 percent of the total) were

summarized. as follows:

G7 See footnote 13, p. 281.

68 See footnote 14, p. 281.

C9 See footnote 12 (4), p. 281.
:308 INFECTIOUS DISEASES8

N\ u in her

N eu ritis - -------------------- - 44)

Indolent lesions -. . . . . . . . . . . . . 24

Recurrent lesions --- 23

Cardliac com plications -. . . .. . .. . . . .. .... . .. .. . 4

Neuritis and definite (ardiac voml( licatitns in the 5Jime patient-_ 3

Inipetiginous eczema--- ... . ... .2 -

Total -----------------------------------

The total number of man-days lost in the 106 individuals on whom data

are available in the South Pacific series was 2,077, an average of 19.6 days

per man. The difference probably lies in the selection of cases. Probably

only the more typical and severe cases were studied in Burma. This perhaps also accounts for the high incidence of neuritis in the India-Burma

theater as compared with the South Pacific Ar-ea.

The followup study of the experience in the India-Burma theater

showed that 60 percent of the men had returned to full duty; 18 percent had

been reassigned, 12 of 25 because of cutaneous diphtheria alone, 22 percent

had been returned to the Zone of Interior, 13 of 30 because of cutaneous

diphtheria alone. It seemed, however, that prolonged inactivity occasioned

by the cutaneous diphtheria had predisposed to the development of psychoneurosis which was listed as the primary diagnosis in some cases. When

this is added to the followup study, the results are that 20 of 25 were reassigned and 22 of the 30 were returned to the Zone of Interior for causes

ascribable to cutaneous diphtheria.

ROLE OF CUTANEOUS LESIONS IN THE SPREAD OF DIPHTHERIA

Evidence that Schick-positive individuals may infect the nasopharynx

from their own cutaneous lesions has already been presented. Much evidence

has accrued that ulcers can be a prolific source of diphtheria in others.

Evidence from contacts in hospitals.-In the late spring and summer

of 1943 at the 39th General Hospital, in the South Pacific group, there were

six instances of apparent contact infections among imiembers of the staff or

patients before tropical ulcers were recognized to be diphtheritic. A nurse

attending an officer with widespread desquamative and ulcerative lesions

had paronychia and an abscess in her arm from which C. dipktheriae and

beta hemolytic streptococci were isolated. Another nurse attending the same

patient contracted a sore throat which was not of membranous type. This

nurse was known to have been Schick negative previously. Another officer,

who had been admitted for jaundice 2 weeks before and who did not, have

a sore throat at the time of admission, was placed in the cubicle next to the

first case and developed an extensive membranous nasopharyngeal diphtheria.

A wardman on another ward, where many patients with tropical ulcers were

kept, developed a paronychial granulomatous and ulcerative lesion from

which the toxigenic corynebacteria were cultured (fig. 44), and shortly
DIPHTHERIA 309

thereafter another attendant on the same ward developed diphtheritic

pharyngitis. Pharyngeal diphtheria developed in a wardman on another

dermatology ward where there were many ulcer cases. All of these members of the hospital staff had been on wards caring for patients with

cutaneous lesions. After isolation procedure was instituted for diphtheritic

tropical ulcers, no other contact cases appeared except one in a nurse, attending an isolated patient with diphtheritic pharyngitis, who acquired a severe

membranous nasal diphtheria. From all seven of these contact cases, virulent

corynebacteria were isolated.

This experience in the South Pacific Area was not unique. In the

India-Burma group,70 11 patients acquired cutaneous diphtheria after a

period of hospitalization for another disease or injury. Faucial diphtheria

developed in another patient in the 20th General Hospital 4 weeks after

admission to the dermatology ward. Two of the patients with cutaneous

diphtheria acquired pharyngitis and tonsillitis. In one patient, virulent

organisms were isolated 3 weeks after admission, and in the other nontoxigenic bacilli were found 6 weeks after admission. Similarly, in a British

experience in North Africa,7 ' one nursing sister and one orderly in the

dermatology ward contracted faucial diphtheria, and the medical officer in

charge developed cutaneous diphtheria.

At the 13th General Hospital,72 Finschhafen, two cases of diphtheria

were recognized in the dermatology ward. Within the next 8 days, 7 clinical

cases and 33 carriers were found by culture and were isolated, and in the

following 7 days, 3 cases and 2 carriers were discovered. Seven patients

in the dermatology section were found to be harboring the organism in

skin lesions. The experiences at Ite, New Guinea, and at Hollandia were

similar. In summary, then, beginning in the latter part of September 1944,

cases of pharyngeal diphtheria appeared in wards devoted exclusively to

dermatological cases and similar outbreaks centered around these wards.

At Harmon General Hospital,73 a case of faucial diphtheria developed

on a dermatology ward. The procedure described in the section on treatment

and case findings was then instituted (p. 304). The results of culturing

42 patients and 11 attendants on the ward at the time the first case was

discovered were that 10 were found to have C. diphtheriae. 2 of which were

proved to be toxigenic. One of the patients with toxigenic organisms was

a nurse.

At Letterman General Hospital, 74 eight cases of diphtheria originated

in the dermatology section between 21 and 29 September 1944. The first

four occurred in wardmen; the next two were in personnel of the physiotherapy section. All were of the pharyngeal type and were moderately

70 See footnote 12 (4), p. 281.

71 See footnote 7 (2), p. 279.

72 Essential Technical Medical Data, U.S. Army Forces in the Far East, for October 1944.

73 See footnote 18 (2), p. 282.

74 See footnote 20. p. 28:3.
310 INFECTIOUS DISEASES

severe except the first, which was fulminating, with hemorrhagic membrane.

All organisms isolated were of the toxigenic mitix variety. Cultures of dust

from the dernatology ward were found to contain ('. dip/ther;ae. which was

virulent for a guinea pig. The noses and throats of the patients and personnel of the dermatology and physiotherapy sections and in the castroom

were also cultured and 14 were found to harbor toxigenic C. diphtheriae.

Six of the fourteen were Schick positive. These observations emphasize the

menace of unrecognized cutaneous diiphtheria.

GENERAL CONSIDERATIONS OF DIPHTHERIA IN THE TROPICS

Diphtheria among the natives.-In the course of investigating the

cutaneous diphtheria among the soldiers in the New Hebrides and later on

Saipan, it was noted that the natives, particularly young children, had

cutaneous lesions resembling those of the soldiers. Many of these were

found to contain C. diphtheriae. Two of four Melanesian natives (figs. 43E

and 45), one with apparently superinfected yaws, yielded atoxic C. diphtkeriae. Six of fifty-three Tonkinese children had multiple punched-out

lesions generally more superficial but like those observed in the soldiers

(fig. 44). Four of these yielded organisms that had the morphological and

biochemical characteristics of C. diphtheriae type mitis but were not toxigenic. Lesions of identical appearance were found in large numbers among

Chamorro children on Saipan. Fifteen strains of C. diphtheriae type mitis

derived from these were tested for toxigenicity and one was found to be

toxigenic. It is of some interest to note, and not easy to explain, that some

of these ulcers occurred in older children who were Schick negative. The

lesions were most numerous where trauma was likely to occur, as about the

knees, but they also were found elsewhere. Scars of such lesions were

alundant in children more than 7 months of age, and they were almost

universal above the age of 3 years.

Many studies have been made of Schick reactions of the natives in the

Tropics. All have shown a high level of immunity. This has been found

to be true among Filipinos, Malayans. Javanese, Hondurans, Brazilians,

and the Bantu of Africa. 75 During World War II, in the British Army,

the incidence of Schick-positive individuals among 900 sepoys was 1.1 percent, whereas among the British troops it was 27 percent.76 In the South

Pacific Area, the Schick reactions of natives more than 5 years of age were

almost invariably negative in the Solomons (Melanesians), New Hebrides

(Melanesians and Tonkinese indentured laborers and their families), and

Saipan (Chamorros). Only between the ages of 7 months and 3 years was

there a high incidence of Schick positives, in excess of 50 percent, among

75 (1) Grasset, E. : Studies on Nature of Antidiphtheritic Immunity Among South African

Bantu by Means of Schick Test and Antitoxin Titrations. South African M.J. 7: 779-785, 8 Dec.

1933. (2) Murray, J. F.: Diphtheria Amongst the Bantu. J. Hyg. 43: 159-169, September 1943.

7.; See footnote 1, p. 276.
I III o IVA ii iaTe haAcit~ i 1114~~r I'iIIaIiiN w Zah u. 1Ii

V tel I es )III 11i' ('nfulr t Ia11 I. u chine., ulIvp alei ,vv i i ltt w. eel lea11, Iiiu alii Ila41l. s it've

we~.eks, I i I :I~ I elew It i1 111 1 f icer wit I Iltl Niti I f s~' I.VI.t -I I t I ell i L e it 1Ie' sit. wII il Ii- e 12
312 INFECTIOUS DISEASES

the natives of the various races investigated. The theory was advanced for

the first time, that the rapid reversal of Schick reaction was the result of

immunization by the cutaneous route. It appears that the antitoxin level

falls sufficiently to give a positive Schick reaction for only a short time,

after loss of the transplacentally acquired immunity. This probably accounts for the rarity of severe nasopharyngeal diphtheria among natives of

the Tropics.

Conditions among soldiers analogous to those of the natives.-It has

been suggested that the same conditions which favor the establishment of

the enormous reservoir of cutaneous diphtheria that has been demonstrated

among the natives prevail also aniong soldiers in combat. These conditions

are:

1. The warni. moist. condition of the skin, which comes to resemble the

pharynx.

2. The lack of facilities for washing.

3. The intimate crowding of the population.

4. The numerous opportunities for minor trauma produced mechanically

or by insects.

5. The abundance of flies.

All of these conditions are extremely favorable for the spread of cutaneous

diphtheria. Among the soldiers, where there are many individuals with

low antitoxin titers, in contrast with the natives, there was a high incidence

of nasopharyngeal as well as cutaneous infection. The barrier of cleanliness

accounts for the fact that colonizers living in the Tropics under peacetime

conditions are generally more susceptible than the natives, as indicated by

the results of Schick tests, and that the former sometimes have nasopharyngeal diphtheria in epidemic form. One such epidemic is recorded by Fox

and MacDonald (quoted by Forbes),77 in a school at Shillong, Assam. the

very region where tropical ulcers have been so common in natives as well as

in U.S. soldiers.

The tropical environment in association with the dirt and crowding is

the determining factor in the spread of the cutaneous varieties of diphtheria.

The original source of C. diphtheriae is difficult to determine. Carriers are

always present in our own population, and the native reservoir may at

times be important.

ASSOCIATION OF CUTANEOUS AND NASOPHARYNGEAL

DIPHTHERIA IN MILITARY UNITS IN THE TROPICS

As in the desert campaigns described so well by Bensted, 78 and Cameron

and Muir,79 nasopharyngeal diphtheria has been coexistent with, but usually

"77 Forbes, J. G. : The Prevention of Diphtheria. Special Report Series No. 115. London: His

Majesty's Stationery Office, 1927.

78 See footnote 41, p. 296.

79 See footnote 42, p. 297.
DIPHTHERIA 313

has been exceeded in incidence by, cutaneous diphtheria. This was true

again in British experience in the Mediterranean, in the South Pacific, and

in the Southwest Pacific, although at the 20th and 69th General Hospitals

in the India-Burma theater " relatively few nasopharyngeal cases were diagnosed. The course of the epidemic in the 27th Division while at the rest

area in the New Hebrides is shown in table 45. The peak occurred on 23

CauRT 14.-Number of cases of skin diseases and diphtheria and tonsillitis in the Afrika Korps, 1942

NUMIBER

2,000

1,8000

1,400

11400 SKIN OISEASES

1,200

1,000

Soo

DIPgTHE fRIA • % %%

400 AND!- N:

. TONSILLITIS Im• j %,. -.,

200 - %o

JANI FEB. MWAN APR. MAY1JMNt JULY AUG.SEPM. OCT. NOV. DEC.

September 1944. In this same group, 17 nasopharyngeal cases had previously been diagnosed on Saipan, shortly after the campaign on that island.

In a more general way, the incidence of skin disease and diphtheria and tonsillitis was closely parallel also in the Afrika Korps (chart 14).

It will be noted in table 45 that, as the patients with ulcers were removed from the division by use of the outpatient clinic described previously,

the incidence of nasopharyngeal diphtheria decreased rapidly. The course

of the outbreaks was almost identical in the 25th and 43d Divisions previously studied in New Zealand.

Skin-to-skin contact seems the most usual method of the spread of the

bacilli among the crowded combat troops in the Tropics. This is supported

by the fact that in general the nasopharyngeal carrier rate among U.S.

troops in the Tropics has been low. It was less than 1 percent among 800

men from two divisions tested in the South Pacific Area. In a series of 174

patients with ulcers, the incidence of asymptomatic carriers was 4 percent.

so See footnote 15, p. 281.
314 INFECTIOUS DISEASES

TAB.Lx 45.-Cases of diphtheria in the ;Tth Dirision in rest area in the New Hlebrides, 16 Sep- tember- Z8 (ktober 1944

Skin La" . hrot . Throat

Date o Throatt Throat Throat carrier Total

negative ; carrier cuWs i

1944

Septemblr 16.. 1 1 0 0 4 6

17 2 0 0 1 ! 4

10 5 0 1 7

. 0 0 0 2 3

20 0 0 01 0 !

21 3 0 1 0 4 8

22 3 o 0 1 4 

23 11 0 0 I 2 14

24 7 1 0 0 9

25 7 1) 1 0 0 8

26i 5 0 0) 5 5

27 ) 0 0 0i . 1

28 I 0 0 0 0 1

29- 2 ! 0 0 0 3

30- . 0 0 0 0 0 0

October I -. .... 0 0 0- 0 o0 0

2 - ---... . 2 o 0 21 ! 5

3- I 1.......... 2 0 1 5

4.-------------------21 0 fl)

5------------------ 2 0 0 1'o 3

- - - - - 1-- 1 0 0 0 

7. . ... - ) 0 00 0 1

8. . 0 () 0 0 0

97 . -..------- I o o! 0 3

. . .o0 0 0 0 0 0

----------- 3 0 0 0 2 3

12.------- 1 0 0 0 0

13 ..--0 0 1 3

14- .. 0 0 0 0 1I

15-......... 0 0 0 0 0 (

16 --- 1 0 0 0 I '2

17-.. . .. . .. I 0 0 0 1 2

18 . 1 0 o 0 0 '

1.. . 3 0 0 0 0 3

20. ........... .0 0 0 0 0 o

23-. 2 0 0 0 0 2

24 1 0 0 0 0 1

25 ... I 0 0 0 0

26 1~

27 .... 27-1 .... I 0 0 0' 0 0j 0! 1I

28- 3 0 0 0 0 3

Total ------------------- 77 6 6 3 120
DIPIITHERIA 315

The one group in which the carrier rate has been extremely high in the

absence of clinical diphtheria was among German prisoners of war 8l at the

camp in Merano. Here, it was 17 percent in apparently healthy individuals

ini a camp where there were many cases of neuritis. This carrier rate was

exceeded only in convalescents from clinical diphtheria at the same camp.

Evidence has been presented that diphtheria can be Spread not only from

skin to skin but also from skin to pharynx and front pharynx to skin. The

same or other individuals can be involved in this process.

Other factors were considered in Burma. Investigators cultured rice

paddies as possible sources of C. diphtheriae among soldiers in the Myitkyina

area hut found theni to be negative-.8 2 Flies, in places where cutaneous diphtheria was prevalent, were cultured in the Southwest Pacific Area.1 They r 

were found to harbor C. diphtheriae on several occasions, but all strains were

atoxic. The role of flies certainly deserves further study. since their known

persistence and the attraction which the ulcers seem to have for them possibly may make them important in spreading the organism in the Tropics.

DIPHTHERIA TRANSMITTED FROM MILITARY TO CIVILIAN

POPULATIONS

There is some evidence suggesting that tropically acqluiredl cutaneous

diphtheria in soldiers may ultimately be the source of infection to much

larger susceptible civilian populations in temperate climates where it takes

tile nasopharyngeal form. Tile evidence may be summarized, as follows:

1. Cutaneous diphtheria is frequently ignored by the soldier and often

escapes undiagnosed by his physician. Consequently, when the soldier returns from tropical combat to contact with civilians, his movements are

unrestricted. and there is excellent opportunity for the dissemination of

bacilli in the often rich secretions of the diphtheritic lesions of the skin.

A specific example is cited in a case investigated by the New York State

I)epartment of Health. The following is quoted from a letter from Dr.

Hollis S. Ingraham, Chief, Division of Communicable Diseases:

Ai Army captain had been hospitalized in New Britain I Bismnarck Archipelago] in

February 1944, for cutaneous ulcers of the legs, buttocks, and hand. He was returned

to this country and was again hospitalized at Fort Dix, [N.J.] in June 1945. lIe visited

at his home in Hornell, N.Y., from July 27 to August 10, 1945. At the time, there was

still a deep ulceration on his left hand anti arm. A son Iorn in the household on July

26 was circumcised on July 31. This child was noted to Ie ill on August 18 and on

Inspection, the circumcision wound was found to Ie unhealed and covered1 with a diphtheritic membrane. Vi rulernt diphtheria bacilli were recovered from the wound, and the

child responded to specific therapy.

An adult female, the captain's wife, developed sore throat on 24 August. Virulent

diphtheria organisms were found in her throat and she responded promptly to antitoxin.

81 See footnote 23, p. 283.

82 Letter, Maj. J. L. Arbogamt, MC. 9th Medical Service lDetachment (Laboratory), to Commanding Officer. 9th Medical Service Detachment (Laboratory). 16 Nov. 1944. subject: Diphtheria Survey.

, See footnote 1i;. p. 282.
316 INFECTJI•0' DISEASES

A 7-year-old boy. another -Aw. developed mild diphtheria on August 30 and rwsponded

promptly to treatment. Virulent diphtheria organimus were recovered from his throat.

The captain developed no •ore throat and there was no mention of any change in the

ulcers on the left hand and arm. It was reported that a culture taken from his hand

on August 23, 1945 at Fort Dix was negative. These lesions were cultured In Hornell

on September 6, and pure culture of diphtheria organisins were reetivered. On the whole,

it appears highly probable that the infection was introduced by the captain but, as you

will note from the dates, the case was not proved beyond doubt.

2. The return of infected soldiers has in some countries been associated

with a striking increase in diphtheria among the civilian population. This

occurred in Germany and certain occupied countries, and also in New Zealand.

Diphtheria had a high incidence in the summer months of 1941 and

1942 in the Afrika Korps. and in each year it waned during the fall and

winter months. This information is derived from captured German documents in the European Order-of-Battle Section. G-2, Headquarters, Army

Ground Forces. The epidemic began late in July 1941. In September,

there were 416 diagnosed cases, largely in the 218t Panzer Division, but

there were some also in the 15th Panzer D.ivhon.14 In the report of the

chief surgeon of the Panzer Amny in 1941, the following statement appears

(translated) :85 "There were four outstanding diseases, which in increasing measure had an uncommonly high incidence: Dysentery, jaundice (infectious icterus), diphtheria, and ulcers of the skin, especially of the lower

extremities." In the next year, the table of incidence taken from the corresponding report, is very similar (chart 14). Diphtheria of the skin among

German soldiers was reported in several papers in Der deutsche Militdiirarzt. 8 6

One such outbreak in the United States was carefully studied by Fleck,

Kellam, and Klippen.

The high carrier rate in the prisoner-of-war camp at Merano and the

associated diphtheria there have been discussed previously. The evacuation

of Germans from the North African campaign was progressing continuously

in 1941 by hospital ship to Naples, Italy, thence by train to Germany, where

Munich was the usual debarkation point. From April to December 1941,

8,400 were sent from Italy to Germany by train.

Diphtheria underwent a sudden and simultaneous increase among the

civilian populations in Germany, Norway, and the Netherlands in Septem84 Deutsches Afrika Korps. Tiitigkeitsbericht der Abt. IVb. 30 Sept. 1941. [Captured German

document.]

85 Armeearzt. Hauptquartier Panzerarmee Afrika. Erfahrungsbericht, 28 Feb. 1942. [Captured

German document.]

86 (1) Binhold. (NFI) : iber Wundiphtherie. Dent. Militfirarzt 8: 521-527. Septemher 1943.

(2) Funk. C. F.: Die chrinisch-ulcerosen flichenhaften 1'yodermleL.: Ecthyma simplex. Pyodermia

papillaria vegetans et exulcerans. sowle das Ulcus cruris ohne Ulcus :aricosum. Dent. 1iiiitiirarzt

9: 401-404, September 1944. (3) Quartiermetst-r (Rom) IVb, Zurzer Tiltigkeitsund Erfabrungsbericht fiir die Zeit von 6.2.1941 bis 31.12.1941 des Danitiltssoffz. bei QM. Reon (Heer). Sect. VI.

Abtransport Verwundeter und Kranker der Panzergruppe Afrika, 28 Jan. 1942. [Captured German

document.]
DIPHTHERIA 317

ber 1941 (chart 15), at the same time the diphtheria epidemic was at its

height among the German soldiers in North Africa and while troops were

being continually evacuated from that theater. In France, the increase

occurred largely in the northern, occupied parts of the country.8 7 It was not

until after a considerable interval of time that the disease became prevalent

in neutral countries, such as Sweden and Switzerland, to which travel from

Germany was relatively slight (chart 16).

RATE

1.000

1,100

NORWAY

Woo

900

CHART 15.-Diphthcria in Germany, Norway, and the Netherlands, 1989-44

600

[Rate expressed as number of cases per annum per 100,000 population] O00

Source: Charted from data In League of Nations, Health Section of the Secretariat, Weekly 600

Epidemiological Record.

500 -

400 E 1%,

30 GERMANY

200 /

100 NETHERLANDS

0 L; • •-'•"•

1939 1940 1941 '942 1943 1944

It may be objected that dietary conditions in these countries were poor.

However, a similar increase in incidence of diphtheria occurred in New Zealand where the diet was more than adequate. Here, it was associated, at

least in time, with the return of U.S. Marines and later U.S. Army troops

from campaigns in the Solomon Islands. Diphtheria among the Marines

has been described by Norris and others. The influx into the country began

after the middle of 1942. The 25th Division appeared en masse in New Zealand in 1943; the 43d Division arrived later. Diphtheria among these

soldiers is described in detail in this chapter. Thus, the stream of individuals infected with C. diphtheriae had been uninterrupted until the middle of

87 Stowman, K.: Diphtheria Rebounds. Epidemiol. Inform. Bull. 1: 15T-168, 28 Feb. 1945.
318 INFECTIOUS DISEASES

1944. Therefore, the morbidity from diphtheria in the New Zealand civilian

population as of 1940-41, with the rise which began in 1942 is as follows:

Number

1940 ---------------------------------------------------- 38

1941 ---------------------------------------------------- 383

1942 6-------------------------------------------

1943 ---------------------------------------------------- 830

CHART 16.-Diphtheria in France, Denmark, Sweden, and Switzerland, 1939-45

[Rate expressed as number of cases per annum per 100,000 population]

RATE RATE

300~ .300

FRANCE DEN MARK

200' A200

too ,A1

0 1J

300 S300

SWEDEN SWITZERLAND

20O0 200

loo '100

1939 1940 1941 1942 1943 1944 1945 1939 1940 1941 1942 1943 1944 1945

Source: Charted from data in League of Nations, Health Section of the Secretariat, Weekly

Epidemiological Record.

The previous peak in New Zealand was in 1917-18 and may have been

associated with the return of soldiers at that time from Gallipoli and the

Desert.

It is of interest that the great pandemics of previous centuries appear

to have come from the South.s8 According to Friederich L6ffler, quoted by

Nuttall,8 9 "The disease appears to have been perfectly well known in Egypt,

Syria, and Palestine even in ancient times. This is proved by repeated references to it in the Babylonian Talmud." Also, according to Rolleston,9° in

the first century A.D., "an unmistakable description of diphtheria is given

by Aretaeus of Cappadocia under the name of Syriac or Egyptian ulcers

owing to its having originated in Syria and Egypt whence it spread to all

European countries." The "ulcers" refer to the appearance of the throat

and not to the skin in this instance.

These correlations are not held up as final proof of the importance of

cutaneous diphtheria among the military as the ultimate source of the epidemic in Europe. However, as Rolleston says: "Subjects of clandestine

diphtheria, like clandestine prostitutes, are of considerable epidemiological

88 Russell, W. T. : The Epidemiology of Diphtheria During the Last 40 Years. Special Report

Series No. 247. London: His Majesty's Stationery Office, 1943.

S9Nuttall, G. H. F., and Graham-Smith, G. S.: The Bacteriology of Diphtheria. Oxford:

Cambridge University Press, 1908.

90 Rolleston, J. D.: Acute Infectious Diseases. London: William Heinemann. Ltd.. 1925.
DIPHTHERIA 319

importance as both, owing to their innocent appearance, may widely spread

disease before their true nature is recognized." Streptococci may be simiilarly introduced since they abound in cutaneous lesions in the Tropics.

Part III. A New Hemolytic Corynebacterium in Man

A hemolytic corynebacterium was frequently cultivated from nasopharyngeal and cutaneous infections in soldiers evacuated from tropical

islands of tile Pacific and from natives of tile New Hebrides and the Marianas. This organism which was given the tentative designation "Corynebacterium henwlyticum" is similar to a large group 91 of hemolytic corynebacteria, such as C. ovi'8 and C. pyogenes, known to be pathogenic for animals. This organism is important because:

1. It may readily be confused with 07. diphtheriae in direct smears of

exudates and on LUffler's slants, and with beta hemolytic streptococci on

blood-agar plates.

2. There is suggestive evidence of its pathogenicity for main. In smears

of exudates and I,6ffler's slants, the new organism closely resembles C. diphtheriae, although it tends to be more slender. It is pleomorphic and granular, but the granules are not metachromatic. On filtered sugar media enriched with human serum (serum or blood is necessary for abundant

growth), sucrose is fermented without the production of gas, as are also

dextrose, maltose, lactose, galactose, and dextrin, but not xylose or mannitose.

C. hemolyticum also differs from C. diphtheriae in coagulating milk. in

slowly liquefying gelatin, and in not reducing nitrates. When inoculated

intracutaneously into guinea pigs or rabbits, C. henwlyt/cum produces lesions

resembling those caused by C. dlphtheriae, but these are not prevented by

diphtheria antitoxin, in the standard virulence test of Fraser and Weld.

C. hemolyticum produces hemolytic and skin necrotizing toxins in broth that

will not pass the Seitz filter.

On 24-hour blood-agar plates (pH 7.4), the organism is more hemolytic

than C. dtphtheriae type mitis, and its colonies resemble those of the beta

hemolytic streptococcus. When the plates are allowed to incubate for 48

to 72 hours the colonies of C. hemolyticum continue to grow and become

discoid, contrary to those of the Streptococcus, and the zone of heinolysis

becomes enormous, usually after passing through a double phase. Other

colonial characteristics are a lenticular dark spot visible by transillumination

and etching of the surface of the blood-agar plates. Both of these phenomena are manifest in colonies more than 24 hours old and are not seen with

the beta hemolytic streptococcus (fig. 46-55).

91 Brooks, R. F.. and Hucker, G. .T.: A Study of Certain Members of the Genus Corynebacterium.

J. Bact. 48: 295-312, September 1944.
320 INFECTIOUS DISEASES

The pathogenicity of C. henolytictin for man is indicated by its capacity for producing lesions when inoculated into the skin. Its low invasiveness, however, is inferred by the absence of complications after intracutaneous injections in man and by the failure of development of significant symptoms when sprayed on the normal throat. It readily becomes parasitic il

FIGURE 46.-Exudate from diphtheritic

ulcer. Corynebacterium liphtheriae within the leukocytes. Irregular granular bacilli. Graam stain. ( x 500)

the nasopharynx, where it may persist for many weeks. In conjunction with

another infectious agent or a lowering of resistance of the host, however,

it is possible that C. henwlytwurm may become an "opportunist pathogen"

for man. This is supported by the evidence of clinical cases in which C.

hemolyticum was the dominant organism during the course of an acute

respiratory illness, was unassociated with a known pathogen, and disappeared with the subsidence of the disease.

FiouRri 47.-Exudate from ulcer in one of the lesions depicted In figure 37A. Note

double suppository forms of Corynebacterium diphtheriae sometimes observed In direct

smears of exudate. (X 1,100)
DIPHITHERI A 321

U.S. Army photograph

1 1(diII 48.( hi onie ulcer of ankle containing- Gewincbactcriull diph,-

thcruic. This contlitioti was iiontoxigenic in Mfelanesiaii native of Espi ritu Santo, New H ebrides Islands.

Part IV. Use of Penicillin in Treatment of Diphtheria

Interest, in penicillin ais a p~ossible therapeutic ag'ent ag'ainst diphitheria

was higli since it. was knownt front earlier observations of the British that

C. d;Pht/wrife was sensitive to penicillin in vitro. Some evidence of variationi in the susceptibility of various strains has beeni pointed1 out by McDaniels. In the European theater, investigation of the subject was stimulated

by Administrative Memorandum No. 151, Office of the Chief Surgeon, dated

27 -November 1944, outlining ai tentative program for the ob~servation of the

efficacy of penicillin in the treatment, of diphtheria.

All observers were agreed that following use of tile drug in the active

nasopharyngeal form of diphtheria there was often evidence of clinical

inhlrovem-ent, 92 but some ascribed thlis to the effect. oil tie frequently Concomnitailt streptococcal infection. It soon became obvious by the. review of

fatal ihieb and serious complications that penicillin, eveni when given early

andl abinidantly, did not prevent myocarditiS. 93 In the words of Colonel

Middlietoni, Chief Consultant in Medicine, European theater:94 "There is no

substitute for antitoxin administration on suspicion without undue reliance

92 Karelitz, S., Mloloshok, R. E., and Wassernman, L. R.: Penicillin in the Treatment of Diphtheria and the Diphtheria Ca~rrier state. E'rO Me.Bull. 32: 67-72, July-Augilst 1945.

93 (1) See footnote 59, 1). :12 (2) Bermnsn 11. B., ind] Spitz, S. Hi. :Penicillin In Clinical

D~iphtherlia. [Official record.]

94 See footnote 35. pi. 293.
Ile

i~iI:I'i.01 -

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II i I -n I

n "h I.I InrI, "llI'. 's I!11 ul 1.r Il 1111111:lhl .I // 1I"4 titl~ 4Ir;I .,1 q',; jz tl4 144111-. l.I - a~~h h 1111

I ll .11ol.•.Ihl,-. :ILII" C -,11rrWli -'l IIII. 1 '- 1 i 1111 i I I M4;m1 ;Ijnl1l Ii -.., 

iI.-, .II II,, a ,,I~ I 'l fiit.i: l r), I . x \ *. ill ".l i flIII III It IIl.

a I PIi f b 'I I Iui. r fl e 1' ll lt-. Ifl.i; l i lot 1l tl/ /

I illI '0- I- 1-. . a I' ' i It V( -l I 11f i4 I I I ,llI - I "1 I I I I 1- t1 

I~~~~~~1 m -. 141 ~ 1: 4 1a 1i 1i 4! 4 1: 

Ihli , l.. jhll~x. i f4 l, ,n .41 'i i l. I t' ht l w l fit ,, I lrit 

II'4i•c < . " I h ui; Ii, r Iia i, . NI/ I r ll 4 illa ' I l ; 1 ; itX e l' € . h . <~ l ' . 'l
324 INFECTIOUS DISEASES

into each ran'is and tile posterior p)harynx four tijies each day for 5 daysa total of 20,000 units per patient for the 5-day period. iwelve controls

had only hot gargles. All 10 penicillin-treated cases were negative within

the treatment period or on the first day thereafter, and were still negative

4 weeks later. In the untested group, 7 of the 10 cases reverted spontaneously to negative within the fifth week. Bermaln and Spitz concluded that

penicillin seemed useful. but the number of cases is small and the incidence

of spontaeous reversals to negative was not checked 2 weeks after the treatment, period when this might be at its height.

FIGURE 54.-Copt ncbacteiturn hemolyti- FziuR,: 55. -Cworncbacterihm diplithecume. 48 hours on LUifler's serum at 37° C. riae, 48 hours on Lifller's serum at 37' C.

Grain stain. ( X 1,100) Grram stain. ( X 1,100) (Compare with

fig, 54.)

Bagnall and Bain 9 of the No. 14 Canadian General Hospital, in the

Mediterranean, performed careful experiments using 175 patients and giving

penicillin intramuscularly. Two groups were used: Group A received a

total of 600,000 units in 5 days on a dosage schedule of 15,000 units every

3 hours; group B received a total of 1.200,000 units in 6 days on a schedule

of 25,000 units every 3 hours. The percentage of success was higher in group

B than in group A, which was no better than the control group. Bagnall

and Bain pointed out that, in seven instances, positive cultures recurred after

three consecutive negative cultures and in four instances, after four consecutive negative cultures. The writers' conclusions were that the results were

disappointing.

Even less satisfactorv were the results of intramuscular treatment of

individuals who were still carriers 2 to 7 weeks after the clinical disease.

Kocher and Siemnsen 9+ gave 25.000 units every 2 hours for 7 days, a total

of 2,100,000 units. The cultures remained positive in their subjects.

97 See footnote 1. p. 276.

98 Kocher, R. A., and Slemsen, W. J.: Diphtheria Carriers Treated With Penicillin. Ann. Int.

Med. 24: 883-886, May 1946.
DII'IITHERIA 325

These observers concluded, however, on the basis of another experiment,

that local therapy is effective. Their method was to use glycerine-gelatine

lozenges, which required 20 to 30 minutes for solution, one each hour for 12

doses. The early patients in the series received lozenges containing 500

units, but their content was later raised to 1,000 units. Also, penicillin

sprays to the nose were given. Twenty-three of thirty-one individuals

cleared promptly in 1 to 10 days after treatment was started, and eight

cases that were persistently positive had large tonsils. After tonsillectomy,

however, these became consistently negative. Scrutiny of the table presented by these workers, however, shows that 10, rather than 8, cases must

be considered failures. Furthermore, in seven others, the cultures were

already negative before local treatment was started and are therefore "no

test."

It still remains to be proved that penicillin is effective in terminating

the carrier state. Certainly, it is much less effective in persistent carriers

than tonsillectomy.

Part V. Problems Remaining for Investigation

Numerous problems have presented themselves during the course of

these wartime investigations. They are, as follows:

1. Cutaneous diphtheria should be investigated among the natives of

the New World Tropics. If the epidemiological factors are indeed the

tropical environment in association with dirt and crowding, cutaneous diphtheria should be just as common in Haiti or Uganda as in Saipan. A study

in relation to the rapid development of the immunity by performing antitoxin levels in natives in various age groups might be most revealing.

2. Of special interest would be an investigation of whether cutaneous

diphtheria has a significant incidence in the poorer parts of the Southern

United States where it may account for the high levels of Schick immunity

observed there.

3. Further information should be gathered concerning the occurrence

of cutaneous diphtheria in individuals previously Schick negative.

4. The suggestion from the observations of Pasricha and Panja that

C. diphtheriae. which is not toxigenic for the guinea pig, may yet be capable

of producing lesions in the human skin requires careful investigation. The

factor of hypersensitivity may have significance in this connection.

5. Further study should be made of the newly described hemolytic

corynebacterium of the 0. pyogenes group in regard to its distribution

among the peoples of the Tropics and its pathogenicity and origin, which

may be in some species of animal.

6. Sufficient evidence in controlled experiments has not as yet been

gathered concerning the efficiency of penicillin in treating the carrier state.

Further investigation is highly indicated.
326 INFECTIOUS DISEASES

7. It was found that beta hemolytic streptococci were extremely coinmon in cutaneous lesions of the natives. These should be investigated by

typing and also in relation to the Dick reaction. A good deal may be

learned concerning the actual prevalence of streptococci in the Tropics,

contrary to previous opinions of their rarity in these regions.

Part VI. Summary

Dip)htheria was a problem of increasing importance to the Army during

World War II, particularly after the occupation of Germany. Many cases

originated in the Tropics where the disease largely took the cutaneous form,

as it. has in previous tropical campaigns.

The lesions, which usually were preceded by trauma or insect bites, most

commonly assumed the form of punched-out ulcers with declivitous margins

and relatively clean bases, to which occasionally a grey-green membrane or

fibrinous crust was adherent. The borders were usually indurated and blue

or bronze violet in appearance. Exanthematous or moist desquamative

lesions of entirely different appearance could, however, harbor large numbers of C". diphtkeriae.

The complication of neuritis or myocarditis occurred occasionally, or in

some groups of cases frequently, but usually there were no general symptoms

of intoxication.

Aside from these complications, the lesions were important for:

1. The ulcers were usually on the extremities where they reduced the

military efficiency of the soldier.

2. It is possible for a susceptible individual to infect his own nasopharynx.

3. The lesions, when unrecognized, can be a prolific source of both cutaneous and nasopharyngeal diphtheria for others. This is demonstrated

by evidence of spread of diphtheria from patients on dermatology wards to

other patients and to ward personnel; concomitance of nasopharyngeal and

cutaneous diphtheria in military populations in the Tropics; and suggestive

evidence that unrecognized cutaneous diphtheria in Rommel's soldiers was

responsible for the epidemic in Europe where, on account of climatic conditions, the diphtheria took the respiratory form. The epidemic in Europe

began in September 1941, when both cutaneous and nasopharyngeal diphtheria was at its height in the Afrika Korps and while large numbers of

German soldiers were being returned to Germany as patients. It involved

first those countries under direct occupation by the Germans and the neutral

countries not until much later.

The conditions favoring the cutaneous localization of C. diphtkeriae

under conditions of combat in the Tropics are:

1. The warmth and moistness of the skin which comes to resemble the

lining of the pharynx.
DIPHTHERIA 327

2. During combat, there is little opportunity for cleanliness.

3. Many minor infections occur and are neglected.

4. Flies are extremely numerous and travel from skin to skin.

5. There is frequent and extreme crowding of the troops.

These same conditions prevail among the natives in the Tropics, who

constitute a tremendous reservoir of C. diphtheriae. Among them, cutaneous diphtheria is universal by the fourth year of age. Only between the ages

of 9 and 24 months is there a high incidence of Schick-positive reactions

among these people. Immunization by the cutaneous route probably accounts for the rapid conversion to the Schick-negative state. The level of

immunity is probably only slightly depressed during this brief interval of

time, and this probably accounts for the low incidence of nasopharyngeal

diphtheria.

When the susceptible soldiers are forced by the vicissitudes of combat

in the Tropics into the same epidemiological conditions as the natives, then

severe faucial as well as the more common cutaneous forms of diphtheria

become widespread.

The best treatment for cutaneous diphtheria appears to be to put the

patient at, rest in bed and to apply penicillin locally in continuous, moist

saline compresses. Diphtheria antitoxin intramuscularly may prevent the

consequences of autoinifection of the pharynx and possibly may diminish the

incidence of complications.

The best. measure of prevention of a cutaneous diphtheria is to send only

Schick-negative troops into combat in the Tropics. The fact that more individuals who have diphtheritic ulcers are Schick positive than the general

population, suggests that the Schick-negative state is, at least to some extent,

protection against the development of the tropical ulcers.

In both cutaneous and nasopharyngeal infections in the Tropics, hemolytic corynebacteria are common which may resemble C. diphtheriae in direct

smears and on Liffier's media. These require further investigation.

More study is necessary concerning the use of penicillin in terminating

the carrier state and in the therapy of clinical nasopharyngeal diphtheria.

Penicillin alone, even when given early and abundantly, does not prevent the

complications of the disease.
CHAPTER XI

Tuberculosis

Esmond R. Long, M.D.

Part I. Tuberculosis in the Army

HISTORICAL PERSPECTIVE

For centuries, tuberculosis has been a principal cause of death in men

of military age. In the 4-year period 1942-45, pulmonary tuberculosis, although steadily declining in prevalence throughout the country, was still

the chief cause of disease death in the United States in men between the ages

of 15 and 35 years. In most countries of the world, the relative importance

of tuberculosis was much greater than in the United States. In all armies

in all countries, whenever accurate records have been kept, it has proved

to be a leading cause of disability, adding appreciably to the noneffective

rate, making disproportionate demands upon the time and effort of medical

officers as well as upon hospital and transport facilities needed for other diseases and for battle casualties.

The U.S. Army has maintained records uf hospital admissions and military discharges for tuberculosis since the Civil War. An account of this

disease as a military problem appeared in the "Medical and Surgical History

of the War of the Rebellion" (pt. III, vol. I, ',edical History) prepared

under the direction of The Surgeon General art,2 published in 1888. During

nearly 5% years of military mobilization and operation, 13,499 admissions

for consumption and 5,286 deaths in white soldiers were reported. As calculated from these figures, the admission rate was 5.7 and the mortality rate

was 2.2 per 1,000 per annum (table 46). In view of the relatively limited

diagnostic facilities of the period, it is reasonable to suppose that the actual

incidence was very much higher. As a matter of fact the reporting itself

was at. fault, for the figures for discharge are higher than the number of

hospital admissions for consumption. The records indicate that 20,403 white

soldiers were discharged because of this disease, an excess of 12,190 over the

admissions, and this figure does not include those who died of consumption.

The reasons for the discrepancy are complex, involving multiple causes of

disability and the return of consumption cases to duty. The mean annual

rate of discharge for consumption in the Army in the Civil War, calculated

from the figures given in the "Medical and Surgical History of the War of

the Rebellion," was 8.6 per 1.000 for white soldiers and 3.1 per 1,000 for

Negro troops.

639243--63--25 329
330 IY'ECTIOUS DISEASES

TABLE 46.-Admissions, deaths, and disability separations due to tubercular diseases in the

U.S. Army (Union only), by diagnosis and race, May 1861-June 18661

[Rate expressed as number per annum per 1,0W0 average strength]

Admissions Deaths Disability separations Diagnosis and race

Number Rate Number Rate Number Rate

Consumption:

White -------------------- 13, 499 5.67 5,286 2.23 20, 403 K 58

Negro --------------------- 1,331 6.94 1,211 6.32 592 3.08

Total ------------------- 14,830 5.77 6,497 2.53 20, 995 K 17

Scrofula:

White -------------------- 6,022 2.53 99 0.04 907 0.38

Negro -------------------- 2,508 13.08 81 .42 147 .77

Total ------------------- 8,530 3.32 180 0.07 1,054 0.41

Other tubercular diseases:

White 369 0. 16 33 0.01 --------- 0

Negro 20 .10 4 .02 --------- 0

Total 389 0.15 37 0.01--------- 0

Total tubercular diseases:

White -------------------- 19,890 .36 5,418 2.28 21,310 & 96

Negro -------------------- 3,859 20. 12 1,296 6.76 739 3. 85

Total ------------------- 23,749 9.24 6,714 2.61 22,049 & 58

1 Data for Negro troops are for the period, July 1863-June I866; there were no Negro troops prior to July 1863 in the

Union Army.

Source: The Medical and Surgical History of the War of the Rebellion. Medical History. Washington: Government Printing Office 1875, pt. 1, vol. I, pp. 636&37, 646, 710, and 716.

In the short Spanish-American War moderately high rates were recorded. For the decade preceding hostilities the average admission rate in

the Army was 2.7 per 1,000 per annum, but in 1898, following accelerated

enlistment and the call of the National Guard to service, it rose to 3.7, and

in the following year reached 4.0.

In neither the Civil War nor the Spanish-American War, however, was

tuberculosis considered of sufficient moment to call for unusual comment in

the recorded analyses of the medical aspect of military operations. It was

entirely different in World War I. The French Army recorded a great

increase in the incidence of pulmonary tuberculosis during the first 5 months,

especially in French prisoners returned from Germany. The French experience was sufficiently striking to engage the prompt attention of American

authorities, who set up special machinery for the control of tuberculosis in
TUBERCULOSIS 331

the U.S. Army. These procedures have been described at length by Col.

George E. Bushnell, MC, and Col. Esniond R. Long, MC.'

Following demobilization, the incidence of tuberculosis in the U.S.

Army de'ereased continuously for 20 The neairs. incidenc rate was 4.6 per

1,000 troops per annum in 1920 and 1.4 in 1940. General improvement in

measures for the control of tuberculosis in the Army, and a steady decrease

in tuberculosis in the population were largely responsible for this decline.

DISCOVERY OF TUBERCULOSIS BEFORE INDUCTION

The magnitude of the tuberculosis problem in the Army in World War

II, although substantial in the aggregate, was relatively much less than in

any previous conflict. To begin with, a smaller proportion of men eligible

for induction were tuberculous. In 1917, the national death rate front this

disease was approximately 140 per 100,000 population. In 1941, it was

less than one-third of that, or 45 per 100,000 population. The rejection ratio

for tuberculosis, all forms, actual or suspected, among men examined at

camps and by local boards during World War I was 2.3 percent. Nearly 3.8

million men were examined during World War 1.2 Even with the much

superior diagnostic facilities of the Army in the Second World War, the

rejection rate was much lower from the onset, averaging less than 1 percent

for the entire period of mobilization. 3

In World War I, the detection and exclusion from military service of

men with tuberculosis were based almost entirely on the results of physical

examination. Roentgenology was in its infancy, and only a few thousand

soldiers were examined by X-ray. All experience since that time has indicated that physical diagnosis by even the most skillful, is much inferior to

the roentgenographic methods in use at present. During the total course of

mobilization for World War II, not less than 20 million men were examined

roentgenographically in the Army enlistment stations and in the joint ArmyNavy induction stations. Colonel Bushnell's conclusion on the value of

X-ray examination in World War I is striking in the light of subsequent

developmnents. It was based on the work of Matson, 4 and reads: "As comipared with the physical examination, the roentgenological examination, even

when done by an expert, occupies a place of secondary importance in the

diagnosis of tuberculosis of clinical significance." However, as Spillman 5

1 (1) The Medical Department of the United States Army in the World War. Washington:

U.S. Government Printing Office, 1928, vol. IX, pp. 171-202. (2) Long, E. R.: The War and Tuberculosis. Am. Rev. Tubere. 45: 616-636, June 1942. (3) Long, E. R.: Tuberculosis as a Military

Problem. Am. Rev. Tubere. 51: 489-504, June 1945.

2 Britten, R. H., and Perrott, G. St. J. : Summary of Physical Findings on Men Drafted In the

World War. Pub. Health Rep. 56: 41-62, 10 Jan. 1941.

3Medical Department, United States Army. Physical Standards in World War It. [In

preparation. I

4 Matson. R. C.: The Elimination of Tuberculosis From the Army. Am. Rev. Tubere. 4: 398-

416, July 1920.

5 Spillman, R.: The Value of Radiography in Detecting Tuberculosis In Recruits. J.A.M.A. 115:

1371-1478. 19 Oct. 1940.
332 INFECTIOUS DISEASES

wrote, the chest specialists of those days are "not to be reproached for not

having knowledge that camne into existence only later, any more than the

chief of the army air service in 1917 Is to be reproached he*'alus, iiiore eflicient planes are available now than then."

During World War I, there Nwere 22,812 disability separations due to

tuberculosis, or 5.52 separations per annum per 1,000 average strength. If

related to the number of men who served in the Army during the First

World War, the proportion would be about 0.56 percent. Tuberculosis was

the leading cause of disability separation, accounting for 11.1 percent of the

total (204,765) and 13.5 percent of separations due to disease (169,039).6 In

World War II for enlisted men, it was 13th in the list, accounting for only

1.9 percent of all discharges for disability from disease.7

The full magnitude of the tuberculosis problem incurred in World War

I did not, become evident until several years had passed. The postwar cost

proved enormous. Goldberg" calculated that the approximate expenditure

of the Veterans' Administration for service-connected tuberculosis, including hospitalization and pension costs, from the close of World War I

through 1940 was $1.186.000.000. To this vast. monetary expense must be

added millions of dollars spent by the Army and the Navy on tuberculosis

patients prior to their discharge. Admissions to veterans' hospitals totaled

293,761 for the years 1921 to 1940, inclusive.

The peak load for hospitalized tuberculosis beneficiaries was reached in

1922 when a total of 44,591 such patients were treated in Government hospitals at a cost of almost $30 million.9 As early as 30 June 1922, 36,600 veterans, or 1 in 130 persons in the Army, had been granted compensation for

service-connected tuberculosis.

At the beginning of the Second World War. it was resolved not to

repeat the experience of the First. World War. It was recognized that the

earlier high admission rate. was largely due to the acceptance of men who

were already infected. In Colonel Bushnell's opinion, relatively few men

developed fresh infection in the Army. It was clear to the Office of the

Surgeon General that modern methods could be highly effective in excluding the early types of tuberculosis that escaped recognition during the mobilization of 1917. The reader is referred to the chapter on tuberculosis in

another volume in the history of the Medical Department in World War II

for the general procedures employed at induction stations, and for a picture

of the enormous extent of preinduction examination by X-ray.'0 Other

6The Medical Department of the United States Army in the World War. Washington: Government Printing Office, 1925, vol. XV, p. 2.

7 Health of the Army, Office of the Surgeon General, vol. 1, 31 Aug. 1946.

8 Goldberg. B.: Presidential Address: War and Tuberculosis. Dis. of Chest 7: 322-325, October 1941.

q Wolford, R. A.: The Tuberculosis Program of the Veterans Administration. M. Bull. V.A. 21

127-135, October 1944.

it See footnote 3, p. 331.
TUBERCULOSIS 333

sections of the chapter describe imieasres to prevent tile developineent of

tuberculosis within tile Arnmy.

It is obvious that, in ail ariny well screened to exclude mnen with active

tuberculosis, contagion among troops would be slight. However, it must be

realized that not all tuberculosis is visible in chest films and that, a certain

amnount. of pulmonary and nonpulnonary tuberculosis may be expected to

develop as a result of endogenous spread front undetected foci. The longer

the war, the more cases would develop froin such hidden foci, and also from

fresh, exogenous infections. Ini the Second World War, the period of mobilization and of hostilities was more than twice as long as in the First World

War. Hence, it will not be surprising if research ultimately shows that

tuberculosis spreading from lesions not detectable at the time of mobilization, on the one hand, and from fresh infections, on the other, were together

responsible for a considerably larger share of the total number of cases discovered in the Army in World War II than was believed to be the case in

World War 1.11

DISCOVERY OF TUBERCULOSIS IN THE ARMY

The general machinery for discovery of tuberculosis in soldiers after

acceptance for service was the samie as for any other chronic disease; it was

discovered both on the basis of sylnptonis and as a result of routine examination for any cause. Cases manifested by symptoms were diagnosed at

sick call as suspected tuberculosis and were then referred to the station

hospital serving the post at which the call was made for necessary observation and further diagnostic procedures. All station hospitals were thus concerned with the diagnosis of tuberculosis. Not all station hospitals. however,

included on their staffs medical persolnel qualified to recognize tuberculosis

of minimal extent or borderline activity. Doubtful cases were referred to

general hospitals for followup and accurate observation.

I1 Long, E. R., and Jablon. S. : Tuberculosis in the Army of the United States in World War II.

An Epldemiological Study With an Evaluation of X-ray Screening. VA Medical Monograph. Washington: U.S. Government Printing Office, 1 May 1955.

Postwar epidemiological and statistical study based on adequate sampling of men discharged

with and without tuberculosis disclosed that approximately half of the men discharged for tuberculosis had the disease in roentgenologically detectable form at the time of acceptance for service.

the lesions having been overlooked through Induction station errors. There was reason to believe

that of the other half a part represented new Infections acquired In army service and a part the

breakdown of old lesions not detectable by X-ray examination. Since routine tuberculin tests were

not made at the time of induction, it was Impossible to distinguish between these two groups. This

study, in which all the films were read Independently by two Koentgenologists. with subsequent

checking by two others. also disclosed a significant degree of fallibility in single chest X-ray interpretations. Not only did the two roentgenologists fall frequently to agree with each other, but In

numerous cases they also failed to agree with themselves on reading the same films after an interval

of a few months. It is now recognized that such discrepancy is general experience. The paper cites

other reports in which similar lack of agreement was recorded. (See also Long, E. R., Stein, S. C.,

and Henderson, II. J. : Experiences With Dual Reading of Chest Photoroentgenograms. U.S. Armed

Forces M.J. 7: 493-515, April 1956.) In the latter study, actual trial was made of dual reading

in three Armed Forces examining stations. Comparison of the readings by the roentgenologist of

the station of origin of the films and the roentgenologist of another station showed considerable

disagreement in Interpretation.
334 INFECTIOUS DISEASES

In addition, a good many cases were discovered in the course of routine

X-ray examinations. Not a few were found in men applying for admission

to officer candidate schools or for a commission at the termination of study

in these schools. Many were found also in routine examinations for special

service, particularly in the Army Air Forces, where many men were reexamined.

Moreover, tuberculosis was sometimes discovered incidentally to other

illness requiring roentgenographic study. In the course of the long series

of epidemics of atypical pneumonia that occurred during World War II,

vast numbers of roentgenograms were made of the chests of men with tle

symptoms of pneumonia. Not infrequently, shadows in the lung fields persisted after clearing of the consolidation due to pneumonia and were shown

by subsequent examination to represent tuberculous infiltration. A high

percentage of these infiltrations were found to be well-scarred lesions, but

in an appreciable number the process proved to represent active tuberculosis, requiring continued hospitalization.

INCIDENCE AND DISCHARGE RATES

Incidence rates.-The average incidence rate in the First World War,

approxinmately 12 cases of tuberculosis per 1,000 men per annum for the

years 1917 and 1918, was ten times that for World W'ar II, which averaged

1.2 per 1,000 per annuin between Pearl Harbor Day (7 December 1941) and

V-J Day (14 August 1945). (See chart 17.) Nevertheless, in spite of

better diagnostic facilities and techniques in the second great conflict, from

10 to 15 men with active disease per 10,000 accepted escaped detection in

induction stations and were taken into the Army.' 2 Moreover, about a inillion men in World War II were inducted into the Army before roentgenograms of the chest were a routine requirement.

There is reason to believe that in each war a high percentage of the

missed cases were discovered within a few months after induction. As a

rule, although not invariably, symptoms soon became evident in advanced

disease, leading to report at sick call, hospitalization, and diagnosis. This

not greatly belated recognition of tuberculosis in recently inducted men is

believed to account for a peculiarity common to the admission rate curves

of the two wars. In the late months of 1917 and early months of 1918, the

rate of admission to hospital was excessive as compared with that for the

last half of 1918. A similar phenomenon occurred in the last half of 1941

and first half of 1942. It is believed that in each war imperfections in

screening procedure were greater and more frequent at the outset than later

in the course of mobilization and that an excessive number of men with disease that would soon become obvious were inducted at that time.

12 Long. E. R., and Stearns, W. H.: Physical Examination at Induction. Standards With Respect to Tuberculosis and Their Application as Illustrated by a Review of 53,400 X-ray Films of

Men in the Army of the United States. Radiology 41 : 144-150, August 1943.
TUBERCULOSIS 335

A second characteristic of the two curies is a terminal rise. ThiF rise

represents discovery of cases oin demobilization and is in part factitious. A

number of cases pr thousand that greatly cxceeded the previous monthly

average were discovered in the course of the physical examinations at discharge, which in World War 11 were as thorough as the induction examinations and included routine roentgenograins of the chest. The increased

CHART 17.-Incidence of tuberculoais in Mhe U.S. Army in the continental United State.,

World War P and World War II

[Rate expressed as number of cases per aunum per 1,000 average strength]

4ATE

WORLD WAR I

IC0 --- - l---- - - -

0

J A J 0 1 A J 0 4 A J 0 j A

1917 1918 191, 1920)

RATE

WORLD WARN 11

0 1 A ,J 0 J A J 0 J A J 0 J A J 0 A 1 0 J A J 0

1940 1941 1942 1943 1944 1945 1946

1 The World War I data are in terms of admissions and are limited to enlisted men.

Source: World War I-The Medical Department of the United States Army in the World War.

Washington: Government Printing Office, 1925, vol. XV, pt. 2. World War HI-Preliminary data

based on periodic summary health reports, Office of the Surgeon General.

rate was artificially high because the strength of the Army from which it

was calculated in accordance with conventional practice was continuously

decreasing in size as a result of the process of demobilization.

The admission rate was remarkable for its relative constancy over a

period of 3 years from mid-1942 to mid-1945, inclusive. The rate of about

1 case per 1,000 troops per annum reflects the number of cases missed at

induction stations, plus the number that developed from new infections

during service in the Army. At the close of World War II, the necessary
336 INFECTIOUS DISEASES

research to determine the amount of previously existent but unrecognized

tuberculosis, as compared with that developing in the absence of previously

detectable disease, had not been accomplished.

The admission rates for the continental United States (chart 18) were

higher than those for oversea theaters. This difference during the war

might be attributed to the additional screening of troops through the rigors

CHART 18.-Incidence of tuberculosis among U.S. Army troops in the United States fnd

overseas, January 1942 to June 1946, inclusive

[Preliminary data based on periodic sumumary health reports]

[Rate expressed as number of cases per annum per 1,000 average strength]

RATE 4

UNITED STATES

2

TOTAL ARMY

OVERSEAS KrR

! 942 1943 1944 1945 JAN -- JUNE ,946

of basic training in the United States. The months of physically strenuous

service, with daily sick call, and the frequent medical examinations for promotion. or special service brought to light many men with tuberculosis, who

we,'P accordingly excluded from oversea, assignment. Still more would have

been excluded had it been possible to examine by X-ray all men leaving

for foreign service. This was impossible because of limitations both of time

and personnel, although there was a reasonably effective inspection before

departure, and roentgenograms of the chest were made in individual cases

whenever indicated by symptoms.

To the factors fu•,oring the lower admission rates overseas, there existed

a counterforce. In every theater of operat ions, the incidence of tuberculosis

in the general p~optilation was higher than in thle United States. There is

k.'~ 77
TUBERCULOSIS 33 7

reason to believe that this higher exposure was a significant factor before

tile end of the war. Of men retained at separation centers in the late months

of 1945 and the first half of 1946 because of X-ray evidence of tuberculosis,

a significantly large majority had seen foreign service. This correlation is

indicated graphically in chart 19 and is in marked contrast to the rates

recorded for troops overseas and in the United States while at their respective stations. Until exhaustive research determines the origin of the lesions

CHA.T 19.-lWithdraiwals from separation processing for pulmonary tuberculosis 1 in

U.S. Army separation. centers, July 1945 to August 1946

[Rate expressed as number of withdrawals per 1,000 processed] RATE

1.5

WITH FOREIGN SERVICE

1.0

.5e \-- -- %

%%,S - %'

WITHOUT FOREIGN SERVICE 7 '

0 1

A S 0 N D J F M A M J J A

1945 1946

1 Some cases withdrawn for suspected pulmonary tuberculosis, not later confirmed by further

examinaaion, are included. Not included are cases withdrawn as "other defects of lungs and pleura"

and later found to be pulmonary tuberculosis.

concerned, consideration will have to be given to two possibilities: (1) The

higher rate of apparent tuberculosis in men on their return from foreign

duty was the result of late development of lesions acquired during Army

service overseas, and (2) the relatively low rate during foreign service was

due to a less effective case-finding program overseas, leaving many cases for

discovery at separation centers. The latter explanation would seem not implausible, in view of the superior facilities and more stable conditions in the

United States. As with other complex problems, it is probable that each

of the factors named was in part responsible for the observed discrepancy."3

13 Long, E. R., and Hamilton, E. L. : A Review of Induction and Discharge Examinations for

Tuberculosis in the Army. Ami. J. Pub. Health 37: 412-420, April 1947.
338 INFECTIOUS DISEASES

Discharges from service-With minor fluctuations, the discharge rate

for tuberculosis ran parallel to the admission rate throughout the war, averaging approximately two-thirds of the latter (chart 20). The other onethird comprised patients hospitalized for care and study, whose tuberculosis

proved not to be active.

Physical standards governing discharge from service by reason of tuberculosis are discussed in another volume of 41- 1 tory of the Medical

Department in World War J1.14 The genera IS discharge of all

CHART 20.-Disability discharges for tuberculosis among cilited men in the U.S. Army,

19p2-45

[Rate expressed as number of discharges per annum per 1,000 troops]

qATE

2 0 . . . . .. . . .

01 A , 0 J" A J 0 J A J 0 1 A J 0

1942 1943 1944 1945

men with active tuberculosis, with the excel)tion of officers when there was

reasonable likelihood that the disease could be thoroughly arrested under

treatment and the officer assigned to duty of a, type for which he was fitted

by training and capacity. As a rule, discharge was not granted for inactive

tuberculosis. Exception was made for lesions of proved activity within the

period of military service and for lesions of such extent that breakdown was

considered likely even though no signs or symptoms of activity were detected

within the period of medical observation in the Army.

Of the several fluctuations in the rate of discharge, the only one of

significance, in relation to the general admission rate for tuberculosis, oe14 See footnote 3, p. 331.
TUBERCULOSI S 339

curred in 1943. At that time, a change in administrative policy (War Department Circular No. 161, 14 July 1943) brought about a sudden mass discharge for disability of a large number of men classified as limited service.

These men did not meet current mental and physical standards for induction

although at some previous period they had passed a preinduction physical

examination. Tuberculosis was not anl official cause for limited service in

enlisted men, but it is believed that a good many borderline cases that had

constituted a problem as to disposition were discharged from service during

the operation of this circular, which "brought about some relaxation in the

general policy of granting CDD's [certificates of disability for discharge]

during that period." 15 This policy was modified (War Department Circular

No. 293, 11 November 1943) by prohibiting the discharge for physical reasons of enlisted men who, although incapable of serving in a physically

exacting position, might render useful service in a less exacting one.

The total number of enlisted personnel discharged from the Army for

tuberculosis in the years 1942-45 was 15,387. These were divided as follows:

Year Number

1942 --------------------------------------------------- 2,400

1943 ------------------------------------------------------- 4,643

1944 ------------------------------------------------------- 3,533

1945 ------------------------------------------------------- 4,811

Total ------------------------------------------------ 15,387

The disease, as previously noted (p. 332), accounted for an average of 1.9

percent of all discharges for disability from disease, and was in 13th position in the listing of causes of disability discharge, the rate being exceeded,

in numerical order, by psychoneurosis, musculoskeletal defects, psychosis,

gastric and duodenal ulcers, respiratory diseases, arthritis, defects of the

feet, neurological disease, ear disease, eye disease, organic cardiovascular

disease, and genitourinary diseases.

Enlisted personnel discharged from the Army because of tuberculosis

were transferred to the Veterans' Admi :istration for further treatment if

still in need of medical care, or to their own care if no longer in need of

medical therapy.

Part II. Occurrence in Oversea Areas

EUROPEAN THEATER OF OPERATIONS

Incidence rates.-The incidence rate of tuberculosis in troops in the

European Theater of Operations, U.S. Army, for the years 1942 to 1945,

inclusive, was less than in troops in the continental United States, as a result

of factors that have been described for the Army as a whole (p. 336).

15 See footnote 7, p. 332.
340 INFECTIOUS DISEASES

Some men had entered the Army with undiscovered lesions, but many

of these were detected before assignment overseas. Subsequent study, ]lowever, indicated that the relatively low rate in oversea theaters could not be

ascribed solely to the exclusion of cases discovered during basic training.

during special training, or incidentally to other illness. The rate of discovery at separation centers in 1945 and 1946 in troops with foreign service was

signitiecantly higher than in those who had served only in the continental

United States. It does not appear that this discrepancy was due entirely

to new infections acquired overseas, but, as has been noted, there is reason

to believe that ease-finding procedures were more effective in medical installations in the Zone of Interior, which were relatively stable in location and

personnel, than in installations subject to all the vicissitudes of conflict.' 6

Lt. Col. (later Col.) Theodore L. Badger, MC, Senior Consultant in

Tuberculosis, European theater, reported a relatively low rate for all forms

of tuberculosis in the theater, compared with that in the Zone of Interior.' 7

Incidence rates for troops in the European theater during 1942-45 and corresponding rates for troops in the continental United States are presented

in table 47 for comparison.

TABLE 47.-Incidence rates for tuberculosis in the Army in the European theater of operations and in the continental United States, 1942-.5

(Data based o.. sample tabulations of individual medical records]

[Rate expressed as number of cases per annum per 1,000 average strength]

Year of admission

Area

1942 1943 1944 1945

Europe ---------------------------------- 0.70 0.77 0.85 1.03

Continental United States ------------------------- 1.86 1.27 .97 2. 13

The admission rate to a considerable extent reflects hospitalization of

men reporting symptoms at sick call. X-ray surveys of unselected groups of

supposedly healthy men, as a rule, reveal lesions in an early form that might

not be expected to show symptoms for months. Such surveys were carried

out under Colonel Badger's direction in England in 1943, on a total of 7,243

men. Seven cases of active tuberculosis were found, or 0.97 per 1,000 men

examined. Ninety-one cases were discovered with small scarred lesions that

appeared to be of no clinical significance; it may be assumed that a large

proportion of them were within the group of healed lesions specified in

Mobilization Regulations No. 1-9, 31 August 1940, as acceptable after a period

of deferment and subsequent revaluation.

16 See footnote 10. p. :332.

17 Semiannual Report. Senior Consultant In Tuberculosis. Office of the Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army. 1 Jan. 1945 to 30 June 1945.
TUBERCULOSIS 341

Another survey, reported in 1945, is of interest for comparison. 18 Chest

roentgenograms of officer candidates at the Army Ground Forces Officers'

Training Center, near Fontainebleau, France, carried out in April 1945 by

Mobile X-ray Team No. 3 of the 1st Auxiliary Surgical Group under the

direction of 1st Lt. (later Capt.) Harry W. Burnett, Jr., MC, brought to

light, only 2 cases of active tuberculosis and 2 cases of healed infiltrative

tuberculosis among 5,240 men examined. This yielded the low rate of 0.38

per 1,000 men each for active and healed tuberculosis, and a combined rate

of 0.76. This group cannot be considered as fully representative of the

enlisted men in the theater, for it was made up of selected men who had

lbeen sent to the officers' candidate school after field demonstration of superior mental and physical fitness.

Another survey on a selected group was that made by the 365th Station

Hospital. In a rep.Žrt covering 2 years, from April 1942 to May 1944, while

this hospital was stationed in Iceland, the section for respiratory disease

.nade chest roentgenograms of 2,897 men from detachments of troops en

route to the European theater from the United States. The commonest disease in these men was atypical pneumonia. Among the total number examined, however, there were 38 cases of infiltrative active tuberculosis and 10

cases of pleurisy with effusion of presumed tuberculous etiology. In passing.

it may be noted that this relative proportion of cases of pleurisy with effusion to infiltrative tuberculosis was observed generally throughout the Army.

The high proporion of active tuberculosis, namely, 1.7 percent, is not surprising in a group admitted to a hospital on the basis of respiratory symptoms. In the course of the survey, 24 cases of healed infiltrative tuberculosis

were seen, yielding a rate not greatly different from that reported for the

theater by the Senior Consultant in Tuberculois.

Disposition of tubrceulous patients.-The disposition of personnel discovered to have tuberculosis was based on the extent and severity of the

lesion. An administrative memorlujin., of 22 February 1944,19 directed

that all patients with active pulmonary tuberculosis or with large inactive

fibroid lesions the stability of which was open to question, that all patients

with serofibrinous pleuritis of known or suspected tuberculosis etiology, and

that all patients with nonpulmonary tuberculosis should be "boarded" to the

Zone of Interior.

Personnel with residuhl calcificsitions of healed primary tuberculosis or

small fibrocalcific scars of infiltrative tuberculosis, apparently inactive, were

returned (o duty. Provision for limited duty and observation was made for

borderline cases. The directive listed the tests commonly made to determine

activity, including laboratory study and observation by X-ray, and ordered

is See footnote 17, p. 140.

19 Administrative Memorandum No. 22, Office of the Chief Surgeon, European Theater of Operations. to Surgeons, All Base Sections, Commanding Officers, All U.S. Army Hospitals, 22 Feb. 1944,

subject: Disposition of Tuberculosis Patients.
342 INFECTIOUS DISEASES

that "individuals presenting all undue risk of reactivation" be evacuated to the

United States.

The European theater, unh11 .e the Mediterranean Theater of Operations.

U.S. Army, had no hospitals formally established as tuberculosis centers

(p. 354). Patients with tuberculosis were treated in special sections of niany

hospitals, with established precautions to avoid exposure of hospital personnel and other patients. Circular Letter No. 100, Office of the Chief Surgeon,

European theater, dated 25 July 1944, directed that "active pulmonary tuberculosis, however small the lesion, will be treated by absolute bed rest as

soon ,s the diagnosis has been made." It was directed also that cases of

serofibrinous pleurisy of presumptively tuberculosis etiology, should be

treated by bed rest until at least 2 months had elapsed after return of pulse

and temperature to normal. Pneumothorax was used only for emergency

cases of pulmonary tuberculosis with hemorrhage and for cases of such character that safe transport to the Zone of Interior appeared dependent oni the

establishment of collapse prior to evacuation. Finally, it. was directed that

"all cases of active tuberculosis * * * including serofibrinous pleurisy, will

be boarded to the Zone of Interior in Class II, as litter patients." Evacuation was by sea and by air. Air transportation was prohibited in pneumothorax cases and for certain other patients with pulmonary tuberculosis by

Circular Letter No. 102, Office of the Chief Surgeon, European theater, 4

August 1944. Air transportation was authorized for patients with early

tuberculosis not sufficiently advanced to disturb respiratory function.

Incidence in nurses.-Many papers have been written on the special hazards of tuberculcnsis to nurses, usually ascribing it to exposure to the unrecognized open case. According to most recent reports, the incidence in nurses

is higher in geuieral hospitals than in institutions for tuberculosis. The explanation usually given is that in the latter the hazard is recognized and

proper precautions are taken. In general hospitals that have no special

section for the care of tuberculous patients, undetected cases admitted to the

wards may constitute a significant, minguarded source for spread of the

disease.

The semial, iual report of the- ,nii,-- consultant in tuberculosis in the

European theater, dated 3 July 194o. called attention to an excessive and

steadily rising prevalencte of tuberculosis, all forms, in nurses for the 31,_,

years of the war. The rates, calculated from reports from the chief nurse

of the theater, iv' given by the senior consultant, are presented in table 48.

The mean raite for the 31/2 years was 3.8 times as high as the general

tuberculosis admission rate for troops in the theater. The report indicated

that 19 nurses developed pleurisy with effusion of presumptive tuberculous

origin, and in 3 nurses other forms of active tuberculosis were found. The

pleurisy with effusion accounted for about 26 percent of the total number

of cases of tuberculosis, a figure holding throughout the Army.
TUBERCULOSIS 343

TABLU 48.-Prevalence of tuberculosis, all forms, in U.S. Army nurses in the European theater,

1942-45

[Rate expressed as number of eases per annum per 1,000 average strength]

Number

Year of Strength I Rate cases

1942 ---------------------------------------- 0 5,832 0.00

1943 --------------------------------------- 4 24,824 1.93

1944 --------------------------------------- 30 133,723 2.69

19452 ....................................... 38 87,004 5.24

Aggregate of end-of-month strengths.

First 5 months only.

Colonel Badger, in analyzing the responsible factors, called attention

to the carelessness in technique that develops in times of strain and stressed

the failure of medical officers to maintain proper measures designed to prevent spread of the disease in hospitals. He instituted special control measures in those hospitals in which the greatest amount of open disease was

encountered; namely, the Army hospitals in France that cared for large

numbers of recovered Allied military personnel liberated from German

prison camps by the advancing American Army in the Saar and Rhine regions.

After the close of hostilities in Europe, when it was expected that large

numbers of troops would be deployed to the Orient, specific directions were

issued to make routine X-ray examination of all nurses and other Medical

Department personnel prior to their departure.20 It was impracticable to

survey all personnel to be redeployed, but the special hazard of tuberculosis

to personnel of the Medical Department, and particularly nurses, warranted

special consideration. A few weeks later, the Japanese surrendered, redeployment to the Pacific areas was stopped, and special measures for the

detection of tuberculosis were discontinued.

Incidence in Army Air Forces personnel.-Except at the beginning of

World War II, enlisted and commissioned personnel in the Army Air Forces

were accepted for enlisted services or appointment as officers in the same

manner as Army Ground Forces and Army Service Forces troops; that is,

through regular induction stations, stations for enlistment, and stations qualified to give final-type physical examinations. In the early months of the

war, the demand for air force personnel was so great that aviation cadets

and others were frequently accepted on the basis of a physical examination

that did not include roentgenograms of the chest, with the proviso that

X-ray examination was to be made at the first duty station where it was

practicable. The delayed X-ray examination was effective in discovering

20 Circular Letter No. 60, Office of the Theater Chief Surgeon, Headquarters, Theater Service

Forces, European Theater, 2 Aug. 1945.
344 INFECTIu'S IISEASES

cases but. had the disadvalntage, froili tlie poilit of view of go'erlinent al

obligation, that the uiiei discovered were in the A riy an id us.ually eligible

for compensation. Later. this iuusuially rapid prok.essing was diconitiniued,

and prospective troops for the air* forces were examuliliedl like sehletive .rv'ice

registrants in general.

Careful followup studies indicated a low incidence of tulerculosis after

montits or years- of service in the A\riuiy Air Forces. A representative survey

on 77.016 troops of tle V.S. Army Air Forces made in E' ngland. in N' pteinber 1945, with the aid of two mlobile trailer 35 111111. l)hotoroeitgei units,

brought to light, only To cases of tullrculosis considered active (5 of primary and 65 of reinfection type), or 1 person in every 1,100) examiined. Of

the (65 cases of reinfection type, 4 were far advanced, 10 nIoderately advanced, and 51 minimal.-21 The group, which was atlost exclusively male,

and compose.d of 14 percent tlying anid 86 percent nonflving personnel, was

carefullv examined to determine if there was any relation between developmlient. of disease and length and type of service. The evidence of the disease

discovered in flying personnel was signilicailtly lower than ill nonflying personiel, a fact attributed to the miore met iculous and often repeated physical

and roentgenographic examination of the former. The incidence was

greater thau average in memi who had not had aii X-ray fllhn on entrance,

or had served a longer than average period of time without a second or later

film. These finldings are as might be expected in view of the usual slow

and insidious (levelopmnent. of tuberculosis.

A study showed that a greater number of men who had consumed raw

milk in England were among the troops with active disease than in those

without disease, but the finding was believed related to the length of service

rather than merely to the ingestion of the milk. The earlier a soldier arrived, the longer lie stayed, and the better acquainted lie became with the

civilian population, the more likely lie was to consume raw milk. Vigorous

efforts were made by all those responsible for the health of troops to prevent

consumption of raw milk in the British Isles, in view of its frequent contamination with tubercle bacilli. It. was not. served in army messes nor, after

an initial laxity, in Red Cross canteens (p. :3618).

On the whole, the Anrmy Air Forces exhibited a gratifyingly low micideuce of tuberculosis and, at the same time, disproved the view occasionally

expressed that flying service predisposes to the development of active disease.

Incidence in recovered American prisoners of war.-Whien large inumbers of American soldiers were recovered from German prison camps in the

spring of 1945, it was no great surprise to medical officers to find an incidence of tuberculosis apparently surpassing the average incidence in the

Army as a whole. Unfortunately. no relial.1e figures for tuberculosis in the

thousands of recovered prisoners are available. War Department orders

21 Wayburn. E. : Mass Miniature Radiography. A Survey In the United States Army Air Forces.

Am. Rev. Tubere. 54: 527-540, December 1946.
TUBERCULOSIS 345

to make roentgenograms of all recovered prisoners before their return to

the United States were in effect at the time, but all acute shortage of X-ray

film and stringent measures to conserve it nullified the effect of the orders.

Figures for the large group processed at Lucky Strike Camp and other

camps near Ie Havre are available only for those who were hospitalized.

Even though hospitalization was not for respiratory disease alone it. is fair

to assume that a higher rate would be found than in a population not in

obvious need of hospitalization. The majority of recovered prisoners who

were hospitalized suffered from severe malnutrition. A number had infectious hepatitis, and acute respiratory disease was common.

In his semiannual report of 3 July 1945. the senior consultant in tuberculosis in the theater reported the incidence of tuberculosis in 2,750 recovered American prisoners hospitalized at the 77th Field Hospital, Lucky

Strike Camp, as follows:

Number Rate

of per 1,000

cases per pear

Minimal tuberculosis ------------------.----------------- 6 2.2

Advanced tuberculosis ----------------------------------- 6 2.2

Pleural effusion ----------------------------------------- 9 3.3

Total --------------------------------------------- 21 7.6

The rate found for all forms of active tuberculosis was thus several

times the rate of approximately 1 case per 1,000 men prevailing in the

Army as a whole. It is interesting to note that the incidence of pleural

effusion, namely, 43 percent of the total, was higher than the usual average

of 20 to 25 percent observed in hospitalized troops in the European theater

and in the continental United States.

In the lack of exact studies on recovered prisoners, analysis of the reason for higher rates is speculative. Colonel Badger stressed as predisposing

factors malnutrition and exposure to an environment with greater potentiality for spread of tubercle bacilli. Malnutrition is believed to be a factor

in the reactivation of small arrested lesions, which, as noted in various surveys, were present in approximately 1 percent of troops. Excessive exposure

to tuberculosis, if it occurred, was not direct. Recovered American military

personnel were not quartered with other nationals, except in some instances

where they shared barracks with British prisoners, but frequently, in the

migration from camp to camp, as the senior consultant in tuberculosis

pointed out in his report, they lived in dirty quarters, grossly contaminated

by previous occupants, many of whom may have had tuberculosis.

At the time of writing, no significant new facts had emerged from followup studies in the United States.22 Former prisoners of war were r 0proc22 The study made by Long and Jablon disclosed that a significant excess of tuberculosis over

the incidence for the Army as a whole occurred In recovered prisoners of war. The risk for white

prisoners, chiefly captives of the Germans in this study, was three and a half times as great as for
346 INFECTIOUS DISEASES

essed at Arniy (rouind and Ariuy Service Forces Redlistrilution ('enters, and

X-ray examination was usually included in tie routine physical exaimination. The largest single survey reported to the Office of the Surgeon General was

from the Army Ground Forces Redistribution Station in Asheville, N.C. Ten

cases diagnosed as tuberculosis were found in 1,939 prisoners of war. a rate of

approximately 5 per 1,000. All of the men concerned were hospitalized and

not all cases were of proved activity, so that the rate of active tuberculosis

was lower. On the other hand, it must be recog.nized that the group examined

by X-ray was to some extent an already screened group, from which men

obviously ill had been removed.

In summary, it appears reasonable to conclude from the evidence that

the incidence of tuberculosis did rise in men who had been prisoners of war

in the European theater, to as much as tive to seven tinmes tile rate prevalent

in the rest of the Army (p. 391).

Incidence in recovered Allied military personnel.-Ili a directive from

the Office of the Chief Surgeon, European theater, to the surgeons of bases,

sections, and aldvanced sections, attention was called to the high incidence

of tuberculosis in prisoners of Allied Nations recovered when the U.S. armies

liberated them from prison and concentration camps in Western Germany.

and to the implications for the medical and nursinig l)ersonnel of the A.rmly.

Later, an order, 23 based on the sudden startling experience of Army units in

the forward areas, directed a chest survey of recovered Allied military personnel, and displaced civilians, as follows:

1. Pulmonary tuberculosis of a virulent order has proved a serious problem among

displaced civilians of all nationalities. The magnitude of this problem cannot be estimated at this time. It is probable that Recovered Allied Military Personnel will show

an incidence of tuberculosis well above the experience of the Theater. It is implrative

to establish the gravity of the situation.

2. All displaced civilians and Recovered Allied Military Personnel admitted to hospitals of the United States Army will be carefully surveyed with this thought in mind.

History, physical examination, appropriate laboratory studies, and, when indicated, x-ray

of the chest, will be made on all such subjects, insofar as facilities permit. Due to

film shortage, x-rays will not be taken routinely.

In recovered prisoners of war of Allied Nations, U.S. medical officers

found, for a time, the principal problem in tuberculosis confronting them in

the European theater. At one time, the 46th General Hospital at Besanqon,

France, with more than 1,000 tuberculous patients of foreign nationality, was

the largest tuberculosis center under control of the U.S. Army, exceeding

men with service overseas who were not taken prisoner (Long, Esmond R., and Jtiblon, Seymour:

Tuberculosis in the Army of the United States in World War II. An Epidemiological Study With

an Evaluation of X-ray Screening. Washington: U.S. Government Printing Office, 1955).

In a special study of disease among recovered prisoners of war, Cohen and Cooper found a high

rate of tuberculosis among former prisoners of the Japanese, which did not take into account the

many soldiers believed to have died of tuberculosis in Japanese prison camps (Cohen, Bernard M.,

and Cooper. Maurice Z.: A Follow-up Study of World War II Prisoners of War. Washington:

U.S. Government Printing Office, 1954).

23 Circular Letter No. 41, Office of the Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army, 11 May 1945.
TUBERCULOSIS 347

Fitzsimons General Hospital, the specialty center ill Denver, Colo., in its

census of tuberculous patients.

Colonel Badger's report on tuberculosis ill recovered Allied military personnel is quoted substantially as follows: 24

a. Nature of the problem

On 18 December 1944, 304 patients of varied nationality, though mostly Russian,

were admitted to the 50th General Hospital, Commercy, France. All were tuberculous.

Four were dead on arrival. Ninety percent had moderate to advanced disease. Twentyeight died of tuberculosis in the first week in the hospital, and up to 21 May 1945, 5

months after admission, a total of 101, or 33 percent, had died. Signs and symptoms

of serious nutritional and vitamin deficiencies were the principal associated complications of tuberculosis or malnutrition. In the middle of March 1945, some 1,600 military

and civilian nationals were sent to the 46th General Hospital in Besant;on near Dijon.

There were among them Rus.sians, Yugoslavs, French, Italians, Poles, Turks, Belgians,

Dutch, Czechs, Greeks, Hungarians, and Serbs. Seventy-five percent of them were Russians. A little less than half had tuberculosis, most of which, once again, was advanced

disease, complicated by very severe malnutrition. Other pockets of displaced tuberculous

nationals, under Third U.S. Army care in Germany, were some 7,000 men at Mauthausen,

5,0OM at Nuremberg, 3,500 at Ebensee, and 3,000 at Klam. This is a glimpse of the end

result of the effects of war on Allied national prisoners, both political and military.

c. History

The story these men told was much the same from wherever they came. They

were prisoners for an average of 34 months in the Stalag camps of Western Germuaniy.

They were for the most part captured in 1941 in the Black Sea area and tile Ukraine.

They were shifted from camp to camp, finally winding up in the mines and heavy industries near Metz and Sarreguemines, France, and tile Ruhr region in Germany. Men

were worked 12 hours or more a day with 1 day off a month, when the coal quota was

filled. Maltreatment for failure to do a full day's quota of work was common. IHousing was for the most part in wooden barracks of 40 to 100 feet in size, crowding in

100 to 150 men. Diets varied in different camps, but from their history and starvation

state, it was apparently seriously deficient. Hygienic conditions were bad, recreational

facilities were prohibited, sleeping and living conditions were congested, and hospital

treatment for illness was apparently reserved for those with high fevers combined with

a good prognosis. The sick were left to die in their bunks beside the living. Before

capture, these men were recorded as being in excellent physical condition. Supposedly,

admission to the Russian Army was by complete physical examination with an X-ray

of the chest; but, if the latter was accomplished in the Russian Army, it was a monumental task. Furthermore, if only those with negative X-rays were admitted to the

Army, the influence of starvation upon unseen tuberculous infection is the more striking.

d. Clinical picture

The typical picture of tuberculosis as seen in these patients was that of acute

fulminating, rapidly fatal disease, mixed with chronic, slowly progressive, fibrotic tuberculosis. They were acutely ill with emaciation which was the combination of tuberculosis and starvation. The clinical course of approximately 30 percent was rapidly and

progressively downhill. Extensive bilateral pulmonary disease was complicated by gastrointestinal, laryngeal, and bronchial involvement. Fever was varied. Many patients

showed progressive, moderate to far-advanced disease in the presence of a normal temperature, some elevation of pulse, and reasonably good general appearance. The physi24 See footnote 17, p. :340.
348 INFECTIOUS DISEASES

cal lfindings were cihiarcteristic Ilk tithe Varliety3 (t" .•igls, but the illist 4-o15-juic ngu05,4h1ge

feature was the presence of widespread disease with few or no physical signs. Cough

and expectoration producted sputa which were heavily lhdeld with tubercle bacilli. Exainlhationi of direct swnears showed4 larger numbers of tubercle bacilli than we are actIustowned to see in tile routine examination of sputa in the Uniteld States.

e. Paftholoyjll

MIl At post morteni examitlint ion,. tilt, tubliervillosis was alwlays bilateral with wide

Ilenilatogenous dissenuinatiion to a Variety of organs with extelislve cavitation of the

lungs. There was revealed nmore than thill usual Iynilph gl3d4 involvemnelt with illassive

enhlrgenment of glands ill both thit vhest and ahdollell. N.ot uulteonillinoly, pileural adhesions were multiple and usually olbliteratLive. giving evitleict'e of chronicity of the disease.

A.illary tuberculosis wias conspicuous by its rarity, though sporadic heniatogenous splread

wits (1nu0iiuit0i.

(2) 'Microscopically, the lesions were chtaract'eristicalily tilbrocaiseous tulercle forIlation with evidltne of normal tissue respi•st, to tilt, presence of the tubercle bacilli.

H lowever, nanny cases presenttti a inicrosciopic appiearalnce of widespread contluent ne'rosis, without tubercle formatlion and with very little tissue reaction about tile periphery

of tile lesion andl little or Ito epithelloid cell fornmation and complete abselnce of giant

cells. Lymlllhatie tissue often presentedl conplete dest ruictition Of all lynzVUpoid Velis with

tissue necrosis and often very little cellula r reaction ill tuulercle formationu.

f. Etioloffli

Etiological factors which productd this fulinllatin^g disease were undoubtedliy the

unusual opportunities for intenise aln frequent recurrent contact with seriously Ill, openi

cases. Conditions at tile ("ernuan Stalag camps and at lluchenwald were such that at

the latter, 4611).M people were housed in a unit originally constructed for 15,t00). Sanitary conditions did not exist and where three to five men were in one small bunk and

tile ill were left to (lie nnattendled beside tile living, the oplportunities for cross Infection

with tuberculosis were such as have probably rarely been observed before. Everything

favored the development and spread of the dlisease. The starvation diet with tile serious

degree of malnutrition undoubtedly contributed to the rapid progress of the disease.

The pathology in utaniy cases was indicative of an absence of tile individual's resistance

to Infection.

g. Trcatnpctt

(1) These patients had treatment, first directed toward relief of starvation and

the establishinent of discipline. Language difficulties and years of living under the conditions which existed iln larger work canips and Stalags nalde it difficult to establish

any hygienic principles, or the segregation of open from closeld cases. The dietary problenis were not difficult to handle and those patients who were not dying of their disease

Improved clilically, rapidly overcoming the malnutrition per se.

(2) The initial problenm was that of reexamining by X-ray entire groups for

proper identification, diagnosis, evaluation, and therapy. Sputumn-positive cases were

eventually segregated from sputum-negative cases and all attempt was made to establish absolute bed rest. However, the latter proved to be practically impossible. The

concept of bed rest was foreign to these men under ainy circumstances, and, with the

Russians, it was against their principles of treatment of tuberculosis, which commanded

exercise anti sunshine.

(3) Collapsc trcatnmcnt.-Deflnitive measures of collapse were not Instituted in the

early weeks of treatment, except in those cases where hemorrhage indicated its necessity, or the character of the disease was unilateral and favorable to this form of treatment. It was deemed wise for these men to have 4 to 8 weeks of bel rest before pneumothorax was started, as the acuteness of the disease and the frequent presence of

tracheobronchitis were not suitable for collapse therapy. Adjustment of their nutritional
TUBERCULOSIS 349

deficiencies was immediately of greater concern than the tuberculosis itself. In acute

widespread, bilateral disease, pneumothorax has not proved to be beneficial. ('ollapse

therapy was never undertaken simply for the sake of "doing something" for the patient.

(4) Seen a month after the institution of treatmcnt, those men who had not died

of acute tuberculosis showed marked improvement. Order had emerged from initial

chaos and reasonably good discipline had been established through the assistance of a

Russian officer anl aidman. It was still quite impossible to establish a regimen of absolule bed rest.

h. Prevention

Precautions against spread of tuberculosis were instituted first of all for the protection of U.S. Army hospital personnel and second toward segregation of the open and

closed cases.

(1) Isolation technique was carried out in all the tuberculosis wards. All staff

personnel wore masks and gowns. Patients wore masks when examined or treated and

were taught to conceal their cough, to expectorate into small pledgets of paper which

were deposited into paper bags to be burned.

(2) Floors were treatcd with spindle oil obtained from the British, which was

applied according to directions extracted from a report prepared by the Eighth Air Force.

(3) "Clean rooms," as islands of sterility, were meticulously observed adjacent to

tuberculosis wards for the protection of nurses and other personnel. No contaminated

person. X-rays, records, or objects of any sort were permitted in these sanctums of

cleanliness. No gowns or masks were worn or removed in these rooms. Scrub-up soluitions and contaminated clothing were maintained in an adjacent room.

(4) By these means every effort was made to cut down airborne infection to a

minimum and reduce the opportunity of contact to a minimum.

On 10 May 1945, Colonel Badger, Senior Consultant in Tuberculosis in

the European theater, and Col. Esmond R. Long, MC, Chief Consultant in

Tuberculosis, Office of the Surgeon General, conferred with Col. B. A. Osipov.

member of the Military Mission of the U.S.S.R. in Great Britain and Russian

liaison medical officer in the theater, with regard to the care and treatment of

Russians with tuberculosis. Points of difference in treatment in the two countries were recognized, and shortly thereafter, it was decided in the Office of the

Chief Surgeon, European theater, to repatriate those Russians who were physically able to travel, as rapidly as was consonant with their safety. The 46th

General Hospital was made a collecting hospital for this purpose. It received

recovered Russian prisoners previously hospitalized in many hospitals in

France and England and effected suitable preparations for the long journey

back to Russia.

Incidence in concentration camps.-In the final weeks of the war in

Germany, Allied troops overran a large nunber of the notorious concentration camps in which the German government imprisoned political nonconformists, Jews, nationals of surrounding states, and others who had offended

the Nazi Party. These camps included Buchenwald, Nordhausen, Dachau,

Belsen, and many others. Thousands of dead were found in the camps at

the time of their liberation, and many more thousands of sick and dying.

Among the latter were hundreds of persons with advanced tuberculosis, who

constituted an immediate problem for the evacuation hospitals of the advancing armies. U.S. Army hospitals rapidly developed machinery for re-
350 INFECTIOUS DISEASES

moving discovered cases from camps and placing them under definitive care.

Barracks outside the camp were usually used, and in these the tuberculous

were bathed, deloused, examined by X-ray, and put on immediate bed rest.

In the transfer from camp, they were ably assisted by doctors of the concentration camp; that is, doctors who had themselves been inmates and had

maintained primitive hospitals for tuberculous patients in the camp. Subsequently, these patients were transferred to German hospitals in the region,

against the time when they could be transferred again to their own countries,

or to sanatoriums in Germany. The crowding, the lack of sanitary provisions,

the malnutrition and the general medical neglect. all favored progression of

the disease in concentration camps. Although few figures are available, it

was believed by .fidical Corps officers that much of the high mortality in

these canips was lue to tuberculosis.

A vivid description of conditions at the Dachau concentration camp, and

the extent of tuberculosis in hospitalized inmates of that camp, has been given

by Piatt.25 He made a statistical analysis of 2,267 roentgenograms of the

chest of patients removed from the concentration camp hospital and examined

by X-ray on admission to the receiving and evacuation section of the 127th

Evacuation Hospital. In only 45.3 percent of the films was no abnormality

discovered. Tuberculosis, pneumonia, and heart disease were the chief abnormalities. Six hundred and twenty-six definite cases of tuberculosis, or 27.6

percent of the total number examined, were detected. In more than half of

these, the disease was bilateral, and in four-fifths of the cases, the process was

either moderately or far advanced. In addition to definite tuberculosis there

were 94 patients, or 4.1 percent of the total, with pleural effusion, probably

tuberculous in origin. There were five cases of miliary tuberculosis.

Piatt, among others, expressed the view that the incidence of tuberculosis

in Europe would increase appreciably in the years to come as a result of the

return of numerous persons with undiagnosed active disease from concentration camps to their homes.

The following extract from the report of the Consultant in Tuberculosis,

Office of the Surgeon General, dated 1 May 1945, also illustrates the task

which faced evacuation hospitals when prisoners in concentration camps were

liberated: 26

1. Assignment of task to 45th Evacuation Hospital.-When the Buchenwald camp

[near Weimar] was liberated a problem immediately apparent was the care and disposition of several hundred tuberculous patients under treatment in the camp. It was

recognized Lhat these were a source of dissemination of the disease, and from the point

of view of medical care represented a long range problem. The processing and evacuation of these patients to a hospital appropriate for their continued care was assigned

to the 45th Evacuation Hospital.

25 Piatt, A. D. : A Radiographic Chest Survey of Patients From the Dachau Concentration Camp.

Radiology f7: 234-238, September 1946.

26 Semiannual Report, 45th Evacuation Hospital, 1 Jan. to 30 June 1945. Appendix A, subject:

Processing of Tuberculosis Patients From Buchenwald Concentration Camp by 45th Evacuation

Ihospital.
TUBERCULOSIS 351

2. Background of tabcyrculiosis proble, at Buchentcald.-a. Tile conditions under

which prisoners lived at iuchenwahl were conducive in every way to the development

and spread of tuberculosis. The malnutrition, from which every inmate suffered, together with heavy labor and harsh treatment, inevitably led to the progression of tuberculous lesions in men previously infected, whether these were originally of serious or

minor character, and the intense crowding and lack of any sanitary precautions led to

dissemination of infection throughout the barracks. "Block physicians," themselves prisoners, appointed by the prison administration, constantly discovered cases and sent them

to hospitals established within the camp, since distinguished as the "old," the "little,"

and the "great." The "old" hospital, an indescribably crowded and filthy place, in which

patients lay on dirty shelves in a long series of tripledecked compartments, five feet

long and two feet high, six patients to a compartment, was in no remote sense a place

for treatment, and in effect simply a breeding ground for the disease. In the others,

thanks to the interest and intelligence of prisoner doctors, standard treatment was carried out insofar as it was possible under the desperate circumstances prevailing, with

little food available, and that of the worst quality, and no relief in sight. In all of

these hospitals the mortality from tuberculosis was tremendous. No accurate estimate

can be made, but it is probable that many thousands of the 50,000 known to have died

in the camp succumbed to tuberculosis.

b. Following the liberation a medical organization was promptly put into effect by

Dr. Horn, an eminent Czech surgeon, who had been a hostage in the camp, arrested

originally as a supporter of Dr. Benes. Dr. Horn was at the camp 6 years. Ills distinguished position was recognized by the Germans, and after November 1943 lie did a

large proportion of all the operative work. His capacity was universally recognized by

the physicians of various national groups in the camp. Under Dr. Horn the following

physicians were appointed as tuberculosis consultants: Dr. Jozef Szineja, a Polish tuberculosis specialist, Chief Consultant; Dr. Stanislaw Machotka, a Jugoslav, who had

been superintendent of a tuberculosis sanatorium in Jugoslavia, Second Consultant; and

a Russian doctor who had specialized in tuberculosis.

In addition, three physicians with experience in the treatment of tuberculosis were

retained in direct charge of the "great" and "little" tuberculosis hespitals (the "old"

hospital having been closed with liberation of the camp): Dr. Gerhard Arnstein, an

Austrian, in charge of the treatment ward in the "great" hospital; Dr. Edmund Adamns,

a German political prisoner of English descent, in charge of the far advanced cases in

the "great" hospital; and, Dr. [Paull Heller, a Czech, in charge of bilateral cases not

suitable for specific therapy, but not hopelessly advanced, in the "little" hospital.

c. The treatment ward of the "great" hospital, with 116 cases, almost all of them

under pneumothorax treatment by Dr. Arnstein, was a crowded, malodorous place in

which patients slept in double-decker beds. Discipline was maintained, and patients

received three times as much food as before the liberation, but no substantial improvement could be expected in such surroundings. Dr. Arnstein was conscientiously doing

everything possible under the circumstances. The ward for advanced cases was simply

a death room. There were thirty-two cases where there had been seventy a few days

before. The "little" hospital, containing ninety-six patients, was a former stable, which

had been improved by the patients themselves by the construction of windows. It was a

highly crowded place filled with ambulant patients who used three-decker beds at night.

There was a total lack of discipline in spite of Dr. Heller's best efforts. Three to four

patients a week died there. The most that could be said for it was that it served for

the isolation of ambulant patients with infectious sputum.

d. The three hospital groups just cited, made up of 244 patients, did not account for

all the known cases of tuberculosis. The different national groups into which the prisoners were gathered immediately after liberation had retained some cases. Altogether

it was believed that 100-150 tuberculous patients could be located in the various groups.
352INFECTl M'S l)ISEAMSP

3. Eraeuvition Proccdurci.-a. T1he above Outline indicates what had Ieeii atcouimp11shed, thailks to tile intelligent 2ictioln of it few liberated phlysicialns, Ill it short period

prevviliitg thle assig-nment of the 45th 1Evactiatiott H ospital to the evactiation probtlemn.

Tilt- princeipal a iccompisthmiient of thIi&~e phlysiciansl was~ discovery, isOlatioti, andt~ (.las

huat ionl of patijents, Which eniormoi~usly facil ita ted thle procedunre (o evacuiation. The

institution01 of jIfit'11intotliorax oil the( scale established wasl heroic, hilt 11u1ch success ill

treatment, under tile circiumstancees, was not to he expected.

1). A prior'ity system, based'4 oni the emtergenicy care retluired, the adlvisab~ility of remo~val for early conitinuaitioni Oft care elsewherte, .111d other conlsiderati oils, was Set up1,

whereby patients already inl the Buchienwald cautup hospitals were to be dheliveredl to thlt

45thI Evlc~tiationl liospital at the rate oft ten tit hour ditrinig the working (lay, cotitienciug (bit 28 April 1945. Ont the 2911 tithe syst eml was found to he funict ioninug siloob1 hin lyI

spite of miechan iical difi hcultis ill tile W.1ter lilt(e and~ VOIR-tcotiitattt cleanin1g Of thle htospital. iUlder the dhirectionl of tilt, coniitiandiitg offhicer, C oloniel Abiter I Zeitti, a remlarkatbly rapwid anid effective jotl) hadl beenl doite in taking over a terribly dirty building.

fouled by uniirest rainedl, suiddently freed prisoners, wvithi no hy3grieniic staindards, Who hall

swatrmted into tilie buil ding (on thteiri release. D ead bl 04 es were itn the c'orrido~rs and~

excremtent all over the floors oit ,,.rival of tilt staty. rwob days hater, whiet evacutiat 14)

operationts commttencedI, tile place was cle.1ii andi I otititil IOperat ioni Was in pr)mI*gTS-.

c. A dIispenlsary oirganiizat iona has been set tit) by D r. B orn in Bucheniwald (Camip for

diagmiosim of ntew cases, fromt suspects setit in by Ibhysiviaits itt thle barracks. which st ill

htoulsed sonte 15,000 ex-lbtisonters. The selectiont is based enttirely ott symuptomts. Ini the(

opintion of thle uttdersignedl tile itulinher of cases would trutn far b~eyond~ the expbectedl E15

cases if a more careful mtethod0( of selt-Vtiont itncluditng X-ray~ exaliimtintiont wvere pOssible.

Iit view' of the tremendous expbosure to Which thte grouip has been subjected, cases will

inevitably a rise in considerabtle number for years to comte. At preseiit obily the meth1104

intdicated is practical. Tile dispensary itill hold 35 patients for Obserivationl at onei tittie,

and~ it Is, expected that by the time the presettt 240-250 patients have beetn evaicuatedl

Itet dlispentsary call) coniclude the rettiniting task in a few (lays.

4. 01rmillizatioll of thec 45th Eruacmtiop IIoxpitalI.-a. 'lThe staff contsists of the coatitiatiding- officer anid 20 medical officers. Lt. (Col. I1sidore A.] Feder, 'MC , (Chief obf titeMedlical Service, has instituttedl .it Orgatnization Wvhich adlimir'ably comlbinles sitmpl icity' andt

efficient operation. Ten 40-bed ward1s, eacht li charge of a mtedical officer, have been set

upl. Itt ad~ditionl to these there is a m'eveivinig officer, a general initernist, an X-ray chiief,

a laboratory chief, and a specialist in ear, nose, antd throat wvotk. The rest of thle staff

of 20, comtposed of miembers of the surgical teamil, ate at p~resenit oil other dluties ill t ite

a rea.

1). Onl arrival at thle hmospital, p~atienmts are taken to) the receiving- ward4s (ome for

ambulant atnd~ oble for litter patientts) and their tecords are initiated 1)y the receiving

offhicer. By arrangement with thte (doctors at Bluchmenwal1( cattp, thleirt prev ious itiedical

recobrds are sent witht thein. EMNT's [emiergency titedical tagsl it( rade mr ouit, andl a

simlple' meica4li(l recornd devisedl by tite 45tht Evacuationt Hospital, entirely suitable for

the p~urpose, is started. After thtis, patienits move across the hall, where their clothes

-it-* takeni awvay fromn thetin to be destroyed, thtey bathe iii hot showers, ando are dried

andit sptrayedI with IDDT [dIichlorodiphltetiyltr-ichiloroethaniej. Then they receive cleatt pajiamias antd are sent to thle X-ray roomt, whlere a roentgenogratin is mtad~e of each inalt,

with a Picker fit-L' unit, thle subject, biolding, thte cassette iii his arnts-. Thte pictures mnade

aire tettiarkahbly -oo(1, wvitht all thle tequiredl detail attd excellentt contrast. Much credit

is (lilt to the( technician lin the dlark room. for the condition of tlte electrical line retiuires relat ively long, fixed expo(suire andi fixed kilovoltage so that c'areful individual

processing- iii the developtiettt tantks iN necessary. After tite X-ray film is made each

p~atient is senit to his Wardl. Shortly afterwards, clinical histories are takent through

ant iliterpre-ter, utdsevileris a aeotintedfo hioatr e ain i 1 ioni--splitttttit blood,
TUBERCULOSIS 353

and urine being examined routinely. Blood sedimentation rates are determined in cases

where tuberculosis is diag.nosed but the patient is afebrile. The whole procedure is

handled quietly and expeditiously.

c. Special mention should be imade of the work of the enlisted metn. Good technical

work is done in the X-ray department andl labioratory as well as the bath (lepar'tmenit.

and the care given by the litter bearers, is observed by the undersigned, was superb.

Very sick, suffering patients were transferre(d froni litters to cots with infinite gentleness, which, in the light of the bestial brutality which had been the lot of the patients

In Buchenwald camup prior to their liberation, was extraordinarily impressive.

5. Assessment of the c•'cuation proccdurc.-a. The work (lone by the 45th Evacnation Ilospital in processing tuberculous patients is excellent. IDr. Ilorn, who had observed the care of tuberculous patients at Buchenwald for years, was strong in his tribute to the spirit and standards of the Medical IDepartment of the U.S. Army. No words

can describe the relief and joy of the patients. After their long misery in the filth and

torture at Btuchenwald, the clean sheets and blankets ainl personal solicitous attention

of the 45th Evacuation Hospital were incredible luxuries.

b. The medical processing nieets its purpose in every way. The objective of the

hospital is to effect machinery for suitable transfer of patients to permaneint quarters.

Status as ambulant and litter patients is being established in a sound maimner. A certain number of cases misdiagnosed as tuberculous are being discovered, and will bre

returned for such medical care as they require. Some patients will be found who are

too sick to move further under any circumstances, and teriinal care is being provided.

Treatment is quite properly by rest and good food, which is enormously appreciated by

the patienits. Pneumothorax treatment is not being given and does not appear indicated in the expected short period of retention of the evacuation hospital. It is believed

that refills, if necessary in any cases, can be given, by special arrangement, by the camp

physicians who initiated the procedure.

U7nder arrangements effected by the Office of the Surgeon, Head(luarters,

First U.S. Army, the tuberculous patients evacuated from the Buchemwald

concentration canim| were transferred to a permanent German hospital at

Blankenhain near Bad Berka and Weimar for continued care pendingr later

transfer of suitnble cases to their homes in liberated countries. It was recognized that a. niajority of the patients were too ill to recover and would

remain a charge of that department of military government concernied with

the hospitalization of displaced persomnel (pp. 397-399).

NORTH AFRICAN AND MEDITERRANEAN THEATERS OF

OPERATION

Admission rates.--As in the European theater, the recognized incidence

of tuberculosis in the Army in the North African and Mediterranean theaters

was lower than in the Zone of Interior. During 1942-45, approximately

1,300 cases with active or inactive tuberculosis were admitted to medical treatiment facilities for observation or care, an incidence rate of 0.85 per 1.000 per

year. In a study involving 800 cases, 57 percent were classified as active and

20 percent as probably active, the remainder as inactive or uncertain. 27

*7 1. cKean, George T., and King, I)onald S. : Survey of 'r'uberculosis and "Primary" Pleural

Effusion for the Period of Activity of NATOUSA and M1TOUSA to 1 Apr. 1945, vols. I and II,

[Otlictal record.]

6392431--631-26
354 INFECTIOUS DISEASES

In the aforementioned stuidy, diagnosis, treatment, disposition of cases,

and the epidemiology of tuberculosis in the theater were discussed at length.

In addition, special attention was devoted to p)rimary pleural effusion, which

was a problem of unusual significance.

In a high proportion of cases, symptoms, principally cough, led to hospitalization; a smaller number were discovered in various types of routine

survey. Laboratory facilities varied in the theater, but even in forward hospitals means for staining tubercle bacilli were available and X-ray examiination could be made. Films from field and evacuation hospitals were. of good

diagno(tic quality; in l elral, tile dliaglost ic work was of supierior c'haracter.

Differential diagnosis frequently involved distinction from atypical pneumonia, and occasionally from chronic pulmonary diseases other than tuberculosis. The chief difficulty in diagnosis was determination of activity. In

sputum-positive cases this was no prol)lem, but decision was difficult in the

numerous cases where a small fibrotic lesion was evident in X-ray films. The

usual and most. important single aid. namely, a long series of films for coinparison, was not available, because circumstances did not permit retention of

patients for the necessary length of time. Consequently, individual judgnent,

based on all data available, was most important.

The annual rate of admission in terms of troop strength was approximately the same for Negro as for white soldiers. Negro soldiers constituted

9 percent of the total strength, but contributed only 7.5 percent of cases up

to April 1944. On 31 March 1945, Negro troops constituted 13.5 percent, of

the total strength in the. theater and, by that time, accounted for 15 percent

of the cases of tuberculosis. Analysis by type of case indicated that the disease was of distinctly greater average severity in Negro than in white soldiers.

In the former. there were more bilateral cases, more cases with cavity, more

of exudative character, and a lower proportion of cases considered inactive.

According to data obtained from individual medical records, there were. 60

deaths during 1942-45 among U.S. Army personnel admitted for tuberculosis

in the Mediterranean theater. Many patients who were evacuated died elsewhere. Of the 60 deaths, 50 were among male enlisted personnel; 30 of the

50 deaths were among Negroes.

Hospitalization.-,fn the Northi Afric.an amid Mediterraneaii t heaters, as

in all theaters, tuberculous patients were initially admitted to hospitals of

all types. Akdmissions were about equally divided among soldiers fromt the

Fifth U.S. Army. the Army Air Forces, and Army Service Forces. Idnlike

the other theaters, the North African antd Mediterranevn theaters established

tuberculosis centers for the reception of cases from other hospitals and for

stuidy with a view to appropriate disposition. The following hospitals ISrvel

this purpose: 6th General Hospital, Casablanca. French Morocco, 24th General HIospital. Bizerte. Tmmisia; 17th General flospital, Naples. Italy. and the

64th General Hospital. Leghorn, Italy. The coicentration of medical officers,

with special training in a few centers e(uipl)ed for definitive treatment, in-
TUBERCULOSIS 355

sured an adequate number of beds and a high type of professional care for

patients prior to their evacuation to the United States. These hospitals were

frequently visited by Lt. Col. (later Col.) Donald S. King, MC, Chief. MeIdical Service, 6th General Hospital.

Analysis of data for a representative group showed that the average duration of hospitalization of active cases, prior to evacuation to the Zone of Interior, was 58.5 days. From this figure, based on a large sample, it was calculated that active cases of tuberculosis were responsible for 22,405 days of

hospitalization in the theater. Only 24 patients, however, remained in a

theater hospital more than 3 months.

Also admitted to Army hospitals in this theater were tuberculous patients

from the armies of our Brazilian and British allies, tuberculous prisoners of

war, and occasional patients in other categories.

Therapy and disposition.-Hospital care being, as a rule, of relatively

short duration in the theater, definitive treatment was not so intensive as in

tuberculosis centers in the United States. However, in many cases, temlporizing was contraindicated; collapse measures were instituted promptly to prevent serious progression, although this practice anticipated the type of care

to be given during prolonged hospitalization in the United States and the

pneumothorax had to be maintained during evacuation to the Zone of Interior, at ports of debarkation, and en route from the latter to tuberculosis centers in the United States.

The indications for pneumothorax were the usual ones; namely, unilat era I

excavation, spreading infiltration, and persistent hemoptysis. The following

policy was drawn up in the late months of the war with respect to collapse

therapy and the type of transportation most appropriate for different c(ategories for evacuation to the United States.2 8

1. Pneuniothorax treatment in the theater should be limited to predominantly unilateral cases, with evidence of cavity formation or rapid extension, for which transportation to the United States is not immediately available, and such cases should be evacuated on hospital ships equipped to continue pneumothorax after this treatment has been

established.

2. Bilateral advanced cases and advanced cases for other reasons unsuitable for pleumothorax should be treated by continued rest and returned to the United States by

hospital ship as soon as space is available.

3. Unilateral and bilateral cases of active disease of minimal extent, without gross

evidence of cavitation, should be sent to the United States by air at the earilest possible moment, and treatment, other than rest and hygiene, in such cases should not he

attempted in the theater.

4. Cases of pleural effusion without other demonstrable etiology should be considered as probably tuberculous and evacuated to the United States by hospital ship, after

termination of the acute phase of the illness, for treatment and disposition.

5. Under ordinary circumstances moribund cases should not be evacuated ti, the

United States.

28 Memorandum, Col. Fsmond R. Long, MC, Consultant in Tuberculosis, to The Surgeon General,

U.S. Army. 18 Apr. 1945, subject: Visit by Consultant in Tuberculosis, Office of the Surgeon General, in Mediterranean Theater of Operations.
356 INFECTI')IOS )ISEASES

f. Individual judgitneit shIl 1If l- exerci.,.I in the ca.ve of siall.ll, swarred and probl|)1y inative I*eSiolls, with t-,IiVavIithion to i)the Zone of Intorior hi ihos.e vases where the

lesin in ut question is of triuly doutlbtfuIl ilstaliliIty., ii)j•p'iotUiity for Coot linued observation of

the case is unlikely and key pierstatiiel are not involved.

Pleurisy with effusion.- -Pleurisy wilit etri.siot, I)restiliptively WuiercuIons, was frequent in l)roI)ortion to the total tuniuber of ca.,ws of tuberculosis.

In 1944, there was all apparent increase during the summer itontiths, the reason

for which never became clear. It was considered possible that ainimerols infectionts uitight have occurred in crowded quarters during the winter, becomting manifest several monthis later in the forni of effusion.

In 16 out. of 33 carefully studied cases, the bacteriological diagnosis (determined by gruinea pig itnoulation. culture, or other Ineans, was positive for

tubercle bacilli. A diagnostic problem was distinction front the effusion that

sometimes accompanies atypical pliuenioiia. Ih, general, however, it was believed that large effusions were rare with this type of pneumonia, whereas

the effusion of tuberculosis was frequently inassive.

Altogether, 265 case.,; of primary pleural effusion were encountered, of

which 229 were evacuate(d to the Zone of Interior. Two were reclassified to

limited service atn(l 30 were returned to duty. The wisdom of the latter course

was later seriously questioned, in view of the frequeney with whiich late tuberculous parenchiynmal infiltration follows pleurisy with effusion. Three-fifths

of the cases were in soldiers 25 years of age or less.29

Epidemiology.--Mfch atteition was (levoted( im medical affleers to the

el)ideiiiology of the disease in the No(rth African-Mediterranean theater. ITp

to ,lite 1944, the number of cases evacwlated to the Zone of Ineerior, although

not considered alarming, was recognize(d as sigoiaitj(ant.'t.3 In the summer of

1944, the centralization of patients in special hospitals brought, to liglt, tile

fac that not infrequently there was an abnormally high incidence of disease

in inlivi(dual units, and ati index system was set Il) to aid in tracing sources

of infection. New patients were questioned as to previous contacts in tlihe

Army, and fron timei to time, new additions to already known endemic foci

were thus discovered. Ini one medical battalion headquarters and headquarters comp)any, consisting of 50 enlisted men and 7 officers, 8 cases of pulmonary

tuberculosis or pleural effusion were found. Contacts with Italian civilians

that man i have been a source of contagion were believed to (occur, but. could

not 1w traced with similar accuracy.

It this connection, Circular Letter No. 41, Office of the Surgeon, I[ea(dquarters, North African Theater of Operations, dated 2.) July 1944, directed

the following :

2!o, lioswar st4ily of 141 i aesi , of prilan ry stiroiiliria:m s llehural fftision In World War II

soldlers, in whici olbservationl ,.4 m S contimile iam ) for 57 or ma ore yelars after e]|ilaignosi,, tJisliN.i'ti a high

ilnciden('ce of re hIipip ini m len ret' rin(i tid • hlitv followinig lh.i rlonitin of it ii' milrail 'x tial .ii, he n i '|

where hospitalization was brief aind return to duty correslpondiingly 4-ariy reiltpse ocelrreil iln atproxinIately i. lm im'rll it or iml-rs ls c(olier. W. H.. anid Wa ri ng.. .1.. 1: 1'rinlt ry Soritfiri toms PlIetirail Effuilsion in Military P'ersonnelI. Am. Rev. T'lberv. 71 : 616 634, May 1954).

Ctster. 0to R, A. : Tulberculosis in the North Afriean Theater or Olperations [arid appended Comments by the Thlieuter Surgeon 1. M. Butll. North Afrli'n iTeat. Op. (No. 6) 1 : 30 31. June. 1944.
TUBERCULOSI S 357

It will be the responsibility of the counnandIig offtlers of "tuberculosis reception

centers" to notify the inedical officer of any mrganization, ik which nit "open case" of

tuberculosis is discovered, of the existentc of such a case, and it will theii be the

responsibility of the unit medical oflicer to initiate promptly such studies as are (cnsidered necessary for the detection of pulmonary tuberculosis Iin intiniate contacts of

the patients.

Routine surveys, made on several units, were occasionally fruitful. In

one survey made after discovery of an open case, no case of definitive active

tuberculosis was found among 718 persons, including 52 officers and 123

women, but 16 lesions of minimal extent were discovered, 8 of which were

considered possibly active, the remainder, probably inactive.3 '

Although Italian civilians were always suspected as a source of serious

contact, adequate study was not made until after the end of hostilities. Some

evidence of special danger was found by the Chief of Medical Service, 15th

Evacuation Hospital in a survey of approximately 300 civilian foodhandlers in

the Milan-Turin region. Of these, 15 (or 5 percent) had clinically significant

tuberculosis of reinfection type.

Evacuation.-Patients were evacuated by sea and iy air. In the early

days of the theater, most tuberculous patients came home on troop transports.

Later, the majority returned in hospital ships. when these were available in

sufficient number. It was recognized that far better care could be given them

on hospital ships, where special quarters could be assigned and wlhere X-ray

and pneumothorax equipmen t and laboratory facilities were readily available.

At the same time, isolation technique protected other soldiers from exposure

to contagion. Fortunately, there was little communicable (lisease other than

tuberculosis requiring evacuation from the theater. Accordingly, it was possible, in many voyages from Italy to the United States, to use for tuberculous

patients the entire section of the ship that had originally been set aside for

contagious diseases. This section usually provided airy 8- and 12-bed wards.

SOUTH PACIFIC AREA

Incidence.--In reports for the year--s 1942-45 for the South Pacific Area

(New Caledonia and the Solomon Islands), an admission rate for tuberculosis

of 1.5 per 1,000 men per annum is shown, except for the year 1942, when the

admission rate for the last quarter only is recorded and was 2.1. Incomplete

reporting, mistakes in diagnosis, inclusion of readmissions and transfers are

mentioned as factors causing inaccuracies. It was believed by the reporter,

however, that the errors did not exceel 10 percent. The totals for the 4 years,

as reported, were: 1942 (last 3 months), 42; 1943, 214; 1944, 264; 1945, 57.

The incidence rates, taken from the statistical health report (WD MD Form

86ab) in the records in the Office of the Surgeon General, were: 1942, 1.38;

1943, 1.20; 1944 (consolidating South Pacific with Central Pacific Area to

31 Wyman, S. M.: Report of a Roentgenologic Chest Survey. M. Bull. Mediterranean Theat.

Op. 3: 15-16, January 1945.
358 INFECTIOUS DISEASES

make Pacific Ocean Area), 0.71; 1945 (also consolidated), 0.95. The average

rate for tile Pacific Ocean Area for 1942-45, inclusive, was 0.86.

Types of tuberculosis.--The majority admitted to hospital were cases of

pulmonary tuberculosis. It is interesting to note that of 82 cases of chronic

reinfection type pulmonary tuberculosis admitted, 32 were recorded as ninimal, 38 as moderately advanced, and only 12 as far advanced. In a theater

where examninations were usually mnade on the basis of symptoms rather than

through the medium of mass X-ray surveys, the preponderance of mininial

andi moderately advanced cases indicates that medical officers were on the alert

for cases and recognized the need for their discovery before the disease

reached the far advanced and generally hopeless state.

Fifteen cases of tuberculosis of the genitourinary tract were positively

identified out, of a much larger number of cases of genitourinary tract disease

in which the diagnosis was questionable. It is noteworthy that in the Central

and South Pacific Areas (data for the areas separately are not available) 40

cases of tuberculosis of the genitourinary tract were found, yielding a rate of

2.8 per annum per 100,000 average strength. This may be compared with 1.8

for the Southwest Pacific (based on 28 cases) and 2.7 for the total Army

(based on 674 cases). It. may be noted here that, although pulmonary tuberculosis was generally excluded through X-ray examination at induction stations, facilities for detection of genitourinary tuberculosis were usually inadequate. so that cases that were asymptomatic at the time of induction were

unknowingly accepted.

Of the nonpulnionary forms, tuberculosis of the p)leura was conspicuous

(9 cases). There were a few cases of tuberculosis of superficial lymph nodes,

bones, joints, and mneninges. The list included only one case of generalized

nmiliary tuberculosis.

Diagnosis.-Diagnostic facilities varied with the type of meledical installation and its location. First-class roentgenological facilities were available

throughout the theater and, according to the official reports. liberal use was

made of them at all times. Every patient with symnl)toms of chest disease

was examined by X-ray. Group surveys were made when special circumistances indicated their value. For examl)le, a. Navy steward was found to

have advanced l)ulmonaty tuberculosis and about 20 close contacts were stuidied. It. was interest-ing to note that no active cases were found in this study

but that two or three apparently inactive cases were located.

Facilities for laboratory examiinations depended upon the l)roxi:unity of

the installation concerned to the front. Laboratories as far forward as clearing companies had all the necessary equipment for making stains for acidfast

bacilli. In installations to the rear of clearing companies, facilities were

available for concentration methods for the detection of tubercle bacilli, and in

such installations gastric lavage was performed. General hospitals made considerable use of cultural methods for detection of tubercle bacilli. Guinea-pig

inoculation was resorted to occasionally in medical laboratories, for example,
TUBERCULOSIS 359

in the 6th Medical Laboratory on Guadalcanal. In view of the scarcity of

the animals, this was largely restricted to cases in which tuberculosis of the

kidney was suspected.

Hospitalization and care.-Few officers who had specialized for a long

period in tuberculosis were on duty in the theater, which in this respect was

worse off than tile European and Mediterranean theaters. Because of the

great distances involved, the consultant system was not used. The diagnosis

and treatment of tuberculosis thus del)ended upon the judgment and general

medical ability of officers in the various installations.

Patients were transferred from installations where the diagnosis was

made to general hospitals in the theater for observation, care, and disposition.

Theral)y was restricted largely to rest and measures directed toward improvement. in general nutrition, supplemented by symptomatic treatment for relief

of cough and pleuritic pain. Collapse therapy was seldom attempted, since it

was the policy of the theater to return all cases needing definitive care as

promptly as possible to the United States.

Special problems.--Medical officers were on the lookout for special effects

of climate and other adverse conditions peculiar to the region.

Climatic conditions were highly variable throughout the area, which, at

one time or another, extended from the equatorial latitudes of the Bismarck

Archipelago to the Temperate Zone of New Zealand and from the 150th

meridian of east to the 150th meridian of west longitude. The majority of the

troops in the command lived under tropical and semitropical conditions in the

Solomon Islands and in New Caledonia, although a certain number were stationed in New Zealand for extended periods for training or rest. No specific

effects attributable to the climate were emphasized by medical officers in tie

area.

Service in these regions was arduous. Corresponding with the number

of troops involved, the amount of tuberculosis discovered was highest in the

infantry, in which more than a quarter of the cases detected were found. It

is remarkable that the next highest number of cases were discovered in personnel of the Medical Department, and a slightly lower number, in the Corps

of Engineers. These three branches accounted for more than half of all the

cases of tuberculosis discovered. The highest rate of tuberculosis recorded in

the theater was during the period of most intense combat. This, however,

was a period when a large proportion of troops that had been relatively poorly

screened in the United States were on duty in the theater.3 2 In the opinion

of the reporting official, the relatively high incidence discovered in the first

3 months of recorded data for the theater (end of 1942) was probably the

result of this imperfect screening rather than the unusual severity of the

service itself.

Likewise, no specific correlation with nutrition was discovered. Nutrition was in fact relatively poor at the time that the troops were most heavily

•2 See footnote 3, p. 331.
360 INFECTIOUS DISEASES

engaged in combat and the incidence of tuberculosis was at its highest. Some

medical officers attempted to determine if tuberculosis decreased after impr.a ,-ement of the diet, which consisted largely of C and K field rations ill

the earliest part of the war, but no significant conclusions in this respect could

be drawn. Certainly, nutrition improved enormously after the first difficult

period, but it was true also that the troops chiefly concerned at this later time

had been subjected to much better screening.

In view of the high prevalence of malaria and other tropical diseases,

a number of medical officers attempted to determine if they had any effect in

activating tuberculosis. No specific evidence of activation of tuberculosis as a

result of concomitant malaria or other disease was detected. This corresponds

with the results of a number of prewar studies, which failed to show any

specific connection between malaria and depression of resistance to tuberculosis.

Mortality.--The number of deaths froiln tuberculosis in the theater was

extremely small. In the theater report, only five fatal cases are listed. all of

themi of acute type. The death rate deduced from these figures was 1.3 per

100.000 men per annum. The figure merely inlicates that cases of ultimately

fatal issue were transferred to the United States before death occurred.

Evacuation.-All patients with active tuberculosis of any part of the body

were evacuated to general hospitals in the United States. A total of 158

patients were evacuated from New Caledonia and 65 from Guadalcanal. In

the early months of the war, a few patients were sent to Melbourne, Australia.

Evacuation was ordinarily by direct transfer to a medical installation in the

United States. The largest number of transfers was to Letterman General

Hospital, San Francisco. Calif.

Patients with active pulmonary tuberculosis were almost invariably evacuated as strict litter patients, whether the transfer was by air or by sea. Patients with inactive or arrested tuberculosis and those. with involvement of

superficial lymph nodes only, as well as a good many cases of genitourinary

and other forms of nonpulmonary tuberculosis, were evacuated as ambulatory

patients. Evacuation by air from New Caledonia commenced in 1943 and

increased notably in 1944 and 1945. However, even at the end of the war,

from this distant area, the majority of patients were returned to the United

States by ship. Approximately 13 percent were returned by air. Of the 158

patients returned by ship from New Caledonia, 66 percent were litter patients. 23 percent ambulatory patients. and 11 percent troop-class patients.

SOUTHWEST PACIFIC AREA

Incidence.-In comparison with other medical l)roblems, tuberculosis was

considered of minor military significance in the Southwest Pacific Area.33

The official report from the area states:

Timlpanelli, Alphonse E. : Tuberculosis in the Southwest Pacific Area I world War 11I. [I fltcial record.]
1TI"II A1 '' ISIM 361

* * * in 40,000 tcontinuous admissions for all causes from all sections of the

Southwest Pacific area in two large general hospitals operating at various times in

three selperate areas in New (Guinea and the Philiplpines, o01ly (4 (.ases of tuberculosis

were found * * *. Of these 64 vases studied, 62 were instances of puIlmonIIary tuberculosis and 2 of tuberculous (ervical adenitis without clinical pulhmonary involvement.

Extra-pulmonary tuberculosis was rarely encountered in the area. A review of the

pulmonary cases showed that 12 were diagno.se, as inactive or arrested, 33 as mninimal

active, 16 as moderately advanced, and 1 far advanced. None of the patients were critically ill and none died in the theater.

The incidence rates for tuberculosis in the Southwest Pacific Area and

other theaters and areas, as computed in the Office of the Surgeon General,

(.'HART 21.-Inciidcnec of tubercuiosis in the U.8. A'my, by theatcr mid year, 1942-45

[Preliminary data based on periodic sunimary health reports]

[Rate expressed as number of cases per aminu per 1,000 average strength]

RATE RATE

2.5 2.5

TOTAL ARMY CONTINENTAL CONTINENTAL CONTINENTAL CONTINENTAL

2.0- / U. S. U. S. U.S. U.Sa. 2.0

1.05 1.0

.7

.5 TOTAL TOTAL EUROPEAN MEDITERRANEAN NORTH AMERICAN .5

OVERSEAS OVERSEAS THEATER THEATER THEATER

2.5 2.5

CONTINENTAL CONTINENTAL CONTINENTAL CONTINENTAL CONTINENTAL

2.0 U.S. U.S. U.S. U.S. U.S. 2.0

/1. / 5

1.0 - 1.0

LATIN AMERICAN WEST PACIF PACIFIG OCEAN INA-BURMA-INDIA MIDDLE EAST

AREA AREA AREA THEATER of 1 -1 1 I F L __ 0

42 43 44 45 42 43 44 45 42 43 44 45 42 43 44 45 41 43 44 45

are shown in chart 21. The rate for all theaters and areas during World War

II was 1.25.

Diagnosis and care.-Medical installations in general were, provided with

X-ray and laboratory facilities, so that diagnosis was ordinarily made at an

early stage. Cases discovered in forward areas were evacuated to general

hospitals where, in most instances, one or more members of the medical staff

had had specialized training in tuberculosis. Laboratories were regularly

equipped for examination of sputum and gastric washings and the determination of sedimentation rates.

Special medical problems.-As in the South Pacific, an effort was made

to determine if climatic conditions or prevalent tropical diseases played a

role in the activation or progress of tuberculosis. No evidence was found that

these factors played any part in ;ncreasing the incidence or severity of tuber639243--63- 27
362 INFECTIOUS DISEASES

culosis. ('omp)arative studies showed that prevalent. bacterial infections and

parasitic infestations were no more common in tubercutlous patients than in

the general population of patients. The official reporter records:

While the groups of patients admitted in various periods from areas of prolonged

and active combat showed, in general, varying degrees of undernutrition and physical

exhaustion and a greater incidence of parasitic infestation, they presented no more

tuberculosis than was seen among patients front service forces operating undler more

favorable conditions.

Evacuation.-Cases of active tuberculosis were evauated a- 7:ipidly as

possible after the final decision was reached by the disposition lboards of the

hospitals concerned. Wherever possible, tuberculous patients were transferred

to the U nited States by air. It was felt that. the best assurance possible for

recovery was to minimize delay in the initiation of definitive treatment in a

specialized Army medical institution in the Zone of Interior. "In the few

instances in which evacuation from the theater for old. well-healed pulmonary

lesions did not. seem warranted, arrangements were made for periodic examination and evaluation."

In general, definitive therapy was not attempted in the theater: it was

felt that the type of treatinent to be employed in individual case- should be

left to the installation charged with the final care of the patient. The report

states further that. "the short, period of time which the patient spent in the

oversea theater hospital was utilized in educating him in regard to the nature

of his disease, in his personal care, and in isolation technique. Ile was kept

in isolation and on bed rest. (hiring his stay in the hospital and en route to his

(lest inat ion."

The official report states that "air travel was well tolerated by patients

iu all stages of the disease. No complications incident to air travel arose in

patients with tuberculous pulmonary lesions."

The average period of hospitalization between diagnosis and evacuation

was 18 days.

WESTERN PACIFIC BASE COMMAND

Incidence.-The official report for this command states that about 0.6

percent of a series of approximately 18.000 medical cases were diagnosed as

tuberculosis. The, incidence rate in the command for the period June through

September 1945, as recorded on the statistical health report, was about 1 per

annumn per 1,000 average strength. The great majority of the cases were of

l)lmonary tuberculosis. In addition, there were a few cases of geenitourimiarv,

miliary, bone, and gastrointestinal tuberculosis. and tuberculosis meningitis.

Diagnosis.--The most frequent, problem encounte,-d was in early differentiation of tuberculosis from atypical pneumoni;,. Repeated examination of

sputum and gastric washings for tubercle bacilli in many cases resulted in a

diagnosis that. could not be made on the roentgenogram alone. Bronchiectasis

and coccidioidomycosis also required differential diagposis. Cases of bron-
TUBERCULOSIS 363

chiectasis were not unconmnonly seen, but were not accurately diagnosed. for

the medical officers ill the area were reluctant to use Lipiodol because of possible future confusion on reexamination at tuberculosis centers in the United

States. Cultural methods were employed in isolating tubercle bacilli; guinea

pigs were rarely used because of their scarcity in the theater. The standard

methods were used for determination of activity of tuberculosis as bearing

upon disposition.

Treatment.-As a rule, initial treatment only was attempted. The plrimcipal therapeutic problem was whether to institute pneumothorax prior to

evacuation. This was rarely done, because of (1) uncertainty concerning

route, mode, and speed of evacuation, (2) uncertainty whether competent persoinmel would be in attendance en route to give refills and handle possible

complications, such as tension pneumothorax. and (3) the need for a long

period of bed rest and observation prior to institution of collapse. Collapse

was, however, induced in cases of persistent hemorrhage, cases in ,dich excavation developed in rapidly progressive lesions, and cases in which there was

reason to believe adhesions were forming.

Special problems.-The official report stated that " * * no medical officer contacted had definite basis for believing that the tropical climate per se

influenced the development of tuberculosis, although it was a factor in determining disposition of certain cases * * * Nor could the type of military

service be correlated with the incidence of tuberculosis. Most of the officers

who dealt with repatriated prisoners of war believed that their poor nutritional status undoubtedly influenced their high rate of tuberculous infection."

The subject of tuberculosis in recovered prisoners of war is treated elsewhere.

It, will be noted here that a survey of troops from Iwo Jima, where supplies

of fresh food were probably least adequate. failed to demonstrate a clinical

deficiency status that. could be correlated with the progress of infectious disease of any type. Subclinical vitamin deficiencies were slight,, and of no

greatel severity than were seen in a similar group in the Hawaiian Islands.

Evacuation.-Evacuation by air was considered the ideal form of tranlsportation, but was not. available as often as was desired. Prior to evacuation,

whether by sea or by air, sedation with barbiturates was given, and provision

was made for such complications as spontaneous pneumothorax. All patients

with active tuberculosis were evacuated, and a good many with lesions that

were without symptoms or signs and appeared to be inactive on X-ray examination were, nevertheless, evacuated to the United States because medical

officers in the command (lid not feel justified in calling such cases arrested

without prolonged observation. With the end of hostilities, as the report

notes, the tendency of the theater was to be more liberal with the diagnosis

of inactive tuberculosis, and, for this reason, numerous patients of types previously forwarded to the United States were held for prolonged observation,

and not infrequently returned to duty.
364 INFECTIOUS DISEASES

MIDDLE PACIFIC

Incidence.-TLhe incidence of tuberculosis in the Pacific Ocean Area, which

consisted of the combined Central and South Pacific Areas, is shown ill chart

21. A sampling coml)rised of admissions in the MiddleI Pacific command

during the first 11 months of 1945, shows a. total of 1(4,957 cases of disease of

all types, including 287 cases of tuberculosis, or 0.17 percent of all admissions.

Diagnosis and care.-Nothing unusual in diagnosis, not seen in other

parts of the Pacific area, was noted in the official report in the Middle Pacific

command. Hospitals in the Hawaiian Islands were excellently equipped, so

that every procedure that, could be carried out in the Zone of Interior was

readily available. Because of the accessibility of six excellent general hospitals, definitive care was instituted more frequently than in the more remote

areas in the Pacific. Active cases were transported as soon as convenient to

the mainland. As in other parts of the Pacific area, medical officers concerned

with the care of tuberculous patients did not attribute any particular manifestations of the disease to climatic peculiarities of the region, tW the type of

service, or to the malnutrition that from time to time affected substantial

numbers of troops in combat.

Evacuation.--The majority of patients with tuberculosis were transported

to the Zone of Interior by water, except that those who were sent by way of

the Hawaiian Islands accomplished this part of the journey by air.

CHINA-BURMA-INDIA THEATER

Tuberculosis in military personnel was not considered a serious problem

in the India-Burmna theater.3 4 The consultant in medicine in the theater reported that 334 cases were admitted to hospitals there between the first of

January 1944 and the end of July 1945. The annual incidence rates per 1,000

average strength and numbers of cases for the China-Burma-India theater,

based on preliminary sample tabulations of individual medical records, are

as follows:

Number

of cases Rate

1942 ----------------------------------------------- 6 0.69

1943 ----------------------------------------------- 27 .68

1944 ---------------------------------------------- 157 .93

1945 ---------------------------------------------- 240 1.04

On the other hand, Army installations in the China and the India-Burma

theaters recorded a high incidence of tuberculosis in Chinese troops. The

great majority of tuberculous patients in U.S. Army hospitals in China and

34 (1) Blumgart, Hlerrman L., and Pike, George M.: History of Internal Medicine in IndiaBurma Theater, p. 118. [Official record.] (2) The U.S. Forces. India-Burma Theater, was created

on 24 October 1944 by dividing the U.S. Forces. China-Burma-Indla into two separate theatersthe China Theater and the India-Burma Theater.
T'UBERCULOSI S 365

Burma were Chinese. Because of this high incidence and the notorious lack

of sanitary precautions observed by sick Chinese soldiers, medical and nursing

l)ersonlel in these hospitals were heavily exposed to contagion. Routine

checks by the 48th Evacuation Hlospital of hospital personnel failed to disclose cases of tuberculosis that could be traced to contact in the theater.

Since, however. tuberculosis is slow in its evolution, and years may elapse

between infection and manifest disease, it was recognized by adlninistrative

officers of these hospitals that persons who had been employed in them shouli

be carefully observed for some time after their return to the United States.

ALASKAN DEPARTMENT

Fronm tine to time, concern was expressed over the extent. of tuberculosis

in Alaska. Reports from units in the Alaskan semrice called attention to the

excessive admission of men with tuberculosis through the enlistment, process

at Alaskan stations, where facilities for the detection of the disease were inadequate. Attention was also called to the danger of exposure of servicemen

to tuberculosis in Alaska, where the prevalence of the disease greatly exceeded that in the U~nited States. D)uring the war, negotiations were underway for the construction of a hospital for the care of tuberculous patients in

Alaska, and the danger to servicemen, through contact with nonhospitalized

cases, was cited as emphasizing the need for such a hospital. The number

of nonhospitalized open cases in the territory was estimated by the Office of

the Surgeon General as approximately 1,000 and, although the distribution of

these cases was unknown, it was assumed that their presence in comnmunities

where troops were stationed constitutedo a hazard in contagion. 35 In addition,

the factor of exposure to harsh climatic conditions, with an adverse effect

on small latent or unrecognized tuberculous lesions, was also cited as reason

for special consideration of the problem of tuberculosis in the Alaskan Department.

The actual incidence rates for tuberculosis during the war years, however,

did not reflect an unusual hazard. The annual rates per 1,000 men, based

on prelilminary summary reports, were much like those recorded elsewhere:

Number

of cases Rate

1942 ----------------------------------------------- 81 1.61

1943 ----------------------------------------------- 99 .86

1f944 ----------------------------------------------- 70 .84

1945 ----------------------------------------------- 44 1.07

Whether evidence of infection acquired by soldiers in Alaska will develop

later, could not be predicted.

35 Memorandum, Lt. Col. Robert j. Carpenter, MC, Executive Officer. Offie of the Surgeon General. for Assistant Chief of Staff, G-4, attention: Col. Carroll H. I)eitrtck. GSC, Calef, Policy

Branch, 15 Mar. 1944, subject: Hospitalization for Tuberculosis Cases In Alaska.
INFEC'TIOUS DISEASES

LATIN AMERICAN AREA

As in Alaska, troops in tile Caribbean area and in ('Cenral and South

America, served in regions of relatively high prevalence of tuberculosis in the

local plopulation. Also, as in Alaska, the troops on duty included a goo)(d

many recruited locally from a territory of the U nited States where the prevalence of tuberculosis was high: for example, Puerto Rico. The total incidence rates, however, up to the end of the war did not furnish evidence of

special hazard. The ammal incidence rates per 1,000 average strength and

the mnumber of cases, based on tabulations of individual medical records, are

as follows:

N u m ber

of cases Rate

1942 . - - - - - - - - - - - - - - - - - - - -159 1.54;

1941 -------------------------------------- 134 1.11

1944 ---------------------------------------------- 115 1.:4

1945 ------------------------------------------------ 85 1.19

MIDDLE EAST

As the nmmumber of trooI)s on duty in the Middle East was not large, the

rates were not highly significant. Climatic conditions were variable, and

exlposure to contagion, as reflected by the mortality in the local polulation,

was high. The heat, in Iran was excessive and made it impossible for troops

on duty to get normal rest. The annual incidence rates per 1.000 average

strength and the number of cases, based on tab)ulations of individual medical

records, are as follows:

Nuu mber

of cases Rate

142 ------.-------------------------------------------- 3 0.50

1943 ----------------------------------------------- 47 .89

1944 --------------------------------------------------- 50 1.08

1945 ----- ---------------------------------- 20 .72

FAR EAST

The number of cases of tublerculosis developling in the U.S. Army in

.Jalman. between the date of initial occupation and the end of 1945, was ver,

small. Only 24 cases were recorded, which yielded an ammal rate of 0.24 per

1,0400 1)er anmnm. Tile surgeon of the occupying forces, however, in a. later

report on tuberculosis in Japan. called attention to the prevalence of the disease in the native population, which suggested a correspondingly grave exp)osure of troops on duty An the islands. The annual mortality from tuberculosis in Jal)an was recorded, on the basis of figures obtained from the

Jal)anese Ant i-Tuberculosis Association, as ranging front 209 per 100,000 in

1941 to 282 per 100.000 in 1940. In view of the known great deficiency of

beds for the care of the tuberculous in Japan, it may be assumed that large
TUBERCULOSIS 367

numbers of open cases were scattered through Japanese communities without

isolation or care.

During 1946, the hospital a, on rate for tuberculosis, as recorded in

the theater, rose notably. Pat uis rise, however, particularly in the

months of June, July, and Augi. ,, us the result of rapid discovery of cases

in Philippine troops on discharge from the U.S. Army. As the report indicates, however, rates considerably higher than those for troops in the United

States prevailed in the theater at the close of 1946.

It was evident that the problem of tuberculosis in troops on duty in the

Far East was serious. It was complicated by the presence of numerous Philippine soldiers among the occupying troops, a group with a relatively high

incidence of tuberculosis as compared with those recruited in the United

States. Continual attention must be given in the future to the factor of contagion in this region.

Part III. Particular Aspects of the Disease

EXTRAPULMONARY TUBERCULOSIS

Extrapulmonary tuberculosis may be a complication of pulmonary tuberculosis, or may occur in the absence of significant pulmonary disease. Figures indicating its prevalence in the general population are based on mortality records, rather than incidence during life, and indicate that about 10

percent of all fatal tuberculosis is predominantly nonpulmonary. In the

approximate order of frequency of involvement are the urogenital tract,

bones, lymph nodes, serous membranes, and other sites, such as the adrenal

glands. In many cases, the contributing, final cause of death is miliary tuberculosis or tuberculous meningitis. The position of intestinal tuberculosis is

indeterminate. In the great majority of cases, this form is simply a complication of pulmonary tuberculosis, but not infrequently its manifestations are

so severe that they dominate the clinical picture, so that death is reported

as due to intestinal, rather than to pulmonary, disease.

Nonpulmonary tuberculosis, the scrofula of ancient times, is most prevalent among primitive peoples and those whose hygienic environment is poor.

It is also frequent where the alimentary intake of tubercle bacilli is common,

as in localities where bovine tuberculosis is widespread and milk is not

pasteurized.

Troops of the U.S. Army met both of these conditions overseas. Among

the natives in the Pacific islands the scrofulous types of tuberculosis were

relatively common, while bovine tuberculosis was frequent in the British

Isles and continental Europe. The reasons for p)revalence of nonpulmonary

tuberculosis in primitive cultures are complex, including racial factors as

well as habits and customs. In the United States, as a result of a combination of circumstances, nonpulmonary tuberculosis is more frequent in Ne-
36(8 INFECI.' )I'Sll"EASESF; US'I 

groes and Indians than ill white people, and thii, fact held for troops of

t lhese races.

The contagion of nonpullionaruv tuixerculsis, even Illiore thail of pulmonary tuberculosis, delends on the closeness of coitilct. lhere was no

reason to believe that the Contlacts of Amiierican tiroolps with a pla)llthilion in

which nonpulnionar" tuberculosis is liilOe. coiliin ill thail in the U nited States

would lead to a higher incidence of this type of tiubercuhlosis than niormiilly

plrevaiis in our poplulatihion. Such a result would imply prolonged intimate

contacts., as by adoption of primitive custolus, such i•s eating from a comiimon

bowl or careless skint contacts with openi ulcers or dlraining .itilltses of ilfected persons.

On the other linaid, infection fromn raw milk. partiiularly i the British

Isles, was clearly recoglnized as a diiver frolli the outset. anld prevalltions

agirainist it during our troops* residence oversleas were taken early.

All observation nliide in the course of military operatlions ill Worhl

Wlar I is pertient.:2 Trhe nimericall pathologist. Maj. Eulgelne L,. Opie,

M(C. stationed in 1'rance, called atitention to tlhe fact that calcitied tublerculosis of lprimlary ilfection was very frequently observed in the niesellteric

lynllph liodes of British troops. indicatiig an alimentary origih. presulialdv

yl) ingesting infected miilk. In the bodies of Americans. illii iarked coitrast,

p)rimnary infectlious were almost always inl the lungs or rira'helloroclihial

lynllh niodes, and so preslinlilbly hald been acquired by inhaliation of tullbi'e

bacilli.

By far tlhe greatest amount of the milk consumed oil Armlly posts oversels was dried paste urized milk shilpped from the U nited States. There was

always, however, some danger from milk from p)rivate sources. Ili the early

Months overseas, some of the ]led Cross canteens served local milk, the safety

of whiich was not assured. Later, about February 1943. this lpr~actice was

stopped entirely. The U.S. Army Veterinriy (orly s i the British Isles was

constantli on the alert for danger. Up to fuly 19i42, the IU.S. Armiy was Oil

thie British rationi. which included milk from certain approved sources. The

"Veterinary Corps cainie to the conclusion that, in spite of a variety of precautions. "ithere were too many hazards involved for its general use." ('ircuillars Nos. 40 anl( 712. Headquarters, European Theater of Operations, dlated

5 September and 10 November 194-2. reslpectively. shairply restricted piurehase

of milk and imposed rigid standards with respect to the Source. Relatively

few sources satisfied these stanlards: consequently, after the early months,

little British milk was consumlned in the official ration. Consumption of raw

milk by soldiers in the homes of friends 'could not be so well controlled, and

sole infection Inlay have been transmitted in this way. but the total hazard

was not great, as relatively little milk was available to the general population.

M Ople. E. L.: First Infection With Tuberculosis By Way of the Intestinal Tract. Am. Rev.

Tubere. 4: 641-648. November 1920.
TU BERCU LOSI S 361)

Since tuberculosis is a dJisease of slow development, it is not easy to deternmine the source of infection in at given case. D)isease acquired o\verseas

may not become manifest for several y'ears. Therefore, it is not known how

much nonpuhnona-- tuberculosis observed in American troops originated

there. It can only bie said that the incidence (of forms other than pleuritis)

showed no rise before the end of the war. The overall rates per 1D44) for

the total Army for all forms of nonpulhnonary tuberculosis, including tuberculosis of the larynx, trachea. bronchi, and pleura, for the years 1942, 1943.

1944, and 1945. were 0.13, 0.13, 0.17, and 0.23. respectively. Tuberculosis of

the pleura is of special interest and is considered under the next heading

and elsewhere in this account. Figures for the incidence of the other more

common forms of nonpulnonary tuberculosis are presented in table 49.

TABLE 49.-Incidence of nonpulmonary tuberculosis (excludes pleural tuberculosis) in the U.S.

Army, 194;2-45

[lPreliminary data based on sample tabulations of individual medical records)

[Rate expressed as number of cases per annum per 1,000 average strength]

1942-45 1942 1943 1944 1945

Type Number I Numlbr Nunber Number Number

of Rate of Rate of Rate 1 of Rate of l{Wte

-a cas 5s castss es ases

Genitourinary -------------------- 671 0.03 50) 0.tr2 199 0.(13 1 210 0.03 2=5

Bones or joints ------------------- 673 .03 100 .03 174 .03 194 I .02 205 i .03

External lymph nodes ---- - .- 6 .,2 19 .01 ?224 .03 169 .M 175 .!

Skin ---------------------------- 1405 . W 9 *00 36 .0 0 9 .01

Generalized miliary- -------- 133 .01 22 .01 48 .01 53 I.01 I0 (.)

Meningitis- . --------------------- 3 .01 19 .01 23 M0 56 .01 45 M.0

Other I - - - - - - . - - - - - - - - - - - - - - - - - - . 12 .04 214 .07 242 .04 242 .03 2:9) .03

I Excludes tuberculosis of trachea and of bronchi in 1942 and 1943. During 1942-43. these two conditions were coded

to pulmonary tuberculosis. In 1944 and 1945 there were 30 and 45 cases, respectively, which have been included in the

"Other" category.

Differences in incidence overseas and incidence in the Zone of Interior

were not significant, and accordingly combined figures for the total Army

are. given. The total amount of nonpulmonary tuberculosis, other than

tuberculous pleuritis, was between 5 and 15 percent of all tuberculosis reported each year, a figure approximately the same as that for the civilian

population. It should be noted that the methods of exclusion of nonpulmonary tuberculosis at induction were inferior to the X-ray p)rocedure for

detection of pulmonary tuberculosis. It became evident in retrospect that

small lesions of tile epididymis not infrequently escaped notice, and tuberculous superficial lymph nodes were also not conspicuous enough ill niany

instances to be noted in the course of the usual rapid induction examination.

Tuberculosis of the kidney was frequently evident on the basis of symptoms,

history, or presence of pus in the urine, but some cases in an early stage were

certainly undetected.
370 INFECTIOUS DISEASES

Racial differences with respect to nonIuhnlloiarv tuberculosis arte discused in the section oil 'Mortality From Tuberculosis." Aronson's studies 3

indicated that urogenital tuberculosis was mlore comnnon in tihe white race,

and tuberculosis of tfhe lyniih nodes, of the ,serous membranes, and of tile

bolies was illore common in Negroes.

PLEURISY WITH EFFUSION

Special interest. is attached to the subject of tulbrculous pleurisy with

effusion, because of the indications discovered by Canadian medical officers

that this form of tuberculosis in soldiers was a manifestation of recent prinlary tuberculosis in adult life, occurring with particular frequency in trool)s

front lIllits of Callnada with a low rate of exl)osure. Figures for the 1.S.

Army are mnore difficult, to analyze in this respect than those for the Canadian Army, but there are sonie indications that a similar piienoiieinon occurred (1p1. 403-105).

The medical treatment of pleurisy with effusion in the Army was variable. Tlhere was a tendency. particularly in oversea theaters, where demand

for personnel was critical, to return mnen to duty after copil)lete albsorl)tion

of fluid and a pewriod of hospital convalescence and restYa In an appreciable

number of cases of frank pulmonary tuberculosis that developed in the -trmly,

clinical history disclosed a, previous attack of pleurisy with etfusýion. In the

Zone of Interior, the niedieal rule that pleurisy with effusion should be. conisidered tuuberculous if no other etiology couldI be proved was generally, althouigh not invariably, followed, and many soldiers with effusion were sent

to the Armiy hospitals Usedl as tuberculosis cenlters and ultnimately were dischalilrged on certificate of disability as t uberculous. Clarificat ion of procedure was brought about by TB ME3 ) (War D)epiartment lechnical Bullet in)

71, dated 28 ,July 1944, iand Change 1, dated 26 November 1946. in which

the tuberculous nature of the disease was emphasized. instructions for diagniosis given, and principles for disposition set forth.

In 1942 and 1943, tuberculosis of the lplellrai was coded with pulmnoniary

tuberculosis, with pleurisy as all associated disease. In 1944 aind 1945, separate specific accounting was mande of clearly diagnosed tuberculosis of the

lpleura anld serofibrinous pleuritis of undenionst rated origin (table 50). The

figures for these 2 years may therefore be Used as suitable for comparing

llCenrisy with effusion with pulmonary tuberculosis, and the occurrence of

h)Iiirisy with effusion in troops overseas and in tile United States.

It. will be noted that the rate was appreciably higher in troops overseas

than in tl'ose in the United States, where, it will be recalled, the admission

rate for pulnonary tuberculosis was higher than in troops overseas (chart

18). However, great significance should not be attached to this apparent

37 Aronson, J. D. : The Occurrence and Anatomic Characteriatics of Fatal Tuberculosis in the

U.S. Army During World War II. Mil. Surgeon 99: 491-543, November 1946.

'is See footnote 29. p. 356.
TUBERCULOSIS 371

discrepancy. The advent of pleurisy with effusion is generally sudden and

dramatic with fever, pain. and other synmptoms: the diagnosis, therefore, is

relatively early and easy. Pulmonary tuberculous infiltration, on the other

hand, is usually insidious in )rigin and diagnosis on a symptomatic basis,

relatively late. It is quite reasonable to suppose that almost all of the serofibrinous pleurisy developing overseas was diagnosed there, whereas pulmonary tuberculosis acquired overseas in many instances was not detected

until the return of the afflicted soldiers to the United States.

TABLE 50.-Incidence of tuberculosis of pleura and serofibrinous pleuritis in the U.S. Army,

1944-45

[Rate expressed ats number of cases per annum per 1,(M average strength)

Continental Outside

Category Total Army United States continental

United States

1944

Tuberculosis of pleura --------.---------------- 391 75 316

Serofibrinous pleuritis - 3,320 1,500 1,-20

Total cases -------------------------- 3,711 1,575 2, 136

Total rate ----------------------------- 0.48 0.40 0.56

19415

Tuberculosis of pleura --------------------------- 745 160 585

Serofibrinous pleuritis ------------------------ 2,520 900 1,620

Total cases ---------------------------- 3,265 1,060 2, 205

Total rate- - - --- 0.44 0. 36 0.50

All clinical experience indicates that the prognosis of cases of pleurisy

with effusion, even without radiologically demonstrable pulmonary infiltration, is doubtful for at least 5 years. Texts and articles on the subject, in

general, emphasize the fact that. 2.5 to 50 percent of the cases of effusion

inadequately treated. that. is, not subjected to a period of rest of several

months following absorption of the fluid, develop pulmonary tuberculosis

within 5 years; thereafter, the incidence is like that in the general population

of corresponding age.3 9 The Army figures cannot be expected to reveal the

total incidence of pulmonary tuberculosis developing in cases of pleurisy

with effusion, for the critical 5-year period had only commenced in the majority of cases when demobilization began. It is possible that men who had

had short attacks of pleurisy with effusion and were returned to duty with9 (1) Thompson, B. C. : Pathogenesis of Pleurisy With Effusion; A Clinical, Epidemiologlcal

and Follow-up Study of 190 Cases. Am. Rev. Tuberc. 54: 349-363, October-November 1946. (2)

Thompson, B. C.: Prognosis of Primary Pleurisy With Effusion. Brit. M.J. 1: 487-488, 12 Apr. 1947.
3 72 1NFFCTIoI:* D)ISEASES

outl rt'sitliia. and ult imatelyv d ist-i irged fioiii thle Armly uW ili ntegat ive X-ray

fili ns of til vl'cest or. Ito aiioiiia lv ot her I bai a cost al d iaphlragmuat ic atilliesilil nIIav vtet dlevelop) jJpiivolr'iavi t~iIbet-Icloiis) as a result ofte linfec11tion11

mtanifested originlally only by tile pleuriisy. (Care aind volipeulsat loll In these

cbases Will be adjudication problemus for tilie fuiture.

As has kweti pointe'd ouit. Ini the variouls hleatersý tilie rate of adIII ISSiou1

for serotibritious plteurisy inl the Arm %iv asgrnral 25o 30 lx-rct'nt of the

rate of adlmtissiont for piul iioiia 1w tilericitlosis. III view of thle probablnle t ulbert'ii1lous nature of tile great miajority of vases of effuisioni inl which tidwerilosis

coul1d ntot be 1uiiequivo-al ly dliaginosedl by laboratory methlods. it mnight see?,1

approp~riate to add tilie admissions of serotibri nolls pleuirisy to those for PI)II

mlonla i tutberculosis to arriVe at a t rue rate for. thlt latter. nIlis wouih not

be accurate, hlowever, as there Wouild be a not inlsignitihcaut dupl)1icat ion of

Vases. Meni With Ii di( agnosis of pleurisy wit h effuision il lthe admitissioti rec(-

ortls %%.Io retutirnied to diuty a fter recovery were subsequent ly. inl aul undetermitined nuinlier of cases. griven a not her diaguo0sis, and entered inl tilt' miedical

statistics of tile, Army as pat itnts W ithi pulmtoinary (tubercullosis.

Ill suminiiarv. it appel's~~ Warraintedi to believe thlit tuhie retilolls p)Ilerisy

did4 occurll miore frequuellv, i.iil troo ps serving overseas than hil t hose Who neve~r

left the U nited States. and it seemis reasontable, even With duelt allowance for

g4rieater P)hYsica1 strainl aind ot her factors that iliiglit be pert inenlt. to at tribute

helt greater frequencey, as did( the Canadians, to the greater exposure overseas, where civilian poputlat ions wvere, itiore heavily infected titan in t he U nited

States. 'Much further research, taking into accounit tilie age and1 home residence of soldiers, who developed tuberculous p)lt'lrisy Withi effusionl. will be

n~eededl to suppor-t tilie ( aiiadian view that thie majority of cases of effusion

rep~resented recent primaitry t uhercid ous infect ionis.

'Fthe Amierican exiperieitcle also indicates te lievieessit v for a honig-raitgt'

View of time p)rognosis of pleturisy Withi effusion, Withi recogniitionl not merely

of imimediate necessities for mianpower. butt also thle quest ionable prognosis

ill thle. long run, cf mnim seemiingly recovering without residuat and ret it-Ited

to military dutty.

SPONTANEOUS PNEUMOTHORAX

Thle view once p~revailed1 that the great majority of cases of spmittaiteouls

pneuniotlmoriux were c'ompllications of pu~lmonary tublerculosis. In 1932A. in his

textbook~~~~~~ ontbruoi.Fsbr "epesed tile general opinion that So

percent of cases were in that categrory. Subsequent investigation showed

spontaneous pneumuiothiorax to IK' no0t 1iinCOlntnoimly anl independent dlevelop)-

mlelit. 41 Such, as seen in thle Armyv. it was uisually found to be.

411 Fiiihberg. Maurice : 11ini1ona~ry Tuberculoiý'h. Volumew 1. E~tiology. P'at hogeniesis, 5ym~to~nlatotogy. Roentgenoiogy. Clinical Formse. 4th edition. Piliiadelphia : 1A.l & Febiger. 1932.

41 For a studiy of 58 cases. bibliograph1y. and disem-loiqn of plathogenesl~is see Ornstein. G. G.. and

Lercher. L.. : pontaneousa i'nouniotiioratx in Apparently ilenithy Indiividiuials. Clinical S-tuday of

Fifty-eight Camem WVith a Discussidon of Me. P'athogenesisa. Quart. Bull.. Sen1 View Ilosr. 7: 149 187.

April 1942.
TUBERCULOSIS 373

During the years 1942 to 1945, inclusive, 3,831 admissions to Army hospitals for spontaneoub pneumothorax were recorded. The great majority

were nentuberculous. This number, ini a total of approximately 11 million

men. represented about 1 case per 2,700 men in the cumulative experience of

4 years.

The incidence of spontaneous lieunlothorax, as indicated by rates of

admission and readmission for the continental United States and the oversea

theaters during the 4 war years, is presented in table 51.

TABLE 51.-Admissions and readmissions for spontaneous pneumothorax in the U.S. Army,

by area and year of admission. 1942-45

[Preliminary data based on sample tabulations of individual medical retords]

[Rate expressed as number of new admissions per annum per 1,000 average strength]

Admisqions Year and area of admission Readmissions

Number Rate

194•

Continental United States --------------------------- 384 0.14 8

Outside continental United States ------------------------ 56 . 10

Total Army --------------------------------- 440 0. 14 8

1943

Continental United States ------------------------- 930 0. 18 25

Outside continental United States ------------------- 163 . 10 2

Total Army --------------------------------- 1,093 0. 16 27

1944

Continental United States --------------------------- 805 0.20 15

Outside continental United States ------------------- 353 .09 6

Total Army --------------------------------- 1,158 0.15 21

1945

Continental United States -------------------------- 585 0.20 20

Outside continental United States ------------------- 555 . 12

Total Army --------------------------------- 1,140 0.15 20

1942-45

Continental United States -------------------------- 2,704 0. 18 68

Outside continental United States ---------------- 1,127 . 11 8

Total Army ------------------------------- 3,831 0. 15 76
374 INFECTIOUS DISEASES

A\s the figures show. tlie admnission rate over,'eas was consistently less

thani in the Uinited States, a1 fact perhiaps nerelt v indicatintg that a ý.ohlier

predisposed to spontaneous pnelmeniolhorax by anatoImiical defect or other

cause was likely to develop it in his early Army training if at all.

In 10)43, when there were 930 hospital adimissions ill the coniinental

I[nited States for this cause, aiid niedical ollicers were inl doul t as to propwr

treatnient. tile Sub6oinlniittee on I'llIK'rulilosis. Nat ionial lResea rch (CUli ilc i, was

asked to study the sutbject. and inake recomnmnendations on trealtnent. This

request. resulted in tile 1l1l1i'atloll of t dO'Iliiient 1y vhe ()fliee of Medi':ul

Infornation of tihe I)jvision of Medical Sciences, National Researvl' ('ouncil,

which was given wide (list ribuit ion in I'.S. ArIi iiedic.al installations. 42 At

lile same thile. an article was published in tilie hil/cf/; of /th U...I r,,.,

.Medlvatl Depart,/ment calling attention to the frequelcy of Slltaneous pneuiiiothorax, tile deticiencies in pIresent-day treatinlent. the need for ilidividutalization in treatmnient. and thlie dangers inherent in tile several mlethodis available.43 Whi note ointed out that up to tile t lime of it., writing. spoiita nell s

piieilinothorax had been considered of sufficient gravity to warrant separation

froil the service ill 15 percent of cases and that tihe av'lrage duiration of liospitalization for this condition had been 40 days.

In the doemnenit published by the National Research Council. a useful

Classification was given, with pertinent material on diagnosis and prognosis.

The relationshiip to mullec in tlie lung was indicated, although it is known

that very frequently such bIillae cannot. be denlonst rated during life by ally

radloholgical or other met hod. (onserva t isll ill t|realtilent was recommliiellnded.

Phronipt hospitalization was required, with avoidance of physical ef'ort. Special warning was giver against translportation by air. It was noted that the

air in the pleural space is ablsorbedl sponitaneously in ]lost cases within a few

weeks. Aspiration at. short initervals may be desirable for a, few days at the

st a rt.

'File vliief problen it, spontaneous lieuiiiotlhorax ill tile Arinyv was recrlllrelice. \Warinigvs review ift tie literatuire indicated recurrence in 10 to 24i

percent of cases. Most of the discharges from lite A.rmny for spontaineotis

pliellnolholrax were for recurrence or persistence. In iany of these cases.

various methods of olditerating lte pleural space to prevent recurreniie were

tried. Two that mllet with soiiie success were injection of whole blood fronm

tile patient and insuillationi of powdered tale. In Warings report, the dan42 Waring, .1. .1. SpontaIneo l u'OI.s Vio-tllihorax. Of lhtve of Medival linformaii (on. Division of M.di lcvat Scienh cP,. National RtI m erch €(omiell. .Jily 11144.

43 ( i l• r so•n'. 1P. P.. Stt cier. L,. G .. anid (ChIlii 3. .n . S. Spoilntaollt'oils Pnet 10tilothont i in Sohlhe rm.

Mill. U.S. ArmyN M. De)t .No. 82 1:2 107, No.i.'aiiwr 1944. 121 Spionltaneio'oius 1lnemnnot horix. Bull.

U.S. Armny M. Dleipit. No. S2: 2!l. Nov,'iilmir 1944.
TUBERCULOSIS 375

gers of induced "'chenmical pleuritis." particularly uniicoiILrollable thickening

of the pleura, were discussed. 44

In general, the Armny experience indicated that spontaneous pneulnothorax is a not uncommon phenomenon; that, it is favored by exertion, but

may occur independently of any physical strain; that recurrence is not. infrequent and may necessitate discharge; and that individualization is neeessary

in treatment. Account was taken of its importance for induction by thle

requirement, in late revisions of .'riny Regulations pertaining to physical

standards, including Mobilization Regulations, that men with a verified history of spontaneous lneulnothorax within 3 years, or recurrent spontaneous

peunmothorax at any time, should be excluded from service.

MORTALITY FROM TUBERCULOSIS

[Figures on mortality from tuberculosis in the Army are not highly significant. Active tuberculosis was rarely compatible with return to active duty,

and accordingly Army Regulations required diseharge of patients after diagnosis and such initial hospitalization as was necessary to insure the best results in a Veterans' Adininist ration hospital or civilian hospital after discharge. It was specifically stated in AR (Army Regulations) 615-361, 14

May 1947, however, that moribund cases were not to be discharged. Hence,

the deaths that occurred from tuberculosis in the Army represented cases in

which the disease was far advanced on discovery, acute in its progression, or

first diagnosed and hospitalized in regions where early evacuation was not

possible.

During World War II. the annual mortality from tuberculosis in the

Army averaged about 3 per 100,000 while in the civilian population of corresponding age the rate was about 50 per 100,000. The corresponding figures

for World War I were, 67 in the military population and over 150 per 100,000

in the civilian population.

The incidence and characte" of fatal 4uberculosis in the Army formed

the subject of a special investigam n.45 in which comparison was made of the

pathology of the disease in white and in Negro troops. In general, the evidence favored the view that the Negro race has a lower inherent resistance to

tuberculosis than the white race, for, in spite of approximate uniformity of

environment, Negro troops. representing only 10 percent of the population

of the Army. contributed 43.4 percent of the deaths from luberculosis. Unusual differences were not observed in the extent or character of tuberculosis

44 (1) See footnote 42. p. 374. (2) For a further discussion of the treatment of spontaneous

pneumothorax see Blades, Brian B., Carter, B. Noland, and DeBakey, Michael E. : Surgical Aspects

of Diseases of the Chest. In Medical Department. Vnited States Army. Surgery in World War II.

Thoracic Surgery. Volume I1, ch. X. [In prepaaration]-J. B. C., Jr.

45 See footnote 37. p. 370.
376 INFECTIOUS DISEASES

in the different organs in tile two races. Highly destructive tuberculosis was

somewhat more frequent in tihe lungs of Negro than in white troops, and

healed tuberculosis was a more common incidental finding in white than in

Negro troops. In white sohliers, the central nervous system and genitourinary organs were more commonly affected than in Negro troops, and in the

latter there was higher incidence of tuberculosis of lymph nodes, bones, and

peritoneum. Tuberculous miemii ngitis was slightly more common in Negro

than in white soldiers.

In both races, the d(uration of the disease appeared remarkably short as

compared with that in the civilian population. The reason for this has already been given; namely, the likelihood of discharge of chronic cases before

death could occur. A relatively high incidence of fatal tuberculosis occurred

in recovered prisoners of war who had suffered privations for many months

in prison camps overseas.

Although the mortality from tuberculosis among troops actually in service does not yield statistically significant figures, such figures can be obtained

by combining the mortality totals for the military population in service and

discharged. Figures so compiled indicate that a steady rise has occurred in

the mortality from tul)erculosis in the group) of men accepted for service in

the Army since the beginning of World War 11.40 During 1942, the comnbined rate for troops in service and troops previously discharged was approximately 3 per 100,000 per annum; thereafter, it rose to 6 in 1943, 10 in

1944, and 12 in 1945.

This steady rise indicates that tuberculosis continued to increase with

time in a group generally well screened by X-ray examination before induction. There is reason to believe that the rise was due to several factors, including slow and ultimately fatal development of previously unrecognized

disease present at the time of acceptance and the acquisition of infection

from outside sources during the years of military service. For comparison,

it may be noted that during the years under consideration the tuberculosis

death rate for the civilian population of corresponding age remained, with

minor fluctuations, at approximately 52. Thus, the rate for the screened

population was far below that of the corresponding unscreened population,

which included those screened out because of tuberculosis. The rate which

the disease will ultimately attain will depend on many factors, including

measures against tuberculosis in the general population and special measures

for veterans taken by the Veterans' Administration.

Eight hundred and six deaths from tuberculosis were recorded in Army

personnel from 1942 to 1945, inclusive (table 52).

46 Long, E. R.: Tuberculosis in a Screened Population. Ani. Rev. Tuberc. 54: 319-320, September 1946.
TUBERCULOSIS 377

TADBLL 52.--Deaths due to tuberculosis in the U.S. Army, by broad area of admission, rank, sex,

race, and year of death, 1942-45

[Preliminary data based on tabulations of individual medical records]

[Rate expressed as number of deaths per annum per 100.000 average strength]

Male personnel

Total Female

Army Enlisted men personnel

Year of death anod area Totnl Officers

of admissionTotal I Non-Negro Negro

Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate Nune- Rate Num- Rate

her her her ber ber ber her

1945

Continental United States.. 92 3.46 91 3.44 1 0. 57 90 3. 65 58 2.53 1 32 17.94 1 7.89

Outside continental United

States -------------------- 15 2.56 15 2.57 1 2.76 14 2.56 12 2.30 2 7. 66 0----- 0

Total Army-.------107 __ 3.30 _l__ 106 3.28 _ 2 0.94 104 I 3.45 _____ 70 _ _ I2.49 34 16.63 1 1 6.5&2

1943 .8 [

Continental United States-. 146 2.82 145 2.83 4 0.96 141 3.00 73 1.70 68 16.&16 1 1.63

Outside contbiental United

States ----.--------------- 46 2.73 46 2.74 ------ 0 46 2.97 35 2.45 11 8.99 ----- 0 0

Total Army ---------- 192 2.79 191 2.81 4 0.74 187 2.99 108 1.89 79 14.86 1 I 1.40

1944

Continental Unittd States.. 89 2.24 89 2.28 7 1.72 82 2.35 40 1.26 38 12.12 0

Outside continental United

States -------------------- 112 2.93 112 2.96 2 .66 110 3.15 58 1.85 49 14.09 . 0

Total Army --------- -201 2.58 201 2.61 9 1.27 192 2.75 98 1.55 87 13.16 - 0

1945

Continental United States.. 63 2.11 61 2.12 7 1.63 54 2.20 26 1.15 26 13.17 2 1.99

Outside continental United

States ----------------- 243 5.46 243 5.51 13 3.69 230 5.66 134 3.69 82 19.05-- 0

Total Army ---------- 306 4.12 304 4.17 20 2.56 24 436 160 2.72 108 17.20: 145

164.9-45

Continental United States_ 390 2.64 386 2.65 19 1.33 367 2.80 197 1.64 164 14.93 j 4 1.63

Outside continental United I 4 

States --------------------- 2416 3.9.5 416 3.98 16 1.96 400 4.15 239 2.74 144 15.54 1 ------ 0

Total Army ---------- 806 3.18 802 1 35 1.56 767 3.37 436 2.10 308 115.21 4 1.23

I Because it includes "race unknown," the total number of deaths among enlisted men may be larger than the sum of

the figures shown for the separate racial categories.

SOf the total deaths in 1942-45 that were admitted overseas approximately 52 percent had been evacuated to the Zone

of Interior during 1942-45. By year of deaths, the proportions were- 7 percent for 1942, 37 percent for 1943, 54 percent for

1944, and 57 percent for 1945.
378 INFECTIOUS DISEASES

Part IV. Hospitalization and Treatment in the Zone of

Interior

GENERAL PRINCIPLES OF EVACUATION

For accounts of evacuation of tuberculous patients from the different

theaters, the reader is referred to sections of this chapter in which the experience of each theater is described. In the early days of World War II,

evacuation was by transport, for neither hospital ships nor planes were available. The best facilities available on troopships were accorded tuberculous

patients, but this mode of transfer to the Zone of Interior had obvious disadvantages. Quarters were crowded, nursing attention was minimal, facilities for proper care were inadequate, and suitable provision could not be

made for isolation.

In contrast, when hospital ships became available in sufficient numbers.

the transfer of tuberculous patients from oversea theaters was handled in a

creditable manner. As a rule, quarters designed for contagious diseases were

used, so that isolation was feasible, and both nursing and medical care were

more nearly adequate. Hospital ships had good laboratories and suitable

X-ray apparatus and, as a general rule, a sufficient number of nurses. Port

surgeons issued directives in early 1945 covering the care of patients en route

and the sanitary precautions to be taken.

Early in 1945, when the number of tuberculous patients returning from

overseas was fairly high, attention was drawn to the fact that convoys were

often so large that the surface water, which was pumped into ships for bathing and other purposes, was contaminated to a noticeable degree by sewage

from the ships of the convoys. Recognizing the fact that tubercle bacilli

might be present in the discharges from tuberculous patients, and be unwittingly drawn into the water supply for scrubbing and deckwashing in rear

ships of convoys, the Office of the Surgeon General forwarded a letter in

March 1945 to the New York Port of Embarkation outlining principles to

be followed to prevent this type of contamination. Suggestions from the

Office of the Surgeon General, including a statement on general measures in

the care of tuberculous patients en route, were embodied in Circular Letter

No. 10 from the Port Surgeon. New York Port of Embarkation, 26 'March

1945, entitled "Care. of Tuberculous Patients During Water Transportation."

This circular established important provisions for sputum control, emphasizing (1) education of patients. (2) use of gauze for cough, (3) use of sputum cups, and (4) decontamination of quarters following their use by tuberculous patients, as well as the principles of isolation and proper care of utensils and laundry.

It was required that gauze, tissue, sputum cups, and bags containing

gauze and other contaminated material be destroyed each day. It was recommended that if burning, the most satisfactory method of disposal. was not
TUBERCULOSIS 379

practicable, the material to be destroyed should be placed in cloth bags of

appropriate size to be weighted and sunk. It was pointed out that this infectious material should not be cast overboard indiscriminately to possibly

contaminate the water pumped into the other ships.

The danger from indiscriminate use of sea water around convoys does

not however appear to have been great, for tests for the presence of sewage

carried out at the rear of large convoys failed to reveal any great amount

of ('ontailillation, but the effort was considered worthwhile from the standpoint of public health practice.

Circular Letter No. 10 emphasized rest for the patient, avoidance of all

unnecessary activity, proper ventilation of quarters, and an adequate diet.

It was indicated that a diet including liberal quantities of milk, eggs, butter,

orange juice, tomato juice, and meat was practicable on board ship. Ordinarily, the standard diet of the ship appeared suitable if supplemented by

midmorning and midafternoon feedings of orange juice, tomato juice, or milk.

Not infrequently it was necessary to administer pneumothorax en route

to patients in whom this form of therapy had been instituted overseas. Qualified medical personnel were not always available for this purpose, but in the

late months of the war every effort was made to insure the presence on each

hospital ship of a medical officer trained in the administration of pineumothorax.

Airplane transportation ultimately proved most desirable for the majority of tuberculous patients. It was suitable for all those with early disease,

and for the majority with moderately advanced illness. Patients with large

tension cavities and those with artificial pneumothorax were usually not

transported by air. A specific study of the effects of air travel on patients

with tuberculosis was made by the Army Air Forces. The Office of the Air

Surgeon, on request for an opinion, sent the following communication to the

Office of the Surgeon General: 17

With respect to transportation of tuberculous cases, experience gathered during the

past 24 months has shown that patients whose medical condition warrants movement

suffer less shock and embarrassment when moved by air than by other means of transportation. Patients with active pulmonary tuberculosis have been flown for long distances at altitudes of 20,000 feet or more (with constant use of oxygen) without ill

effect. Air movement of patients is routinely carried on at altitudes between 2,000 and

8,000 feet, except when weather, terrain, or military operations force the planes to higher

altitudes.

Sound medical judgment of the responsible medical officer in each individual case

must remain the final answer as to suitability for movement of tuberculous patients.

A special report on the transportation by air of tuberculous patients was

prepared by the Section for Research on Minimal Tuberculosis, U.S. Army

47 Transmittal Sheet, Col. A. H. Sebwichtenberg, MC, Air Liaison Officer to The Surgeon General, to The Air Surgeon, 20 May 1944, subject: Evacuation of Tuberculous Patients by Air, first

Indorsement thereto, dated 18 July 1944.
380 INFECTIOUS DISEASES

Medical Research and I)evelopnment Board and University of Colorado Medical Center, at Fitzsimons General lhospital.48

Transportation of patients with artificial pneumothorax had always to

be given serious consideration.4 9 Intrapleural gas doubles in volume at 18,000

feet, and proportionate increases take place at lower altitudes. The excessive

expansion at high altitudes might be expected to lead to tearing of adhesions

and other untoward results. The problem was one of importance not, only in

oversea transport, which occasionally required flight at high altitudes to avoid

storms and enemy interference, but also in the Zone of Interior, for large

numbers of patients were flown to Fitzsimons General Hospital situated at an

altitude of 5,000 feet in Colorado and Bruns General Hospital situated at an

altitude of 7,000 feet in Santa Fe, N. Mex. Ordinarily, transportation of

tuberculous and other patients was accomplished at the usual altitudes of

commercial flying.

As the war progressed and the return movements of patients reached

large dimensions, it was found that air transport, with proper safeguards,

was without hazard. It was so well developed by the end of the war that it

was considered the method of choice wherever practicable. Most important,

it insured early definitive care in the United States, for such treatment, including collapse therapy, in many cases was not initiated in the theater but

left to the judgment of the hospital charged with long-term treatment of the

patient.

On such flights, it was essential to provide, against possible emergency,

adequate nursing care and technical medical assistance. Ordinarily, a physician did not accomnpany a flight, but a trained nurse was always present. and

the total time spent between the oversea theater and the Zone of Interior was

short. As in transportation by water, proper isolation had to be insured.

Occasionally, tuberculosus patients were sent on the same plane with other

patients, but whenever feasible an entire plane was reserved for their use.

This frequently meant holding patients at hospitals of embarkation overseas

for some days until a sufficient number had gathered.

The Office of the Surgeon General sent a civilian consultant, Dr. James

J. Waring of Denver. Colo., to the San Francisco Port of Embarkation and

Hamilton Field, Calif., to advise on transportation by air and by water of

patients from the Pacific areas. Air transport from these. areas was particularly important because of the great distances involved. From July to December 1944, about 6,000 patients were flown from the Pacific areas to Hamilton Field, and of these 140 were tuberculous.

48 Roper, W. H.. and Waring, J. J.: Air Evacuation of Tuberculous Military Patients. Am.

Rev. Tuberc. 61: 678-689, May 1950.

49 (1) Minutes, Subcommittees on Tuberculosis, Committee on Medicine. National Research Council. 21 Feb. 1942 and 10 June 1944. (2) Bridge. E. R., and Bridge. E. V.: Effect of Altitude on Abnormal Accumulations of Air in the Chest. Am. Rev. Tuberc. 51 : 532-537, June 1945. (3) Tuberculosis Abstracts, National Tuberculosis Association 19. No. 10. October 1946. (4) Duff, F. L.:

Physical Factors itn Air Evacuation. Bull. U.S. Army M. Dept. 7: 860-868. October 1947. (5) Air

Transport of Tuberculous Patients. Bull. U.S. Army M. Dept. No. 87: 8. Anril 1945.
TUBERCUIA)SIS 3S1

In the United States, tuberculous patients were delivered at debarkation

hospitals, whether arriving by ship or by air, and after appropriate triage

were transferred for further care to Fitzsimons and Briuis General Hospitals,

a large number of them by air. Hospital commanders made every effort to

forward tuberculous patients in plane and carload lots to avoid exposure of

nontuberculous patients.

The final conclusion as a result of this experience was that airplane

transportation was most appropriate whenever it was practical. For cases

not suitable for air transport, hospital ships rather than transports should

be used. Emphasis should be laid on proper isolation of cases, on safety,

sanitary precautions, and avoidance of emergency. Finally, experience

showed that medical officers with training in tuberculosis should be assigned

to duty at embarkation hospitals overseas and debarkation hospitals in the

Zone of Interior to insure proper care throughout the course of transfer.

SPECIALTY CENTERS FOR TREATMENT

l)iscovery and treatment of tuberculosis in hospitals overseas has been

described for the several theaters. Hospitals at stations with a troop strength

of over 5,000 men were authorized to discharge. patients with tuberculosis on

certificate of disability, and a large proportion of the total number of certificates of disability for discharge for this cause were granted at station hospitals. In all cases of doubt, however, where the diagnosis could not be established in a station hospital, the patient concerned was sent to a general hospital. Many were sent to Fitzsimons General Hospital which was a center

for treatment of tuberculosis throughout the entire period of the war and

received the majority of commissioned officers and noncommissioned officers

hospitalized for tuberculosis. 50

In the course of the. war, two other hospitals were made specialty centers

for tuberculosis: Bruns General Hospital, and Moore General Hospital, Swannanoa, N.C. Bruns General Hospital, which was activated on 18 February

1943, was made a center in August 1944",' for the treatment of "patients requiring special evaluation or prolonged care in an Army hospital specializing

in tle treatment of tuberculosis." It. had become necessary to supplement

Fitzsimons General Hospital to provide care for the numerous patients with

tuberculosis evacuated from overseas. It was directed 52 that. if male tuberculous enlisted personnel and officers whose homes were in the Eighth Service

Command were evacuated from overseas, they were to be transferred from

debarkation hospitals to Bruns General Hospital. Women were sent to Fitzsimons General Hospital. It may be noted incidentally that Bruns General

Hospital, chosen for reasons of climate and availability, by happy coincidence

was named after one of the Army's outstanding specialists in tuberculosis,

50 War Department Circular No. 338, 18 Aug. 1944.

51 War Department Circular No. 347, 25 Aug. 1944.

52 See footnote 1:, p. 337.
382 INFECTIOUS DISEASES

Col. Earl Harvey Bruns, MC, who had trained many medical officers during

and after World War I and was for years after the, war, Chief of Medical

Service at Fitzsimons General Hospital.

The third specialty center for tuberculosis,. Moore General Hospital, was

established in the late months of the war, when many tuberculous patients

were being found at separation centers.

The official annual reports for the three hospitals named, which are ol

file in the Office of the Surgeon General, give full details on the size of the

medical and surgical staffs, the l)ersonnel changes that, occurred during the

war, the number of tuberculous patients treated, the types of therapy employed, and special problems encountered. At all hospitals, standard methods

of therapy were employed, with principal emphasis on rest and the use of

collapse nieasures in appropriate cases. The extent to which different collapse

procedures were employed depended on the type of case. the special skills

of the hospital staff, and the length of stay of patients. The frequency of

collapse therapy was in inverse ratio to the length of stay in the hospital.

Prior to 1946, except. for a few special cases in which Proinin (glucosulfone

sodium) and Promizole (2-amino-5-sulfanilylthiazole) were employed, chemotherapy was not practiced in the Army. Subsequently, the Army participated

actively in study of the treatment of tuberculosis with streptomycin.5

In addition to their function as treatment, centers, the lhospitals trained

medical personnel for positions of responsibility overseas and in the Zone of

Interior. Indeed. frequent. changes in personnel, inevitable under the circumstances, interfered seriously with the efficiency of the treatment given.

Fitzsimons General Hospital.-Col. George F. Avcock. MC, was chief

of medical service throughout. the period covered by this history. Lt. Col.

(later Col.) John B. Grow, MC. was chief of surgical service, and Maj. (later

Lt. Col.) Richard I1. Meade, MC. was assistant chief and later chief of the

thoracic surgery section.

Cases of tuberculosis exceeded those of any other disease, since the chief

purpose of the hospital was "to give treatment under [the] most favorable

conditions to patients [suffering] with tuberculosis." 54 During 1942, 1.273

enlisted men were admitted to the tuberculosis section 55 and 106 officers including nurses were admitted for tuberculosis. At the end of the year, 800

enlisted men were under treatment. The practice was to retain cases of pulmonary or predominantly pulmonary tuberculosis on the medical service, and

cases of genitourinary, bone, joint, and lymph node tuberculosis on the surgical service. Artificial pneumothorax and pneumoperitoneum were practiced

on the medical service, and phrenic nerve operations, intrapleural pneumonolysis and extriipleural thoracoplasty, as well as less frequent operative proce53 U.S. Veterans Administration: The Effect of Streptomycin Upon Pulmonary Tuberculosis.

Preliminary Report of a Cooperative Study of 223 Patients by the Army, Navy and Veterans Administration. Am. Rev. Tubere. 56: 485-507, December 1947.

54 Army Regulations No. 40-600, 6 Oct. 1942.

O Personal communication, Executive Officer. Fitzsimons General Hospital. to Col. E. R. Long.

MC. 19 Mar. 1947.
TUBERCULOSIS 383

dures, were carried out on the surgical service, with return of patients to the

medical service following convalescence. During 1942, 320 artificial pneumothoraces were induced and an additional 147 were continued after previous

induction. Thus, more than a quarter of all the patients admitted were

treated by pneumothorax. On the surgical service, 171 thoracoplasties, 187

pneumonolyses, and a small number of pneunmonectomies and lobectomies were

performed during 1942.

The report for 1942 indicates that 20 percent of all cases of tuberculosis

had nonpulmonary tuberculous complications, of which tuberculous laryngitis, tuberculosis of the genitourinary tract, tuberculous enterocolitis, and

tuberculosis of the bones were most, common. Of nontuberculous complications, diabetes was most frequent. One-third of the cases under pneumothorax

treatment developed pleural effusion, a figure that had held during several

years of previous experience.

In 1943, there were. marked fluctuations in admissions and discharges of

tuberculous patients. The tuberculosis section remained the largest section

on the medical service; 1,405 enlisted personnel were admitted. However, the

census dropped sharply following publication of War Department Circular

No. 109, 26 April 1943, which directed discharge to the Veterans' Administration of men unfit for military service and so abrogated the. previous practice

of holding patients for at least 6 months. During the year. there were 1,332

direct admissions of enlisted men for tuberculosis, and 634 tuberculous patients remained at the end of the year. There were 1,585 discharges from the

section, chiefly on certificate of discharge for disability, and 65 deatths.

The proportions on different forms of collapse therapy were approximately as in the preceding year. There were 239 pneumothoraces initiated

and 12,044 refills given. On the surgical service, 428 operations for tuberculosis were performed, including 180 thoracoplasty stages, 184 phrenic nerve

operations, and 49 intrapleural pneumonolyses.

As in the preceding year, pleural effusion developed in 33 percent of the

pneumothorax cases, usually (85 percent) serofibrinous, but occasionally (15

percent) purulent. Nonpulmonary tuberculous complications were of the

same frequency and nature as before. Among nontuberculous complications,

coccidioidomycosis was the most frequent, its incidence in the Army having

notably increased as a result of desert maneuvers.

During 1943, with the longer progress of the war, there was a noteworthy

increase in the number of officers admitted (277 males and 86 females). Of

this number, 132 were discharged, chiefly by retirement.

In 1944, the number of admissions for tuberculosis (1,895) was somewhat

larger than in preceding years. The number of cases given collapse therapy

was somewhat smaller, and the number given pneumoperitoneum slightly

larger, the indications for the latter therapy having become more clearly defined. Pneumoperitoneum was considered of value in those cases of tuberculosis in the exudative phase in which it was unwise to attempt pneumothorax,
384 INFECTIOUS DISEASES

as well as in cases with basal and perihilar excavation. A remarkable constancy was apparent in the incidence of pleural effusion as a complication of

artificial pneuniothorax, as it occurred in 32 percent as compared with 33 percent. of cases in each of the preceding years.

In 1944. there was a sharp curtailment in the. use of surgery: only 33

thoracoplasties were performed. This was due to the shorter average stay of

patients, owing to the heavy demands on the. hospital not only for cases of

tuberculosis but also for other illness. During this year, however, 15 lobectomnies were performed, the indications for this operation having become

clearer within the preceding year. In general, cases with an excavated, but

well-stabilized lesion, confined to one lobe, were considered most suitable for

lobectomy.

During 1944, the number of cases in enlisted men evacuated from overseas. which had heretofore formed a substantial proportion of the total, decreased markedly, as a result of the designation of Bruns General Hospital

as a center for such cases, However, the number of officers from both overseas and the Zone of Interior increased greatly. with 647 admissions (56t

male and 86 female). There were 419 tuberculous officers discharged by retirement or other procedure.

A significant development during 1944 was the activation, in January.

of the Section for Research on Minimal Tuberculosis. This section was developed by the Office of tihe Surgeon General on the advice of the Subcomumittee on Tuberculosis, National Research Council. It was sponsored and suplprted financially by the Army Medical Research and Development Board.

The subcommittee felt that the Army, with its large number of well-studied

cases, afforded a unique opportunity for investigation of the prognosis of mimnimal tuberculosis and the reasons for the breakdown of small or incompletely

stabilized lesions. A contract. was drawn by the board with the School of

Medicine, University of Colorado, Denver, located only a few miles from

Fitzsimons General Hospital. an( I)r. Waring, Professor of Medicine, School

of Medicine, was designated as responsible investigator, with Coionel Aycock,

Chief of Medical Service, Fitzsimons General Hospital, and Colonel Long as

consultants. Capt. (later Maj.) William H. Rop'-r. MC. formerly chief of the

.,etion for chest, diseases at the Station Hospital, Fort Bragg, N.C., was

assigned, through Seventh Service Command Headquarters, to Fitzsimons

General Hospital for the detailed prosecution of the investigation, which

was to be based on an intimate study of the history and progress of 1.000

cases of tuberculosis of minimal extent.

By the end of the year, 400 cases had been studied with care. In .Tme

1946. the final number was 1.108. This number included 648 cases of active

and 3(50 cases of inactive minimal parenchymal disease; in addition, there

were 110 cases of pleural effusion presumed or proved to be tuberculous in

origin. In 397 cases, the investigation included an intensive psychiatric

examination to determine the influence of emotional and personality factors
TU B EtRCULOSI S 385

upon breakd )wn with tuberculosis. This exanmination was conducted by Dr.

John M. Lyon. D)epartmnent of Psychiatry, School of Medicine. University

of Colorado.56

I)uring 1945, the tuberculosis section of Fitzsimons General Hospital was

more active than in any preceding year. There were 2.474 admissions to the

enlisted men's section. The average numnber of patients was greater, and collapse therapy was carried out on at larger scale than heretofore. There were

448 initial pneunmothoraces, and the total number of refills, in spite of the

relatively short duration of residence that was necessary in order to accoin1u1odate new cases. was 11,265. Pneumoperitoneum was induced in 136 cases.

,he surgical service there were 3 pneumonectoinies, 34 lobectomies, and 7

al lobectomies for tuberculosis.

During the 4 years of the war, Fitzsimons General Hospital admitted

,re than 8.100 patients with tuberculosis. The mnorale of both staff and

tatients was excellent, and the treatment was equal to that in the best civilian

hospitals in the country. In view of the usual early transfer of patients, rehabilitation measures were not extensively employed, although there was provision for occupational therapy. Long before the maximum results of treatment. could be attained, regulations required discharge of patients to the Veterans' Administration or other institutions for care. Results in terms of cases

arrested or improved, or stationary or unimproved, cannot, therefore, be given

for evaluation or comparison with results at, other hospitals. Only through

careful followup of cases handled by the Veterans' Administration will it be

possible to determine the effectiveness of several months of treatment at Fitzsimons General Hospital in bringing about lasting arrest of cases.

The pathology service, under Col. Hugh W. Mahon, MC, made careful

studies of necropsies and maintained a series of records that were of unusual

value, because of the wealth of photographic reproductions included. The

majority coming to autopsy were chronic cases, fibroulcerative in character,

although there were some more acute cases, including a number with fulminant, tuberculous meningitis. In general, post mortem observations made in

the Army were not significantly different from those in large civilian hospitals

and sanatoriums for tuberculosis.

Discharge and retirement constituted a problem that was, at times, difficult. Since patients could not be held for the many months required for complete arrest of the disease, discharge had to be effected on the basis of disability, with such compensatory benefits as accrued. In cases of advanced

tuberculosis, no problem was involved. In cases of early tuberculosis of minimal extent, apparently well scarred after a few months of treatment, the

appropriate course generally appeared to be to discharge patients on the

basis of disability, even though no symptoms persisted and prognosis was

excellent. This disposition also appeared generally indicated in cases of

56 Waring. J. J., and Rolwr. W. H. : Minimal Pulmonary Tuberculosis in Military Personnel:

World War II. Ani. Rev. Tubere. 75: 1-40, January 1957.

639243--63--28
386 INFECTIOUS DISEASES

hleale(I lleliral effulsionl ill which all fluid wiIs albsorbed, no0 pulmonary infiltratioll wats evidenit, and exclulsion studies indicated that the procss witrs presumpjtively tuberculous. Since tuibercullosis is t dlisease prone to relapse if at

proper regimen is not followed, it wits nlecessatr to conlsider such cases ats px)-

tentially active for some years. Similar collsidlerations ap~plied to tulberciilosis of lympIh nodes wheni nodes with dloubtfuilly active t iilereliilolls lesion~s

had been remuovedl and tiibercullous foci were not found elsewhere lin the lxxiv.

Such cases were finally resolvedl inl favor of the soldier. and usuially onl thle

basis of proved tuhercuilouis activity during minliitary service.

Bruns General HospitaL.-This hospital was designated a specialty center

for tuberculosis in Akuguist 1944, with ani allocation of 750) beds for tuberculosis. Lt. Col. (later Cot.) George .1. Kastlin, MC, was chief of Medical Service until D~ecemiber 194.5, when hie wits suicceededl by Maj. (latter I.A. Col.)

George C. Owen, MIC, with assistant chiefs inl charge of two large sections

for tuhercillosis. Whien tie (directive of August 1944 wats issuedi, 26 wards

wvere set aside for patients with tuberculosis. Thle. relatively small numtber of

physicians Onl the staff at tile tilme who were well (1 ulalihie( inl thle. treatment

of tuberculosis wa~s auigmenltedl as rapidlyv as possible. Capt. (latter 'Maj.)

Lawrence 11. K~ingsbulry. MC, wisbrouight inl froin thle. surgvical seriea

Fitzsimuons General H~osp~ital as chief of thoracie surgery, and the work at time

two hospitals was coordIinatedl Iby mnutual visits.

Thle hospital hlad t (lifficuilt task, however. for the report 51 for 1944 noted

that tile ralte of growth was miore rapid than the officer. nurse, and enlisted

p)ersonniel could p~rop~erly hiandle. All services felt the impact of the ab~ruplt

(lesignationl of the hospital as at specialty center. At the endl of the year, 697

tuberculous patientts were ill tile hospital. D)uring 1944. 6,118 X-ray films of

the chiest were muade, out of at total of 1:3.7-52 films of all parts of the body.

1Pulitnonary tubercuflosis accounited for 17T percenlt. ( 123 cases) of the (dischlarges

for disability. Tile mnajority of diischmarges were to the Veteranls Adininistrationl andl conlvoys seriously dlepletedl the force of officers necessary to care for

p~at ieilts.

Sincee Brims General Htospital wats (designated to care for cases of tuberculosis fromt overseas, thle morale prob~leml was exceptionally (lifficult. Tile hiospital wats isolated and filled with p)at ients who 1had( not seeni their families for

mlonlths or years. 1nimsilal measures, whlicih proved1 notably successful, were

projected to meet tile problemi (pp. 388-390). Education wats at Irincilpal objective, directed particularly to teach accep~tanlce of continuing care at thle hands

of tile Veterans' Adminmistration after (dischlarge from the liospital.58

lit 194.5. it became necessauw to increase tile allocation of beds to more

than ai tllousanl( because of tile colit innling influx of cases front overseas. The

p~roble~m wats comnplicated in the second hialf of the year by the arrival of mnany

.%Annual Report. Brims Ge~neral Hmospital. 1944. 5~Tin Care' of Tuihrefflowi P'atienta I'eiuina Ilsbacargoý From tie~ Army. IliI .S ryM

1)vimt. 'No. 74 :44- 46, Mlarch 1944.
TU BERCI' IA)8 387

patiients with severe disease who had been liberated from Japanese prison

camps. Personnel needs were great ani, in ifortunately. could not be well

iiiet, because demobilization of medical officers was under way.

Ihi spite of these difficulties, an excellent professional spirit, was maintained. Staff conferences, on the model of those held at Fitzsimons General

Hospital and leading civilian hospitals for tuberculosis, were held at regular

and frequent intervals. and cases were expertly presented and discussed. A

pulnonary function unit was established in order to introduce the latest

methods used in the study of respiratory physiology.

Close contact was maintained at all times with the Office of the Surgeon

General, which was called upon for more direct assistance than was required

by the longer established Fitzsimons General Hospital. The system of supervision, the methods of treatment and disposition, the proportion of cases on

collapse therapy. and the system of clinical conferences were similar to those

at Fitzsimons General Hospital and civilian hospitals for the care of tuberculous patients.

Moore General Hospital.-The third specialty center for tuberculosis.

established in 1945 at Moore General Hospital, was necessary because demobilization of men at separation centers resulted in the discovery of cases of

tuberculosis in numbers exceeding the capacity of Fitzsimons and Bruns

General Hospitals. The lesions found were usually symptomless and of miniinal extent, although occasionally moderately advanced cases were encountered in men who, surprisingly, had been doing full duty and were not aware

of any respiratory disease.

Since Moore General Hospital was not staffed or equipped for tuberculosis, it was necessary to bring in new personnel and to specify that patients

requiring thoracic surgery were not to be sent there. Army Service Forces

Circular No. 456. 29 D)ecember 1945. established the center and specified that

1) cases of minimal extent, (2) unilateral cases of moderatelv advanced

tuberculosis appropriate for pieumnothorax treatment. (3) cases of suspected

tuberculosis requiring prolonged observation for diagnosis. and (4) cases of

l)leurisy with effusion were to be sent to Moore General Hospital. Cases requiring extensive surgical procedures and cases in which the prognosis was

bad were to be referred to other general hospitals or discharged directly to

the Veterans' Administration. Tuberculous patients were l)laced on the mfedical service. of which Lt. Col. .1. Murray Kinsman, MC. was chief when the

hospital was designated as a sl)ecialty center for tuberculosis.

Case, within the first three categories named were frequently found at

sel)aration centers, and the space assigned for tuberculosis at Moore General

Hospital filled rapidly. Within a few months, there were more than a thliosand patients at the center. Most of these had lesions of minimal character,

many of theni difficult. to establish definitely as tuberculous, being of slight

extent. and without demonstrable tubercle bacilli. Thus, many patients remained for several months for exhaustive study to establish diagnosis of the
388 INFECTIOUS DISEASES

disease itself, and its state of activity. 'File principles inl practice were later

summarized inl T11 MEl) (Wvar D epartmient Technical Bullet in) -221, dated

29) April 1946, and chiange, 1 thereto. dlated[ 27 D~ecember 1940'. Moore General

Hospjital wats ultimately ( 1946) transferred to the Veteran,;* Adujinist rat tonl.

obviating physical transfer of patients designatedl for Veterans' Admin iist ra -

tion care.

'[le three general hospitals designated as specialty venters for tiuberelllosis iiorniallv received medical recordIs and X-ray filitis of cases originating

overseas wheni the patients were transferred to thew- hospitals. The reports

frouin Brtuns General H~osp~ital iii(icatt, that. the records were of good quality.

All three hospitals also mlade extensive uise of indluct ion filins of patients

ob~tainied from the X-ray file of the Veterans' Adlministration ill Washington,

ID.C.. where they hiad been stored linuimeiately after indutction. These filmns

proved highly uiseful inl evaluating lie age- of lesions as a guide inl treatmiient

an1d dlisposit ion. The experience at. Fit zsi mons General Hospital ind1icated

that. early- inl the war. whleni cases were not inifrequently overlooked at induction. the patients sent to the hospital were predoiminantitly those inl whos-e inl-

(ltction filmi a lesion ('0111( be seen. Ini the second half of the war, lesions

requiring hospitalization did noin the majority of cae,.apart(ersn

an extension from a lesion visible in the inlidlction fillin. but rather a new

(level ohmieiit dluring( Arilly service.

ORIENTATION AND REHABILITATION

'[ie lproblivin of rehiabilitation of tubercilols, lpat ients in Army hospitalscould not. le met inl the same muannier as with diseases of short duitiation or

woundls and1 accidents leaving a mechanical handicap. With these, the recoi-

(litioninig serv-ices of Army hoscpitalls were highly effective during the p~eriodl

of conIvalescenlce. As r'egardls tuberculosis. however, it was impllractical to retain patients inl Army lioslpitals long enough for arirest. of the disease and rehabilitation. AR 615-361, 14 May 1947. requliredl discharge when the dingnosis of active dlisease and tile need1 for prolonged care were established, although specifically pr'ohibit ing transfer ats long as tile health of the patieint

wohildl he jeopardized.

Ill pI'acti(ee. this regulation was initerprietedl as authorizing that degree

and extent. of care inl an Army hospital necessary to prepare patieints for

transfer-eni istedl ineii to thle Veterans' Admininistrmat tiln and1 officers to their

own care-in the best conditionl to profit by continued lhoslpital tr'eatiment.

Ini the three tuberculosis centers of the Army,, enlisted mene were retained onl

-inl average for 4 months. Officers were hield longer oii the b~asis of the possibility of thieir retention for cointinued service."9

Alt bog eoil tn ftbrulous patients ill Armly hospitals was

thus nlot possible inl the same sense as for p~atients recovering from pneumonia

5Mo Ser footnote' 3. 1). 3:11.
TURBEIIC' IA)SW ;[)

or. fracture of bones, the need for thorough orientation with respect to the

disease was clearly evident. In 1945. on the. advice of the Office of the Surgeon

General, a. department for orientation was establislied at Bruns General Hospital under the direction of Capt. (later Maj.) Bernard 1). Daitz, SiuC. Captain Daitz, with an extensive background of civilian experience in rehabilitatiol of patients with tuberculosis, introduced modern methods of instruction

of patients. winning their confidence, and stimulating an improved morale.

He prepared TB MEl) (War I)epartment Technical Bulletin) 222, dated 16

May 1946, while assigned to Bruns General Hospital, which proved a model

for other Army hospitals caring for tuberculou, patients, and this was later

modified to meet, the special problems of patients under care of Veterans'

Administ rat ion hospitals.

The ideal program in the care of tuberculous soldiers embraced a proper

integration of medical treatment, social work, vocational counseliig, and intelligent. use of the .patient's leisure time. The immediate and most. important

objective was to educate patients concerning their need for continuing medical

treatment. This involved, first, educational measures on the nature of tuberculosis and. second. measures to overcome the apathy, or even resentment, with

which soldiers reacted to provision for their treatment by the Army or other

Federal agencies.

"To train ward officers and other hospital personnel as teachers, a system

of staff indoctrination was devised, which included lectures and discussions

on ( 1) problems of tuberculous patients, (2) pathogenesis and treatment of

tuberculosis. (3) psychology of tuberculous patients, (4) problems in nursing,

(5) problemls in nutrition, (6) occupational therapy, and (7) the best utilization of the Red Cross in the program. A tuberculosis advisory council was

established to implement the program of staff indoctrination and teaching of

patients. All of the services concerned in) the care of patients were represented.

The. orientation program for patients was coordinated by an officer from

the medical service. Since the great. majority of the tuberculous were bed

patients, ward officers were made resl)onsible for instruction of patients on

the natuie of the ,disease. ()n arrival at the hospital, each patient. was given

a copy of "What You Should Know About Tuberculosis," an educational

pamphlet, published by the National Tuberculosis Association and modified

for Army use by the Consultant in Tuberculosis, Ofhce of the Surgeon General. Medical officers with proved special capacity for instruction were sent

from ward to ward to discuss medical problems with patients.

Coum;ehing on other than medical p)roblems was made the respon~ibility

of those best qualified in the various fields concerned, including the educational reconditioning services, the personal affairs division, the Red Cross,

the librarian, and others. It was important at the outset, and concurrently

with the program of medical instruction, to reassure patients as far as possible with regard to the future and to ascertain and develop their educational
390 INFECTIIOUS DISEASES

and vocational interests and capacities. Since most of the patients would

ultimately be beneficiaries of the Veterans' Administration, thle system of care

at Veterans' Administration hospitals and their rights and privileges as veterans under the Vocational Rehabilitation Act (Public Law 16, 78th Cong.)

and the Servicemen's Readjustment Act of 1944 (Public Law :346, 78th

Cong.). more commonly known as the G.l. Bill of Rights, were carefully explaine(i. At the same time, patients were asked to discuss freely their 1personal

prob)lems and their complaints. These principally centered on their isolation

from friends and relatives. Most of the patients had been overseas for many

months, and the long separation from home brought. their morale to a low

ebb. Everything po~ssible within reason was done to overcome this sense of

isolation. The specific complaints most frequently heard were about diet.

and these were more concerned with its p)alatability and serving than with

its basic quality. Serious attention was given to these complaints, and noteworthy improvement in dietarv service was accomplished.

Motion pictures of both educational and diversional character were presented on a sche(lule adapted to the strength of the different groups of patients, and extensive use was made of the library. 'Many patients undertook

studies that yielded academic credit. The vocational interests of patients

were studied by the Kuder vocational interest, test (Kuder Preference. Record). and patients were inade acquainted with the correspondence courses

available through the United States Armed Forces Institute.

Occupational therapy was carried out on a scale commensurate with the

patients' strength. The various forms of light occupation used in Army hospitals were employed. and a large majority of patients availed themselves of

some forii of occupational therapy. Indeed, a major difficulty was to restrain

them. Light occupation was often sought by l)atients whose medical regimen

demanded strict. bed rest.

Orientation programs on a less formal basis were in effect at the other

Army hospitals for the tuberculous. The period of time during which the

p)lan formally established at Bruns General Hospital was in operation was

too short to determine how effective it could be. Some good was definitely

accomplished. This was substantiated by the information obtained from

questionnaires filled out by patients and by their attitude later in veterans'

hospitals. Had the need developed for continued hospitalization of tuberculous patients in Army hospitals. it is believed the program as developed at

Bruns General Hospital would have proved highly effective.

Part V. Care of Recovered and Captured Prisoners of War

RECOVERED PRISONERS OF WAR

Tuberculosis in recovered prisoners of war has already been discussed in

the sections on the individual theaters in this chapter. An increased incidence. as compared with the general rate for troops in the theater, was found
TUBERCULOSIS 391

in men who had been prisoners of the Gernman and Japanese military forces

for some months. Exact. studies of the incidence were not. made, because of a

number of circumstances arising at the time. In the European theater, the

liberation of prisoners in the course of rapid movement of American troops

through Germany occurred at. a time of grave shortage of X-ray film in the

theater. Accordingly, roentgenograms of the chest were not made on all

recovered prisoners, as had been the hope of the Office of the Surgeon General, but only on those who were hospitalized for one or another reason. As

has been pointed out (pp. 344-345). the incidence of tuherc.ulosis discovered in

the hospitalized recovered prisoners in the European theater averaged about

6 men per 1,000, or approximately six to eight times the general average for

troops in the theater. However, the group examined by X-ray were selected

simply because of inalmutrition or evi(dent illness, and it is reasomna)le to suppose that. iet, incidence, of tuberculosis was higher in this group than in

recovered prisoners who appeared in goot health.

Rates recorded for p)risoners recovered in the Pacific area were somewhat

higher. Several reports indicated that approximately 1 percent of the men

recovered in the Philippines had what was believed to be active tuberculosis.

However. plrisoners were recovered at such a wide number of points, where

facilities for X-ray study were not available, that an overall rate for the

Pacific is unobtainable. A board appointed by The Surgeon General, including representatives of several medical specialties, examined 4,618 repatriated

prisoners at West. Coast debarkation hospitals. Out of 3.742 who were

checked with roentgenograms of the chest, 101, or 2.7 percent, showed evidence

of active pulmonary tuberculosis.8 0 A preliminary examination by Major

Roper of films made at Letterman General Hospital on prisoners recovered

in the Pacific area brought to light 8 cases of active minimal and 3 cases of

active moderately advanced tuberculosis, and 2 cases of pleural effusion. Of

this group, only 2 of the minimal and 2 of the moderately advanced cases,

and 1 of the cases of pleural effusion, had been reported on admission to the

hospital. The total incidence of active cases, assuming that the pleural effusions were tuberculous, was thus 13 in 966 or about 13 per 1,000, a figure much

higher than the average incidence in nonprisoner groups at. separation. (See

chart 19 for incidence at. separation in troops with and without foreign service.) Various other individual reports on sample liberated groups, all showed

rates much above the average for troops on duty in the Pacific theaters.

Hence, there is good reason to believe that a general increase of tuberculosis

occurred in prisoners. This was attributed to one or both of two principal

reasons: (1) Breakdown of small latent lesions that might otherwise have

remained stable, and (2) actual acquisition of new infections as a result of

exposure in prison camps. The latter was believed to be much more of a

factor in the Pacific area than in the European theater.

60 Morgan, H. J.. Wright. I. S.. and Van Ravenswaay, A. C. : Health of Repatriated Prisoners

of War From the Far East. J.A.M.A. 130: 995-999, 13 Apr. 1946.
3~92 INFECTIOUS D)ISEASES

In the European theater, as a rule, American p~risoniers were, quartered

inl barracks separate from those used for other p~risonlers. or were qluartered

with British prisoners. Ill either event, there wits relatively little olpportuInity for exp~osure, as the incidence of tuberculosis was compjaratively low inl

both armies. However, as medical officers inl the theater pointed ouit, and as

noted elsewhere in this chapter, frequently prisoners livedl ill quarters that

had been grossly contaminated b~y previous occupants.6 1 The incidlence of

tuberculosis in fiussian alnd other prisoners of war was very high. and from

timle to time p)risoners fromi the U.S. Army' were housed inl quarters that. had

been p~reviously occupIied by Russian and other troop~s and still conutained urnaterial that might. have been infected. such as bedding, furniture, and kitchen

utensils.

Inl many recovered prisoners of war inl whomi tuberculosis was dliscoveredl.

thle disease was comupl icatedl by mnalnut rit ion. Prisoners inl hothI European

and Pacific theaters had been onl anl extremely low caloric (diet anid in genieral

had suffered great loss inl weight. Whether this had a. specific effect upon the

progres-s of tuberculosis could not be. determinedl onl the basis of exact studies.

hut. it relationship between malnutrition andl tuberculosis is generally accep~ted. and it is logrical to assume that impaired nutrition in U.S. troolps

favored tile. development. andl spread of tuberculosis among thenm.

Not at few of the troops had other dliseases, such as dlysentery and malaria.

a111( it. is rea soilab~le to suppose. that resistance to tuberculosis was lowered also

to some extent. by these. concomitant. diseases.

Special attention was (devoted to prisoners onl their return to the United

States, as notedl elsewhere in this chapter, and a good followup was maintainied. Inl view of the hardships that nmany of these nien endluredl. andl the

notorious tendlency for tuberculosis to make its appearance year's after the

acquisit ion of infection, it was considered adlvisable that these mien be followed as a1 special grioulp inl thle Veterans' Admiinistration for years to come.

CAPTURED PRISONERS OF WAR

The miedical treatment of captured German and( .Jalpanese soldiers who

were found to be afflicted with tuberculosis was a part of the general program

of hospital care inl each theater. As p~risoniers were taken, they were trainsferred to applropriate hospitals inl the comnmiunicat ions zone, which were

usually of stat ion hospital type. 'When the iiuiiier of patienits became suflicienitly large. emitire ho-spitals- were reserved for sick pirisoiners of wvar. Each

of the hospitals dlevotedl to the care of sick a1nd woundedl eneimy prisoners

had some lpatijents with tuberculosis. As the number inlcreasedl. it was found

advaltalgeouls to (lesignPlte certain hospitals with suiitab~le miedlical p~ersonniel

for concentration of patients with tuberculosis. The sanme practice. it may~i he

statedl, was followed by the Giernmans.
TUIBERCUtT IOIS 393

Insofar as possible, hospitals designated for the care of sick and injured

prisoners of war were staffed by captured members of the Italian, German,

or Japanese medical departments. Certain hospitals moved forward with the

advancing army, so that the transportation problem in taking care of sick

prisoners wias minimized. For example, the 7029th Station Hospital, which

was in the neighlbrhood of Pisa in the last weeks of the war and housed a

good many tuberculous Italians, had been designated for the care of prisoners of war many months previously in North Africa. The 334th Station

Hlospital (German staffed). near Florence, served an adjoining stockade for

German prisoners and contained a few patients with tuberculosis. A group

of hospitals near Isigny in Normandy were combined to form a hospital center for prisoners of war: one of these, the 8274th General Hospital (Provisional), Calvados, France, was designated to house a considerable number of

captured Germans proved to have tuberculosis. Certain hospitals in England. particularly those that had been previously well staffed with officers

experienced in tuberculosis, including the 304th Station Hospital near Henleyon-Thames and the 327th General Hospital near Blockley, were designated as

centers to which German patients with tuberculosis could be sent.

The general principle followed was that prisoners with tuberculosis

should be sent to those hospitals where. German doctors with particular experience in the disease were members of the staff. A wide variation was

found in the caliber of the men concerned, but in general it was good. Diagnosis by radiological and laboratory methods was excellent in certain of the

hospitals just named, and care was superior within the limitations of equipment available. The discipline among patients wias especially noteworthy.

The same amenability to discipline in German prisoners was noted when they

were treated for tuberculosis in the United States. Pneumnothorax was practiced expertly by German physicians, many of whom were graduates of medical classes after 1935.

After the termination of hostilities, as conditions became more stabilized

for medical care in Germany, patients with tuberculosis were transferred to

hospitals within the American occupied zone in Germany.

Treatment in the United States

Cases of tuberculosis were discovered in all groups of prisoners in the

United States, and care entirely comparable to that given American patients

with tuberculosis was accorded them. Special provision was made for tuberculous prisoners of war by War Department Prisoner of War Circular No. 11,

8 February 1944, which directed that those afflicted with pulmonary tuberculosis be sent. to the prisoner-of-war camp station hospital in Florence, Ariz.

At this hospital, they were to be examined by a mixed medical commission of

representatives from neutral countries with a view to repatriation. It was

directed that cases of nonpuhmnonary tuberculosis be sent for care to certain

6"392431---6": - -29
394 INFECTIOUS DISEASES

general hospitals designated in ea'h service command for the care of prisoners of war. Suisequently. when the station hospital at Florence was abanidoned its a center for such patients, about 50 tuberculous German and Italian

prisoners of war were sent to Fitzsimons General hospital. where a number

had already been sent front other p)laces peid(ling final determination of policies g'overn1inig tile treatiement and disposition of sick prisoners of war. Oin 5

January 1945, a telegram from the Office of the Provost Marshal General to

several service comnmand headquarters directed that. p)ending further revision

of 1)olicy, prisoner-of-war 1patients with pulmonary tuberculosis should be

transferred as follows: German prisoners to G'lennan General Hospital, Okinulgee, Okla., Italian prisoners to Bruns General Hospital. and Japanese

prisoners to the prisoner-of-war camp station hospital, Camp McCoy, Wis.

Wherever German prisoners of war were concentrate(l, a sharpt difference of

opinion was found to exist in the Nazi and anti-Nazi groups. and it was generally necessary to house them in entirely sep)arate wards.

Relatively large numbers of Italians were found to have tuberculosis.

The German Army appeared to have been screened in a much more thorough

manner than the Italian. In fact, the number of tul)erculous Italians was so

high in certain areas that it was considered advisable by Army Service

Forces Circular No. :142. 14 October 1944, to make mass X-ray surveys of all

Italian service troops for the discovery of cases of tuberculosis.

The total number of Japanese prisoners in the United States was relatively small, and therefore the problem of tuberculosis in Japanese prisoners

was minor. A small numl)er were. kept for care at the station hospital of

Camp McCoy. No significant differences were noted in the character of

tuberculosis in the different groups. but the experience at Fitzsimons General

Hospital indicated that the Gernman prisoners, as a rule, made better progress

than Italian. a fact attributed to their better discipline and acceptance of

medical direction.

A comprehensive report on the medical care of prisoners of war in a

general hospital in the United States was made by Col. Louis B. LaPlace,

MC, at Glennanm General t[osl)ital.6 2' Glennan General HIospital was in close

proximity to a number of large prisoner camps and was well adapted to care

for prisoners. Ninety percent of the patients were Germans and Austrians.

and the remainder were nationals of Axis satellite or invaded countries. It

functioned as an installation specifically for prisoners of war from August

1944 to May 1945. Glennan General Hospital was ultimately converted to a

general hospital for American l)ersonnel, and all of its prisoner patients were

transferred to Prisoner-of-War General Hospital No. 2. established at Camp

Forrest. Tenn., which had the great advantage of a large barracks area where

patients unfit for duty. but not requiring hospital care, could be accommodate(l.

62 aIll'iace, L. B.: Tubercilosis at a Prisoner of War Hospital. Bull. U.S. Army M. Dept. 7:

398-399. April 1947.
TI' IwitTiA)S! s 395

To the greatest extent possible. Glennan General lospital and Prisonerof-War Greneral Hospital No. 2 were staffed with (Gernian medical department personnel. including inedical officers and enlisted men. The professional

aptitude of the. German inedical officers varied considerably. A ii umber with

excellent qualifications were on duty, but ais among the patients, there was a

definite difference in attitude aimong them. based on adherence or opposition

to the Nazi party.

The staff of the medical service at Glemnan G(eneral Hlospital was coiliposed of two Americans and eight German medical officers. The mumber of

(Germimami ward attendants averaged 50) for the 11 wards utilized by the mnedical service. Only one American enlisted man was needed to supervise the

entire medical service. American nurses were not utilized on the wards.

Approximately 31 percent of the German patients at Glennan General

Hospital had tuberculosis of the respiratory tract. This relatively high incidence was due to the fact that Glennan was the only hospital for prisoners of war designated for the specialized care of tuberculosis. As Colonel

LaPlace pointed out, the tiberculosis section constituted a special problelm.

It admitted 304 patient-, III whom the diagnosis of tuberculosis of the lung

or pleura was established. Because of anticipated repatriation, active cases

could receive only con sPVative treatment, including pneuniothorax. Since

repatriation was slow, these patients accunmulated in the hospital until they

filled 6 of the 1I medical wards. lit spite of the severity of a Jarge percentage of the cases, only five deaths occurred on the tuberculosis section; of

these, three patients were prisoners of Russian origin who had accepted service in the German Army. The clinical course of the disease, in the majority

of instances, was relatively benign.

Special diets were available to patients who needed them. All patients

on the tuberculosis section at Glennan General Hospital, according to Colonel LaPlace, received a routine diet of 2,500 calories daily, with vitamin

supplements. Colonel LaPlace's report pointed out that Glennan General

h~osp)ital was a noteworthy example of this country's full adherence to the

terms of the Geneva Convention. Prisoners of war were hospitalized in one

of the best constructed and equipped of any except permanent Army hospitals.

The number of tuberculous patients admitted to the medical service constituted 2.6 percent of all admissions to the hospital. Among the 10 percent

of patients in the tuberculosis section who were not Germans or Austrians

were Russians, Poles, Czechs, French, Yugoslavs. Arabs, and others. Most

of these had been persuaded to join the WVehrmacht or Arbeitsdienst by a

period of starvation and exposure in a concentration camp. In many cases.

it is believed that mistreatment had caused activation of tuberculosis.

In this connection, it may be noted that. the admission rate for tuberculosis in German prisoners of war, as recorded in the Medical Statistics Division of the Office of the Surgeon General, was 1.9 per 1,04H) per annuml in
3M,) ! N FE'j'()jTI(S. DISEASES

1.944. nhis, for the moist part. reIresented admission because of symptoms.

Occasionally, groulps were surveyed more specificallv for tuberculosis: stuch

surveys increaseti tile rate. An unusually high rate was observed in one

eondueted iin tile First Service ('ommand. 'rhie .oiblined figure for active

and inactive tuberculosis of reinfection type and chronic fibrolic tubercuhlosis

found in this survey was 5.5 vases in 4.041 examinattions.

hie tilwreulosis section at Gleiriaii (General Hlospital was a subdivision

of the nedieclcnl service anid was a'cominiolated in seven standard wards. ()iie

of these, a so-called internalional ward, wats desiglatled for the Russians.

Poles, and anti-Nazi Germnans who required protective segregation from the

other Gernmans in the hospital.

The tuberculosis setion wais sulpervised by ai Am ierican chief andil assistant chief of tihe medical serviv'e and one s.erg'eant. nhe international ward

was adminiistered directly '%.\neriva A1 i medical officers. Ot)herwise. all medic.al officers in attendance were ieiillrs of the German Sanitiitsdienst who

were Classified by the (Geneva ('onivention as p)roet'cted lre.'sonnel ralher than

as prisoners of war. The lierman ichief of section was a relatively well qualified Specialist in tulberculosis who, prior to capture. had served in a sill)-

marine and at till outpost on the Arctic Circle.

('ertiticiation of pa)ients for repatriation was an imlloranil part of tile

work and cai.sed many diff•culties. Accordinig to thie Geneva Convention•, all

prisoners of war who had activie piulmnoary tuberculosis, as indic•ted by the

finding of acidflfast bacilli, were to be returned to Germany as soon as p)ossible. As a result, patients attempted to substitute a known positive split umn

for their own. Aceording to ('olonel LaPlace. ilie Gernian-protected perso.o)nnel were acused of being collaborationists if they did not help ill this sill)-

terfuge. Spitmu relm)rts were therefore considered unreliable, and the aitivity of tulerculosis was often almost inipmssible to determine.

Treatmient inclluded lprincilmlay restt, a high caloric diet with vitakin

supplements, anil lieuiothorax as indicated. Radical s.urgic.al therapy wtas

not undertaken because of tlie 1)r'ospect of rep)atriation for definitive care.

Many patients became arrested cases in the hospitial and were returned to

light dilty.

0)f the :304 eases of tuberculosis, 267 were pulmoni ry ainld :31 had tuberculouhs pleuirisy with effusion. Ii 14 cases. both pulnonary involvement. and

pleuiral effusion were present. Extrapulhonary eases inc'luded tuberculosis of

the larynx, epididymiis. joints, kidney, nieninges. peritoneum. and cervical

lymph nodes. In all, there were 14 nonpulmlnary cases.

The experience of Glennan General HIospital has beetn recorded in detail,

because of tile compirehensive character of the report on tulberclulosis at that

hospital. The problems and(- care its outlined may be coonsidered as representative of the service at the other hospitals for prisoners of war iin this country.
TUBERICULOASIS 39

TREATMENT UNDER THE MILITARY GOVERNMENT IN

GERMANY

The control of tuberculosis formed an impjortanlt part of thle puiblic. healthI

programn of the office of military government inl Pach of the occupation zones.

It wats a1ccenittuatedl inl Germany by the total disrupt ion of tuberculosis serv--

ices following time collapse of the Nazi govwernment. Prior to W1or(ld War 11,

Germany had at well -organ i zedl progra~m, which wats rapidly dimiinishing thle

p~revalenlce of tulbercuilosis inl thle Reich. Following the First W~orld War.

Grerman public health exper'ts hkad adop)ted at prograimi based on iiiilrov-ed

dispensary facilities for discovering cases of tuberculosis. better care in homes

and sanatoriums, increase inl facilities for treat iment, and central izat ion of

finance inl general measures for control. At thle outset of thle Second World

War, case-finding surveys with roeiitgrenogrants were progressing oili a hug-e,

scale. but after the middle of 1943 the intense bombing of Germanl cities

dlestroyed so many facilities that the X-ray program (-aitle almost to at stand~-

still.

The breakdown inl the general public health program had resulted inl

admitting to industry at good nmany workers with tuberculosis who, inl prewar timies, would not have beenl accepted for work. It is generally believ-ed

that this breakdown inl service resulted inl time spread of tuberculosis withinl

thle Grermlanl populationi. Tile admiission of tuberculous persons to industry

was rationalized by thle Nazi officers for tuberculosis control bv official coimmun ilicat ionls stating that the danger of transmission of tube~rculosis had beeni

exaggeratedl in the paSt.113

In adldition, (luring the warl, large numbers of laborers were imported

from adjoining countries with little or no screening for tuberculosis. It is

Probabl)e that many cas-es of coinnun icable t uberculous disease were adhmnittedl

inl this way, for thle general tuberculosis rates in sumrroundling countries were

mu11ch higher than illi Germany.

Whmen the U.S. Armyv took over the public health program for thle Anmerican Zone, the control of tuberculosis wats proceeding onl a purely local basis.

Central control, previously locatedl in Berlin, was no longrer inl op~erationm and.

in fact, many of the former leaders of the program. having been proininenit

adherents of the Nazi p)arty, were und~er dletention inl Army headquarters.

The. local unit. of tubereulosis control, the Fiirsorgestelle. was inl operatioii inl mlost ('oinuillit ies, ostenlsibly inl the same nmanner as before the war'.

Howev-er, qualified personnel was miuch redlucedl inl number, andI many of the

G1ermian clinics had been forced by bombing to leave. their regularly constituitedl quarters and to take lip operation in inferior dlwellings. often with inladlequate equipmient. 'Moreover, the visiting by Fiirsorgrestellerinneni to time

homes of tuberculous patients had b~een almost dliscontinuedl because of thle

0;31)r. Kuiyger-Pett-rs.'n. Generad 5mrietary: Ariwiti~einsittz Yon Tutwrkiculflwn. ilrerlht fiber eins

(;eschfifts Jalir 1940-1941. Reicbs-Tniberkii~ose-.k iissehiin4. Berlin. [Ca',ptured Germaun (iowumneft.
398 INFIECTIOUS D)ISEASES

hack of tranisportat ion. No motor cars were available, its a rule. and inl the

rare circumst ances where miotor 1 rals~lxirtat iou could be obtdi tied, gasoli tie

wits veryv short, so that few %-]sits could he mlade. At thle Same tine, facilities

for rel)ortitlg tub~erculosis were much reduced, so that no clear picture of the

prevalence of tutbercuilosis wats o1bta inable iii most hxtal it ies.

Ii) Sep~temlber 194.5, at tublerculosis sectionl wits organized1 inl the P~reventie Medlicine Branch of thle Public I lealtit Branch of M ilitary G overinment

for Germany (U nited States) inl Frankfurt and Blerlin. Prel iminiary sulrveys were made by (Capt. S. C'. Stein. MC, antd the office wats takeni over iky

th (Cotnsultant in 'luherculosis from tilie Office of the Surgeon General oti at

temlporary ditty basis oin 1 September 1945. Every effort wats miade ilti le

succeedilylitlgonthls to promlote restoration of the ( iertltaii p)rogram to its p~rewar cond~it ion. ItIsofaur as pers)iitlel (altuif Villg tin1der thle denlaziticat ionl ruIles

w~ere obta11inab~le. sutitalble p)ubIlic helthtl offiers, exp~erienced in tuberculosis

controNl, were app~inte(1 inl thle IiAnder. Kreisett, and( stmaller untits. lit November 194.5. the section wats taken over by L4t. C ol. Ieo A'. Schnteider, 'MC,

who, ill addit ion, acted as aide to the chief of tlue publdic htealthI brat-ici. I'li-

(der his (lirectionl, great progress wits made inl inliprovingt rep)ortinig .an(1 inl thle

pr~ovisionl of beds for tutl)erc.Illouts patients thlrouglhout tile U .S. zoute. Suibs-e1ulent ly, [Lt. C ol. G ilberto S. Pesquera. M( X was apploinltedltilectoi contutatfor the O ffice of Military Govertinletit. In a1 series of reports to tile

JDireetolr of tile 1,1bl4c H eatltht ( )tive of Military ( iovernnaent inl May 1946.

fiutrther. progtess wats intdicatedl. includitng better uitilizat iont of beds-part icularly with respect to the (list ributt olt of beds for (Werutan civiliatis and (isp~laced persotis-atid the conltrol of dissemiinat ion of disease from opent cases.

Ill eatchi tuajo. dliv ision of tile (wnictled zotie. ait Amterican mledlicatl othicer inl the office of tile chief of tile local publdic health brailci was assigned

the sp)ecific task of timinulat ing tile pr)ri)glhl for conltrol of tIii wrctlljosis.

Formis were p~rep~aredl for proper reporting, and conistant effort was Iiiade to

tincrease the nutimber of beds available for care of tutbercul~ous p~atienits (usCovered ill thle Germanl populationl.

Thle 9) O ctober 194.5 mtemorandum of tite ( 'ostilt ant inl Tulberculosis.

Office of thle Surgeon Greneral, called atttenition to tilte progress effected inl

the transfer of titlwrvulous German prlisonters of war front Army htosp~itals

to Gertman hospitals and Sanatoriumns for civilianls and to the tmeasures followedl inl handling tuberculosis amntig dislplacedl persons. Tlte latter pro)vedl

a large anid difficult probldem. whticht was joint ly attacked by the artmy of

occupation ( Third. Seventh, and Ninth U.S. Aritties) . thle Office of Military

Governmient, and~ tlte Ui tted N ations Relief and~ Rehabilitation Adutinistra-_

tion. tite chlief public health officer of whichl was supp~lliedl by the U.S. P~ublic

Health Service. Tltis reptort outlined itt detail (1he respl~olsil)ilities and1( short -

comingms of the Germtan civilian puiblic htealth organization for titbercitlosis

control at. and1( below t he 1Land( level. It laidl special st ress onl tilte iuiadeqtiacv*

of rep)ortinig. tile imistifficiencey of clinics and of hospital andl sanatoriumil beds
TUBERCULOSIS 399

for tuberculosis, the number of open cases in homes, the serious housing problem and resultant crowding, and the impaired nutrition of the population.

It. was pointed out that in a typical city of about 140,000 (Augsburg, (iermany. was citedi as the example) more than 2,0•4) persons with open tuberculosis were believed to be resident in homes, rather than in sanatoriums. Tie

housing shortage in the American Zone was such that the number of oc•.-

pants per room in the large cities had more than doubled as compared with

the prewar figure. The official food ration at the time provided only 1,300

calories it day, and although this was supplemented by 300 calories of nonrationed foods by many persons with access to rural areas around cities, at

best the diet, fell far short of that believed essential to maintain lnormal resistance to disease.

The mortality front tuberculosis was fair greater in Berlin tham ill other

parts of the American Zone. Recorded annual rates for Berlin regularly

exceeded 20X) per 1(00,0W0 population, whereas the rates reported in other

parts of the zone occupied by American troo.ps seldom exceeded 70. It is

Iilieved, however, that in the majority of instances tile records were inaccurate and incomllete. Before tile end of tile year, a reasonably grool prograill

was in effect, tile future of which depended upon tile full organization of the

general public health l)rogl'ail in (Germany.

In tile report last cited, ill addition to recomnmendations for American

supervision of German medical organization and the continied effort to increase. facilities and personnel for the care of tuberculosis in tile IV.S. Zone,

the need for some central German civilian advisory service was indicated.

This recommnendation was entirely in line with generalI policies beiing (leveloped not only in tile public health field lbut also in tle. realm of economics and

civil govermnent. Unfortunately. German civilians of the required caliber

were not available. ihe former General Secretary of the lReichs-TuberkuloseAusschuss was living in the zone but was not eligible uinlder tihe regulations

prevailing with respect to persons with previous Nazi affiliations. nor was it

possible during tile periom covered by this history to find anyone with con|-

parable qualifications who was eligible.

At the end of 1945. it appeared likely that a rise in tihe tuberculosis rate

would ensue, as it did after World "War I, but it was believed that imnln'oiement in the local organizations, supplemented by assistance from a partially

unified Germany. if this were ultimately effected, would stein this in time.

Part VI. Tuberculosis in British and Canadian Military

Forces

Published accounts offering valuable material for comparison with the

experience of tile U.S. Army are available from the Royal Navy, the Royal

Air Force, and the Canadian Army.
400 INFECTIOUS D)ISEASES

ROYAL NAVY

TUle milit ary forces inl ('reat Brit a in required at physical examiinat ion

but not an X-ray examination prior to induct ion into service. A substantial

fr~actionl Of the Royal XaV,.64 howev-er, was examliaied b~y 35mni.tuorographv

after v-arying periods of service. and1( many of those so examniledl were reexaminiedl 1 to -2 years later. The following summnary of the first. exanmination was madle by the Consulting Physician inl Diseases of the ('hest to the

Royal Navy, who was inl resp~onsibl)e charge. of the examninat ions:

F~luorography of 479.373 appalrently healthy male iwrsoxnnel of the Royal Naivy

showved thait 61,077 ( 12.7 per 1,000) hadl radiological signs of adult-type pulmonary tuberculosis. lit 47.9 percent of these the lesion wats "miinimail."

Of 23.344 W1INS, 213 (9.1 per 11.400) hall similar evidence of tuberculosis, andl the

lesion wats minlimal lin 55.4 percent of these.

Similar Investigations among civilians will no doubt bring to light large mnubers of

cases5 of pullnionairy tubercuvilosis of this slighIt degree. raisinga difficuilt problems of disposal and treatment.

In sonic of these tminimal esises the disease is arrested, or is retrogressive, but lin

others it Is progressive. Careful study is needed4 to (levide wvhether the infection is

active, andl investigation lin hospital is essential. Whenx 2.911 sailors with minimal

lesions were first stu(Iied inl hospital 16 percent showved evidence of active infection,

while lin M percent the disease appearedt to b~e inacetive but the stability of the lesions

wits djoubtfull. lt-In 21pecent the dlisease wats arrested.

Nav-al personnel with apparently inactive minitlmial tuberculosis have lieeim placevd on

light shore dtiffes and kept undler observation. Study of these cas~es shows that the

younger the patient the more, likely is the dfisease to become active, and the relapse to

he serious.

,k significant finiding, quite comparable to tile resuilt,, inl indulctioni stationis ini the Uniited States, was ai rise ill the (liagniosis of tuberculosis with

adlvancillg age inl bothI males andI femtale-s. lIn the four dlecadles from 10) to 50

years of age the rate per 1,000 for males was 8.8, 10.74, 19.7 and 32.8, and for

females (6.9. 9.1, 14.9). and 12.7. (The number of females inl the 40- to 49-year

periodl was too smnall to miake the figure fully v-alid.)

An equally signiificanit. feature of tile exalminationl w~as the numuber of

cases discovered inl the minimal stage, the percentage being muich hligher than

that discoveredl by the conventional methods of phyvsical examiniiation.

Trhis is inl accord with greneral experience inl mass radiography. It is of

interest to note that the percentage of all tuberculoums cases discovered inl the

minimal stage did not vary significantly ill tile dlifferent agre periods. Followvup studlies indlicated clearly tllat the younger the patient with radliological

evidence of minimal tublercullosis, the greater time likelihood of its displaying

activity.

64 History of the Second World War, U'nited Kingdom Med~ical service". Medicine and Pathology. London : Her 'Maje~ty's stationery Office, 1952, pp. 319-332.

65 Brooks, W. D. W.: management of Minimal Pulmonary Tuberculosis Disclosed by Fluorography. Lancet 1 : 745-748, 10 June 1944.
TUBERtCUILOIS 401

The average for the whole force examined was 12.7 per 1,000 for men,

and 9.1 for women, figures slightly greater than those for rejections for pulmonary tuberculosis at induction stations in the United States.

A later summary of the experience of the Royal Navy "' threv further

light, on tile relation of age to prognosis. Naval personnel with apparently

inactive tuberculosis were placed on light shore duty and kept lii-ler observation. Almost all of thoze whose lesions proved active with the passalge of

time were under 25 years of age.

This last sunmmary discloses that by the end of 1944, 91,959 ratings

passed as normal on a first fluorographic examination were reexamined, and

479 cases with radiological evidence of tuberculosis were discovered. Comparison with the original film showed that in 123 the lesion was previously

existent but missed. This yields a figure of 1.3 per 1.000 of those fluorographed, which agrees very closely with the estimate of 1.0 to 1.5 cases per

1.04)0 of significant. tuberculosis missed at, induction in the U nited States, as

calculated by Long and Stearns from a rereading of 53.400 induction films.

In both groups, the reasons for failure of detection and recording were the

small size of the lesion, presence of the lesion behind skeletal structures that

cast a denser shadow, proximity to the dense hilus structures, and, in some

cases apparently, clerical error.

Of the 479 cases found on reexamination, however, the great majority

showed no evidence of disease in the initial film. These must have represented new infections or manifestations of endogenous spread from an unknown focus elsewhere. It was signiificant that of the new group 73 percent

were found in the minimal stage. a figure contrasting sharply with that, of

48 percent found for minimal tuberculosis on initial fluorography. Further

analysis showed that the total anmount of new tuberculosis discovered on the

second examination increased with the length of laps•d time since the first

fluorography. In men who had their second examination within a year or

less. the rate was 2.4 per 1.004); in those reexamined only after an interval of

3 years, the rate was 7.3. The average for all groups was 3.4. In about onethird of the cases, there was definite evidence, of activity.

It studying these figures, it is of interest to note that an appreciable

number of cases of tuberculosis developed in the course of time also in United

States and Canadian troops who had been screened before accep)tance and

that this increase was greater in those who had had military experience overseas than in those who had not ;87 also, that the annual mortality from tuberculosis in the Army and in the ex-Army population rose steadily during the

war years.68

4w, Some Problems of Fluorography. Roy. Nay. Med. Bull. No. 20: 1-9, 1945.

67 See footnote 13, p. 337.

6H (1) Adamson, J. D).. Warner, W. P., KeevIl. R. F.. and Beamish. R. E.: Tuberculosis In the

Canadian Army. 19:19 to 1944. Canad. M.A.J. 52: 123--127, February 1945. (2) See foolnote 41,

p. 372.
40W INFECTIOUS DISEASES

The analysis published by the Royal Navy of the invasions by disease

and deaths of ratings from 1934 to 1944 indicated that approximately 2.5

men per 1,0()0) were invalided each year for tuberculosis from 1941 on. The

rate for officers was somewhat lower. This figure is several times the discharge rate for tuberculosis ii the U .S. A rmny, in which the relatively low

rate is explained by the radiologival screening carried out ,jrior to induction.

Ini this place, it is not out of order to point out that the British were at

all times less conscious of the problem of compensation than the Americans.

Whether tuberculosis was discovered before induction or after was a vital

matter in tile United States :1n1 canalda. The disposition of cases (ii,,covered

in both categories was al)proximately the same in ('reat Britain. but the

finaincial issue was of less concern.

The death rate for tuberculosis in Royal Navy personne1 dropped after

1942. following several years at a constant level. It was the hope of the offi-

(ceS concerneld that this was the forerunner of the benefits to be expected in

the future front mass radiography in the service and discovery of cas-es in

an early aud favorable stage.

ROYAL AIR FORCE

The Royal Air Force also made extensive use of 35-11n. fluorograpiy.

A report on 19.(070'i males and .59.951 females was made by Air (Commodore

R. It. Trail and associates in 19 4 4 .1111 All of the subjects of the survey were

already in serviice, and all had been accepted for service on the basis of phvsical examimation. The men iald been l)hysically examined 3 to 12 months

previously, some very strictly bcwause of their special duties. and the women.

all members of the WAAF, 6; monthIs preyviouslv oin the average. The great

majority of each group was under 30) years of age.

The total incidence of tuberculosis was 7.7 per 1.0H4) in Men, the difference, in comparison with the 12.7 discovered in the Royal Navy. being in part

attributable to the younger age of the Air Force personnel. Ill women. the

incidence was 9.4: that is. approximately the same as the rate of 9.1 discovered in women in the Royal Navy. Followup examination indicated that the

incidence of active tuberculosis wau- 2.8 per 1.000 in nien ainl 3.6 in women.

In men, the figures with respect to age differel froiti those of the Royal Navy

in that active disease was not discovered )rel)ondera litly in the youngest age

groups. l)ut in inc'reasivno extent in the groups tip to 40 to 44 years. In

wiomnen, the peak in the incidence of active disease was in the 20- to 24-year

period.

Aln interesting finding common to the experience of b)oth the Royal Navy

a-l(l Royal Air Force was the rise with advancing years in the incidence of

calcified lesions interp)reted as the residua. of healed tuberculosis of childhood

69 Trail, R. R.. an]d others: Mass Mliniatitre Radiography in the Royal Air Foree: Report on

250.027 Consecutive Examinatioi:- of R.A.F. and W.A.A.F. Personnel. Brit. JT. Tubere. 38: 116-140.

oetober 1944.
TUBEICUUIA)SES 403

type. This rise could signify that childhood-type tuberculosis was 11u(ch .oniMuoner years ago thaln now, or that the type of lesion termuinating in caIcification '•ccirred in later vearn, so that a cumulat ive rise occurred in the numher of healed residua.

As in the U.S. Army, a higher increase in incidence was observed in I'ecovered prisoners of war who had spent many months in prison camps in

Germany. A survey of 7,146 recovered Royal Air Force personnel in April

and May 1935 showed an incidence of active pulmonary tuberculosis ablxt,

twice as gyreat. as that found in Royal Air Forec personnel who had not [weei

1)risoner:.

7 0

CANADIAN ARMY

T[le control of tuberculosis in the Canadian Army was remarkably effective. and the scientific study to which data on tuberculosis were subjected

p)roved illuhminating in the general understanding of the pathogenesis of

t iii erculosis.

X-ray exanvimattion -was a requirement on induction in the ('anadian

Army. As in the U .S. Ar'hy. solme troops were not exanimiied by X-ray in

the early months of ilmobilizat ion. Subsequently. roentgenograms were made

of the chests of men who had been ind(hcted without a film, and those found

to have significant lesions were discharge(d. Approximately I millioi and ail

half persons, equivalent, to a quarter of the male I)ol)ulation and half of all

persons of Army age were examined by X-ray in the induction exainmat iois.71 The incidenc'e of lesions discovered was albout 1 percent; a third of

the cases discoveredl, abolit. 5,000, were considered clinically significant ald

reported to the civil authorities. This byproduct of the war was of notable

value to the general program of tuberculosis control in Canada.

A feature of great importance, rendering the results of exceptiolnal value

for understanding tile hazards of tuberculosis in military service, MY in lhe

sharp1 distinction maintained by the ('anadian military organization between

the Army in C(anada and the Army ovenseas. In both. the prevalence was

very low by civilian standards, as would be expected in a group well screened

by roentgenographic examination. The distinction lay in the fact that, the

Army in ('anada was subjected to a hazard of exp)osure no greater than that

in the civilian Ipopulation of the provinces, while the Army overseas was

exposed to .ontagion in countries in all of which the death rate, and p)resuiabyl)l op)ortunity for contact with open cases, was much greater than in

Canada. For the years 1939-44, the average incidence of tuberculosis discovered in troops in the Army in Canada was 24 per 100,000 per annuni,

while in troops overseas it was 40. These rates were estiinmated, resp)ectively.

as 15 and 25 l)ercent of the rates in the civilim'n population in Cmanda. The

70 Personal (,ommunicat;ion, Air Commodore R. R. Trail to author.

7T AdaIuson. J. R.. and Kecvil, R. F. : Tberuilosis In the Canadian Army. J. CanId. NI. Serv.

1: 404-411. July 1944.
404 INFFCTIOUS IDISEASES

rates in each group) in'reased with length of service, ranging, however, frtom

9 per 100,000 for home troops and 35 for oversea troops in 1941 to 40 and 60

per 100,000, respectively, in 1944.

An even greater diffeience between troops at home and those overseas

was evident in the incidence of tuberculous pleurisy with effusion. In 1941,

the rate for the Army in Canada was 30 per 100,000 and that for the Army

overseas was 20. In marked contrast, the rates for 1944 were, respectively,

23 and 7T5 per 100,000.

The increase in the tuberculosis rate with length of service in both groups

was attributed, in part. to the foreseeable development with the lapse of time.

The excessive increase overseas, however, was explained on another basis;

namely, the excessive exposure to tuberculosis in countries with a much

greater prevalence of the disease than Canada.

The fig-ures for pleurisy with effusion were believed particularly significant in the latter respect. Analysis of the figures according to the native

provinje of the men who became ill showed that the highest percentage of

new cases developed in men from Ontario and the western provinces, where

the incidence of infection, as already known from civilian surveys, was low.

It semeld logical to believe, therefore, that the high rate of effusion in troops

overseas represented the acquisition of primary exogenous infection, a frequent early manifestation of which is pleurisy with effusion. In reaching

this conclusion, the Canadian medical officers made allowance for the fact

that. some of the pleurisy with effusion, diagnosed as tuberculous, might have

been due to acute, transient respiratory infections. It was in fact noted that

a rise in wet pleurisy occurred in every epidemic of acute respiratory disease.

However, after due allowance was made for the discrepancy between home

troops and those overseas, the similar trend in cases of pulmonary infiltration

and pleurisy with effusion lent strong weight to the view that the latter

represente(l exogenous tul)erculous infection overseas. Adamson and his coworkers believed the phenomenon "the natural epidemiological results of a

tul)erculin-negative group coming into contact with a tuberculous environment."

Canadiaii authorities carried the lesson into practice by sp)ecifying in two

directives (14 November and 21 August 1944) that more strict attention be

given to a history of pleural pain and to the examination of soldiers with

known contact with tul)erculosiS. 7 2

The second directive, and a subsequent note appended to it, indicated

that about 4.3 percent of all medical discharges from the Army had been for

tuberculosis and that approximately 2.9 percent of medical repatriations were

for this disease, of which 1.9 percent (or about two-thirds) were for pleurisy

with effusion.

"72 (1) AGO D)irective. 14 Nov. 1944. to departmenral eommanders. (2) DMS Order 286. 21

Aug. 1944.
TU BERCIUIA)S 44)5

These figures for the C(anadian Army are of uiuisual interest. It is

unfortunate for the study of ep)idemniology that in statistics for the 1.S.

Army. ill the Zone of Interior and overseas, a comparable easy separation of

tr(x)l)s on the basis of origin cannot be made. Whereas in Canada a large

share of the liomle Army was from the eastern provinces and remained in

Canada, in the t'nited States the home Army was constantly a transient force

in training for oversea service, and the Army overseas had lproportional representation from all parts of the country. Snubsequent analysis on the basis

of geographic origin may be possible. In the meantime, it. appears significanlt that an unusually high rate of pleurisy with effusion, l)resulied to be

tuberculous, occurred in young U.S. Air Force troops in Italy (lpp. 353-357).

Part VII. Significance of Army Experience for Control of Tuberculosis

For many years prior to World War II, tuberculosis mortality in the

l-nited States had been declining. The reduction in mortality continued

during the war. but at a somewhat lowered rate. Among the reasons for the

slowing in the curve of decline were shortages in l)ersonnel for civilian public

health and hospital p)ractice, increased tempo of work, with corresponding

general strain, and absence from the country of a large number of men of an

age p)eriod with a low geeneral death rate, who were removed from the p)op)ulation on which mortality rates were calculated.

Counterforces were in effect, however, which offset these factors. Although the intensity of labor was increased, wages were far higher than before the war, and although prices were elevated also, the general result was a

rise in the standard of living in segments of the population ill which mortality

from tuberculosis is usually high.

During the war. also, in spite of personnel shortages for public health

work. a. notable advance in machinery for tuberculosis control took place in

the establishment, for the first time, of a Tuberculosis Control Division in the

U.S. Public Health Service. This was organized by congressional action in

the Bureau of State Services of the U.S. Public Health Service in July 1944.

Funds became available shortly thereafter to supplement measures for combating tuberculosis through grants-iii-aid to States, enabling the latter to

expand their programs in clinics, case finding, and hospitalization.

The examinations at induction stations, as indicated in detail elsewhere

in this chapter, brought to light thousands of cases of previously undiscovered

tuberculosis. A substantial number of these were placed luider treatment imniediately. In addition to the saving and prolongation of life thus effected,

there resulted a reduction in community exposure to tuberculosis, with presumably a corresponding decrease in development of new cases. The accomplishiment. in this respect was far from maximum, as reporting of cases was

not complete, and followup p1rograms to insure hospitalization of open cases
406 INFE("TI4)Ur IS)EA5ES

discovered were not well developed in many parts of the country. In large

comiiunities. with well-organized p1blic health p1rograills. followup was goxxI,

but in other regions little or none was attenipte(l. Although not specifically

mentioned in AR (Army Regulations) 40-180. dated 31 D)ecember 1934 and

10 I)ecember 1943. tiberculosis was considered a communicable disease to

which the reporting requireiient applied. Because of a recognized laxity in

reporting cases of tuberculosis. a reminder (specifically mentioning ttuberculosis) as to the reporting requirement in AR 40-1080 was issued on 2_4 July

1944 ii War )elpartment. Circular No. 313. In some cities, however. by

slpecial arrangements between health dealrtments and induction stations,

direct report was made immediately. without waiting for report through the

normal channels of the State selective service organizations, and State health

(el)artmnents. In New York City, for examl)le, a rel)reseiitative of the Blireau of Tuberculosis of the D)epartment of Health visited the large New

York City induction station every night and received direct report, on cases

of tuberculosis discovered during the day.

The system of hospitalization for tuberctulosis in the Arny and the norrna1l discharge of l)atients to Veterans' Administration hosl)itals for further

care, resulted in the treatment of thousands of cases and in correspon(ling

reduction in opportunity to sl)read the disease to others. Army hospitals

and Veterans" hosl)itals were required bv their respective regulations to rel)ort

cases to State health departments. Special check, however, indicated that

reporting was not complete. With changes in personnel, which occurred constantly in Army hospitals, required proceduires were not always continuous.

To n0make u!p in part for deficiencies in reporting. the Consultant in Tuberculosis. Office of the Surgeon General, established a direct relationship in 1944

with the newly established Tuberculosis Control D)ivision of the U.S. Public

Health Service, so that all discharges for tuberculosis were reported by

States of origin of the men concerned. The Tuberculosis Control Division.

in turn. forwarded these reports to individual State health departments.

With all the imperfections in the reporting measures, and the lack of suitable

followup programs in many States, and in spite of the many tuberculous

veterans who refused sanatorium care in the months inmnediately succeeding

(lischarge. steadily increasing control from the point of view of public health

resulte(d, which shoull be reflected in a. decline of tuberculosis mortality in

the future.

In evaluating the effect of the Army's control program on the general

ant ituberculosis campaign, the e(lucational efforts of Medical Corps officers

should not. be overlooked. In addition to direct counsel given patients with

tuberculosis or suspected tuberculosis, they were provided with literatime

from the National Tuberculosis Association and its affiliates, and hospital

patients in general saw motion pictures on the diagnosis, care, and aftercare

of tuberculosis. Probably a still greater educational effect resulted from the

vast aniount of roentgenograp)hic study of the chest (lone in the Army. X-ray
TUBERCULOSIS 407

examination at induction and separation, and the huge number of chest examinations by X-ray in dispensaries and hospitals, made millions of young men

and women aware of the danger of tuberculosis and the special measures

available to combat it.

On the whole, the tuberculosis control program of the Arniy was well

integrated with the public health program of the country and may be expected to be of continuing favorable influence in the reduction of tuberculosis

in the population in postwar years.
CHAPTER XII

Diagnosis and Treatment of the Venereal

Diseases

Paul Padget, M.D.

HISTORICAL NOTE

The history of the treatment of the venereal diseases in World War II

may well begin on 7 June 1940.1 The development and application of the

methods of i sent used in the U.S. Army prior to this time have been

admirably t and summarized by Siler,2 and need not be recapitulated.

On1 7 Jumu :40. a meeting of the National Research Council was held in

Washington, D.C.. to form a1 subcommittee 3 on venereal disease control.

The Subcommittee on Venereal Diseases by its terms of reference was charged

with making general recommendations to The Surgeons General of the Army

and the Navy concerning the prevention and treatment of the venereal diseases

and with acting in a consultative capacity on questions in its special field that

might originate from the armed services.

Following this, meetings were held at frequent intervals (six between

7 June and 19 July 1940), and on the latter date, detailed recommendations

were approved concerning the diagnosis and treatment of each of the commonly recogmized venereal diseases. These recommendations were submitted

to the parent committee and eventually were transmitted to the respective

surgeons general as the official recommendations of the National Research

Council. They were subsequently incorporated in Circular Letter No. 18,

Office of the Surgeon General, 10 March 1941, which became the first official

statement of a policy for the treatment of these infections to come from the

Office of the Surgeon General during the period of the emergency which culminated in World War II. Much later, Circular Letter No. 195, Office of the

Surgeon General, 1 December 1943, ordered that the treatment of all patients

I The author is indebted to Dr. Thomas H. Sternberg and Dr. Ernest B. Howard for material

on care and treatment which has been incorporated in this chapter. Acknowledgment is also made

of the invaluable assistance gained from the tie of the private files of Dr. Joseph Earle Moore,

formerly Chairman, Subcommittee on Venereal Diseases, National Research Council.

The final editing of this chapter was completed after the death of Dr. Padget.

2 Slier, J. F.: The Prevention and Control of Venereal Diseases in the Army of the United

States of America. Army 31. Bull. No. 67, May 1943.

3 The subcommittee was composed of Dr. Joseph E. Moore. chairman, and Drs. Edwin P. Aiyea,

Walter Clarke, Oscar F. Cox, John F. Mahoney, and John H. Stokes. members. With the exception

of Dr. Alyea. who withdrew after the 14th meeting on 11 March 1942, the members served throughout the wartime period. Dr. Perrin H. Long (later Colonel, MC, USAR) served from time to time

ex officio in his capacity as chairman of the Committee on Chemotherapeutics and Other Agents,

National Research Council. and as problems dealt with grew in complexity, other specialists were

invited to join the subcommittee either temporarily or as permanent members.

409
410 INFECTIOUS DISEASES

hospitalized for venereal disease be on the medical service or under the direction of the chief of the medical service unless there were cogent local reasons

to the contrary. Distinction was thus uiade early between the prevention and

control of venereal diseases and treatment of tihe infected soldier. In the

field, it was sometimes the practice to separate these functions entirely and,

as in the European Theater of Operations, U .S. Army. to have control and

preventive measures administered by the Preventive Medicine D)ivision. Office

of the Chief Surgeon, while treatment was supervised by the ap)propriate

consultant of the Professional Services Division. Office of the Chief Surgeon.

In the Office of the Surgeon General, both preventive and therapeutic measures were eventually supervised from one office under the Preventive Medicine Service, with free exchange of consultation with the Professional Service

and without losing sight of the fact that the individuals in charge of these

activities were dealing with separate problemns.

It is in keeping with this medical phihsophy that a section on the treatment of the venereal diseases appears here. It should be noted that although.

to a large extent, the venereal diseases may be grouped for preventive measures and although the two most important (gonorrhea and syphilis) at the

end of the war responded to the sanie antibiotic (penicillin), nevertheless the

several venereal diseases are wholly separate and distinct clinical entities.

For purposes of diagniosis and treatment. they will be considered individually.

GONORRHEA

At the beginning of World War II, there was probably no prevalent disease comparable to gonorrhea in the wide disparity between the therapeutic

recommendations of the experts and the care usually accorded the average

patient. Fortunately. the new methods of treatment were so simple that by

the end of the war the management of gonorrhea in the Army followed in

large measure the directives prepared by the experts and issued by The

Surgeon General.

Prior to the publication of Circular Letter No. 18, there was little or no

uniformity of practice in the diagnosis and treatment of gonorrhea by medical officers. The older officers of the Regular Army Medical Corps, who had

been trained in the disciplines described by Siler, had in general advanced to

supervisory or administrative positions; the medical officers who were actually treating the patients were young physicians from civilian practice.

Each of these groups had had different training and experience: most of them

had little or no special knowledge of the management of patients with gonorrhea and few knew little more about the opinions of the experts than a dim

awareness that tile relatively new sulfonamide drugs were useful in treatment.

Circular Letter No. 18 brought a semblance of order out of the chaos

which these conditions had fostered. The Army was rapidly expanding, but

with unimportant exceptions, tile troops were stationed in training camps

within the continental United States. These camps were adequately supplied
VENEFREAl. D ISEASES' 411

with cantt1tonluent-tyl) hospitals, ill which it was usual practice to han'

veitereal disease wards to which an adequate numter of medical officers were

permanently as'signed. All patients with gonorrhea were hospitalized. so

that they caine under the care of a relatively small group of medical officer'.

Accordingly. the information contained in Circular Letter No. IS1 had to be

di&smninated to only ai relatively small numlber of medical oftieers. many of

whom had had no previous training int the management of gonorrhea, but all

of whom. actually or from necessity, had a special interest in the problem.

This pxiint is important because tile contrasting sit iat iol will he brought out

later in the di.cu.ssion of the treatment of gonorrhea oil a (luty status.

It was the conmsentsus of observers durihtg 1941 and 1942 that iin geniernal a

determ'tiited and satisfactorV effort was made to carry out the provisions of

Circular Letter No. 1S. 'rlTe observed deviations were morst frequently carelesness in diagnostic technique, for example. preparation and examination of

smears by a relatively untrained techmician using only methylene blue for

staining: a tendency to prescribe larger total doses of the sulfonamides than

recommended, either by giving greater individual doses or. mttore commonly.

by a longer coulrse of treatmtent : and the early and often vigorous use of local

methods of treatmtent, eslp.cially urethral irrigition. prostatic massa•ge, and

the passage of sounds.

The provisions of Circular Letter No. 18 with regard to the diagnosis and

treatment of gonorrhea are of more than passing interest. lUnder the heading

entitled 'D)iagnosis in tile Male.- the circular says -a diagnosis of gonorrhea

must not be made in the absence of laboratory confirmation * * *,- although

it does prov)ide for emergency treatment without diagnosis in case laboratory

facilities are not readily available. The setion on the diagnosis in the female

is much less definitely phrased and contains the clear implication that the

history of exposure to a known ,-ise of gonorrhea may be utilized as presumpt i vely support ing tite diagnosis.

The regimen recommended for the treatment of acute gonorrhea consisted

of 19t gin. of sulfathtiazole to be given n 11) days (3 gmt. the first day. 2 gut.

daily thereafter) in cases which responded well: if the clinical response to

sulfathiazole was not satisfactory by tile fifth day. sulfapyridine (3 gmt. the

first day. 2 gmn. daily thereafter) was substituted. If this exchange proved

beneficial by the 10th day. this drug was continued until a total of 15 days

of chemotherapy (5, days of sulfathiazole. 11) days of sulfapyridine) had been

given. If the clinical response to this regimen was not good. the patient was

to be transferred (presumably to a general hospital) for special care.

The test of cure advised for the male was based upon tthe examination

of gram-stained smears of material expresseed by prosltatic massage done

weekly for 8 weeks. The use of culture was mentioned, but not emphasized.

The test of cure advised for the female was based on smear from the urethra.

cervix, and Skene's and Bartholin's glands every 2 weeks for 3 months, with

cultures from the sam• e areas monthly on the last day of the menstrual period.
412 INFECTIOUS DISEASE-4

The recommended followup for both sexes included one serologic test for

syphilis done 3 to 4 months after the origiiial infection with gonorrhea.

With the deviations noted, these procedurles were followed for over a

year, but in the winter of 1941-42, D)r. P. S. Pelouze. directly representing

The Surgeon General, made personal visits to a number of the larger Army

camps. and his report occasioned The Surgeon General to write to the chairinan of the National Research Council, in part, as follows: "I)r. P. S. Pelouze

has just presented to us some evidence that the recommendations of the Counicil on the treatment of gonorrhea may need revision in the light of recent

advances in this field * * * '-4

Accordingly. a revision of Circular Letter No. 18 was considered and

approved by tile Subcomnnttee on Venereal D)iseases in March 1942, and this

eventually appeared in Circular Letter No. 74, Office of the Surgeon General.

25 July 1942. The important changes included alteration of the criteria for

diagnosis of gonorrhea in the femiale to bring them into line with those previously defined for tile male: the reconmemdatioi of sulfathiazole or sulfadiazine as the drug of choice to be administered in a dose of 4 gin. daily for I

days, this course to be repeated no more than once; tile direction that if

sulfapyridine must be used it be given iii a (lose of only 3 gin. daily for 5

(lays; a relaxation of the test of cure: a marked reduction in the period of

followup (3 weeks advised, but not insisted upon) : and finally tile recommendation " * * tirot carefully selected patients with sulfonamide-resistant infections be given ten hours of sustained fe%'er therapy * * *" without. however, directions or suggestions as to how the selection should be made. This

deficiency was partially rectified by Circular Letter No. 86, Office of the Surgeon General, 18 Augist 1942. which designated eight named general hospitals

as fever therapy centers and implied that the final] decision as to whether the

patient should be treated with fever should be left to the staff of the hospital

to which he was referred for this treatment.

These eight hospitals soon proved to be insufficient to care for the mounting load of patients with sulfonamide-resistant gonorrhea. The average rate

of cure with the sulfonamides was falling below 75 percent, owing to tile

delelopment of sulfonamide-resistant strains of the gonococcus and to the

substantial number of chronic cases that probably represented relapse after

inadequate self-administered treatment. Every station and general hospital

had a mounting backlog of patients with chronic gonorrhea for whom the

only prospect of cure and return to duty at that time lay in treatment with

fever. Accordingly, at tile request of Tile Surgeon General, a conference was

held on 6 April 1943. under the auspices of the Subcommittee on Venereal

Diseases on the use of combined fever and chemotherapy in the treatment of

sulfonamide-resistant gonorrhea. The aim of the conference was to prepare

a draft of a circular letter to be sent out by the Surgeon General's Office to

4 Miniutes, Fourteenth Meetiug. Suhbcmmeitltte on •w Venerenal )iseases. National Research Counell. 11 Mar. 1942.
VENEREAL DISI EAS•ES 413

apfpropriate military h)pitalls. The draft wias approved by the Subconmnittee

on Venereal Diseases on 7 April 194:, forwarded to The Surgeon G(eneral,

and published as Circular I.etter No. 97, ()ffice of the Surgeon General, 12

May 114•.. This broadened the base of the number and type of hospitals

autthorized to administer fever therapy to patients with sulfonamide-resistant

gonorrhea and at the same tine protected the patient by defining with great

care the criteria for the selection of patients and details for management of

therapy. It had been found that one session of s hours at. approxinately

1W60 F. (rectally) would accomplish cure in about .W) percent of patients with

silfonamide-resistant gonorrhea, that half of the failures would achieve a satisfactorv result from at second ,inmilar treatment. but that fever in excess of

two such lbouts aplarently was valueless. No patient, therefore, was to be

subjected to more than two S-hour sessions of induced fever, even though

manifestations of the disease persisted.

Not long afterward, Circular ILtter No. 121). Office of the Surgeon General, 22 .July 19.43, amended C(ircular Letter No. 74 in two important particulars. It poIilted out that prostatic massage should not be done as a test of

cure of acute gonorrhea and. thereby. served to prevent at substantial number

of relapses and coimplicationis occasioned by this procedure. It advised that

for patients with gonorrhea treated in hospital the (lose of sulfathiazole or

sulfadiazine should be increased to a total of 33 gin., given as an initial dose

of 4 gui. followed by 1 gin. every 4 hours night and day of 5 days. This, it

was hoped, would soniewhat reduce the umnber of sulfonamide failures.

Treatment on duty status.-Prior to the advent of chemotherapy, it had

been the custom ;a the Army to hospitalize soldiers for the treatment of

gonorrhea,' in spite of the fact that the vast majority of civilian patients

with gonorrhea were treated on an ambulatory basis. The reasons given for

this are well known: The Army in peacetine felt it imnpracticable to assign

a light-duty status. the philoso•hy being that the soldier either was able for

full duty or belonged in the hospital. During World War I. however, working quarantine was extensively employed for the treatment of selected cases

of gonorrhea (especially the chrohic and recalcitrant). and this procedure

was later authorized by paragraph 7. AR (Army Regulations) 40-235, 11

October 1939. Quoting this regulation as authority, Circular Letter No. 18,

10 March 1941, said in part: "Even under ambulatory conditions, acute gonorrhea, may be cured by appropriate measures in a large proportion of cases.

Ttherefore. when considered desirable a nd local conditions permit, acute gonorrhea may be treated on an ambulatory basis in working quarantine." However, very little use was made of working quarantine or ambulatory treatment. Accordingly. Circular Letter No. 74. 25 July 1942, dealt realistically

with the matter, as follows: "In the Zone of Interior and in the commuinications zone. venereal disease cases will ordinarily be hospitalized for treatment

durimig the infectious stages. In order to maintain effective strength of organ-

, Sep footnots- 2. 1. 409.
414 INFI'E CII S I)15E.AES I 

izatiollS during comibat, consideration nlaV be given to tihe tlreatmient of

veneral (lisease cases on at duty status withi tlieir organization ill the colnibat

zone."

In the mleantline, however, dissatisfied both withi the large iiniber of

hospital beds occupieed by patients with goniorrhea and with the lots of tinie

from training, certain Imxsts in thi Fourth Service Command (Camnp Forrest,

Tenn., wis apparently the first) hiad undertaken the treatment of gonorrhea

with the sulfonanlidp, compoundls ol a duty status. The niethod seemed to

work and, if it could be shown to be therapleutically efficient, might be used

mnore widely. Accordingly, in Noveniber 1942, a board S was appointed to

evaluate the experiences which had so far been gained.7 The lhard members

proceeded from the Office of the Surgeon General to p)osts within the Fourth

Service Command where gonorrhea was being treated on a ilduty status. Their

report recomlmended ( 1) that the policy of treating ulncolnplicated gonorrhea

on a itduty status be approved and that the adoption of such a policy wherever

feasible be encouraged and (2) that because this Imethod may not be equally

practicable under all conditions its adoption not be made mnandatory.

The recomnmendations inade by this board were officially authorized in

January 1943,1 and on I February 1943, Circular Letter No. 32, Office of the

Surgeon General, gave inl detail directions for the Ianagemlenlt of l)atients

with acute gonorrhea while ambulatory.

Following this, tile d(ity-statuls treatment of acute gonorirliea wias undertaken oin a large. scale, both in the continental United States and in the oversea theaters, but the sultonamides were so quickly thereafter replaced by penicillin that there wias no opl)ortunity to gain a largre-scale evaluation of the

usefulness of the method. Even a complete study, however, would have been

difficult to evaluate unless the alnbulatory lnethiod were a muarked inlprovenient over treatment in hospital. This is because of the declining percentage

of cures already being observed among hospitalized l)atients and the great

variation in the interest, training, and experience of the large number of unit

medical officers who suddenly became responsible for the diagnosis and treatnhent of gonorrhea. and for the evaluation of results.

Penicillin.-The verbal report, early in 1943 (subsequently pulblished in

September 1943), by Mahoney and his collaborators," on the use of penicillin

in the treatment of sulfonamide-resistant gonorrhea, rapidly removed the

6 The board was composed of Brig. Gen. Henry C. Cohurn, Jr. : Col. (later Brig. Gen.) Hugh J.

Morgan,. MC; Lt. Col. (later Col.; Thomas B. Turner, MC: Col. Alvin L. Gorby. MC: and Maj.

(later Lt. Col.) Robert I)yar. MC.

"7 (1) Letter, Col. John A. Rogers. MC, Exec't!vo Officer. Office of the Surgeon General. to

Commanding General. Headquarters. Services of Sup-ly. 19 Nov. 1942. subject: Appoitnment of

Board for Investigation of the Treatment of Venereul ;,isease on a Duty status. 421 Letter. J. F.

MeGuire. The Adjutant General's Office, to The Surgeoa General. :30 Nov. 1942. subji-et : Board of

officers.

"W War Department IMemorandum W40-2-43. Treatment of Individuals With Uncomplicated

Gonorrhea on Duty Status, 19 Jan. 1943.

" Mahoney. J. F., Ferguson, C.. Buchholtz. M.. and Van Slyke. C. J. : The Use of Penicillin

Sodium in the Treatment of Sulfonamide-Resistant Gonorrhea in Man.Am. .J. Syph.. Gonor. &

V\n. lDis. 27: 525-528, September 1943.
V EN FR EA 1 )1 IE A SES 415

practical importance of determining the best way of treating with sulfonlamide. It appeared that penicillin inl almost any dosage effected cure inl t high

percentage, of case,, aind inl aliiiost miiraculous fashion. This was confirmed

by 1-lerrell and his coworkers.ltb

This promise of a solution for an increasinigly harrassimig I)Io)Ilelim of tile

so1ldier ledl, lin May 1943. to at clinical inve~stigation lin 15 Atrmly hospitals of

the ulse of penicillin in thle treatment of this condition. Within a relatively

short time, resuilts of the treatment with penlicillinl of 1,686 p~atienlts with

sul]fonamide-resist ant gonorrhea were available. The dletails of this study

were later published by Sternberg and TIurner.1' All of the 1,686 patients

were men: their ages reflectedl the usual distribution inl the Armly ait the timie:

t-hey had had onl the average. 58 giml of at sulfonamlide ending at least .5 dayvs

be-fore penicillin wats administered, and 236 had also had treatmient with

fever. The patients were dividedl into groups, each group treated with it

different (lose of penicillin. With at dlose of 160,000 units or more, 98 percent

of the patients achieved cure; as the (lose was reduced[ below 100),000 units. tile

cure rate fell off rap~idly. There were ill all ( regardless of dosage) 126 failures. Of these, 85' were re-treated, all with 100),000 units and 91.8 Ipercenlt

of them were cured. This raised the overall cure rate for t~wo courses of treatillent to 99 percent.

These dIramiatic results ind~ucedl The Surgeon General, onl 23 September

194:3, to addlress at letter to the service coimmnand surgeons authorizing th~e Ilse

of penicillin inl tile treatment of sul fonamide-resistantt gonorrhea. Time dosage

authorized wats 50,4M),H units inl doses of 10,000) units at 3-hour intervals, wit],

permission to re-treat wvith 100,000 units adlminiistered ill 10,0(M-unit (loses

hourly inl case of failure. of thle, first cours-e. It muist be recalled that p~enicillin

was lin excessively short supplyl at thle time, a, fact that, seriously jinfluencedl

thle size of the (lose recoimmlend~ed. As the supplyl impllrovedl, this wits illcreased to 100,000) units given inl 20,000-unit (loses by T11 MM)E (War D~epartnllelit Technical Bulletill) 9, 12 February 1944. About a nimontli later,

6 'March 1944, TB MED 16 authorized the use, of penicillin for the treat~ment

of sulfonamide-resistant. gonorrhea, in station hospitals and directedl t-hat. it

should be. administered to patients with gonorrhea, imumedliately after failure

to resp~ondl to oine. course of a sulfonamide.

As thle supply of peniicillin Inicreasedl. its Ilse wats extended. Onl 21 September 1944. T11 MEl) 96 Iprov'idedl for complete replacement of suilfonam ides

lby penlicillinl inl tile treatment of gonorrhea. except for those individuals who

failed to respoind to penicillin. This bulletin said further that the treatment

of uncomnplicatedl goniorrhea with p~enicillin might be carried out as,, a hosp1itall

or d ispensary l)1vedlur1e. but recommended thiat wvhere sat isfactor'y medical

facilities were available hospitalization be avoidled. The recommended (lose

10 Heqrrieii. W. K.. Cook. F. N.. andi Thompson. L: Use of P'enicillin~ in Saifonamilde Resistant

Gonorrhe~al Inifections. J.A.NA. 122: 289-292. 29 May 194:1.

11 Ste~rnberg. T. 1L. and Tu~rner. TI. B.: The~ Treaitme~nt of SZaifonanm dde Res~istant Gonorrhea

With Pe~nicillin Sodium :Resulits or I .nsq cases. J.A.M.A. 126: 15i7-161. 16; Seplt. 1944.
416 IXFECTIOUS DISEA S

was 100,W)0 units, given in 20.0(0)-unit injections intranius.ularly every 3

hours for those in hosl)ital, or five injections spaced over an S-hour period

for outpatients. In the event of failure, re-treatment with the sane (ose was

suggested, and if the failure persisted, a third course of treatment with

300,0000 units given in 20,O0-unit injections at 3-hour intervals was advised.

In the event of failure of these three courses of penicillin, tnc treatment of

choice would be sulfathiazole in the 33-gin. (lose recomnniended by ('ircular

Letter No. 129. Finally, TB MEl) 196. 20 August 1945, redefined the criteria

for diagnosis and cure and increased the initial dose of penicillin to 200,000)

units administered in four injections of 50,0(M) units every 2 to 3 hours, depending on whether the p)atient was hosp)italized or being treated on duty

status. Patients failing of cure after the first course were to be re-treate(l

similarly with 2(0),0(0) units. Those patients who did not respond to these

two courses were to be hospitalized for more complete urological and bacteriological investigation and, if gonococcal infection were proved. to be

given at least 5(0),000 units of penicillin in 50,000-unit (loses every 2 or 3

hours.

It was at first feared that, with the widespread use of penicillin in the

treatment of gonorrhea. the gonococcus might. develop penicillin resistance

analogous to the sulfonamide resistance already encountered. None of the

Army material, however, has proved any evidence to that effect, either clinically or in vitro, although the production of penicillin resistance in vitro

has been reported by Dr. Joseph E. Moore.12 As further experience was

gained, it became clear that 10 to 15 percent of patients with gonorrhea failed

to respond to 100,000 units of penicillin but that. most, if not all. would respond to repeated courses or increased (loses. Toward the close of World

War II, several cases were reported in which penicillin resistance was suspected clinically, but it was not determined whether these failures of treatment were due to true penicillin-resistant strains, to insufficient, deteriorated.

or substandard penicillin, or to failure to detect the true etiological agent,

thereby confusing gonorrhea with nonspecific urethritis.

And so the end of the war saw a therapeutic triumph. Penicillin in

adequate dosage had solved the problem of sulfonamide-resistant gonorrhea,

had provided a substitute for dangerous, troublesome, and unpleasant fever

therapy, had relieved general hospitals of rapidly increasing numbers of

patients with gonorrhea, and had made of the disease a relatively minor infection, with few complications and with a small noneffective rate. In 1937,

complications developed in about one-fourth of all cases of gonorrhea in the

U.S. Army: in 1944, complications occurred in approximately 1 percent of

all cases.13

Penicillin in oil-beeswax.--One remaining difficulty was the fact that the

only effective method for the administration of penicillin then known was by

12 Moore. Joseph Earle : Penicillin in Syphilis. Springfield. 1ll. : Charles C Thomas, 1946.

13 Monthly Progress Report. Army Service Forces. War Department. 28 Feb. 1945, Section 7:

Health.
VENEREAL DISEASES 417

injection. preferably intralnuscularh yet in the u.,ual aqueous or salitie solution, penicillin was so rap)idly absorbed and excreted that in order to mainitain therapeutically effective blood levels 14 it had to be given no less frequently than every ,3 hours.15 A number of investigators had approached

this subject--one group attemlptiing to delay excretion by blocking the kidney;16 others, to delay absorption by local vasoconstriction17 or by local

application of ice packs.'I None of these methods was particularly successful. The first satisfactory method for delaying the absorption of penicillin with relative uniformity was devised by Romansky and Rittman at the

Walter Reed General Hospital, Army Medical Center, Washington, D.C.

These investigators found the injection of a suspension of 300,000 units of

penicillin, preferabliv the calcium salt, in 1 cc. of a vehicle consisting of peanut oil containing 4.8 plercent by weight of beeswax, was followed by assayable blood levels of penicillin from 24 to 36 hours after injection 19 and

produced excellent therapeutic results in patients with acute gonorrhea.-0

The Surgeon General then initiated an investigation of the subject to be

carried out, both clinically and in the laboratory, at the Regional Hospital,

Fort Bragg, N.C. Partial confirmation of the results of the original investigators was achieved. Over 90 l)ercent of 88 patients with acute gonorrheal

urethritis were cured with a single intranmuscular injection of 300,000 units

of calcium penicillin suspended in the oil-beeswax vehicle..2 The substance

was not entirely without its objectionable features, however. Uniforml blood

levels were not always obtained, and after appropriate investigation these

later investigators concluded that the blood levels produced depended on both

14 In October 1948, the previously accepted concept that assayable levels of penicillin concentration in the blood must be maintained in order to gain maximum therapeutic effect was being

sharply questioned. At the time of the development of POB (penicillin in oil-beeswax), however,

there was general acceptance of the concept that maintenance of a relatively uniform concentration of penicillin In the blood was necessary for maximum therapeutic effect.

15 Rammelkamp, C. H., and Bradley, S. E. : Excretion of Penicillin in Man. Proc. Soc. Exper.

Biol. & Med. 53: 30-32, May 1943.

16 Beyer. K. H., Woodward, R., Peters. L., Verwey, W. F., and Mittis, P. A.: Prolongation ot

Penicillin Retention in Body by Means of Para-Aminohippuric Acid. Science 100: 107-108, 4 Aug.

1944.

17 Parkins, W. M., Wiley, M., Chandy, J.. and Zintel, H. A. : Maintenance of the Blood Level

of Penicillin After Intramuscular Injection. Science 101 : 203-205, 23 Feb. 1945.

18 Trumper, M., and Hutter, A. M. : Prolonging Effective Penicillin Action. Science 100: 432-

434, 10 Nov. 1944.

19 Romansky, M. J., and Rittman, G. E. : Method of Prolonging Action of Penicillin. Science

100: 196-198, 1 Sept. 1944.

20 (1) Romansky, M.J., and Rittman, G. E.: Penicillin: Prolonged Action in Beeswax-Peanut

Oil Mixture; Single Injection Treatment of Gonorrhea. Bull. U.S. Army M. Dept. No. 81: 43-49,

October 1944. (2) Romansky, M. J., Murphy, R. J., and Rittman. G. E. : Single Injection Treatment of Gonorrhea With Penicillin in Beeswax-Peanut Oil; Results in 175 Cases. J.A.M.A. 128:

404-407, 9 June 1945.

21 (1) Kirby, W. M. M., Leifer, W., Martin, S. P., Rammelkamp, C. IT., and Kinsman, J. M.:

Intramuscular and Subcutaneous Administration of Penicillin in Beeswax-Peanut Oil. J.A.M.A. 129:

940-944, 1 Dec. 1945. (2) Leifer, W., Martin, S. P., and Kirby, W. M. M.: The Treatment of

Gonococcal Urethritis With Single Injections of Penicillin-Beeswax-Peanut Oil Mixtures. New England J. Med. 233: 583-586, 15 Nov. 1945. (3) Kirby, W. M. M., Martin, S. P., Leifer, W., and

Kinsman, J. M. : Maintenance of Therapeutic Blood Concentrations of Penicillin for Twenty-four

Hours Following Single Injections of Penicillin-Beeswax-Peanut Oil Mixtures. J. Lab. & Clin. Med.

31: 313-316, March 1946.

639243"--63-:30
418 INFECTIOUS DISEASES

the concentration of penicillin in the vehicle and the total amount admiliistered. They also found the mixture so viscid as to require incubation at

370 C. to go through a 17-gage needle and so inmmiscible with water that the

slightest amount of moisture in the syringe would produce a completely unmanageable gummy, sticky mass. As the war ended, it seemed that the preparation represented a large step forward but that several improvements, even

perhaps an entire alteration of its composition, would be necessary before it

would be suitable for widespread adoption.

NONSPECIFIC URETHRITIS

Although not officially classified as one of the venereal diseases, nonspecific urethritis2 2 bears consideration here because of its close association

with gonococcal urethritis, both because of its etiology and because of the

diagnostic confusion which it so often produced. The condition was common,

amounting in various experiences from 10 to 40 percent of all cases of urethritis, but unfortunately it was never subjected to careful study. The diagnosis was made entirely by the excluhion of gonorrhea, and treatment usually

began with the method that currently was being employed in the management of gonorrhea. This was commonly unsuccessful, in which case the

patient was referred to the urologist and subsequently treated by various

manipulative procedures at the physician's direction. These were also frequently unsuccessful, and eventually the process was allowed to run its natvral course, which tended to be one of great chronicity. There probably was

no disease of comparable numerical importance during World War II that

was so completely neglected both as to lefinition of etiology and as to development of satisfactory methods of treatment.

SYPHILIS

Before and during the early stages of mobilization, that is, prior to the

publication of Circular Letter No. 18, 10 March 1941, the diagnosis and treatment of early syphilis in the Army essentially followed the recommendations

of the Cooperative Clinical Studies Group 23 as elaborated in the standard

textbooks. 24 hNeoarsphenamine was the arsenical drug most commonly employed; many bismuth compounds were used, although a suspension of the

subsalicylate in oil was perhaps the most frequently employed; and rest periods by either design or accident tended to be more common than the experts

would advise. On the whole, however, standards of practice compared favor22 There is no useful source material on nonspecific urethrltls In the official records. The material on which this section Is based was assembled by Col. Paul Padget, MC, from conversations with

many medical officers from 1942 to 1945 and recorded in his personal diary.

23 Cooperative Clinical Studies in the Treatment of Syphilis; Early Syphilis. Ven. Dis. Inform.

13: 207-231, 20 June 1932; 253-293, 20 July 1932.

24 (1) Moore, Joseph Earle: The Modern Treatment of Syphilis. Springfield, Ill.: Charles C.

Thomas, 1933. (2) Stokes, .John H.: Modern Clinical Syphilology. 2d edition. Philadelphia:

W. B. Saunders Co., 1934.
VENEREAL DISEASES 419

ably with those of the aierage health department clinic at the time. As in

health department clinics, however, tlere was much less uniformity of practice in the manag-ement of the various forms of late syphilis, and from a

review of old records, one has the impression that many medical officers treating patients with late syphilis were actually treating the positive blood test

rather than the patient. For this, of course, the medical officers concerned

should not be blamed since it was then, and unfortunately still is, likewise

common in civilian practice.

In supplying the material upon which Circular Letter No. 18 was based

(p. 409), the Subcommittee on Venereal Diseases made no recommendations

concerning the management of syphilis which were peculiar to the Army.

Instead, this material represented simply a. summary of accepted good practices in the. diagnosis and treatment of syphilis which were then current, in

best civilian practice. In this circular letter, accuracy of diagnosis was

emphasized: necessity for clocklike regularity of treatment was reiterated;

Mapharsen (oxophenarsine hydrochloride), at that time the only commercially available arsenoxide, was recommended as the arsenical drug of choice;

and treatment at weekly intervals was to be continued for 15 to 18 months.

The 18-month system of treatment was impracticable even under the relatively static conditions of training. In view of the extent to which all practical administrative difficulties would be magnified in an oversea theater,

particularly after combat was joined, the need for a shorter method for the

treatment of syphilis became obvious. Accordingly, representatives from the

Office of the Surgeon General had informal meetings with members of the

Subcommittee on Venereal Diseases, and at a formal meeting on 27 May

1942, the subcommittee approved recommendations made by this subgroup.

These were published in Circular Letter No. 74. 25 July 1942.

The principles of accurate diagnosis and the criteria for cure were not

significantly changed from the form in which they appeared in Circular Letter No. 18, but the treatment, scheme was compressed into 40 doses of Mapharsen andi 16 (loses of bismuth given over a 6-month period. By this system,

Mapharsen was given in two courses of 20 injections, each twice weekly for

10 weeks separated by 6 weeks of therapy with bismuth, the additional bismuth being given in two groups of five weekly doses concurrently with the

beginning of the first and the end of the second courses of Mapharsen.

According to Sternberg and Leifer,25 this treatment system was used in

the management of approximately 200,000 soldiers with syphilis, with a mortality rate ascribable to treatment of about 0.003 percent. In a study of the

short-ternm results in 3,00() soldiers with early syphilis, 72 percent of whom

had been observed for more than 1 year after the completion of the 26-week

treatment, they say " * * * the results appear excellent with satisfact orv

progress in 98.2.5 percent of seronegative primary, 94.48 percent of seroposi2.5 Sternberg. T. H.. and Lelfer. W. : Treatment of Early Syphilis by Twenty-six-Week Mapharsen-Bismuth Schietle. Am. J. Syph.. Gonor. & Ven. Dis. 31: 124-134, 'March 1947,
420 INFECTIOUS DISEASES

tive prinmary. and S9.34 percent of seconidary cases. Tlere were but 18 (0.64

percent ) ati'orlnial (nerehospiuual fluids aniong tlie 2,842 exaniined."

Intensive arsenotherapy.-As the war progressed, this treatment scheine,

later shown to be therapeutically effective by Sternberg and Leifer, became

increasingly impractical. Six months under the pressure of war was, comparatively speaking, longer and more intolerable than 18 nmontihs in peacetime: biweekly injeotions for 20 of the 26 weeks interfered even with i military

training. Maintenance of uninterrupted medical control for the time necessary to coinlplete treatment. became increasingly difficult. Only 38 percent of

tile troops with syphilis registers who came to the European theater during

March 1943 had had as much as two-thirds of the optimal amount of treatment, up to the time of their embarkation. 2 6 None had been treated in tranisit, which often had imposed an additional lapse of many weeks. ('onsequently, there was widesp)read pressure to persuade the Army to adopt one

or another of the rapid treatment systems which were in use or could be

made available. The 5-day intravenous drip mnethod27 was particularly

strongly urged because this scheme, unlike other proposed methods, had had

considerable clinical use just prior to this time. The Sulconnmittee on Venereal Diseases reviewed the subject in detail on 13 January 1942 and 10 June

1943, and it was taken under advisement by the Committee on Medicine,

National Research Council, 16 October 1942. This committee concluded:

That the intensive arsenotheralkY of early syphilis (including the five-day intravenous drip method) be considered as still in the experimental stage; that the optimum

time-dose relationship still requires to be established by further animal and subsequent

clinical experimentation: and that at present the method cannot be recomnmended for

routine use by the Armed Forces.

The need for a rapid treatment method was so great, however, especiallv in oversea theaters (fig. 56), that at its 19th meeting, 10 June 1943,

the Subconmmittee on Venereal Diseases bowed to the continuing pressure of

the advocates of the 5-day intravenous drip technique and passed a series of

recommendations which had been made at a conference on intensive arsenotherapy of early syphilis held on 19 May 1943. These recommendations read

in part, as follows:

1. Owing to the relatively high mortality rate, no system of intensive arsenotherapy

compressed into a period of 2 weeks or less is as yet suitable for routine adoption by

the Armed Forces.

2. For the routine treatment of early syphilis in the Armed Forces the 26-week system now in use in the U.S. Army should be continued pending further information concerning intensive treatment systems.

3. It is hoped that the U.S. Public Health Service will amplify a statistical evaluation of the several methods of intensive arsenotherapy of early syphilis * *

26Annual Report, Senior Consultant In Dermatology, Office of the Chief Surgeon, European

Theater of Operations, U.S. Army. 1943.

271 Leifer, W., Chargin, L.. and Hyman, H. T. : Massive Dose Arsenotlierapy of Early Syphilis

By Intravenous Drip Method: Recapitulation of Data (1933 to 1941). J.A.M.A. 117: 1154-1160,

4 Oct. 1941.
VE;NEREtl~AL 11SI i:ASES 421

Fxuuzz 56.-Poisoning- by Mapharsen in treatmnert of syphiilis. Fixed arsenical erupI eil4 1 on -' 2 '14ks i* III s. rieck, chest /P i mii d I hig*1Viht W 1; 114)1 h :,'I Ia i i411 ' lm. P.e111 iv iiiiht'rI

hI vi4led :0i t'1 ilit-21 t4wvi iI hiti' I~ oail i 4 11.1 ali ;iilila111 Io Ili;lss 111ti1 (Ifii 111f tha 19a uCo.i

-1. i I 4IVf'I'S it;1it"l" lt el il 8V lfl 11it 11iS i o inlillit'ilt'( for I 'ailm SZjl~lles Iw eie t11.-11ile

(ImIth 1 4)18 * in t en ive~l -w e IlC Vtl ii' ayphil is. ' im 1 4-)III ie t d'wit i h nt ;I08

periodu fiZt't l vo ek Wit- oss, m Ili-(' iioa lie. 11-)et ie ol : 1Sri1 '11.1 O :1its 0 Ilis e Irv:(liii l 1jilt's 4)

Thl e I %%"ee )~s eIt 'I~v ere14,11s f~~iI ,At IIt ei III I hIrel. i . e tl

l)(.1'vii(li Stiigeloii (11) ekilda~ (0dIN ) 11111 it 8del toled1,x Io VC1givIe I Iti- wnIisie

Ixl~erll'uitteilt 11t t 1a Illote 1aug0 IlOv ntn ~ taI ivet'Ii't' t'C1iilI&Il(il -it h~i getienild

ilil'I Ilw lit' .\riiiv.1 1'ti ed'~t~ Il0 Sle frsit&'cie. lt .\OOi~lisilelIll'.id1 .I ivlnII)v 4-' vm I 

(litWi~ts. lil)ern~vts-.0't Anl 12i ee st XUo hiilitj N\ Is ldie sed Ill Illveisvem 11j,11 &'s
422 INFECTIOUS DISEASES

ber 1943, when the sup)eriority of penicillin becanie obvious. No new information was obtained from study of the patients treated up to that time.

In the imeantime, in the Office of the Chief Surgeon. European theater

(which was, because of the disrupted state of voinilinicatiols, virtually isolate([ troii knowledge of ctiu'reit developiiiets in the Sur"o•ll (celieral's

Office), it had been decided(I to i 'y an entirely new scheine for the treatment

of sypphilis with A1apha rseii. It was uuidertakeii becatuse of the utter iillpoS- sibility of even approximately regular treatment under the existing conditions. (Consideration was given to tile known facts regardling the toxicity of

Maplia rsen as deterinied b'y tile ti ime-dose relationshlip. Theoretical conisideratiolis and experimlental work with rabbit syphilis, culled from the nliost

recent source inaterial availal)le on inassive arsenotherapy, indicated that the

total curative (lose of .Mapharsen for early syphilis in the liuiall shouhl be

of the ordler of 20 nlg. per kilograim of bo(dy weight.3:0o Further. it apl)eared

that. the incidence of reactions is dleterminel almost entirely by the time-

(lose relationship). with a very rapid rise in rate as the total interval for

treatment is (lecreased. l)ecomiug intoleral)le if the treatment interval is reduced sign ificantlv b)elow 5 davs, buit not decreasing with particular rapidity" as the span of treatiiient is increased above 20 days.

With this information, and iht considerat ion of the practical military

prollenms involved, it was decide(l, for the patient with early syphilis, to give

clinical trial to the following scheme of treatment: One rag. of Mapharsen

per kilogram of body weight (but not to exceed a single (lose of 75 mag.) was

to be given by syringe daily for 20 days. The choice of a 20-day treatment

scheme was not only convenient, as it allowed (loses of 1 rag. per kilogram

per day to total 20 mug. per kilogramn in 20 days. but was also determined by

sound theoretical consideration2 1 The treatment was carried on in hospital:

the patient was carefully observed both clinically and by laboratory tests. In

addition to the Mapharsen. he was given at regular intervals 8 doses each of

0.2 gin. of bismuth subsalicylate suspended in oil; that is, approximately a

dose of bismuth every other day.

Over 4.000 p)atients were treated by this method in the European theater,

with no deaths. Th,• treatment was completed in 96.3 percent of the first 775

patients and in a somewhat higher percentage of the remainder. In one

series of 1,343 consecutive cases of early syphilis treated by the 20-day form

of intensive arsenotherapy, results of serological tests for syphilis were reported after 6 or more months in 982. In 258, followup reports were received

more than a year after completion of therapy. Ninety-five percent of both

groups had a negative serological test and a. normal cerebrospinal fluid at the

time of last examination. The time relations of the observed serological relapses were such. however, that approximately twice as inany definitely un30 Moore, Joseph Earle: The Modern Treatment of Syphilis. 2d edition. Springfield, Ill:

Charles C Thomas, 1943.

31 See footnote 26, p. 420.
VENEREAL DISEASES 4;23

satisfactory results were noted at the end of 12 months as at the end of 6 months

after treatment.

The authors who reviewed this material conclude( 132 that the 20-day

scheme for intensive arsenotherapy will yield very satisfactory 1-year results in the treatment of early syphilis but that when compared to penicillin

or penicillin plus chemotherapy given on a less toxic schedule it carries an

unjustifiable risk. This is illustrated s by an analysis of 500 consecutive

patients who were treated by this method. Four hundred and seventy qix of

these eventually completed the treatment, sometimes with delays necessitated

by minor reactions, but in 24, or 4.8 percent, the procedure had to be abandoned because of severe reactions. Seven of these patients had definite signs

of cerebral irritation, and two more presented the classical picture of hemorrhagic encephalitis. Jaundice occurred in six, toxemia and agranulocytosis

in three each, while severe fever occurred in two and severe albuminuria in

one.

Penicillin.-In June of 1943, Mahoney and his collaborators treated four

stilons with early syphilis with penicillin in a dose of 1.2 million units which

they had calculated as being the theoretical optimum 34 from observations on

experimental animals. The results were so dramatic that the experiment was

immnediately extended within the limits imposed by the short supply of penicillin at that time.

This information sl)read 'rapidly, largely by word of mouth (all the datL.

concerning p)enicillin were then classified information). At the 20th meeting

of the Subcommittee for Venereal Diseases on 29 September 1943, "It was

agreed that the clinical and experimental evidence so far available justified

an extensive trial of penicillin in human beings * * *," and recommendations were passed for the formation of a penicillin panel, under the National

Research Council, to coordinate experimental and clinical trials of penicillin

in humans with syphilis which were to be conducted by appropriate facilities

of the Army. the Navy, the U.S. Public Health Service and eight :; participating civilian clinics. At the first meeting of the penicillin panel a month

later. six treatment schedules for investigation were agreed upon. Five of

these were to be Indertaken imnmnediately, one was deferred because of the

shortage of penicillin, and the Army agreed to contril)ute observations upon

:r2' Pillsbury, I). M.. and Lovwnian. A. B. : Six- to Twelve-Month Follow-Up Results in Early

Syphilis Treated by a Twenty-Day Intensive Arsenobisinuth System. Am. J. Syph., Gonor. & Von.

Dis. 31: 115-123, March 1947.

3• Cormia, F. E., and Blauner, S. G. : Reactions to Twenty-Day Intensive Therapy With Maphar- sen and Bismuth for Syphilis With a Note on the Use of BAL in Their Management. Amn. J. Syph.,

Gonor. & Ven. Dis. 31: 135-149, March 1947.

34 Mahoney, J. F., Arnold, R. C.. and HIarris. A.: Penicillin Treatment of Early Syphilis:

A Preliminary Report. Ven. Dis. Inform. 24: 355-357, Dec. 1943; also Am. J. Pub. Health 33:

1387-1391. December 1943.

35 The number was greatly increased later, so that at one time there were nearly 40 clinics

pat rticl paiting.
424 INFEC'TIOUS1 DIISEASES

120) paltienlts treated by~ two( of thtse schedIules withinl thle first 1 miolitits of

tile t'xpejiettneit.' 0,

F.~ront thins point (October 1943), thle (itveiolptllellt of the luse of penlicillinl

ill thle I reatmtetit of syphill WIiS a eSS~t in liV a1 civil muactivit tilie liSI0Isy of

wiviHi has beenl stillIllin rized ill detil 1) ,i % Mo0re. Tilhe Art~tily (cotit tined to

part ici pate 'Ill thle clilii tal in vest i gait iolls onl a small Wcale, but it was qulite

priopely'i much mIiore VOIicRIiled withi tilie appl icat ion of t iiis niew. sa fe. anid

simnple therapelt ic mietho oi(1(l 1 uinass treatnienit scale t ban inl ati enipt i ti

cliiiical hinvest i iat iv %v ork.

()it ') April 1944, Brig. ( Iteii. 'Jntiies S. Sitnitlios, Chiief, l

t revemit i ve Medicinle

Servic'e. Office o*f the Surgeon ( ellernI. n addres.sedl the followingo le'tter to D~r.

Moore. ( mirtaStiv111comillit tee onl Veiiereai D iseases, Nationlal Resen relil

It is detsiredl that the~ Slicoi)(lllittett oilVn ereal I lil'.as, National It.search ( otilvil. voisliler at its April 201th I 19441I meetinog the present state of knowledge of the

p*'il ieii lii t reat ment of syphli s lIn reltai onship to Its suitability for application to Armiy

Practice. Thue presen'lt jrolotiged trtat iliehlit Schedultles plate. at great chorei (III theit MedicliI

I 'pa rt I11.eIit aIkd interfere seriously With t raining 11111l Combat. Fu'trthaermoare. ill active

Thleaters ofOpr ation'll it is impjossible to tiia iota ili ally~ tieg'r ofre^It'llarity Ii all n I11111stering treatmtaent.

For t hese reasons The Su rgeon GP~Ia ivoUll aj11jareteiatP all eXPr'eSliOI Of op~inkion

of tile( Sullcoih4lljittt'4' 4)11 Venereal D iseases as to the ea rliest plossible ti oe, pen kliill lii

treatmtent ot syphilis mayv be applied to Armly p~ractice'.

ills ws astggreringt r*e. juest. Arsphllealllle alidl its (derivativyes had

been emplIloyedl in tile treatment of syp)hilis for niearly 35 years withiouit reachlng sat isfactory agrreemenit onl tile details of its littI ilizat ionl, yet hlere was a

requiest. for adlvice' regardliig the large-scale apIliication of an i enirely new

thlerapeutici agent which hlad first been usedl in tile t reatmnent of syphilis only

9 monthis before and withi whichl experience. onl any stat isticaily sipgniiheallt

scale was only 6) monthis old. Well aware of the Inaptlitud~e of the responsibility beingr assumed. but equally aware of the p~roblemns confront ing tile

.Army, the. minutes of the 22d meeting of the Subcommittee on Venereal

D)iseases. 20 April 1944, mnerely say:

The purposte of the request and its relatijonship to ('llinpijNig cotndit ionis was furtlier

ainpliitl~ lin general discussion. This led to the following- reeojnienhitlion: It Is rtwoflimndeitlel t hat InI active thteatersý of operat ion tilt' pen icillin treatmeneit of earl3 syphilis

(i.e.. infections of less tha~ll 0114' year's dujrat ion, whet twr or not partiailly treatedl with

arsenIicall cht'ttotht'rarpy Imt adotedijt& immed~iaeilt'y. Ti'le liIllitldillui total uiosaige of petlivi illi shouldl~ he 2.5 miil lion uinits, givon over anI tigiit-tlay p.'rioitl aultilnlsteretl Iln 64

Int ramiuiscuilar iIIJec-t hut every three hours dlay and4 nighlt. It is further desirable' that

suich peniacillin treated patients be followed with lit sub~sequeltint altsyphilitl tieIreatmient

(unless Ini the event of clinica'l or serologie relapse) as frequently ats is practicable and

that all suchi eases ble t iaoroijghly resurveyed as to syphilis prior to separation fromi thle

service.

.16 Minutes, Conference on P'enicillin in tile Treatment of Syphilis In Human Beings by a Panel

Compoutsed oft Menbers of the Sutueammnittf'e ton AVenrerua i )tiso-umei and tthe Commtulltee ou Chemo4tu'alheruaim-ultiqe aind Other Agents, National it#seatrvh Cotunrcilt, 211 00i. 11943.
VENEREAL DISEASES 425

A subsequent letter from The Surgeon General to the coimanding generals of the overseat theaters for the attention of the chief surgeon summarized current knowledge of the use of penicillin in the treatment of syphihs and directed (1) that all new cases of primary and secondary syphilis

be treated with penicillin, (2) that thli schedule of treatment be 40,000 units

intramuscularly every 3 hours for a total of 60 doses or 2.4 million units for

each case. and (3) that followup examinations should be obtained at monthly

intervals for a miiinimum period of I year.37

The receipt of this directive in the European theater coincided almost

exactly with the date of the invasion of continental Europe. It was, therefore, particularly welcome in the attempt to provide facilities for proper

diagnosis and treatment of the venereal diseases, especially syphilis, within

the Army areas. Evacuation and the loss of a trained soldier to his organization was to be avoided, but at the same time it was important not to increase the patient load which must be carried by field or evacuation hospitals.

Accordingly, venereal disease treatment centers were planned within the

Army areas staffed by at least one medical officer with experience and ability

in the diagnosis and treatment of the venereal diseases, and equipped with

adequate laboratory facilities and technicians detached from the Army medical laboratory. The plan proved efficient and was greatly expedited by the

availability of penicillin for the treatment of syphilis. This made is possible to return all patients treated for syphilis to their organizations within

10 days or less.

The necessary followup was operated by a central syphilis register set

up in the Office of the Chief Surgeon, European theater, where the soldier's syphilis register was filed as soon as treatment was completed. The

followup was accomplished by letters to the commanding officer of the patient's organization requesting the desired observations at the appropriate

time.

The Subcommittee on Venereal Diseases made further recommendations

at its 23d meeting on 29 June 1944 for the use of penicillin in the treatment

of syphilis by the Army. These provided for the treatment of all soldiers

with early and latent syphilis with 2.4 million units of penicillin according

to the scheme advised to the oversea theaters. The necessity for frequent

followup of patients who were treated for early syphilis was emphasized,

and it was pointed out that knowledge concerning the action of penicillin in

neurosyphilis was so imperfect as to prevent any advice on its use in such

cases. TB MED 106, 11 October 1944, developed in detail the general principles contained in the committee's recommendat ions.

As the war ended, TB MED 198, 20 August 1945, defined the criteria

for the diagnosis of syphilis, restated the advice to treat early and latent

37 Letter, Maj. Gen. Norman T. Kirk. The Surgeon General, to Commanding Generals. all Theaters of Operations, attention of Chief Surgeon. 24 May 1944, subject: Penicillin Treatment of

Primary and Secondary Syphilis.

639243'-63--31
426 INFECTIOUS DISEASES

syphilis with 2.4 million units of penicillin in 7.5 days, defined the details

of the necessary ip)sttreatment followup, and advised that all patients with

any manifestation of late syphilis, including, of course, neurosyphilis, be

transferred to tile appropriate neurosyphilis center. Like its companion TB

MEl) 196 oni gonorrhea. dated 20) A ugust 1945. this bulletin on the management of syphilis represented tihe best information available at the time for

the proper management of early and latent syp)hilis among Army personnel,

but events which could not be foreseen at the time of its preparation necessitated important changes in the dosage schedules recommended.

At its 24th meeting on 23 February 1945, the Subcommittee on Venereal

Diseases recognized that there were several fractions of the substance known

as penicillin. that none of these fractions was available commercially, and

that tihe constitution of coininercially available penicillin was not known. It

made recommendations for extending the assay sul)ervision of commercial

penicillin and most imiportantly made provision for investiigation of the

chenmical and biological properties of the several known fractions. By the

following spring, a great deal of infornmation had been assembled and published !i" Moore. thlie highlights of which were (1) that the substance known

as penicillin was made up of at least four chemically individual fractions

which in the American nomenclature were known as G, F, X, and K, (2)

that originally the commercially supplied penicillin was largely made tip of

penicillin (" (3) that with the substitution of IPen1ivrl/m ehry.,ogeium

Q-176 for I ~ni,./him notattim. in the manufacture of penicillin the commercially available preparations contained an unknown, certainly large (the

average was estimated at about 50 percent) amount of fraction K, and (4)

that fraction K while exceedingly active in vitro was apparently in some

way deulat ired by the animal or human beh'y to l)ecome comparatively inert

and therapeutically ineffective when injected. As these facts were brought

out, the manufuacturers of penicillin immediately took steps to convert to the

produiction of a crude penicillin consisting larg.ly of fraction G and eventually to the production of crystalline penici~lin G on a. commercial scale.

This took time. however, since so large and complicated an industry cannot

convert. itself overnight. For the protection of the soldier patient, Change 1

to TB MED 198 was published on 21 November 1946. This change directed

(1) that patients with seronegative primary syphilis be given 6 million units

of penicillin in 60( doses of 100,000 units each at 3-hour intervals for 71/2

days, (2) that those with seropositive primary, secondary, and latent syphilis

be given s million units in 80 consecutive intramuscular injections of 100,000

units at 3-hour intervals for 10 days, and (3) that the re-treatment of failures

be by the 8 -million-unit schedule with the addition of 10 (loses each of 60 nig.

of Mapharsen given twice weekly and five weekly intramuscular injections

each of 0.2 gin. of bislnuth subsalicylate suspension in oil. Failures after

this combined penicillin, Mapharsen, and bismuth schedule were to be treated
VENEREAL DISIEASES 4 2)7

by the 26-week Maphanrseni mid bismutth system outlitied inl Ciretular- I.tter

-No. 74. -25 *July 1942.

Comparison between Circuilar L~etter 'No. 1S. 101 March 194i. nmd TBI

MEl) 198, 20 Auigust 1945. affords a inumbexr of interesting contrasi . To the

criteria. for diagniosis has heeii adlded the concept of the biological false-posit lye serologival test for syp)hilis which was first introduced to the Armyx in

Circular Letter No. 93. Office of the Surgeon General, 30 April 1943:1 methlods

of treatment are totally differenit. but the miost interesting change is in the

conicept of proper lposttreatluelut followup. Under the scheme of treatment

reC0111luln~dCe by (Circular Letter' No. 18. the patient who camne. under treatmnent. with early syphilis and pursuied the treatment faithfully should have

reached anid maintainedl a negative serological test for some time before the

treatment was ended. With rapid treatment with penicillin, this is not the.

case. anld TB MEL) 198 goes to some pains to explain the interpretation of

the titered serological test inl the, post treaitment. folk,-,wup.

Neurosyphilis.-Prior to 1944, the Army had made no special provision

for the care of patients wvith neurosv.philis and the variouis forms of late

svjpliilis. Patients suffering from these maladies. unless by chalmice they fell

inito the hands of someone professionally qualified to individualize their'nitana geitent. were treatedl. if at all, by whatever scheme was in vogue ait the

time for the treatment of early syp)hilis. While cardiovascular syphilis and

the other forms of late syphilis. other thant of the central niervouls systeml.

were nunmerically un11important, examination. hy increasing numbers of iiuedical officers. of the cerehrospinal fluid of every patient with syphlilis was

revealing a substantial number withI asvmptomiat ic neurosyphilis. As this

sit uat ion becamie recognized. a, special committee met in Washington at the

reqIuest of The Surgeon General onl S 'March 1944 to consider the problem

of thle p~rofessional managemuent of neurosyphilis in the U.S. Army. 381 In duie

tiime. Tit MEl) 48. :31 May 19)44. was 1ail~lishied creating a numbe~r of neurosvfhluihis ceilters inl ianliel general hlospita1ls in the continental United States and setting forth standards for diagnosis anIramet h planwst

staff each of the hospitals wvith one or more medlical officers with special

training inl the management of neurosyphihis andl other forms of late syphilis,

and? alhog teehsiaswr signatedl as neurosyphilis centers it was

tacitly lmnierstoodl at the timue. and later formally stated in TB 'MEl) 198.

that all p~rob~leml cases of syphilis would be referred to them.

Thme proiNIsimois of TB 'MED 198 were largely administrative but the

basic principles leadinig to uniformity of diagnosis in the various ceniters;

:18 P'resent at the meeting were lDrs. Mloor.' and Stokes from the Subcommittee on Venereal

1)isa-es: General Morgan. Lt. Col. Thomas H. Sterniberg. MC, Maj. (later Lt. Col.) Charles R. Rein, MIC. Mlaj. (iater [t. Col.) William 11. Evert%, MIC. Major tDyar. and Maj. (later Lt. Col.) Paul G.

Reque. MC. from the U.S. Army . Comdr. W'. H1. Schwartz. MC, and Lt. H. P. Rowe, MC, from the

U.S. Navy:- Drs. Lowis it. WVeed. E. Cowles Andrisi. T. R. Forbes. Philip 8. Owen, and Maj. Gen.

Jamesq C. Magee. USA (Ret.), from the Natilonal Research Council : Maj. Georges Lecierc. NMC.

andm Stirge..a Lieut.-Comdr. Rt. G. Struthersi. MIC. Canadian Liaison Officers : and the following Invit#te coonfere,.,: D rs. Hanrry V. Solomuon. Pauli A. 4 ILeary. Fran W. Thomas. antd A rth~ur G. Sehocit.
428 INFECTI'r 'S I)ISEASES

were deinll[ aind gelleral recoimiilienldatiollns for vi•.i tiicatlioll nidi t leitrniealt

were ililiade. 'riese were extenided Ih a series of tlilree articles39 wliich were

ulliulihed ill the Iiii//llob if the, V .'. .1 r! .oled;1fi/ Department whlere they

serlv'e its authitoritatlive it ibitiolffitcial guides.

The slpecitlfc recomnidiilationlis 1 of TII MEl) 48 for tlreatmnienit were:

1. A trial of routine metal cheiotlhierapv oil i duly status for (i iloiitlis

for all patjients with early sypllilis or syplilis of unikniown dlurat'ioni and

(Grouips I ( nininialn ) and 11 (intermediate) changes ill lhe ceelrbrospilinal

fluid.

"2. The sante wchenke for patients witlh late syphilis ai( (Group I hlialiges.

:i. The imimediate ilnlluct ion of fever (preferably by tertian milalariah for

whites and Nolbthern Negroes. aild hby (iliartan nialaria for Southiern Negroes)

ill Ihosts il t lhe firslt two groilj)s ill whoni 0' miontlis of nietliii chieiiotlieral)y had

ocdasio.illed no imipirovenient il l ile cerebrospinal fluid, and in all p)atiients wilh

(Groupi Ill iinxiniial) chalig•,es ili the cerebrospinal fluid, those with ]lte

asyiliiflolliialle' lelrrosVlhili, ill( G(roup 11 'hangi•, ainid all patijeilts with

s5viildomlliati neilulrosVlhilis exceplt those witlli acite syplhilitic niinit' isiit or

llretlniiilinlit lv vaiscllar lesiOliS.

(inrt stress wtas la:id upoll tihe necessity for b)oth frequent anlild lg cOiltillued followillp examiiniiations of aill patients treated for iieurosypliilis, and

dletililed directiions for accompliishing this were laid down regardless of

whether tlh ienistai tiyed v fi tile Army or wits separated.

Oni 1:1 Novenbiber 1945, Chliange 3 to Tit MEl) 48 alvis;e( thail all patients

willi nieurosyphilis lislioul lie treated witlh lenicillin. The recommiiiiended dose

wais 3. iiiilliion uiiiits given in 120) iniject oliso of 3io,0m) units eac•h in the ulUslil

miiatiler.

The patients wiio qualified for ia trial of metal c|ieniothera')y alone underl

tile p)revious reglilmen were to lbe returnedl to duty after comnpletion of tlhe

treatmllent with - ePenicillin, followed withi clinical examination aind retest of

the cerebroslpinal fluid h at. and 6 montlis after treatmiient, and returned for

ree'valuatiion if eitlher examination gave ainorniial res•ults 6 imionths after treattmnelt, wits colml)eleted.

The saime group of patients as p)revioiusly were considered candidates for

fever therapy, and the suggestion wais inide thiat the first. doses of the prescribed .6; million uinlits of penicilli lie given at. the little of the first febrile

paroxysmn.

Records.-T-he old practice of recordlinig t reatinent of sypliilis, as outlined ini Circulars Nos. 2 and :3, 13 December 1910 and :1 3ltune 191. 1, respectively, Office of tile .Surgeon General, was contlinuedI in more or less its orig39 (1) O'Leary, 11. A., Moore. J1. F.. Solonon. II. C.. SWoke•. J. 11., and Thomasn, R: Aymptomatle Neurosyphili. lBull. U.S. Army M. Dopt. S0: 461 51, Sepitember 1944. (2) Solomon, It. C.,

Moore. J. E., '0I.eary. 11. A.. Stoki,.. J. IT., and Thonimm. E. : Symiptonitial Neu rosy phllls A Clinical

Survey. Bull. U.S. Army NI. lept. 81 . 55-464. Octolier 1944. (l3) Solonon, 1H. '.. Moore. J. K.

O'ILary. P. A., Stokem,, . IL. aind Thomas, E. W. : The Treatment iof Neurotylihillm. Bull. U.s.

Army M. DrIpt. 82: 66 76, November 1944.
VENEREAL ISI8EASES 429

inal form until after World War 1, (hiring which ilhad proved to be unnecessarily laborious and to serve no useful purpose. By this time numerous individual medical officers had created their own record systems and their ideas

were consolidated, eventually to produce WD MD Form 78, The Syphilis

Register. This was authorized by War D)epartment General Orders No. 6,

13 February 1923, and incorporated in AR 40-235 on 30 December 1924.

This form with relatively minor changes (the last was necessitated by

the introduction of penicillin) has been employed since its first introduction.

The form is opened at the time of the original diagnosis of syphilis, contains

all of the relevant information concerning both the infection and the general

physical condition of the patient., provides space for recording treatment,

reactions, the results of laboratory tests, and progress notes and is closed at

the completion of treatment and a specified period of observation. Upon

completion, the record was transmitted to the Venereal Disease Control Division, Preventive Medicine Service. Office of the Surgeon General. where it was

reviewed and, if found acceptable, filed for future record. 40

During the period in which the treatment. for syphilis was prolonged,

this record facilitated continuity of treatment of the patient which might all

be carried out in the Same place or by the same medical officers. During the

first part of World War II, however, because of the rapid and secret troop

movements, it frequently became impossible for the syphilis register to keep

up with the patient. Several different methods of accomplishing this were

explored, including a brief trial of having the syphilis register transmitted

with the service record of the soldier concerned, but none proved to be entirely Satisfactory.

In an effort, to obviate this difficulty. there was inaugurated at Fort

Bragg, in 1941,41 an individual record of treatment patterned after the similar form supplied to seamen under the auspices of the then functioning

Health Organization of the League of Nations. This served to give the

patient. a pocket record of treatment which provided adequate information

for any medical officer into whose hands he might fall. The proper functioning of this accessory form, of course, depended on the willingness of the

patient to report for treatment before his syphilis register caught up with

him, but experience showed that on the average the form substantially reduced the number and duration of lapses from treatment. Similar forms

were introduced in the European theater in 1942 and in the Mediterranean

Theater of Operations, U.S. Army, in 1943. Still another but again similar

form (WD MD Form 78a) which had been authorized by The Surgeon General in October 1943 was made available by TB MED 3, 11 January 1944.

40 By an agreement between The Surgeons General of the Army and the Public Health Service

and the Chief Medical Officer of the Veterans' Administration, the syphilis registers from World

War 11 were filed with the Veterans' Administration to arrange for men in certain categories, especially those treated for neurosyphilis, to be followed through the Public Health Service.

There were also other exceptions to this standard procedure; for example, the Central Syphilis

Registry used In the European theater.

41 Annual Report, Office of the Surgeon. Fort Bragg. N.C., 1941.
430 INFECTIOUS DI)SEASES

After the introduction of rapid treatniueit, methods, all d[one under the coiltinuing control of one small group, a formt of this type wits no longer required for assisting in continuity of treatment, but it may continue t~o serve

it useful purpose in facilitating p~osttreatmienlt followup.

THE MINOR VENEREAL DISEASES

Aside from chancroid, which became t roublesomne in certain areas, thle

lesser venereal diseatses ( yivmphogranuloina venereurn and granuloma inguinatle) were of little numerical imnlportamlce duiring Wor'ld War 11. Although

these three types of venereal (liseases were less conmmon than goniorrhea, or

syphilis, the period of dlisab~ility often produced by each of themi was potentijally great enough to vest them with a certain degree of iuilitar~y importance.

The. earlier deliberations of the Subconmmittee on Venereal D~iseases which had

led to the suggestions upon which Circular Letters Nos. 18 and 74 were

based, included considlerations of the lesser venereal diseatses, and these circulars laid down methods of diagnosis and treatment of these. conditions.

Later, TB MED 157, dated April 1945, with Change 1, dlated 17 December

1946, brought up to (late the accepted p~ract ices in the (liagniosis and treatimient of thie minor venereal diseases.4-

Chancroid.-Up to the endl of World War It. the (diagnosis of chancroid

was one of exclusion and therefore essentially unsatisfactory. Circular Letter., Nos. 18 andl 74 and TB MM)D 157 emnphasized the necessity of excluding

syphilis, both lby (ark-fleldl examiiination and by serological followup, and

thlat this 1111t4 be (lone even if the (diagnosis of chancroid ca.n be proved hacteriologically in ord(er to exclude a mit iXed infect ion. At tilie t ilnie of thle first

(direct ive, thle bacteriology of IHeiophdu.x duerrey; was so unsatisfactory that

C'ircular Letter No. 18 reads. as follows: "Laboratory tests for the ab~solute

(dia~gnosis of chancroid ( Ito-ileeust ierna skill test or the staining or cultural

isolation of tile lDucrev lbacillus) are not reconiendled. 'In T13 MEl) 157,

cli(l(1'iderale adlvance in thle bacteriology of thle causative organlisml is illumstratedl ill tile foilolvimir statement.: "Tfle (diagnosis of chumncroid may be

aided by thle, laboratory examinnat ion of stained smears froiii the lesion, or

by culture of pus1 from the. lesion or the bubo." This reflects a growing inter-

"est, in the bacteriology of chiancroidl andl the fact that the experts have. developedl methods for more accurately staining and for culturing thle IDucrey

bacillus which are satisfactory in their hands. The complete omission of thle

42 TB MEID 157 was based on the reconintfln(intionm of a speia~li commtittee which convened on

25 January 1945 at the request of Trie Surgeon General. Present at the mjeeting were Dr. Moore,

subcommnittee on Venereal Dist-ams; Lt. Col. (litter Col.) Hlarrison JT. Shull, MIC, Colonel Sternberg.

and 'Major Rein. representatives of The Surgeon Generai Dr. Paui 1). Rosahn. Technical Aide to

the Commtittee on Mletlcai Research. Gitice of Scientific Research and 1)eveioptnent: an(1 the foliowing conferees: Dr. Arthur W. Grace. Long Isiand Coiiege of Medicine. Brookiyn, N.Y.; Dr. Geoffrey

W. Rake. Squibb Institute for Medical Research. New Brunswick. N.J.; Dr. Katherine 11. Anderson,

Vanderbiit University School of Medlivine, Nashville. Tenn. :IDr. F~ranco Mortars. New York Univermity Coiiege of 'Medicine, New York, N.Y. - and Dr. Robert B. Greenblatt, U.S. Public Health

Service.
VENEREAL DISEASES 431

Ito-Reenstierna or other similar skin test from this latest directive is apparently a reflection of the growing doubt of the value of skin tests of this type

in general.

In contrast to the unsatisfactory state surrounding the diagnosis of chancroid, treatment with the sulfonamide drugs was eminently satisfactory. Circular Letter No. 18 recommended sulfanilamide in the dose of 33 gin. given

over a period of 14 days and local treatment with powdered sulfanilamide

after primary syphilis had been excluded by a series of at least three darkfield examinations of material from the lesions. Surgical procedures, such as

circumcision or dorsal slit, " * * should be resorted to only oin the basis of

sound clinical judgment." Incision of the fluctuant bubo was allowed but

not advised.

The changes between the recommendations just cited and those contained in TB MED 157 are worth comment. The more recent recommendations were to treat systemically with sulfadiazine in a dose of 1 gm.. four

times daily, for 5 to 7 days; no local treatment except soap and water; aspiration of the fluctuant bubo with a 16-gage needle if necessary but, "the bubo

should never be incised," and regarding other surgical procedures "circumncision or dorsal slit is undesirable and is rarely necessary."

As indicated earlier, chancroid became exceedingly prevalent and consequently troublesome in certain areas. This was especially true in the

Philippines, 43 at the end of the war, and earlier in North Africa 44 and the

China-Burma-India theater." Recommendation by special investigators of

the problem in the Philippines, however, dealt largely with control and preventive measures. In no theaters in which chancroid was troublesome was

there advance in therapy greater than that reported in TB MED 157.

Lymphogranuloma venereum.-Fortunately, this disease was of low incidence both in the continental United States and in the theaters of operations.

In the latter, the disease occurred almost entirely in small sporadic outbreaks

clearly suggesting a single focus of infection. The same three directives (p.

430) deal with diagnosis and treatment.

Between the first and the last, there was essentially no change in the

diagnostic criteria laid down. TB MED 157 explains that the diagnosis

is based upon collateral consideration of the results of the Frei test, the clinical picture, epidemiological information, and the exclusion of other causes

of inguinal adenopathy. It is emphasized that a positive Frei test is not in

itself adequate reason for making the diagnosis of lymphogranuloma vener43 Letter. Dr. Joseph Earle Moore, Consultant to The Surgeon General, U.S. Army, and Lt. Col.

Thomas H. Sternberg, MC. Director, Venereal Disease Control Division, Office of the Surgeon General, U.S. Army, to The Adjutant General, U.S. Army, 6 June 1945, subject: Venereal Disease in

the U.S. Army In the Philippine Islands, and Recommendations for Their Control.

44 Annual Report, Preventive Medicine Division, Office of the Surgeon, North African Theater

of Operations, 1943. 45 Letter, 1st Lt. M. A. Bouton. MC, VD Control Officer, Office of the Theater Surgeon, Rear

Echelon, Headquarters, U.S. Army Forces, China, Burma. and India, to Commanding General, Rear

Echelon, Headquarters, U.S. Army Forces, China, Burma, and India, 8 Apr. 1943, subject: Venereal

Disease Situation in the C.B.I. Theater.
432 INFECTIOUS DISEASES

eum in the absence of the typic, clihncal picture, but it is suggested that a

negative Frei test in the presen( - of a, suggestive clinical picture is of some

value in excluding the diagnos; .

In the treatment of lymphogranuloma veriereunt, conservatism is advised.

TB MED 157 recommnends aspiration of fluctuant nodes where necessary but

avoidance of radical surgical procedures; chemotherapy with sulfadiazine in

doses of 3 gm. daily for 21 days; and the utmost conservatism in management

of rectal stricture when it occurs. Perirecral abscess and fistulo-in-ano may

be dealt with radically in the hope of gaining surgical cure. The use of Frei

antigen intravenously, which was previously touched upon lightly in Circular

Letter No. 18, was not even mentioned.

Granuloma inguinale.--This disease was completely unimportant froin

the military standpoint but was included in the various directives (p. 430)

for the sake of completeness. TB MED 157 suggests that the diagnosis of

the condition can be made by. a competent observer on the basis of morphology

alone but points out the obvious desirability of demonstrating Donovan's

bodies in smears from the lesions.

Fuadin (stibophen) was recommended as the drug of choice. This is

given intramuscularly by a rather complicated dosage schedule, is commonly

well tolerated, and is therapeutically effective in the majority of instances.

Where there was no response to Fuadin, tartar emetic was recommended.

This is given intravenously also on a rather complicated dosage schedule. It

was further recommended that if secondary infection was present. penicillin

be used in doses of 10,000 units intramuscularly every 3 hours for a total of

400.000 units. With the exception of this addition of penicillin for secondary

infection, there were no other advances in the treatment of this condition

during World War II.

Miscellaneous.-The more strictly urologic conditions which are sometimes grouped with the venereal diseases (venereal warts, gangrenous balanitis, and so on) need not be considered here, but the role of scabies as a

venereal disease must be mentioned.

In the early winter of 1942, the Senior Consultant in Dermatology,

Office of the Chief Surgeon, European theater, had noted that the incidence

of scabies severe enough to require hospitalization in the European theater

was greatly in excess of the frequency of the disease among troops in the

United States. A determined campaign was instituted to educate unit medical

officers in the early diagnosis and proper treatment of the disease and to provide them with benzyl benzoate for its treatment.

The incidence of the disease continued to increase and the following

simple facts led to an inference that the disease was venereal in origin.

Troops arriving from the Zone of Interior were free from the disease; the

disease was exceedingly common among the British, especially the civilians;

and the pattern of distribution of the individual cases made soldier-to-soldier

spread most unlikely. From this obvious inference, a comprehensive study
VENEREAL DISEASES 433

of the matter was initiated based on the same type of interview by the same

interviewers used in the contact investigation of gonorrhea and syphilis, and

the study resulted in the conclusion that at least 90 percent of scabies amol'

U.S. soldiers in the European theater was venereal in origin.46 This thesis,

incidentally, was amply verified in the experiences of our troops in Germany

after V-E Day. There the irncidence of scabies made a meteoric rise, exactly

paralleling the increase in the incidence of the venereal diseases.4'

INDUCTION OF INDIVIDUALS WITH VENEREAL DISEASE

In the early period of mobilization, persons known to have venereal

disease were rejected for military service. This policy resulted in the accumulation of a large backlog consisting mainly of men rejected because they

had syphilis. It was the practice, at the time, to defer men with gonorrhea

and chancroid only until they became asymptomatic and then to refer them

for induction. By 1942, this reservoir of manpower had grown to tremendous proportions, the manpower shortage was becoming acute, and the Army

felt that its medical facilities and training program were sufficiently advanced

to undertake the additional burden of inducting men with syphilis. In the

fall of that year, plans were initiated to provide in certain selected posts.

camps, and stations additional treatment facilities with a total capacity of

6,510 beds for the management of inductees with syphilis and to a much

lesser extent the other venereal diseases. The plan was placed in operation

in December 1942 by directives from The Adjutant General 48 and was functioning smoothly by March 1943.

The inductees with syphilis were hospitalized in specially provided barrack-type hospitals which were staffed by officers especially trained in the

diagnosis and treatment of the venereal diseases. Some of these medical

officers had been recruited from civilian life but most had been given a short

intensive course at the Institute for the Control of Syphilis at the University

of Pennsylvania, Philadelphia, Pa., under the auspices of the U.S. Army.

As a result of this program, 200,000 individuals with venereal disease

were inducted into the Army through December 1945. Of these, nearly

170,000 were syphilitics. 49 The treatment which they received followed the

current directives for the management of the venereal diseases occurring after

induction and require no special comment.

One administrative problem was greatly expedited by a directive, in

June 1943,50 authorizing preinduction hospitalization for the examination of

the cerebrospinal fluid of all those found to have a positive serological test for

46 See footnotes 26, p. 420.

47 Quarterly Report, Preventive Medicine Division, Office of the Chief Surgeon, U.S. Forces In

the European Theater, 1 Apr. to 30 June 1946.

48 Radiograms. The Adjutant General, to all Service Commands. 7 and 10 Dec. 1942.

49 Karpinos, B. D. : Venereal Disease Among Inductees. Bull. U.S. Army M. Dept. 8: 806-820,

October 1948.

50 Letter, The Adjutant General, to all Service Commands, 9 June 1943, subject: Induction of

Individuals With Positive Serology for Syphilis.
434 INFECTIOUS DISEASES

syphilis. This made possible the preinduction rejection of registrants with

neurosyphilis, thereby avoiding the laborious process of boarding for a certificate of disability for discharge of the 15 to 20 percent of the men with

syphilis who would be found to have an abnormal cerebrospinal fluid at the

first examination.

THE RESULTS

The extremely energetic venereal (isease control program which was

sponsored by the Army throughout the war was effective in minimizing the

number of venereal infections. In spite of these l)reventive activities, however, gonorrhea and syphilis continued to be among the important disease

CHAUT 22.-A comparison of computed and actual rates I rcflc.ting sarings attributed to

improved treatment of venereal disease, Army in the United States, June 1942 to

Alugust 1945

[Rate expressed as average daily noneffectivene.s per 1,000 average strength]

RATE

3.0

COMPUTED RATE

ACTUAL RATE

0 . I I , i ' SS 0 M d S D M 1 S D M J

1942 1943 1944 1945

1 Rates pertain to all cases of venereal disease, including those cases existing prior to service.

For the computed rate it is assumed that the length of treatment required in June 1942 had not

changed.

problems.51 The yeoman's task of reducing to the minimum the number of

days lost from duty because of these infections remained for the therapist who

may well be proud of the accomplishment which he can report.

The reduction in the noneffective rate and changes in therapy, incidence,

and duration of treatment of venereal disease in the U.S. Army in the con51 Medical Department, United States Army. Preventive Medicine in World War II. Volume V.

Communicable Diseases Transmitted Through Contact or By Unknown Means. Washington: U.S.

Government Printing Office. 1960.
VENEREAL DISEASES 435

CHART 23.-Changes in therapy, incidence, and duration, of treatment of venereal disease,

Army in the United States, June 1942 to August 1945

[Incidence rate expressed as number of cases per annum per 1,000 average strength. Duration of

treatment in average number of days lost per case] ,NGOIENGE RATE OAYS LOST

O ENEREAL DISEASE

40 4

TOTAL VENEREAL DISEASE ' -•"

(EXCLUDING EPTS' CASES)

I- -

PENICILINI REPLACE$ SECOND

MAPHIARSEH-OiSMUTH TREATMENT COURSE OF SULFATHIAZOLE

20 FOE SYPHILtIS REDUCED TO 26 IN GONORRHEA

WEEKS FROM I-2 YEARS I

1=UTYSTATUS UNGOM PLIC*ATEO TREATMENTIFORI OORAPTFR_.ORORIEA 'A PENIGILLIN REPLACES FEVER PENICILLIN USED FOR IRTARATEN OURSE

T00AT P ENICILLIN TREATMENT

~ sOS, ~FOR SYPHILIS

DAYS LOST P R CASE *A ***, - 0-0-0-0-*0 0 -

S D II J S D V J S D NI J

1942 1943 944 1945

1 Existing prior to service.

tinental United States are shown in charts 22 and 23. If the length of treatment required in June 1942 had been maintained without change, the venereal

disease noneffective rate for the continental United States would have been

2.0 per 1,000 per day in December 1944 and 2.5 per 1,000 per day by August

1945. As it was, in spite of the mounting venereal disease rate which skyrocketed after V-E Day, in December 1944 the noneffective rate was less than

I per 1,000 per day and was only 0.66 per 1,000 per day in August 1945.
CHAPTER XIII

Fort Bragg Fever

Worth B. Daniels, M.D.

The recognition of Fort Bragg fever as a specific new disease entity and

the ultimate proof of its etiology is a contribution of the U.S. Army Medical

Department to the science of medicine. The disease was described by Army

clinicians, studied by Army medical personnel with the assistance of Armyconsigned consultants, transmitted to animals by an Army research worker,

and finally proved as to etiology by an Army veterinarian and others working at the Medical Department Professional Service Schools, Army Medical

Center, Washington, D.C.

The story of Fort Bragg fever indicates, too, the superior opportunities

which were available to military medical personnel for clinical research.

Larger groups of patients with the same disease are more often available for

study in military installations than in civilian institutions. It is doubtful

whether this disease would have been recognized as an entity had the outbreak occurred in an urban civilian community; there, each patient might

have been cared for by a different physician and treated in a different hospital, whereas, on an Army post all were concentrated in one hospital under

the care of a closely knit medical service.

RECOGNITION OF A NEW DISEASE

Late in July and early in August 1942, an unusual febrile illness occurred

in a group of soldiers at Fort Bragg, N.C.' It shortly became apparent not

only that these men had identical symptoms but also that they all came from

a few organizations quartered near one another in a limited area of the reservation. Between 29 July and 11 September, 40 patients with this illness

were admitted to the hospital. The history was one of relatively sudden onset

characterized by malaise, mild general aching, lumbar pain, severe frontal

headaches, and postorbital pain. On the first or second day of symptoms,

mild respiratory manifestations consisting of coryza, sore throat, pain and

soreness in the chest, and cough occurred in 30 percent of the patients. The

respiratory symptoms were not persistent and were never suggestive of primary respiratory involvement such as is seen ;n influenza. In about onefourth of the cases, nausea and vomiting occurred, rarely accompanied by

abdominal pain. Shaking chills or chilliness and fever developed. The

fever was consistently spiking and frequently showed two or more peaks each

1 Daniels, W. B., and Grennan, 11. A.: Pretibial Fever; An Obscure Disease. J.A.M.A. 122:

361-365, 5 June 1943.

437
438 INFECTIOUS DISEASES

day. Recurrent chills often accompanied the elevations. During the periods

of temperature evelation, severe, accentuation of the frontal and postorbital

aching was experienced, but during the periods of lower temperature, the

patients felt. relatively well. The fever persisted for 2 to S days--averaging

5.4 days-with maxniuni elevat ions ranging from 99.s° to 105.6° F. In five

patients, a transient evelatioll of temperiture, sometines as lighi as 101.40

F., occurred from 2 to 7 days after the original febrile period. Stiffness of

the neck accompanied headache in three patients, but examination of the

cerebrospinal fluid revealed it to be normal; there was no noticeable relief

of headache following lumbar puncture. Adenopathy was not remarkable.

A firm spleen was palpable early in the disease in 95 percent of the patients.

Splenomegaly persisted in some patients for as little as 5 (lays: in others,

there was still noticeable enlargement after 2 weeks.

The most distinctive feature of the disease. however, was the appearance

of an unusual rash on or about the fourth day of illness. In 60 percent. (24)

of the patients, this was bilaterally symmetrical and limited in distribution

to the pretibial areas: in an additional 20 percent (8 patients), the pretibial

areas were the primary site of the rash, and a few lesions were scattered elsewhere. Two patients had splotchy, generalized cutaneous manifestations including the anterior surface of both legs. One had a single lesion on the

hand. In five cases, typical in all other respects, no rash was observed. Individual lesions consisted of an erythematous localized blush of irregular

outline with ill-defined borders fading into the surrounding skin. These were

often from 2 to 5 cm. in their largest diameter, gradually coalescing with

adjacent lesions. The lesions were raised, warmer than the surrounding skin,

and ,ometimes slightly tender to touch, In some patients, the lesions vaguely

resembled erythema nodosum. In two patients, the rash became diffusely distributed over the entire body, apd in a few it appeared urticarial. Following

the generalized type of rash there was a residual pigmentation which persisted for about 2 weeks. None of the lesions were purpuric. In most instances, the cutaneous manifestations lasted 2 days, but they persisted longer

in a few patients. Figures 57 and 58 illustrate the pretibial and the generalized forms of the rash.

Biopsies of cutaneous lesions were performed in six typical cases. They

showed diffuse edema and a slight to moderate perivascular infiltration with

small round cells and macrophages. It is clear that drugs played no part in

the development of this rash because only one patient had received sulfonamide therapy and no other patient received any drug except acetylsalicyclic

acid and codeine. Leukopenia was noted sufficiently often to constitute a

typical feature; it was present, in all except five patients, at some time during

the acute illness. It developed most often between the third and the fifth

(lay of illness. At the termination of the febrile period, the leukocytes

again rose to normal, and in 14 patients a slight leukocytosis occurred. The

number of leukocytes ranged from 2,800 to 14,000 per cubic millimeter. Dif-
FIGII-fE .5--E-~vt heinat-ots -skin lesions over the pretibial regions.

ferent jul counlts IISually1 sliowed Ho (leviatiml hroiit Iuwiiiul1. :ilt bolug ill a few

(':tses "I mnoderaite reblai ye lvi 1l)IIc~loi wa"I present.

( itiltires, of ilie blood ý.liowedl it) "owthI. Atkr-olut Mal: totis foi roIlv/ls

alit ilo(le-. WNere Ile.ItivaIe. No patijent lhad ileell ill'1 ait ara whlere c()ccidioilo)-

lMkC()tl was1 vi~ldentic. 1-%itjl te~-51stii, ccc~idlimi(lI1 ult 1"'(111 \\*(I'e 1Ie-'t1ive Ill

tOwo pahtients- after I heir. t~v*etV'ov ,V. Il, w I, 'i to-rajii.. m , of (I le chies( wter IIltldb

ill m~any pains but ImtIie sh1mvedl~ all )vloPmm tfilit V.

Akt the IcritIIIaI.t toll oft the fever. thle pallit r alpidll ret urtued to their,

or-igial,1 fie-ltli .\ statle. Iliere was 110 pOm Ielile deplietio 1) oP depres~sion, andii

there were 110) comtp] teat t0onS.

CASE REP~ORTS

Case 1.-A. white stoldier, agedl 25~. adimiitteJl to thle liospiw oinaI 7 A ng-ii 1942. comilplaitted ot' fever and14 headaohle. Hie had bee.. wei~l unt il 2 days previously. whten Ite

felt 14everish and chilly. .4~vero~v froIttvI Ileatlaclie. jtiiskorlit-A pain. and severe hmackache

(leveloptied. I'lle next d~nv he felt sli igtIffy b etter, 1011t1 (n Ihle daly of 11tdittissiot tilte Syrpiltolius Were all accellt t at Pt. ITh~rnleaue v as 10110 F- tile pulse- rate 90I. and the

resptirat4)ry rate 20: thet leuikocytes tiunteired 8.150I per cui. mini. Ž%otlliit unusual was

found otl 0 physical V\xartijitatjolt. Ont the tflth day of the disea-se. tilt spleen w-as firm

ani asily pa Iltahle. ( Iver thle pret'iltia I siurfaces of 1)oth legs. ilrvgrilair, erytlienintolts

lesions Wtn.e tnoted : I hIese Avere lIt ni IY lentder. wariti to toluch, and11 ver-Y sli.-ittly raised

( 1-g 5-)7 I. '. patt tiet's lempnteilt tIlle watS switigittg ili ltacr .t't1l rang1ed fronti 99.80

to 1114.4ý F. wiltliolit a vortt-splldtlth -t taliditty of! putlse. Tite letakocytes niumtbleired 4,9W~
440 INFECTIOUS~ DISEAS~ES

CHART 24.-Temperature, pulse, and leukocyte count of pat iett

)ATIE AUGUST-S 10 1 12 Is 14 15 16

DAY Of 1 ILLIIESS 34 5 6 9 51

T

I04*

U 101,

It too*

go,

ISO

ISO

U~140

L110

10

"70

per cui. mm., with a5 percent polymorphonuclear cells. On the seventh (lay of Illness,

the rash had entirely disappeared, the temperature was normal, and the patient felt

well. The spleen was still palpable at discharge from the hospital.

Case 2.-A white soldier, aged 21, admitted to the hospital on 1) August 1942-the third

day of disease-had as initial symptomns frontal headache and pain in the feet and legs

which later Involved various joints. At the onset there was nausea witlIiut vomiting.

Shaking chills had occurred on two~ occasions in the 36 hours prior to admilssion. Physical examination revealed nasal congestion, pharyngitis, signs of generalized bronchitis,

a temperature of 104* F., a pulse rate of 92, and a respiratory rate of 20 (chart 24).

The leukocytes numbered 9. 150 per cu. mm. Two hours after adimission at rash appeared

on the trunk, neck, and extremities. This consimleil of (discrete, brilliantly erythemuatous,

slightly raised, wqrtn plaqiues varying In size !i'roitI to 8 cem. in their largest diameter.

The rash was generalizedi (fig. 58) and, ats i the -ler cases, the anterior aspects of

both legs were Involved. D~uring the next fe.%N ,~~he temperature ranged from 990 to

104.(P F., with very little acelveration or the pulse. The 4ipleen becaine palpable. The

rash remained erythematous for 3 days, faded gradually, and left a definite purplish

pigmentation that diminished during the succeeding 2 weeks. The leukocytes were reduced to 4,350 on the sixth day and to 3,700) per cu. mmn. on the seventh (lay, with no

abi'orinality in the diliferenthit count. (C oivalemscence was uneventful.
F1 IN I' I F\ I-At

1-T V.1%, VNTI I I H A( ;N( )Sl%ý

A IIIIIIII Ivr 44 (11 Iforvill th-v:i-c- \\ vl*jý 11t)II-I(I"l-i (I III I: I Il'olvill 1:11

I II I lit, v:11.1 iIl1IIIVIlZ;I \\ A- _IIPvvIv4 1. M t I lit, 1 r;I117-IiIIII I'll;[

IIIIItIIIv-- 44 Ill, re'l"11-:114W IIII)f Illw-. III, fv\ 4.1. . 1weýt'lict, III* n

pa 11):11de ýIdvvll. '11141 1 lit, r;I-II (d Vf Ii hill Iiv

-vellit'd it, he vv-111,11.41 hy I he ýImrl 41111-al Iml (d, I lit- I)Y I

cill IrldY Ill II'vivill I * v I )v 4 :11141 1, 1 he W t I I - V( I I x

I )X 1 1, t I le I I I I I k 1

111 vI I'v \ V 1' :1 ý- ý I I I I I 1 :111 * v I I ý I I I I I f 1.4 Ili o lý-Ii lo rn 111 )11. 11' 11 t -I .( - \\ .I I if I I

\ 4 ) I' II I I, - I I Irk- Ill I II 1,ý _- rm lp . AV I I i ý I I I I, ý.t ý I ): I 1 *11 1 111 ý- \\ I 'i I I I I I i ý I " I I I

I'v\ vI. 11:14 1 111 )1 vvI I Ivel I i lvý( 1.11 It., :I I I I I( )I I,!d I I -:I .-mi ý:-ý were I )v I I I ri I I z I I

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I I I I I I ef I t 11:11 1 lit- w n de'l-1.1hed \v v re III )I I I Iv ý, I I I I v ; I I( )-v I,(, I 1 :11

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4 f 1 11 I'vi-I 'if pil- I I I I I I I I I le v e l( q I. I I I I-;I I f I I I I Ic

-v : 1 -0 11 ( .!_r: I I 'I (I I I 11 l I I n ý ý, I ) 1* 1 ) I ( I, ), I I I I I I, d :1 ill I I I i --,; I I I \ i n lit 111:11 1 111 IV -

...... IhI ]1-1. .1 f * NI.-I M . N1 ;1!1.1 K h-11:11*11'. .1. T . : I*.1111i, 1'..ý I, III- S T;II I '- -I 'I w l,

A I I 1:1"I.,111ir I oi- -;I- q ;I I I I I ., do. I I- Id I ;11. 1 rt S; I I I, I IW I , 1,01, 1

A . \1 A I :ý-_' - , I .-, 1; 1 11; 4 1. _, 1 A I I -,. 1 1:
442 INFECTIOUS DISEASES

actions eliminated the typhoid-paratyphoid group. The parasites of malaria

and relapsing fever were sought, but not, found. Dengue was at first thought

to be the probable diagnosis. However, as new cases were observed, certain

prominent features of that disease were consistently absent. No patient had

a "camel back- type of fever curve or any postfebrile depletion or depression.

The usual vector of dengue, Aedex aeflypti. was not found in the vicinity.

It. would be iwuntusual for an outbreak of dengue to be limited 14) such a small

group. The type and the distribution of tihe rash were not similar to that

seen inl dengue. Other d(enguelike diseases were considered: however, the

clinical features of this disease showed definite dissimilarity to tlese in one

or more important respects. Search of the literature did not reveal a description of a clinical entity into which this group of cases would fit.

EPIDEMIOLOGICAL ASPECTS

The organizations from which these soldiers came were quartered in the

northern third of the populated area of the reservation, near a small stream

and its tributaries. Other areas of the post furnished no patients ill with

this disease; therefore. local environmental factors were thought to be of etiological importance. There was no single lohality off the re 4ervat ion to which

the.,se men went during the month previous to illness, and they had no comn11n meeting place oni the reservation. Some of the men had done no swimming, while others swam in several different. ponds. Although there was no

swimming l)lace common to all, more men swam in "McFadgens Pond" than

in any other place-on or off tile reservation.

The factors resp)onsible for the outbreak could not be determined. Tile

medical inspxctor of the post made a search for insect vectors that might be

suspected. Bedbugs, stableflies, chiggers, ticks, and horseflies were found but

for various reasons were considered uilikely vectors.

I)uring the period of this outbreak, the population of mosquitoes on the

post was very low. but various members of tile C(uhx species were found with

Culex 9uinqutfiwffut-u.; appearing most frequently. This mosquito had been

disproved as a carrier of dengue. No representative of the dengue vector,

A. argypt;, was found, but Aedes athan.thiu.s, Aedex ca naden.vis, and Aedes

vexan.q were. Their presence was thought to be of doubtful importance.

After a decrease in the number of admissions to tile hospital in midAugust, the incidence of the disease again increased sharply. The clinical

picture, the long period of incubation, and the leukopenia suggested that tile

disease was probably due to a virus. The localization of the cases in one area

of the post made it seem lprobab)le that it was transmitted by an insect vector.

The local medical personnel were unable to carry out studies as to etiology,

so Trhe Surgeoi (eneral. I .5. Ariy. wzis retiiuested to send especially trained

individuals to study the outbreak.
FORT BRAGG FEVER 443

SPECIAL INVESTIGATION

On 3 :Septenmber 1942, D)r. Norman I1. Topping, Passed Assistant Surgeon, U.S. Public H[ealth Service, Ma j. (later Lt. Col.) Cornelius B. Philip.

Sn(C, and D)r. John I. Paul. Professor of Preventive Medicine, Yale U7niversity School of Medicine, New tlaven, Conn., and 1)irector, ('ommission on

Neurotroljiu" Virus D)iseases, Board for the Investigation and ('ontrol of Influenza and Other Epidemic Diseases in the Army. arrived at Fort Bragg

to study the disease. 'File ('ommission reviewed the records of the case previously studied and examined the patients remailning in the hospital. They

agreed that the sohliers were ill with a disease unknown to them, but D)r.

Topping remembered that an outbreak of a disease with similar features had

been encountered in the town of Wrens, (Ia., in 1940. This illness was locally known as Brushy Creek fever. Inquiry later brought information from

Dr. Charles 1). Bowdoin,:I who had observed these patients and reported thenm

at. a later (late, that about 3.5 cases had occurred. The clinical course and

manifestations seemed to be quite identical with those at Fort Bragg. A

laboratory technician who had nmade some of the cultures of feces was reported as having developed the disease.

The Commission began investigations in regard to the epidemiology and

etiology of the diease. 4 They showed that, although only 34 patients with a

rash had been considered to have this disease by medical officers of the hospital. the number of cases-in one of the regiments involved-without a rash

might have exceeded those with a rash by as much as 50 percent. The Commission confirmed the fact that the disease was not spread evenly throughout the camp population; but, of the 34 cases (with a rash) diagnosed between 27 JJuly and 19 September, 75 percent had occurred in 3 regimental

units. Practically all of the cases (almost 97 percent with a rash) occurred

in trool)s quartered in the northern third of the developed area. A canvass

was made of four artillery regiments quartered in the southern section of

the post, and no "missed cases" were found among 4,800 troops.

These features, plus the fact that the rate of attack was particularly high

ill two units, led the Commission to suspect that some local, although unrecognized, environmental feature was responsible. Particular attention was

paid, therefore, to two units. In each of these, an epidemic amounting almost to an explosive outbreak had occurred. These outbreaks were separated

by about 3 weeks and were limited, to some extent (in the early cases), to a

single company.

These explosive epidemics became apparent when a survey of the records of illness of one unit in particular, namely, the 88th Airborne Infantry,

3 Bowdoin, C. D. : A New Disease Entity ( ? . J.M.A. Georgia 31: 437-438, 442, December 1942.

4 Preliminary Report of the Commimsion for the Study of an Unidentified Disease at Fort Bragg,

N.C.. 3-11 Sept. 1942. by D)r. Norman I1. Topping. P.A. Surgeon. U.S. Public Health Service, Maj.

Cornelius B. Philip. SnC. U.S. Army, and Dr. J.hhn A. Paul, Yale University School of Medicine.

Submitted to The Surgeon General, U.S. Army. 15 Oct. 1942.
444 ENVWET'IOUS DISEASES

revealed that there had been a sharp increase of cases of "influenza," "'1asopharyngitis," or "fever of lndetermined origin" in this regiment during August. Of the 33 cases of "influenza," and other diseases, which were reported

in August, 9 developed a rash after they had been hospitalized and were ultinIlately diagnosed as having Fort Bragg fever. In 14 others, wbose hospital

records were available for study, the i)icture was coml)atilde with that of

Fort Bragg fever, although the rash was lacking.

It was concluded, therefore, that a nonexantheinatous form of this disease existed and (if all forms of the disease were considered) it co•ltih appear

in explosive ep)idemic form resulting in almost 10 l)ercent of the personnel

in a given conipany being infected withiin the period of 2 weeks. Factors

responsible for this type of explosive outbreak were not determined.

Certain inforilnation about the period of inlcubation was obt ained. Five

mneln probably developed the disease while they were away from the post and

several developed it wvitbin a few days after their return, following an absenc'e of 10 days on mianeuvers on Chesapeake Bay. If it is assumed that

tho disease was not spread by direct contact, the data accumulated would

indicate that the incubation period was from 10 to 15 days or longer.

The Commission's entomological observations indicated that if parasitic

arthropods were vectors of the disease, there were only three that were found

or reported in sufficient numnbers anl of sufficient distribution to be considere(l. These were stableflies (Stomioexys ra,(4itava.R), mosquitoes, and chiggers

(Tromnbcu'da rr;tan.w). These parasites had also been reported to have bitten men stationed in units ill the southern part of the post, where none of

the cases occurred.

As to mosquitoes, it was found that a ditched l)ut swampy arm of Tank

Creek separating the two most heavily infected units could have provided the

most available source of breeding, but reports of adjacent troops and of sanitary personnel indicated insufficient incidence of mosquitoes in b)oth July and

early August to account for the outbreak. The evidence of transimnission by

mosquitoes was not considered strong.

Having collected anld frozen material for further study. the Commission

departed on 11 September to carry out investigations of etiology in their various laboratories.

Search for an etiological agent was carried out by members of the Commission at the National Institute of Health, U.S. Public Health Service, at

the Yale University School of Medicine, and at the Medical Department Professional Service Schools. 5

The material obtained for study consisting of blood from acutely sick

patients and a variety of insects (including Stoinoxy.s cakicitran,) had been

frozen and kept on Dry Ice. It was inoculated into embryonated eggs. guinea

5 Final RMport of the Commission for the Study of an Unidentified Disease at Fort Bragg, N.C.,

3-11 Sept. 1942. by Dr. Norman It. Topping. P.A. Surgeon. U.S. Public Health Servief-. Maj.

Cornelius B. Philip, SnC, U.S. Army, and Dr. John R. Paul. Yale University School of Medicine.

Submitted to The' Surgeon (G.neral, U.S. Army. 31 Mar. 1943.
FORT BRAGG FEVER 445

pigs, mnice, monkeys, and one chimpanzee. Human transmission experiments

were tried by inoculating frozen whole blood and by allowing A. aegypti and

Aedes albophtu.v mosquitoes previously fed on a patient, ill with the disease

to feed on volunteers. Each one of these attempts to transmit the disease

failed. In retrospect, however, the negative findings with frozen human material were explained by an inll)ortant discovery made about 2 years later,

when it was shown that the causative agent of this disease is destroyed by

freezing. It is small wonder, therefore, that the experiments of 1942 were

unsuccessful. It was not until 1st Lt. (later Capt.) Hugh Tatlock, MC, succeeded in performing direct transmission experiments with fresh blood in

guinea pigs in 1944 that the disease was successfully transmitted.

Outbreaks similar to that of 1942 occurred during the sumnmier's of 194:3 0

and 1944 7 anmong soldiers quartered in the same area of the post. In 1943.

a rickettsia-like organism was recovered by Tatlock 8 from three of five

gruinea pigs injected with fresh blood from a patient ill with the disease.

Attempts were made to show that this agent was concerned in the etiology of

the disease. However, subsequent studies indicated that this organism was

undoubtedly of guinea pig origin and not concerned in the etiology of Fort

Bragg fever.

In the summer of 1944, Tatlock injected two guinea pigs and two Syrian

hamsters intraperitoneally with blood freshly drawn from a patient ill for 4

days with the disease.9 Both guinea pigs developed fever (1050 to 1060 F.)

8 days after inoculation. Both guinea pigs were found dead on the 10th

day. No passage was attempted from the hamsters. Serial transmission of

the fever-producing agent in guinea pigs was accomplished by the intraperitoneal injection of citrated blood on the first day of fever. The incubation

period was 4 to 8 days and fever persisted from 2 to 4 days. More than 70

passages produced no increase in virulence of the agent. No gross abnormalities were found in sacrificed guinea pigs. Histological sections of the

liver showed areas of focal necrosis. No inclusion bodies or Rickettsia were

seen in sections.

Tatlock found the agent capable of infecting guinea pigs, rabbits, and

Syrian hamsters by both intraperitoneal and intracerebral inoculation. The

disease transmnitted was uniformly fatal for hamsters. Intravenous inoculation of 11-day chick embryos was accomplished. From these infected eggs,

the agent was propagated by the yolk-sac route, and fresh tissue suspensions

were infective for hamsters in 1 to 100,000 dilution. The agent passed a

Corning fritted glass filter but failed to pass a single Seitz pad. Tissue

emulsions in sterile skim milk, frozen rapidly and maintained at -700 C.,

6 Personal observation of the author.

7 Personal communication, J. M. Kinsman, to the author.

8 Tatlock, H. : A Rickettsia-Like Organism Recovered From Guinea Pigs. Proc. Soc. Exper.

Biol. & Med. 57: 95-99, October 1944.

9Tatlock, H. : Studies on a Virus From a Patient With Fort Bragg Fever (Pretibial Fever).

J. Clin. Investigation 26: 287-297, March 1947.
44:6 INFECTIOUS DISEASES

retained viability. However, blood. whole lisues, or tissues suspended in

broth lost infectivity when stored for 24 hours at 20c C., 40 C., or at -700 C.

in sealed glass ampules.

Sera front five patients with Fort Bragg fever were used in protection

tests. Neutralization was obtained in two patients with convalescent, but not

with acute, sera. Comparable results were obtained with two sets of sera

front infected guinea pigs.

By early 1945, Captain Tatlock had brought his studies to a point where

lie and others interested in the disease were contident that Fort Bragg fever

was due to a well-characterized filtrable virus unrelated to any other known

virus. At this juncture, lie wias orderedI to Walter Reed General Hospital,

Army Medical Center. for clinical duties but nmaintained the agent there by

passages and by storage, frozen in an emulsion of milk.

l)uring tile summer months of 1945. no patients with this di.sease were

admitted to the hospital at Fort Bragg. It. is of interest thati a large part

of the post area in which patients had previously seemed to acquire the disease was unoccupied except for a period of "a week or t wo." 10

Isolated reports appeared of single cases of Fort Bragg fever in Connecticut,n New York,' 2 and California.13 From the descriptions given, these

patients may have had this disease, although it would seem difficult to make

an absolute diagnosis in the absence of a:i outbreak.

ADDENDUM

In the spring of 1946, Captain Tatlock was ordered on detached service

to Cincinnati, Ohio. where, through the cooperation of I)r. Albert B. Sabin

and of the Longview State Hospital. he began studies in transmission among

a group of patients undergoing fever therapy. lie inoculated three patients

intranmuscularly and intraeutaneously with at 10-percent suspension of infected, embryoonated chick liver in saline. This material had been through

80 passages in guinea pigs and 23 passages 14 in embryonated eggs. After

an incubation period of 8 to 9 days all three patients developed at short febrile

illness. Successful inoculation of three other patients. using freshly defibrinated pooled blood from the previous patients, was accomplishedl. and a

third passage was successful in seven of eight other individuals. All but one

of the latter patients, after an incubation period comparable to that of the

natural disease (8 to 14 days), developed fever, and the majority exhibited

the clinical picture of Fort Bragg fever with rash and leukopenia. For the

third passage, two patients immune to "New Guinea ("" strain of denigue

fever virus, two immune to tile "Hawaiian" strain of virus. .tnd two immune

10 'ersonal conimunication. J. It. Dingle. to the afuthor.

11 Lipmeomb. L. L.. and McMahion, J. I. : Pretiblal Fever. J.A.M.A. 128 : 90 91. 12 M'ay 1945.

12 Greenfield, I. : Pretiblal Fever; A New Disemase, Entity. Urol. & Cutian. Rev. 47 : 435 4:14o.

July 1943.

13 Personal 'ommtninh'lt Ion. G. Cheney. to the anuthor.

14 See footnote 9. p. 445.
FORT BRAGG FEVER 44,7

to the "Middle East-Sicilian*" type of sandfly fever virus were used. All

were found susceptible to the "virus" of Fort Bragg fever.

"Viremia" was denmonstrated in these patients by the immediate inoculation of fresh, defibrinated blood into young hamsters. The "virus" appeared

in the blood of these patients shortly before the onset of fever and disappeared rapidly thereafter.

It now appeared clear to all interested in the disease that the "virus"

isolated by Tatlock from a case of Fort Bragg fever in 1944 was a new and

distinct agent capable of producing the classical manifestations of the natural disease when inoculated into man.

In 1947, in New Haven, Melnick and Paul 15 inoculated four chimpanzees intracutaneously and subcutaneously, using the "virus" isolated by Captain Tatlock. These animals developed a disease similar in many respects

to the experimental disease transmitted to humans by Tatlock, and subsequent bleedings showed that they had developed neutralizing antibodies.

When "virus" inactivated by freezing was inoculated into five chimpanzees,

no disease or neutralizing antibodies developed. Two of these animals were

later given active "virus" and both developed antibodies. Two animals were

studied for "viremia" during the period of fever. This was denniolstrated in

one of the animals by transmission to a chimpanzee and in the other by

transmission to young hamsters.

During the ensuing years, the "virus" of Fort Bragg fever was r.maintained in several laboratories. The possibility that this agent might be a

Leptospira was considered several times by Gochenour, Smadel, and others

at the Army Medical Service Graduate School, Walter Reed Army Medical

Center.16 However, results obtained with methods then employed failed to

support this idea.

Lat,-r, a large collection of leptospiral strains was assembled by this

group. In the fall of 1951, Gochenour, an Army veterinarian--with Smadel

and other coworkers-found that with antigens prepared from these strains

convalescent and immune sera of victims of Fort Bragg fvver gave a high

titer of agglutinating antibodies against Lepto8pira autum/nli8. With this

lead, a leptospiral organism was recovered by culture from the 365th passage of the Fort Bragg agent since its original isolation. Cross-agglutination

tests showed that the Fort Bragg agent was essentially indistinguishable from

Lept. autumpalis Akiyami A, the cause of autumnal fever in Japan and other

areas of the Far East. There was then no doubt that Lept. autumna-ig was

being carried in this laboratory as the "virus" of Fort Bragg fever. Obviously, it was of the utmost importance to learn whether this was a contaminant or whether it really originated from patients with the disease at Fort

Bragg.

15 Melnick, J. L.. and Paul. J. R.: Experimental Fort Bragg Fever (Pretibial Fever) In Chimpanzees. Proc. Soc. Exper. Plol. & Med. 67: 263-268, March 1948.

16 Gochenour, W. S., Jr., Smadel, J. E., Jackson, E. B., Evans, L. B, and Yager, R. H.: Leptospiral Etiology of Fort Bragg Fever. Pub. Health Rep. 67: 811-813, August 1952.
448 INFECTIO)US DISEASAES

Paired sera fronm Melnick and Paili's four euphonioiusly naelmed (.hijpanzees-Rosebud, Mary Lou, Hlickory, and Catawba-showed high titers of

agglutinins or neutralizing antibodies against Lept. atutna'lu..i in the convalescent, but none in the acute, sera. Paired sera front six of Captain Tatlock's patients infected in Cinteinn:,ti gave the same results.

Fortunately. paired sera from live of the original soldiers who had been

bled by latlock in 1944 were still safe in the Deepfreeze. Three of these

Patients were found to have developed neutralizing antibodies and leptospiral

agglutinins. Two who failed to develop neutralizing antibodies in Captain

Tatlock's experiments also failed to agglutinate Lept. autumnal;,.

It is of great interest that three lots of hyper'inune rabbit sera-one

prepared in 1947 from the hamster line, another in 1951 from cultured Lepto-

,qlpirae of the Fort Bragg agent, and a third from cultures of Lept. atutum nali.v Akiyaini A-protected halnsters against, 100,000 L1)- 0 of the Fort Bragg

Leptospilw.

Stored sera from 45 Fort Bragg patients ill in 1943 or 1944, though not

paired, were studied. Sixteen of these gave clear-cut serological evidence of

infection withi Fort Bragg Lpptospira.

Fort Bragg fever then is caused by a member of the Lept. auturnnal.s

group. No member of .his group was previously known to exist in the

United States. This di_,ase takes its place with Weil's disease, swineherd's

disease, canicola fever, and other lentospiral diseases and is a contribution of

Army medical investigation to medicine.
CHAPTER XIV

Statistics of Malaria

Fred H. Mowrey, M.D.

Malaria, one of the world's greatest causes of morbidity, has played a

dominant role in many military campaigns, although not so d(evastatingly as

the pestilential diseases of typhus, plague, the dysenteries, and smallpox.

HISTORICAL NOTE

Malaria played a vital part in Caesar's campaigns during the Roman

civil wars. Malaria was the savior of Rome from the Germans on many

occasions. Celli ' writes: "The Queen of the World suffered much at the

hands of these Barbarians, but, in her dethronement, she found ample revenge. For in the swamps around Rome there lurked swarms of mosquitoes

eager for fresh healthy blood, and they it was that now attacked the foreign

invaders. These Northern warriors, who were forced to spend the summer

within or outside Rome, died, or lingered on for years weakened by daily

fever, and this happened over and over again for centuries with a terrifying

regularity. The various German troops made their departures more in the

manner of a funeral procession than in a victor's triumph." Celli referring

to Otto I in 964 writes, "The Emperor, however, celebrated the Nativity of

St. John (June 24) and the Feast of the Holy Apostles (June 29) and turned

homewards from the Roman Land. But he was overcome by a fate more

unhappy than he could ever have looked for, for in his army there broke out

so great and deadly a pestilence that almost all died, and those who still

kept their health only dared to hope to live from one evening to the next

morning." In 1167, Emperor Frederick I failed to conquer Rome. "Suddenly, such a deadly fever broke out in his Army that, within seven days,

almost all the princes who fought with him against the Church were unexpectedly snatched away by a miserable death." He was forced to flee leaving uncounted dead.

Malaria was ever-present during the Siege of Mantua in 1796-97. Prinzing 2 states that malaria broke out with great severity and acquired virulent

forms which played a decisive role in the result.

A typical example of the effect of malaria in military campaigns occurred among British and French troops in Macedonia in 1918. Some 80

percent, of 120,000 French troops were hospitalized. Over 25,000 British

troops were invalided home with chronic malaria, and more than 2 million

2 Celli, Angelo: The History of Malaria in the Roman Campagna. London: John Bale, Sons &

Danlelsson, Ltd.. 1933.

2 Prinzing, Friedrich : Epidemics Resulting From Wars. Oxford : At Thc Clarendon Press. 1916.

639243--63--32 449
450 INFECTIOUS DISEASES

man-days were lost in the British Macedonian Army during 1918 because of

malaria.3

Malaria also has been a, problem to the U.S. Army. There are no available statistics on malaria prior to 1818, but. we know it was prevalent before

then. "As early as 1776 the Continental Comigress ordered the Medical Committee to forward :300 pounds of Peruvian bark to the Southern Department

for the use of troops." 4

During the War Between the States, one-half of the white troops and

four-fifths of the Negro troops in the Northern Armies contracted malaria

annually. There were 10,063 deaths due to malaria. In addition, more than

1,000 Confederate troops died of malaria in Northern prisons. The incidence of malaria during the U.S. Civil War, in Northern troops, per 1.000

per annum, is shown in the following tabulation: 5

White Negro

Fiscal year troops troops

186 1-62 . .. .. .. ...... .... .. ... .. ... . .. ..- 390.7 (1)

1862-63-------------------------- 428.3 (1)

1863-64 . . . . .. .. .. . . . . . .. . .. M535.9 811.6

1864-65 ---------- 496.6 703.2

1865-66- --------------------------. 829.5 920.6

1 No Negro troop strength.

During the Spanish-American War, there were 90,461 admissions for

malaria during the calendar year 1898, with 349 deaths. The annual admission rate was 611.78 per 1,000. A rate of 1,924.78 per 1,000 per annum occurred in Cuba with a mortality rate of 14.02 per 1,000 per annum. 6 Theodore Roosevelt stated that malaria was the chief enemy in Cuba. Every officer in his regiment, except himself, was down at one time or another with

malarial fever. "Though the percentage actually on the sicklist never got

above twenty, there were less than fifty percent who were fit for any kind

of work." 7

In the First World War, from 1 April 1917 to 31 December 1919, there

were 15,555 admissions for malaria, 36 deaths, 28 discharges for disability,

and 194,529 man-days lost. Most of the malaria occurred among troops engaged in training in facilities located in endemic malarious areas in the

United States. Only 950 admissions for malaria occurred in Europe."

:1 Wenyon, C. M., Anderson, A. G., McLay. K., Hele, T. S., and Waterston, J.: Malaria In

Macedonia, 1915-1919. J. Roy. Army M. Corps 37: 81-108. August 1921.

4 Blanton, W. B. : Medicine in Virginia in the Eighteenth Century. Richmond, Va.: W. Byrd

Press, 1931.

5 Medical and Surgical History of the War of the Rebellion. Medical History. Washington:

Government Printing Office, 1888, pt. III, vol. I.

6 Annual Report of The Surgeon General, U.S. Army. Washington: Government Printing Office,

fiscal year, 1900.

7 Major, Ralph H. : Fatal Partners: War and Disease. Garden City, N.Y.: Doubleday, Doran

& Co., Inc., 1941, p. 195.

s The Medical Department of the United States Army in the World War. Washington: U.S.

Government Printing Office, 1928, vol. IX, p. 512.
STATISTICS OF MALARIA 451

The incidence of malaria among U.S. troops was of little significance

following World War I, occurring chiefly among troops stationed in Panama, Puerto Rico, and the Philippine Islands. The incidence for the entire

Army during 1941 was 4.74 per 1,000 per annum.

WORLD WAR II

The disease became, however, a problem of serious importance during

World War II, when U.S. Army troops campaigned in highly malarious

areas in many parts of the world. Never before had the Medical Department been called upon to combat a problem of such magnitude. It is indeed

a tribute to the preventive measures adopted that the menace of malaria did

not more seriously interfere with military operations. However, these sanitary measures were not immediately available to combat troops in such areas

as Guadalcanal, New Guinea, China, Burma, India, North Africa, Sicily,

Italy, and elsewhere. Accordingly, malaria exacted its toll in morbidity and

man-days lost.

Malaria assumed a dominant role in many Pacific areas-Green Island,

Emirau, Bougainville, Vella Lavella, Suaba, Efate, Espiritu Santo, Guadalcanal, Tulagi-Florida, Russell Islands, Munda, and the Treasury Islandsseriously depleting combat effectiveness and increasing the workload of the

Medical Department. This was best illustrated in Guadalcanal where there

were 10,206 primary cases of malaria among U.S. Army troops during MarchDecember 1943:9

Number of

194S 1 primary cases

March --------------------------------------------------- 845

April --------------------------------------------- 3,374

May --------------------------------------------------- 1,926

June ------------- ------------------ 1,117

July --------------------------------------------------- 1,123

August -------------------------- - -------- 608

September -------------------------------------------------- 566

October ---------------------------------------------------- 315

November -------------------------------------------------- 177

December -------------------------------------------------- 155

Total ------------------------------------------------- 10,206

1 Data are not available for primary cases occurring in January and February.

The 1st Marine Division ceased to be an effective combat unit for many

months owing to the hospitalization for malaria of approximately 80 percent

of the command. 10 Four out of five units had to be removed from combat

for rehabilitation. The Americal Division was transferred from New Cale9 Essential Technical Medical Data, South Pacific Base Command, for March 1945. Inclosure

13-4, unnumbered table entitled "Primary Cases of Malaria, Army, Guadalcanal, 1942-44."

10 Essential Technical Medical Data, Southwest Pacific Area, for January 1944.
452 INFECTIOUS IDISEASES

donia to Guadalcanal during November and December 1942. ()wing to the

exigencies of combat and failure to appreciate the problem, few, if any, antimalarial measures were taken. The number of cases of malaria rapidly increased, weekly rates as high as 2,500 per 1,000 per annum being rel)orted.

The division had to be transferred to Fiji in March 1943 for rehabilitation.

Mass therapy of the division was undertaken between April and June, when

all medication was discontinuied. Tihe hospitalization rate promptly rose to

4,220 in August. It was still 2,948 in late October when suppressive therapy

with Atabrine (quinacrine hydrochloride) was reinstituted, with a consequent

drop to So by late I)ecember 1943.11

The 25th Infantry Division engaged in combat on Guadalcanal in January 1943. This division also failed to take proper antimalarial measures. As

a consequence, the malaria rate rose to 2,385 per 1,000 per annum during the

last week of April. This division was transferred to New Zealand in December 1943 for rehabilitation, and thence to New Caledonia in February

1944 for reorganization. It is estimated that approximately 46 percent of

the division had one or more attacks of malaria during 1943.

The 43d Infantry Division entered Guadalcanal in March 1943 and subsequently participated in the Russell Islands and New Georgia campaigns.

This division required rehabilitation in New Zealand during February and

March 1944. In order to determine the amount of seeding in the division, a

small control group was taken off Atabrine. The malaria rate for this group

rose to 2,000 per 1,000 per annum; whereas the rate for the remainder of the

division, which continued on Atabrine suppression, did not exceed 236 per

1.000 per annum.

Malaria was a great problem in the Southwest Pacific Area, 47,663 attacks occurring during 1943 alone. Sixty-seven percent of the 32d Infantry

Division had malaria during the 10-month period following their withdrawal

from New Guinea. The effectiveness of malarial control was demonstrated

in the Milne Bay area of New Guinea where the rate was 3,308 in January

1943. Following the institution of control measures, the rate dropped to 100

by May and to only 30.72 by January 1944.12

There were 9,160 cases of malaria in the China-Burma-India theater during 1943, with nearly 115,000 man-days lost. Of the first 2,400 patients admitted. to the 20th General Hospital, located near Ledo in Assam, 73 percent

had malaria. At one time, 55 percent of the beds were occupied by patients

with malaria.' 3 The effect on troops of exposure to the endemic disease is

illustrated by 92 men of the 900th Airborne Engineer Company who traveled from Ledo to Tagap. En route, 54 were hospitalized with malaria; out

11 Essential Technical Medical Data, South Pacific Area, for April 1944. 12 Essential Technical Medical Data, Southwest Pacific Area. for May 1944.

13Essential Technical Medical Data, China-Burnma-India Theater, for August 1943.
STATISTICS OF MALARIA 453

of the 38 who reached Tagap, 20 had malaria on arrival.'4 Ali epidemic of

malaria occurred at the 1306th Air Force Base Unit, Air Transport Conimand, located in Karachi, India, in 1944. There were no cases during August, but the rate rose rapidly to 1,202.3 per 1,000 per annum during the

first 2 weeks of October. The rate dropped to 148 during the first 2 weeks

of November following the institution of malaria control methods.15

Malaria was a serious problem to North African theater forces. It was

prevalent in the areas of Rabat and Port Lyautey in Morocco, the Constantine area in Algeria, the Tunis-Bizerte-Ferryville area in Tunisia, Catania

in Sicily, Corsica, Sardinia, Salerno, Paestum, and the Pontine Marshes in

Italy. There were 69,000 cases during 1943-44 with 944,000 man-days lost.

One and two-tenths percent of patients with malaria were evacuated to the

United States.16 During the Sicilian campaign, the Seventh U.S. and British

Eighth Armies lost, from malaria alone, the equivalent of the fighting effectiveness of two infantry divisions. In fact, there were more losses due to

malaria than there were battle casualties; the Seventh U.S. Army reported

9,892 cases of malaria and 8,375 battle casualties and the British Eighth

Army reported 11,590 and approximately 9,000, respectively.1I

It is interesting to note that nearly all of the total malaria cases (32,796)

in the European theater were imported by troops who had originally served

in the North African theater. There were 4,806 cases of malaria among U.S.

troops stationed in England before D-day 1944.

Altogether, during the period 1942-45, there were 492,299 cases of malaria, 410,727 of these occurring overseas; the total attack rate per 1,000

average strength per annum was 19.43 and was highest during 1943 and 1944

(table 53). Data on the noneffective rates for malaria are not presently

available, but from 8 to 9 million man-days were estimated to have been lost

because of malaria during 1942-45, at an average daily noneffective rate of 1

per 1,000 average strength; the estimated rate based on the average duration

multiplied by the number of admissions and readmissions is 0.94.

Of the 492,299 cases of primary malaria occurring during 1942-45 with

a rate of 19.43 per 1,000 average strength (table 54), the greatest number of

cases occurred in the Southwest Pacific followed by the Central and South

Pacific, the Mediterranean, and China-Burma-India theaters. The highest

incidence rate, 98.46, occurred in the China-Burma-India theater.

14 Recorded Intervi-w. Office of the Surgeon General, 20 Apr. 1944, subject: Report of Medical

Department Activities in China-Burma-India by Maj. John H. Grindlay, MC, Chief, Surgical Service,

20th General Hospital, India.

15 Annual Report, Surgeon, India-China Division Air Transport Command, 1944.

16 GoIz, Harold H. : Human Malaria in the North African and Mediterranean Theaters of Operations, U.S. Army. [Official record I

"11 Essential Technical Medical Data. North African Theater of Operations, U.S. Army, for

October 1943.
454 INFECTIOUS DISEASES

TABLE 53.- -Total attack rate I for malaria in the U.S. Army, by area,2 type of plasmodium,

and year, 19.;2-45

[Preliminary data baq-4d on sample tabulations of individual medical reicords)

[Rate expriesed as num|ber of eases per aunin1 iwr ,o1k) avera-e strength]

1942- 45 1942 19%3 I 1944 (. 5

Nuniler! Raw Niber Rate NItihlrý Hate Nun ibr Rate N urnber Rate

of V: 1-4- of Ia., of cu'vs of vases of vo,'4s

Continental United States

Virax (tertiat) malaria .. . 74, 197 5.02 1,387 0.52 4.625 0.89 27,045 6.81 41,140 13.8)

Faiuiparuin (estivo-autumnial)

malaria ---.---------- 761 .4 18 IM .07 245 .05 175 .04 155 .05

Malaria, mixed type... 248 .Q2 23 .01 20 .WX1 130 .03 75 .03

.1a1ariae (quartan) malaria. 294 .W2 34 .01 45 01 120 .03 1 95 .03

Malaria, unclassified and other- 6, 072 .41 427 .16 1.300 .25 2.055 .52O !1 2WJ .77

Tot al.-.---------- 1.572 5.51 2,057 0.77 6, 12) 525 7. 43 43.,755 14.68

Overseas

Vivax ttertlan) malia ... ...... 267,079 25.33 10,048 17.15 87,596 5L.00 102,765 26.90 66,670 14.96

Falkiparum (estivo-autuinnal)

malaria ----------.---------- 50,519 4.79 4,295 7.33 28,054 16. 62 12, 750 3.34 5. 420 1.22

Malaria, mixed type ------------ 3,196 .30 193 .33 1,173 .69 1,0 20 .27 810 .18

Malariae (quartan, malaria.. _ 1,583 .15 88 .15 640 .38 080 .18 175 .04

Malaria, unclassified and other- 88,350 8.38 ', 586 11.24 51,169 30.32 21.415 5.61 9, 1P) 2.06

Total -------------------- 410,727 38.96 21,210 36.20 168,632 9991 1.6 X36.30 82.'255 18.48

Total Army

Vivax (tertian) mialaria --------- 341,276 13.47 11,435 3.53 92,221 13.42 129,810 16.66 107,810 14.51

Fakciparum (cstivo-autumnal)

malaria ---------------------- 51,280 2.02 4,481 1.38 28,299 4.12 12, 9'25 1.66 5,575 .75

Malaria, mixed type -------... 3,444 .14 216 .07 1,193 .17 1,150 .15 885 .12

Mfalariae (quartan) malaria ------ 1,877 .07 122 .04 685 .10 800 .10 271 .04

Malaria, unclassified and other__ 94.4422 3.73 7,013 2.16 52,469 7.64 23,4470 3.01 11,470 1.54

Total ------------------ 492,299 19.43 23,267 7.18 174,867 25.45 168, 155 21.58 126,010 16.95

SIncludes admissions for the first time, for malaria, readmissions, and admissions for other causes, but in which malaria

existed concurrently or developed subseqn,,otI 1.

2 Area of admission to medical treatment, but not necessarily the area in which the disease wats acquired.

TYPES OF MALARIA

Malaria due to Pla8modium vivax, Pla8modium falciparum, and Pla8-

7nodium, malariae occurred in all theaters. Malaria caused by P. vivax had

the highest incidence rates in the China-Burma-India theater, the Southwest

Pacific and the Central and South Pacific Areas. The majority of the cases

in the United States were of this type. The highest incidence rates due to

P. falciparum occurred in theri Middle East and the China-Burma-India the-
STATISTICS OF MALARIA 455

TABLE 54.-A.ttack rates ' of malaria, all forms in the U.S. Army, by area and year, 1942-45

[Preliminary data based on sample tabulations of individual medical records]

[Rate expretsed as number of cases per annum per 1,000 average strength]

1942-45 1942 1943 1944 1945

Area' f __ -I_ _

Number Rate Number Rate Number Rate Number! Rate Number Rate

of eaS'S ocases of eases I of cases of cases

Continental United States-.. 1. 572 5.51 2, 057 0.77 6. 2M 1.20 29. 525 7.43 43. 75- 14.93

Overseas:

Eurol-k ------ 32, 796 7.81 69 0.83 662 2.48 17,585 10.49 14,480 6.66

Mediterranean 3 80,532 52.60 735 32.06 33,232 72.76 38.830 59.78 7.735 19.25

Middle East-.... 10,715 80.53 746 123.39 6.669 125.73 2.900 62.75 400 14.41

China-Burma- India 44.052 98.46 1,077 123.14 9,160 231.21 26,265 155.68 7,550 32.78

Southwest Pacific... - - 124, 109 78. 25 4.451 62.49 47,663 250.98 33,475 62. 08 38, 520 49.03

Central and South Pacific.; 95,828 66.53 2.934 19.44 65,489 224.62 17,275 39.38 10,130 18.12

North America 1 200 .41 71 .71 89 .46 25 .19 15 .22

Latin America. 17. 891 47.05 11,042 108.34 4,874 40.34 1,245 14.51 730 '0. 19

Total overseas .. .410727 38.96 21.210 36.20 168,632 99.91 138.630 36.30 82,255 18.48

Total Army. - ... 492.299 19.43 23,267 7.18 174,867 25.45 168, 155 21.58 126.010 16.95

SConsists of new admissions and readmissions for malaria as well as admissions for other causes, but in which malaria

e'dsted concurrently or developed subsequently.

'Area of admission to medical treatment, but not necessarily the area in which the disease was acquired.

3 Includes North Africa.

' Includes Alaska and Iceland.

3 Includes cases on board transports.

ater. Ninety-seven percent of malaria acquired in Liberia was due to P.

falciparum.1 8 P. nuza-iae was found chiefly in the Mediterranean, the SouthS-est Pacific, China-Burma-India, and the Central and South Pacific Areas.

The incidence rate f clinical P. mnalariae infections without classification

was highest in China-Burma-India, the Southwest Pacific and the Central

and South Pacific Areas.

P. vivax was the etiological agent in 341,276 cases; P. falciparum, in

51,280; P. malar•iae, in 1,877; and there were 3,444 cases with mixed type

infections, or a total of about 397,000 in which plasmodia were identified.

The remaining 94,442 cases were unclassified, the diagnosis being made on

clinical signs and symptoms without microscopic verification. (See tables 55,

56, 57, 58, and 59.)

RELAPSE IN MALARIA

There ae- no accurate statistical data available on relapse rates. However, it is well known that malaria aseribed to P. vivax was prone to relapse

under the therapeutic regimens in use during World War II. The relapse

rate of malaria due to P. fakciparum was markedly lower than that caused

by P. vivax, although a significant number did relapse.

18 Annual Report, U.S. Army Forces In Liberia, 1943.
456 INFECTMIUS DISEASES

TABLE 55 --- Attack rales I of vivax (tertian) malaria, in the U.S. Ariny, by area and yeap,

1942-45

(Preliminary data based on sample tabulations of individual medical records]

[Rate expressed as number of cases per annum per I,1580 average strength)

1942-45 1942 1943 1944 1945

Area, 3 p

Number Rate Number Rate Number Rate Number Rate Number! Rate

of cases of cases of cases of cases Of CIASe

Continental United States --- 74.197 5.02 1.387 0.52 4.625 0.99 27,045 6.81 41. 140 13.80

Overseas:

Europe------------------- 26.011 6.19 42 0.51 2999 1.12 14,060 8.39 11,610 5.34

Medite-rranean .----------- 55,489 36.24 371 16.18 15.818 34.63 32, 310 49.74 6,990 17.39

Middle East - ------------ 2,349 17.65 95 15.71 934 17.61 1,125 24.34 195 7.03

China- Burma-India ------ 26,122 58.38 412 47.11 4,010 101.22 15,335 90.90 6,365 27.63

Southwest Pacific --------- 83,076 52.38 884 12.41 27, 902 146.92 24,215 44.91 30.075 38.28

Central and South Pacific. 58,600 40.69 499 3.31 34,866 119.59 14,260 32.52 8,975 16.05

North America 4 --------- 119 .24 48 .48 36 .19 20 .15 15 .22

Latin America ------------- 12.657 33.29 7, 5. 3,430 28.39 990 11.54 565 7.88

Totaloverseas .--------- 267,079 25.33 10.048 17.15 87.596 51.90 102,765 26.9 I 66.670 14.98

Total Army ............. 341,276 13.47 11,435 3.53 912,221 13.42 129,810 16.66 107,810 1451

1 Consists of new admissions and readmissions for malaria as well as admissions for other causes, but in which malaria

existed concurrently or developed subsequently.

2Area of admission to medical treatment, but not necessarily the area in which the disease was acquired.

I Includes North Africa,

' Includes Alaska and Iceland.

SIncludes cases on board transports.

TABLE 56.--Attack rates I of falciparunt (estivo-aulumnal) malaria in the U.S. Army, by area

and year, 1942-45

Pi'reliminary data based on sample tabulations of Individual medical records]

[Rate expressed as number of cases per annum per 1.000 average strength]

1942-45 1942 1943 1944 1945

Area Numberi Rate Number Rate Number Rate Number, Rate Numberl Rate

of cases of cases of cases of cases of eases

Continental United States ------- 761 0.05 186 0.07 245 0.05 175 0.04 155 0.05

Overseas: !

Europe ....................... 391 0.09 5 0.06 176 0.66 135 0.08 75 0.03

Mediterranean -.............. 7,446 4.86 144 6.28 6.257 13.70 965 1.49 80 .20

Middle East ---------------- 7.502 56.38 568 93.95 5,299 99.90 1,515 32.78 120 4.32

China-Burma-India .......... 8,265 18.47 280 32.01 2,265 57. 17 5.250 31.12 470 2.02

Southwest Pacific ............ 13,624 8.59 233 3.27 5.166 27.20 3,945 7.32 4,280 5.45

Central ald South Pacific .... 8.756 6.08 248 1.64 7, 628 26. 16 7,30 1.66 :1 151) .27

North America ............. ..29 .06 5 .05 24 *12..........0 0

Latin America ............... 4,3126 11.38 2,803 27.50 1,173 9.71 20 2.33 150 2.09

Total overseas ........... 50.519 4.79 4.295 28,054 16.62 12.750 3.34 5.,420 1.22

Total Army" --------------- 51,280 2.02 4,481 1.38 28,299 4.12 -12.925 1 .66 5,575 0.75

I Consists of new admissions and readmissions for malaria as well as admissions for other causes, but in which malaria

existed concurrently or developed subsequently.

SArea of admission to medical treatment, but not necessarily the area in which the disease was acquired.

SIncludes North Africa.

4 Includes Alaska and Iceland.

SIncludes cases on board transports.
STATISTICS OF MALARIA 457

TABLE 57.-. tttaek rates I of inalariae (quartan) malaria, in the U.S. Army, by area and year,

1942-45

[Preliminary data based on sample tabulations of individual medical records)

[Rate expressed as number of cases per annum per 1,000 average strength]

1942-45 1942 1943 1944 1945

Number Rate Numberi Rate Number Rate Number Rate Number Rate

of cases of cases of cases ofcases o0 Cases

Continental United States ---- - 94 0.02 34 0.01 45 0.01 120 0.03 95 0.03

Overseas:

Europe ----------------------- 192 0.05 1 0.01 21 0.08 140 0.08 30 0.01

Mediterraneui 3.--------------- 473 .31 3 .13 330 .72 135 .21 5 .01

Middle East ................- 125 .94 3 .50 32 .60 90 1.95 --------- 0

Cbina-Burma-india ---------- 241 .54 9 1.03 77 1.94 145 .86 10 .04

Southwest Pacific ------------.. 274 .17 4 .06 60 .32 115 .21 95 .12

Central and South Pacific .... 146 .10 7 .05 84 .29 45 .10 10 .02

North America -.............. 2 .00 2 .02 ---------- 0 --------- 0 - -- 0

Latin America --------------- 102 .27 59 .58 33 .27 5 .06 5 .07

Total overseas-------------- 1.583 1 0.15 88 0.15 640 0.38 680 0.18 175 0.04

Total Army --------------- 1. 877r 0.07 122 0.04 685 0.10 800 0.10 2M70 0.04

I Consists of new admissions and readmissions for malaria as well as admissions for other causes, but in which malaria

existed concurrently or developed subsequently.

SArea of admission to medical treatment, but not necessarily the area in which the disease was acquired.

3 Includes North Africa.

SIncludes Alaska and Iceland.

' Includes cases on board transports.

TABLE 58.-Attack rates I of malaria, mixed type, in the U.S. Army, by area and year, 1942-45

[Preliminary data based on sample tabulations of individual medical records]

[Rate expressed as number of cases per annum per 1.000 average strength]

1942-45 1942 1943 1944 1945

Area 2

Number Rate Number Rate Number Rate Number Rate Number Rate

of cases of cases of cases of cases of cases

Continental United States---- ----- 248 0.02 23 0.01 20 0.00 130 0.03 75 0.03

Overseas:

Europe ---------------------- 6 7 0.02 1 0.01 6 0.02 40 0.02 20 0.01

Mediterranean 3 -------------- 540 .35 2 .09 213 .47 250 .38 75 .19

Middle East ----------------- 67 .50 4 .66 18 .34 25 .54 20 .72

China-Burma-India ---------- 427 .95 20 2.29 112 2.83 225 1.33 70 .30

Southwest Pacific ------------ 1,168 .74 26 .37 267 1.41 315 .58 560 .71

Central and South Pacific .-.. 724 .50 13 .09 521 1.79 150 .34 40 .07

North America .-------------- 1 .00 --------- 0 1 .01 --------- 0 0

Latin America --------------- 161 .42 127 1.25 29 .24 5 .06 ---------- 0

Total overseas I--------- 3,196 0.30 193 0.33 1,173 0.69 1,020 0.27 810 0.18

TotalArmy ---------------- 3,444 0.14 216 0.07 1,193 0.17 1,150 0.15 885 0.12

I Consists of new admissions and readmissions for malaria as well as admissions for other causes, but in which malaria

existed concurrently or developed subsequently.

S Area of admission to medical treatment, but not necessarily the area in which the disease was acquired.

8 Includes North Africa.

SIncludes Alaska and Iceland.

0 Includes cases on board transports.

639243---63-33
458 INFECTIOUS DISEASES

TABLE 59.-Attack rates' of malaria, unclassified and other,' in the U.S. Army, by area and

year, 1942-45

[Preliminary data based on sample tabulations of individual medical records]

[Rate expressed as number of cases per annum per 1,000 average strength]

1942-45 1942 1943 1944 1945

Area3

INumber , Rate Number Rate Numberý Rate IcNumber: Rate Numberl Rate

of cases ofcases Of cases. o cases of cases

Continental United States------- 6,072. 0.41 427 0.16 1,300 0.25 2,055 0.52 2,290 0.77

Overseas:

Europea ------------------- 6,135 - 1.46 20 N 0.24 160 0.60 3,210 1.92._ 2.745 1.26

Mediterr•aean4 -------------- 16,5%4 10.83 215 0,38 10,614 23.24 5.170 9.96 585 1.46

Middle East ..... -.. ... 67"2 5.05 76 . 12.57 386 7.28 145' 3.14 65 2.34

China-Burnma-India --------- 8,997 20.11 356 40.70 2,696 68.05 5.310 31.47 635 i 2.76

Southwest Pacific ------------ 25,967 16.37 3, 304 46.38 14,268 75.13 4,885 9.06 3.510 4.47

Central and South Pacific ._ 27, 602 19.16 2, 167 14 35 '22, 390 76.79 2,090 4.76 955 1.71

North America .--------- 49 .10 161 .16 28 .14 5, .04 ......-... i 0

Latin America --------------- 645 1.70 381 3.74 209 1.73 45 I .52 10 .14

Total overseas 6 - - - - - - - - - - -- 88,350 8.381 6,5861 11.24 51.16 30.32 -1,415 5.61 9,180 2.06

S ... .0131 52.40 7.64 I23.47 3.01 140

Total Army.............4,422 3.73 7,013 2.16. 52.49 7. 11,470 1.54

I Consists of new admissions and readmissions for malaria as well as admissions for other causes, but in which malaria

existed concurrently or developed subsequently.

2 Other than v/vax. falciparum, malariae, and mixed type.

3 Area of admission to medical treatment, but not necessarily the area in which the disease was acquired.

4 Includes North Africa.

3 Includes Alaska and Iceland.

6 Includes cases on board transports.

The problem of relapses can best be illustrated by citing the experience

in several areas. Approximately 30 percent of the troops of the 43d, 37th,

25th, and Americal Divisions had over four attacks of malaria by June

1944.19 Twenty percent of these relapses occurred within 2 months of the

primary attack. The overall relapse rate in the China-Burma-India theater

was estimated at 25 percent for vivaax infections.20 The 26th Field Hospital

reported that approximately 60 percent of the malaria admissions were recurrences. Some of these patients had had 8, 10, and 14 previous attacks of

malaria.21 Forty percent of 11,343 cases of malaria studied in the Mediterranean theater from 1 January to 1 December 1944 were recurrent cases.

The relapse rate in this theater was estimated to be from 50 to 55 percent.22

In the Southwest Pacific Area, 392 cases of primary malaria were studied.

19 Report, Capt. James E. T. Hopkins, MC, Surgeon, 3d Battalion Medical Detachment, 5307th

Composite Unit (Provisional), 22 June 1944, subject : Preliminary Report of Physical and Mental

Condition of Men and Officers of the 3d Battalion With Recommendations.

20 Essential Technical Medical Data, China-Burma-India Theater, for June 1944.

21 Annual Report, 26th Field Hospital, Persian Gulf Command, 1944.

22 See footnote 16, p. 453.
STATISTICS OF MALARIA 459

Of the total, 153 cases had relapses, the first relapse occurring on an average of 50 days after the primary attack. In 49 of the 153 cases, the second

relapse occurred on an average of 54 days after the first relapse. In 18 of

the 49 cases, 3 or more relapses each, occurred: 14 had 3 relapses, 2 had 4

relapses, and the remaining 2 had 5 relapses.2

The following tabulation gives the percentage of relapses in a group of

patients studied in Italy during January 1945.24

Number of

previous attacks Percent

1 ----- ---------------------.--------.--.------------------- 39.2

2 --- - ------------------------------------------------- 21.4

3 _ _ _ _ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1 .4

4 3-------------------------------------------- 10.7

5 ------------------------------------------------ 5.3

Eighteen hospitals in the Mediterranean theater reported the number of

relapses experienced by 3,512 recurrent cases of malaria, as follows:

Number of Number

previous attacks of patients Percent

1 ---------------------------------------------- 1,685 48.0

2 777 22.1

3 ------------------------------------------------ 435 12.4

4 ------------------------------------------------ 267 7.6

5 ---------------------------------------------------- 138 3.9

6 ------------------------------------------------- 9 2.2

7 69 2.0

8 --------------------------------------------------- 31 .9

9 ------------------------------------------------- 16 .5

10 -------------------------------------------------- 7 .2

11 ------------------------------------------------- 8 .2

Total -------------------------------------- 3,512 100.0

DURATION OF HOSPITALIZATION

Data on the average duration of hospitalization for malaria in the entire Army were available only for the years 1942, 1943, and 1945, at the

time this analysis was made.

The average stay in hospital and quarters varied from a low of 13.6

days in 1945 to a high of 22.2 days in 1943 (table 60). Malaria due to a

mixed type of infection required a longer period of hospitalization than did

malaria due to a single species of Plasmodium. It is perhaps significant that

the duration of hospitalization for fever of undetermined origin was much

less than that due to malaria.

23 Essential Technical Medical Data, Southwest Pacific Area, for July 1944.

24 Essential Technical Medical Data, Mediterranean Theater of Operations, for February 1945.
460 INFECTIOUS DISEASES

TABLE 60.-Average number of days in hospital and quarters for admissions and readmissions

due to malaria and fever of undetermined origin, U.S. Army, 1942, 1943, and 1945

[Preliminary data based on sample tabulations of individual medical records]

Diagnosis 1942 1943 1945

Malaria, all forms --------------------------------------- 16.6 22.2 13.6

Vivax (tertian) malaria ------------------------------- 16.7 25.3 13.7

Falciparum (estivo-autumnal) malaria ------------------ 15.6 1& 6 14.0

M11alariae (quartan) malaria ---------------------------- 19.0 21.8 10.8

Malaria, mixed type ---------------------------------- 22.5 61.1 16.6

Malaria, unclassified ------------.--- ---------------- 16.8 17.9 11.5

Fever of undetermined origin_ 8. 1 7. 5 6. 9

DEATHS DUE TO MALARIA

There were 302 deaths due to malaria during the period 1942-45; 292 of

these deaths occurred among oversea admissions; of this total, 157 deaths

occurred in Pacific areas: 113 deaths recorded for the Southwest Pacific and

44 deaths for the Central and South Pacific Areas, table 61. The annual rates

per 100,000 average strength were highest in China-Burma-India followed by

the Middle East, Southwest Pacific, and Latin American areas. The rates

varied from year to year. the highest, 20.19 per 100,000 average strength,

occurring in the China-Burma-India theater during 1943.

The majority of deaths, 125, and the highest annual rate per 100,000

average strength, 0.49, were due to P. falciparum. P. vivax accounted for 68

TABLE 61.-Deaths due to malaria, all forms,' in the U.S. Army, by area of admission and year

of death, 1942-45

[Preliminary data based on tabulations of individual medical records]

[Rate expresed as number of deaths per annum per 100,000 average strength]

Area 1942-45 1942 1943 1944 1945

Number!Rate Number Rate Number Rate Number Rate Numbed Rate

Continental United States 10 0.07 1 0.04 3 0.06 2 0.05 4 0.13

Overseas:

Europe ----------------------- 5 0.12- 0 ---------- 4 0.24 1 0.05

Mediterranean 2 - - - - - - - - - - - - - - 57 3.72 3 13.09 40 8.76 13 2.00 1 .25

Middle East ----------------- 12 9.02 1 16.54 5 9.43 3 6.49 3 10.81

China-Burma-India ---------- 40 8.94 1 11.43 8 20.19 25 14.82 6 2.60

Southwest Pacific ------------ 113 7.12 5 7.02 23 12.11 31 5.75 54 6.87

Central and South Pacific .... 44 3.05 2 1.32 28 9.60 9 2.05 5 .89

North America 3 ------------- --------- 0---------- 0 - --------- --- 0 ---- -0

Latin America --------------- 18 4.73 12 11.77 5 4.14 1 1.17 I--------0

Total.overseas - - - - - 29.2 277 24 4.10 106. 52 87 2.28 71 1.60

Total Army ---------------- 302 1.19 25 0.77 113 I 1.64 89 1.14 75 1.01

1 There were no deaths due to malariae (quartan) malaria.

I Includes North Africa.

3 Includes Alaska and Iceland.

4 Includes one death each year on transports, 1943, 1944, and 1945, respectively.
STATISTICS OF MALARIA 461

deaths and mixed infections for 6. No deaths were caused by P. malariae.

There were 103 deaths due to unclassified malaria. (See tables 62, 63, 64,

and 65.)

TABLE 62.-Deaths due to vivax (tertian) malaria, in the U.S. Army, by area of admission

and year of death, 1942-45

[Preliminary data based on tabulations of individual medical records]

LRate expressed as number of deaths per annum per 100,000 average strength]

1942-45 1942 1943 1944 1945

Area i

Number Rate Number Rate Number Rate Number Rate Number Rate

Continental United States 0.04 ---------- 0 1 0. 02 2 0.05 2 0.07

Overseas: Europe ------------------------ 4 0.10 ---------- 0 ---------- 0 3 0.18 1 0.05

Mediterranean I ------------- 14 .91 1 4.36 6 1.31 6 .9W2 1 .25

Middle East ---------- 0 - . 0 --. 0 ----------- 0----------00

China-Burma-Indla ---------- 5 1.12 ---------- 0---------- 0 4 2.37 1 .43

Southwest Pacific ------------ 25 1.58 1 1.40 8 4 21 4 .74 12 53

Central and South Pacific-.... 10 .69 ---------- 0 8 2.74 ---------- 0 2 .36

North America. -------------.-- 0 0.----------0 - 0 0 . .---- 0----------- . . 0

Latin America --------------- 5 1.32 3 2.94 2 1.66 --------- 0 ----------- 0

Total overseas -------------- 63 0.60 5 0.85 24 1.42 17 0.45 17 0.38

Total Army------------- 68 0.27 5 0.15 25 0.36 19 0.24 19 0.26

I Includes North Africa.

2 Includes Alaska and Iceland.

TABLE 63.-Deaths due to falciparum (estivo-autumnal) malaria, in the U.S. Army, by area oJ

admission and year of death, 1942-45

(Preliminary data based on tabulations of individual medical records]

[Rate expressed as number of deaths per annum per 100,000 average strength]

1942-45 1942 1943 1944 1945

Area

Number Rate Number Rate Number Rate Number Rate Number Rate

Continental United Stat'c ------- 3 0.02 1 0.04 1 0.02 ---------- 0 1 0.03

Overseas:

Europe --------------------------------- 0 ------ 0-- - --------- 0 ----------- 0---------- 0

Mediterranean I -------------- 27 1.76 2 8.73 22 4.82 3 .46 ---------- 0

Middle East ------------------ 11 8.27 1 16.54 5 9.43 2 4.33 3 10.81

China-India-Burma ---------- 20 4.46 ---------- 0 6 15.14 12 7.12 2 .87

Southwest Pacific ------------ 43 2.71 ---------- 0 5 2.63 11 2.04 27 3.43

Central and South Pacific-.... 8 .56 ---------- 0 5 1.71 2 .46 1 .18

North America ------------- --------- ---------- 0 0 ---------- ---------- 0---------- 0

Latin America --------------- 1 0 2.62 7 6.87 2 1.66 1 1.17 ---------- 0

Total overseas' ------------- 122 1.15 10 1.71 46 12.73 32 0.83 34 0.77

Total Army ----------------- 125 0.49 11 0.34 47 0.69 32 0.41 35 0.46

I Includes North Africa.

3 Includes Alaska and Iceland.

3 Includes one death each year on transports, 1943, 1944, and 1945, respectively.
462 INFECTIOUS DISEASES

TABLE 64.-I)eaths due to malaria, mixed type, in the U.S. Army, by area of admission and

year of death, 1942-45

[Preliminary data based on tabulations of individual medical records]

[Rate expressed as number of deaths per annum per 100,000 average strength]

1942-45 1942 1943 1944 1945

Area I

Number Rate Number Rate1 Number Rate! Number, Rate Number Rate

Continental United States 0 ----- 0 0----------0------ 0 ! 0 - -- 0

Overseas: i 0.9 10.4

China-Burma-India ---------- 2 0.45 ----- ---- 0 ---------- 0 1 0.59 1 0.43

Southwest Pacific ------------ 2 .13 ----------- 0 .

53 - - - - - -

- 0 1 .13

Central and South Pacific ---- 2 .14 ----------- _-_ 0 ---- 0 2 .46 ----- 0

Other theaters- ----------- --------- 0 0----------0 ---------- 0 -- 0

Total overseas -------------- 6 0.06 0 1 0.06 3 0. 08 2 0.04

Total Army ----------------- 6- 0.0"2 . 0 1 0.01 31 0.04 2 0.03

TABLE 65.-Deaths due to malaria, unclassified and other,' in the U.S. Army, by area of

admission and Year of death, 1942-45

[Preliminary data based on tabulations of individual medical records]

[Rate expressed as number of deaths per annum per 100,000 average strength]

e1942-45 1942 1943 1944 1945

Area_______ _ Number IRate ate Number Rate Number Rate Number Rate

Continental United States ------- 2 0.01 ---------- 0 1 . .. . 0 1 0.03

Overseas: -I

Europe ----------------------- 1 .02- .

- - - - - - - - 0 ---------- 0 1 .06 ---------- 0

Mediterranean - .............. 16 1.05 ---------- 0 122.63 4 .62 ---------- 0

Middle East---- ------- 1 1-.75 --.. 0 ---------- 0 1 2.16 ---------- 0

China-Burma-India ---------- 13 2.91 11.43 2 5.05 8 4.74 2 .87

Southwest Pacific ------------ 43 2. 70 4 5. 62 9 4.74 16 2.97 14 1.78

Central and South Pacific -. _ 24 1.66 2 1.32' 15 5.15 5 1.13 2 .35

North America .------------- ------ 0 ---------- 0 - ---------- 0 - 0

Latin America ---------------- 3 .79 2 1.96 .82 ---------- •0 0 -----------

Total overseas ---------- 101 0.96 9 1.54 1 39 2.31 35 0.92 18 0.41

Total Army-----------103 0. 41 1 9 0j.28j 40 0.b58 36 .5 19 0.26

I Other than vivax, faldparu m, malariae, and mixed type.

2 Includes North Africa.

'Includes Alaska and Iceland.
STATISTICS OF MALARIA 463

SUMMARY

The role of malaria in military campaigns was reemphasized once more

during World War II. The magnitude of the problem is illustrated by a

brief presentation of statistical data giving the incidence of malaria, the

types of malaria, the relapse problem, and the number of deaths due to malaria. It is indeed a tribute to the Medical Department of the U.S. Army,

that the menace of malaria did not more seriously interfere with military

operations.
CHAPTER XV

The Suppression of Malaria

Benjamin M. Baker, M.D.

From the onset of World War II, it was recognized that tropical diseases could interfere seriously with military operations. Previous military

histories ' had adequately delineated this problem. What was not known,

however, was the extent to which troops might be incapacitated by malaria

under the conditions of modern warfare in the Tropics. Planners could not

count on the opportunity to rid hostile shores or vast hinterlands of endemic

malaria by elimination of mosquito breeding. In the long run, the effectiveness of U.S. troops in many parts of the world depended principally on the

suppression of clinical malaria by the use of new drugs and the development

of techniques of chemotherapy.

Most medical officers arrived on the scene with little knowledge of malaria and even less practical experience. At first, the only sources of information were the few available textbooks and the directives prepared by The

Surgeon General, U.S. Army. One of the directives, Circular Letter No. 56,

Office of the Surgeon General, dated 9 June 1941 recommended the following

regarding chemical prophylaxis:

The use of quinine or Atabrine for prophylaxis is not recommended as a routine

procedure, as the available information indicates that these drugs do not prevent infection. However, they are of definite military value in that they do prevent the appearance of the clinical symptoms of malaria so long as they are taken, and thus they

afford a means for keeping troops "on their feet" during periods of emergency in the

field. When administered to troops in special situations in unsanitated endemic areas,

either of the drugs may be used under the personal supervision of a responsible offieer,

as follows: (1) Atabrine 0.2 gm. (3 gr.) twice a week (every 3 or 4 days) or (2)

Quinine sulphate 0.3 gin. (5 gr.) daily.

'When in a very short time it became clear that the high malaria rates in

exposed troops constituted a serious problem, the few available trained experts on malaria were enlisted to direct hurried efforts to bring about drug

suppression of the disease. Such attempts were made as in September 1942

in one area of high malaria incidence, when a command directive ordered

that Atabrine (quinacrine hydrochloride) in doses of 0.2 gm. twice weekly

be taken prophylactically but because of accumulation should be replaced

after 3 months by quinine for 1 month. With these early efforts at suppressive drug control, malaria rates of combat troops in the range of 1,500 to

2,000 per 1,000 troops per annum were common.2

1 Boyd, M. F.: An Historical Sketch of the Prevalence of Malaria in North America. Am. J.

Trop. Med. 21: 223-244, March 1941.

2Downs, W. G., Harper, P. A., and Lisansky, E. T.: Malaria and Other Insect-Borne Diseases

in the South Pacific Campaign, 1942-1945. II. Epidemiology of Insect-Borne Diseases in Army

Troops. Am. J. Trop. Med. (supp.) 27: 69-89, May 1947.

465
466; INFECTIOUS DISEASES

FACTORS IN EARLY FAILURES IN SUPPRESSION OF MALARIA

Experiences such as these soon led to the conclusion by line officers and

most medical officers as well, that Atabrine was ineffective in suppressing

clinical nmalaria under the conditions of combat. Quinine was in short supply, but it was widely believed that quinine would provide effective suppression and that Atabrine was a necessary but poor substitute for it. Furthermore, when Atabrine was initially administered it frequently led to nausea,

vomiting, and diarrhea. This was particularly likely to occur when the

administration was begun on shipboard. where anxiety and seasickness contributed to the prevalence of gastrointestinal upsets. Confusion. too, between

the skin discoloration due to Atabrine and cases of infectious hepatitis (a

confusion added to by some medical officers) increased fear of the drug.

There were rumors that Atabrine caused impotence. In addition, soldiers soon

learned that if they acquired malaria they would be removed from combat

areas to more adequate hospital facilities. Altogether, the value and safety

of administration of this drug was not wholeheartedly accepted by the troops,

and forward medical officers themselves became lukewarm regarding it. Diminishing supplies of quinine were frequently given by the medical staff to

their fellow officers. The result of all this was poor discipline in the use of

suppressive therapy and consequent failure in control of clinical malaria.

The change in the attitude of command and medical officers alike towa"

Atabrine and its role in the malaria problem was aided by an importal.

study 3 in an Army medical center located in Australia. This study was conducted by Lt. Col. (later Col.) Garfield G. Duncan, MC, Consultant in Med •

cine, Sixth U.S. Army, shown in figure 59, explaining the details ef malaria

suppressive therapy to Gen. (later General of the Army) Douglas MacArthur,

Supreme Commander, Southwest Pacific Area. Here, a group of men, all

known to be subject to recurrent malaria attacks, were gathered in a region

free of endemic malaria and given suppressive amounts of Atabrine. Various

dosage schedules were employed, including 0.1 gin. daily for 6 days each week

and 0.5 gin. on 2 days of each week. There was prompt cessation of clinical

malaria, despite vigorous training which included a final forced march of

25 miles.

This study pointed out the advantage of the twice weekly suppressive

dose. Rigid supervision to insure the actual ingestion of the prescribed

amount was more easily accomplished twice weekly than daily. Further, this

dose, in all probability larger than absolutely necessary for good suppression,

provided an additional margin of safety.

When this suppressive regimen was tried in a malarious area during combat, the results were even more impressive. Malaria rates as high as 1,230

per 1,000 per annum had been observed in a battalion supposedly receiving

3 Duncan, G. G. : Quinacrine Hydrochloride as a Malaria-Suppressive Agent for Combat Troops.

War Med. 8: 305-318, November-December 1945.
0.6; liii I Iof I ahi niie ~Vweek Y ~I )It Ad )Ix.i ( )IIl v III I ( )I1 11 It- 1&I 1 1ii1,ii 0Ie WIW I.U~-ifit)l.

Whlei IeI (i05:[_.re wVI. IagIi,~ toI * I I1. I I WlI4& Week I v. I I :I1 I ;I r Ii e

next 2 muloliths

j()iil: fiv~e f1 Inai k Ingr ail)-ý4)ldIll vY verl :1InII III LiI I lie I IeII II act Ii~ la I I -ýwal 114 mWe4 I ;II I I

I Ie ~I 1t~ ui4 I to v*uu.- 4e I uý.rii- If f~cu I 14i' Iira Si I riu Ii'I e19t~l Iwlali~4)1.

114 -~4'Eli.lSI~.1 fill, Al i ralia. :-% N#)%vmlwr~i W13i . Lefl lip ri-_Iil: C ilim'el I 'iu'' llu i "ii 44it iiers'

ini Ollliiwwiy 111uideulolified IA. I Cil. ~;livA. DI )IIiuiiu. Sixth~ 1.5. Arm.\v Tni'i';ui iuu - ea.r:

L~t. Oil C. ( 1 Miprel house. .\iIe-'i4-( ;uli ill 4 euue11rai al i ir Li. (4 .1i. Ierlivirt Ijijlisdell. 1l.0 1 ishi A )IuII . IJ L i' Inii ( 11bictie. l. 4 ;4.1. IRtliurt I . E i I .IlI I-.4 r. (*1111.114 a iauo 1 I 1. 4 wituvrauI. I 4 t lt:4'i. Franuk LauIliie. 'iuuu~ruitt (lifher. S-iXth U.S. Army Trauinuing C ellter: andi 4 .ttiti1-il .1Ia4Artlitir.

ill olefallilt verl a i iiv account let for u 11,1I1V of tlie fa Illti Ie._ of Ill(- (11l1ur s :1 I

)lfrs-a Iii e dval ill tile wvar.

TI' ieie Was, however. aniothler fact or. Ii IaI almost15 sil relv accoillilt e4 for

SOMP failuires even When Ilite (iAivas flat ifully11 ig-est edl. Early In tilie war.

thle r'ecommiiendoed olosagtr was SmalllI ando laid it) '14-villill Ill e toI () real letiy

b)104)4 levels. as wvIll be shiowni ill miove detail Ilater 11).7:~ This fact was5 ]1)il

th en reco-riiized. C onsequflent ly. whelei t roop b1 e-all Iivia .Nir~ .W Short ly b eforwe

o1r ()I tilie dlay of exposure. c'liniical malarI lia coilt 14ap1 peal b efore thle co aweiiI rat Mil1 of At ahri ne inl tilie blood( Was sliflivient. for Suippress5l0io.
468 INFECTIOUS DISEASES

The experience of 840 men in a construction group which landed on

Guadalcanal in December 1942 illustrates this point well. 4 The men had

never been exposed to malaria before, and on the day of landing, Atabrine in

dosage of 0.4 gin. per week was begun. It was alleged that the drug was

taken faithfully. In the third, fourth, and fifth weeks, 119 cases of clinical

malaria developed, a rate of 1,523 per 1,000 per annum. Beginning with the

sixth week, and coinciding with the predicted time of maximum blood concentration, the cases began to level off to about seven per week. As will be

shown later, 0.4 gm. of Atabrine per week never produces a blood level adequate to suppress all malaria and has very limited effect until the maximum

concentration is obtained from the seventh week on.

EFFECTS OF ATABRINE WITHDRAWAL

In most theaters of operations, there were either nonmalarious or relatively well sanitated base sections. When combat conditions permitted, troops

were usually moved to such rear areas for rest and rehabilitation. It was

thought that after long suppressive therapy, especially with, in addition,

the debilitating influences of forward area duty, Atabrine would no longer

effectively suppress clinical malaria. Administration of Atabrine was usually

terminated in such troops unless local conditions made further disease transmission likely. Withdrawal of Atabrine was made either abruptly or after

preliminary attack therapy with various combinations of Atabrine, quinine,

or plasmoquin.5 It was hoped that troops so treated would be freed, at least

in part, of malaria and be less likely to suffer supposed damage from the

cumulative effects of long continued Atabrine therapy. Finally, it was

thought that, after a period without Atabrine, they might be more susceptible

to its suppressive effect when they had to return to highly infective areas.

The results of this experiment were appalling. Depending upon the

degree of seeding, malaria rates in such troops rose to peaks as high as 15,000

per 1,000 per annum, and sustained rates over a period of months of 3,000 to

4,000 per 1,000 annum were common.6 With some of the strains involved, attacks followed attacks rapidly. It was common to have men hospitalized for the

treatment of clinical malaria stricken with a fresh attack before completing

the accepted period of convalescence. In one group studied in the South

Pacific Area, the interval between attacks of malaria due to Pla8modium vivax

averaged 28 days. The type of therapy that had been given had no significant

influence upon the number of relapses or the interval between them in heavily

seeded troops.

Such men, removed from suppressive therapy, were no longer fit for

combat duty. The general physical fitness of the troops deteriorated; morale

4 Personal communication, Paul Harper to author.

5 Downs, W. G.: Results in an Infantry Regiment of Several Plans of Treatment for vivax

Malaria. Am. J. Trop. Med. 26: 67-86, January 1946.

6 See footnote 2, p. 465.
SUPPRESSION OF MAIARIA 469

suffered: adequate training was impossible; and hospital facilities and the

few convalescent and rehabilitation camps available were overtaxed. Many

men as a consequence were evacuated to the United States, and others had to

be reassigned to limited duty.

Gradually, it was realized that suppressive therapy should be continued

during rehabilitation periods and that the only way of controlling the disease

in troops from whom suppressive medication had been withdrawn was to

reinstitute such therapy. These decisions were reached after careful studies I of

the results to be expected. It was found that general physical and psychological fitness improved remarkably once current attacks of clinical malaria

were prevented by suppression. It was furthermore found that fatigue, or

exposure to cold, wet, and arduous combat conditions did not cause suppressed

malaria to "breakthrough" provided discipline in the administration of Atabrine was good.

EFFECT OF SUPPRESSIVE THERAPY ON PARASITE SPECIES

In intensely malarious areas of the Pacific, the clinical disease that broke

through poorly taken or otherwise inadequate suppressive medication was

predominantly due to Pia.-miodhim faleiparitn. On Guadalcanal. for example, in January 1943 the parasite species recovered during malaria attacks

were distributed, as follows: s

Percent

Plasmodium falciparun ------------------------------------- 55

Plasinodhom virix ----------------------------------------- 24

Unidentified ---------------------------------------------------- 19

When troops were removed to nonmalarious areas and suppressive therapy withdrawn, there was a progressive shift with time in this species distribution. For example, the same troops found to be infected on Guadalcanal

with the parasites previously listed were found 5 months later to have clinical

malaria from which micro-organisms were recovered, as follows:

Percent

Plasmodium falciparuim -------------------------------------- 0

Plasmodium rirax ----------------------------------------- 99

Unidentified ----------------------------------------

Such observations from all parts of the world confirmed the view that all

late relapsing malaria was caused by P. vivax, in accordance with the longrecognized tendency of this species to produce the most stubborn form of

relapsing malaria. Gradually, it became apparent that Atabrine, even in

suppressive doses, was curative for malaria due to P. falcpanrim.

A study by Col. Maurice C. Pincoffs, MC, which pointed out this, as

well as other facts about Atabrine suppression, was carried out in New

7 See footnote 3, p. 466.

8 Levine, N. D., and Harper. P. : Malaria and Other Insect-Borne Diseases in the South Pacific

Campaign, 1942-1945. IV. Parasitological Observations on Malaria In Natives and Troops, and on

Filarlasls in Natives. Am. J. Trop. Med. (supp.) 27: 119-128, May 1947.
47ii INFECTIOLUS iDISEASiES

Guinea and Australi, ill 1143. A grouip of pleviously uininfected men were

moved to a highly malarious area for a 44-day periold. One group took no

suppressive therapy and served as controls. Sulfaluerazine was given in

dosýýs of 0.5 and 1.0 gin. daily to a second group. A third group was given

0.1 gin. Al&abrine daily 6 days a week. In the control group of 51 men, 26

developed clinical malaria. In the group of Il men on sulfainerazine, only

two manifested this disease. Nolte of the 107 men on Atabrine fell ill with

malaria.

Following this 44-day period. all groups were removed to a nonlinalarious

area for a further 3 months' period of observation and all drug.s" withdrawn.

Of the group treated with sulfamnerazille, 36 percent developed clinical malaria due to P. via.r as opposed to 30.8 percent of the group treated with

Atabrine. while not a single case of malaria caused by 1'. fa/d,.io1 1.m developed during this period of observation among the men who had received Atabrine. It is almost certain that malaria, due to P. falciparuim had been

transmitted to them previously as 10 cas.s developeld in the control group

of 51 men.

Further evidence was provided by another study 9 carried out in Australia. Human volunteers were subjected to numerous bites of infected mosquitoes while on various suppressive regimnens. The New Guinea strains employed

were known to produce severe attacks of malaria due to P. f lcipaninm and

P. Ah'(.r, tile latter with a high and rapid relapse tendency. Quinine sulfate

proved to be greatly inferior to Atabrine as a suppressive drug. Several

sulfonamides in doses of 1.0 gin. daily suppressed and cured most P. falcMpartin infections but were inferior to Atabrine in this respect. The sulfonamides proved very poor in their suppressive action on malaria due to P. vira.r.

Atabrine was conclusively shown both to suppress and to cure, all P.

faldciparuln infections under the conditions of the experiment. This drug

was also found highly effective in suppressing P. viraxr infections, but when

it was withdrawn clinical malaria caused by P. rirax regularly developed.

Hard physical work, forced marclhes, extreme cold, anorexia, blood loss, and

injections of insulin or Adrenalin (epinephrine) failed to alter the suppressive action of Atabrine.

There can be little doubt that. the control of P. falciparum infections by

even suppressive doses of Atabrine was in large measure responsible for tile

great. rarity of cerebral malaria a.ld blackwater fever in our forces. Because

these manifestations of malaria are responsible for a large proportion of

deaths from this disease, it is understandable why the death rate was so

extraordinarily low. This in itself was a happy consequence of the enforced

use of Atabrine due to inadequate supplies of quinine.

9 Fairley, N. H. : Chemotherapeutic Suppresstion and Prophylaxis In Malaria: An Experimental

Investigation Undertaken by Medical Research Teams in Australia. Tr. Roy. Soc. Trop. Med. & Hyg.

38: 311-355, May 1945.
SUPPRESSION OF MALARIA 471

LONG-TERM CLINICAL EXPERIENCE WITH ATABRINE

SUPPRESSION

Many examples are available of long-term observations in military units

that served in highly malarious areas. They all illustrate in varying degree

early suppressive failure, amazing rates of clinical malaria when suppressive

medication was withdrawn, and finally good control of malaria when suppressive medication, under praper conditions of Atabrine discipline, was resumed.

One impressive example 10 of this frequently repeated experience was that

of an infantry regiment in the South Pacific which landed on Guadalcanal

in three echelons in December 1942 and early in 1943 when malaria transmission was at a high level. Atabrine in doses of 0.4 gin. per week was ordered.

The malaria rates between December 1942 and May 1943 varied between a

low of 405 and a high of 1,296 per 1,000 per annum. In May 1943, the regiment was removed to a nonmalarious island for rehabilitation and all suppressive medication was withdrawn. Various malaria treatment regimens were instituted in an effort to eliminate some of the malaria seeding present in the

troops; nevertheless, for the next 7 months, tile malaria rate varied between

1,836 and 3,132 per 1,000 per annum. The highest rate occurred in the third

week in one segment of the regiment that previously had had the greatest

exposure to malaria transmission, and in this group the incidence of clinical

attacks exceeded 14,000 per 1,000 per annum. The highest regimental rate,

however, occurred in the sixth month, indicating no tendency for these extraordinarily rapid relapses of malaria caused by P. vivax to diminish with time.

Rehabilitation of these troops had obviously not. been accomplished.

Their working efficiency was in fact, so severely depleted that they were returned to carefully supervised Atabrine suppression late in November 1943.

At first, 0.4 gm. of Atabrine per week was given, but late in January 1944,

the dose was increased to 0.6 gm. per week. As soon as this was done, there

was a prompt and impressive control of the malaria rate with return of the

working capacity of the organization.

Then, after 2 months' duty on a nonmalarious island, the regiment served

for less than 3 months on an island where malaria transmission was very

slight. Next, there was 12 months' service in a nonmalarious area, making a

total of 18 months' service while on Atabrine suppressive medication with

little or no additional exposure to malaria transmission. Atabrine medication

was then terminated. Over the following 3 months' observation period, there

was nothing like the increase in the attack rate that had followed initial deatabrinization exactly 2 years previously. Approximately 400 men had remained with this regiment from its early exposure to malaria on Guadalcanal

in 1942 until the final termination of Atabrine suppressive medication in

May 1945. The malaria experience of these men is shown in chart 25.

10 Baker, B. M., and Platt, D.: VIvax Relapse Rates Following Continued Atabrine Suppressive

Medication: Observations on Malaria in an Infantry Regiment. Bull. Johns Hopkins Hosp. 81:

295-304, November 1947.
472 INFECTIOUS DISEASES

In review then, there was in this group a period of 6 months' extreme

exposure to malaria, 7 months of attempted but unsuccessful eradication of

malaria, and a final period of 18 months' excellent suppression of malaria by

Atabrine with negligible fresh transmission. Suppressive medication was

then terminated, but the latent malaria that developed during the next 3

CHAWT 25.- Malaria cxperiencc of an infantry regiment carefully followed for 34 months,

South Pacrific Area, Deecmber 1942-August 1945

[Rate expressed as number of cases per annum per 1.000 average strength]

UADALO*WAL •555OA 44W NEW 15RAi CAL9001 iWO JIMA

11POSURi TO MALANIA 00 EXPOSURE TO MIALARIA MO LITTLEL No I]POSURE O T W1L TO L AOIS IA TO MALARIA

ATASAINE SUPP SIIISIVE I I OI0*TgON

0.4 6U.*?*511 Pil • VIRIO69. 6OAp 0.6 gM. pan WEEK 0.? so. pan WEIEK 8

RATE

4,000

3,0O0 -

9,000

I'm'

0 D J F M A U J J A S 0 N 0 J F M A M J JA S 0 N 0 J F M A U J J A

1942 1943 1944 1945

Source: Modified from Baker, B. M., and Platt, D.: VIvax Relapse Rates Following Continued

Atabrine Suppressive Medication: Observations on Malaria in an Infantry Regiment. Bull. Johns

Hopkins Hosp. 81: 295-304, November 1947.

months was much lower in incidence than in the earlier period of Atabrine

withdrawal. This was a unique experience in observing the effects of longterm suppressive therapy on troops heavily seeded with malaria, and there

will probably never be an opportunity to confirm these observations. It

seems likely, however, that the relatively low attack rate when suppressive

therapy was finally terminated was due to permanent elimination of a significant amount of latent P. iv,/x infection either by the long-term drug

therapy or by a gradual increase in biological resistance.
SUPPRESSION OF MALARIA 473

CONCENTRATION OF ATABRINE IN THE BLOOD AT LEVELS

EFFECTIVE FOR SUPPRESSION

Basic understanding of optimum methods for suppression of malaria by

Atabrine began only when field experience could be accurately controlled by

determinations of the concentration of Atabrine in the blood. There were

four large studies relating clinical effectiveness to Atabrine blood levels, and

it is upon these that most of the accepted concepts of suppressive therapy

depended. They were conducted in the United States," in the Southwest

Pacific, 12 and in the South Pacific.'3 Such field studies yielded a reasonably

precise means of testing Atabrine discipline, made possible determination of

effective suppressive dosage, and provided basic pharmacological information.

It was shown that when a constant dose of Atabrine is administered daily

to a group, individual blood levels vary widely, but that individuals who

attain high, average, or low blood levels, do so regularly. Furthermore, the

group mean level can be calculated accurately and is a function of dosage and

duration of administration. The maximum blood level yielded by a given

dose is attained slowly over a period of 6 weeks, and then remains constant

for the remainder of the period of drug administration. Fifty percent of the

final equilibrium level is reached at the end of the first week, and 50 percent

of each remainder in each of the 5 succeeding weeks. A dose of 0A. gm. of

Atabrine per week produces a group mean level at the end of 6 weeks of 12

gg. per liter; a dose of 0.6 gm. per week, a level of 18; and a dose of 0.7 gm.

per week, a level of 21. A group mean level of 21 gg. per liter can be achieved

either by giving a daily dose of 0.1 gim. for 6 weeks or by administering 0.3

gm. daily for 4 days. Once the desired level has been attained, regardless of

whether this is done with small doses over a long period or by larger doses in

a few days, the group mean level can be maintained by the daily administration of the dose that would yield that level after 6 weeks of daily administration.

Interest naturally was strong in determining the blood levels that would

protect working troops from primary and from relapsing attacks of malaria.

One study addressed to this question was made in a segment of a division

heavily seeded with malaria. Without suppressive medication, the troops

were having a malaria rate that varied between 2,000 and 4,000 per 1,000 per

annum. Two groups of 600 men each were selected for the study. One group

11 (1) Final Report on Investigation of the Effects of Activity and Environment on Atabrine

Therapy, Project No. 18, Armored Research Laboratory, Fort Knox, Ky., 23 Dec. 1943. (2) Shannon. J. A., Earle, D. P., Jr., Brodie, B. B., Taggart, J. V., and Berliner, R. W.: The Pharmacological Basis for the Rational Use of Atabrine in the Treatment of Malaria. J. Pharmacol. & Exper.

Therap. 81 : 307-330, August 1944.

12 Bang, F. M., Hairston, N. G., Maier, J., and Trager, W. : Studies on Atabrine (Quinacrine)

Suppression of Malaria. I. A Consideration of the Individual Failures of Suppression. Am. J.

Trop. Med. 26: 649-661, September 1946.

13 Schaffer, A. J., and Lewis, R. A.: Atabrine Studies in the Field. I. The Relation of Serum

Atabrine Level to Breakthrough of Previously Contracted Vivax Malaria. Bull. Johns Hopkins Hosp.

78: 265-281, May 1946.
474 INFECTIOUS DISEASES

was given 0.1 gin. of Atabrine three times daily for 1 week (yielding a group

mean Atabrine level in excess of 21 jig. per liter). Half of this experimental

group then took 0.1 gin. Atabrine daily and the other half 0.05 gm. daily.

The second group of 600 men had no medication and served as controls. During 4 weeks of observation, 157 of the controls but only 14 of the group on

suppressive treatment developed clinical malaria. It, was of interest, that the

Atabrine blood levels of these 14 treated men were all considerably lower

than those of the treated group that remained free of clinical disease. In

order to investigate the relationship of Atabrine blood levels to the probability of breakthrough of malaria, plans were made to expand the study with

larger numbers of subjects.

A moderately seeded infantry division in a malaria-free area was selected.

For longer than 10 months, these troops had had suppressive medication. first

0.4 gin. Atabrine per week and later 0.6 gni. per week, continuing on the latter

(lose when transferred to the rehabilitation area. Results of the study were

as follows:

1. Preliminarj Atabrine serunt let-els.-Of the nine infantry companies,

1,021 men had serum determinations made as soon as possible after reaching

tlie rehabilitation area. Suppressive Atabrine was ordered, but as yet no

special effort has been made to improve Atabrine discipline. Of this group,

65 percent had Atabrine levels of 19 Mg. per liter or less. The arithmetic

mean level of the entire group was 13 pg. per liter whereas the arithmetic

means in the various companies varied between 9 and 20 Ag. per liter. Obviously, some officers were enforcing more rigid Atabrine discipline than others.

To confirm this conclusion, a large group of men were assured protection

from disciplinary action and confidentially questioned regarding their actual

intake of the ordered medication. Of those who claimed to have taken the

suppressive doses faithfully, only 27 percent had acquired malaria, whereas

50 percent of those who admitted to poor discipline had the disease. Furthermore, relapses had beop. four times more frequent in those who admitted to

disobeying orders as . Atabrine intake.

When this information was presented to command, extraordinary precautions were taken to see that all men who were offered six Atabrine tablets

a week actually swallowed them. The arithmetic mean of the serum Atabrine

levels of one company rose in 4 weeks from 11 to 20 M~g. per liter with a sharp

concomitant reduction in that company's malaria rate.

2. Atabrine levels at time of breakthrough.-Serum Atabrine levels were

determined in 410 soldiers at times when they developed clinical malaria.

Of these men, 97.4 percent had Atabrine levels of 10 pg. per liter or below with

an arithmetic mean in this group of 5 pg. per liter. This figure should be

compared both with the arithmetic mean of 13 Mg. per liter of the "suppressed"

group just discussed, and with the mean level of 20 ug. per liter achieved in

the best disciplined company, which had no clinical malaria during the study

period.
SUPPRESSION OF MAMARIA 475

3. Controls.-In this same division, 404 men belonging to one company

were removed from all suppressive medication at the beginning of the study.

This control group had a malaria rate of 1,340 per 1,000 per annum as compared with the rate of 212 per 1,000 per annum in the group given suppressive treatment.

A roughly similar study 14 was conducted in an intensely malarious area

at a time when an epidemic of malaria due to P. faleiparum developed in an

infantry regiment in combat. Again it was demonstrated that the Atabrine

blood levels in "protected" troops were significantly higher than those in men

who developed clinical malaria, this difference presumably being a result of

better discipline in the former. There was suggestive evidence in this study

that it took a higher blood level of Atabrine to suppress primary malaria

caused by P. falciparum during combat than to suppress relapsing malaria

due to P. vivax in a rear area. This impression, however, was not confirmed

beyond question, although another study 15 in another area also suggested this

conclusion.

This last was a further important study of the plasma levels of Atabrine

in effective suppression, conducted in the Southwest Pacific. Again, it was

demonstrated that there is no definite concentration in the plasma that divides protected individuals from those that break through suppressive therapy. However, it was pointed out that such plasma levels were obtained

after the symptoms had started and might well have been quite different from

those that prevailed at the time parasite multiplication began. Further, it was

observed that the plasma level of Atabrine varied considerably during a 24-

hour period depending upon the time the dose was given.

From this study, the conclusion was drawn that success of any suppressive program was related in part to the actual efficiency of Atabrine administration but that failure of suppression, even with low Atabrine plasma levels,

was not always a result of failure to take the drug.

At the same time, it was realized, however, that during suppression there

was no way to tell how much malaria was actually present though latent in

troops. In the absence of this information, evaluation of any suppressive program could never be more than approximate. A study in the Southwest Pacific

provided some information upon this important point."'

A previous study 17 had demonstrated that after the termination of attacks of clinical malaria by therapeutic doses of Atabrine a few parasites could

14 Final Report on an Investigation of the Blood Serum Level of Atabrine at Which Malaria

Develops In a Hyperendemic Area. Special Report to The Surgeon General by Lt. Col. A. J. Schaffer, MC, and Capt. R. A. Lewis, MC, 3 July 1944.

15 Bang, F. B., Hairston, N. G., Maler, J., and Trager, W.: Studies on Atabrine Suppression

of Malaria. II. An Evaluation of Atabrine Suppression In the Field. Am. J. Trop. Med. 26: 753-

759, November 1946.

16 Bang, F. B., and Hairston, N. G. : Studies on Atabrine (Quinacrine) Suppression of Malaria.

III. The Epidemiological Sign•iflcance of Atabrine Suppression. Am. J. Trop. Med. 27: 31-38, January 1947.

17 Bang, F. B., Hairston. N. G., Trager, W., and Maier, J.: Treatment of Acute Attacks of

Vivax and Falciparum Malaria. Bull. U.S. Army M. Dept. 7: 75-89, January 1947.
476 INFECTIOUS DISEASES

often be found in the blood. These numbered usually less than one parasite

per 500 leukocytes and alivays less than four per 500 leukocytes. Similar parasite studies were now conducted upon troops under suppression and not infrequently, even in the absence of symptoms and in the presence of adequate Atabrine plasma levels, there were positive blood smears. This was particularly

true when the troops had previously had little clinical malaria. The more

attacks they had had the less likely they were to have positive smears. When

in such surveys the number of parasites found exceeded four per 500 leukocytes, careful inquiry and determination of plasma Atabrine levels usually

disclosed that insufficient Atabrine had been ingested to prevent parasite

multiplication.

When this method of study was applied to a group in which malaria was

believed to be heavily seeded but well suppressed, parasites were found in

the blood smears of 14 percent of the men. The degree of seeding of the

group was subsequently shown by withdrawing suppression and observing

that 80 percent of the entire group developed clinical malaria within an

S-week period.

Parasite surveys of this sort were correlated with malaria rates under

suppression, Atabrine discipline and determination of Atabrine plasma levels. The conclusion drawn was that when the suppressive dose of Atabrine

is 0.5 gin. twice weekly, protection is afforded roughly 98 percent of troops

even though engaged in combat in a highly malarious area.

An important result of Atabrine suppressive therapy not generally appreciated goes more fundamentally beyond postponing the evil day of clinical

attacks until suppression is withdrawn. Atabrine in suppressive doses faithfully taken not only kills the gametocytes of P. vivax but prevents the development of P. vivax and P. falciparum gametocytes.'s Epidemics of malaria

result from the availability of nonimmune susceptibles, anopheles mosquitoes,

and gametocyte carriers. The latter can be controlled by Atabrine suppression and the relation of this control to outbreaks of malaria in troops was

clearly demonstrated by observations in the Southwest Pacific.

UNDESIRABLE EFFECTS OF ATABRINE

Staining of the skin was a distinct detriment to the use of Atabrine as a

suppressive agent. The sickly yellow hue of most soldiers who took the drug

was unsightly, imposed an appearance of lack of vigor, and undoubtedly

played a part in poor Atabrine discipline.

Gastrointestinal upsets resulting from Atabrine were not infrequent,

particularly when the drug was first started and more particularly when

loading doses were required. These initial intolerances almost invariably

Is Bang, B. F.. and Hairston, N. G.: Studies on Atabrine (Quinacrine) Suppression of Malaria.

III. The Epidemiological Significance of Atabrine Suppression. Am. J. Trop. Med. 27: 31-38, January 1947.
SUPPRESSION OF MALARIA 477

subsided in time but they turned men from the drug in the beginning and

some of them never accepted it willingly.

More serious reactions occurred in numbers that are not exactly known.

It was demonstrated beyond question that Atabrine in doses employed in

the treatment of clinical malaria caused some psychoses.' 9 It seems probable that even in suppressive doses the drug made a contribution to less serious

psychiatric disorders, but accurate information on this is not available.

A peculiar form of lichen planus was clearly related to Atabrine in suppressive doses. 20 A few cases of exfoliative dermatitis 21 were related causally

but how much contribution suppressive Atabrine made to ordinary dermatological disorders cannot be determined. 22

The subject of Atabrine toxicity is discussed more fully elsewhere in this

history (p. 538). The attendant discomforts, and the small risk of more serious potential dangers, does not detract from the enormous contribution that

suppressive therapy made to the maintenance of the effectiveness of troops

throughout the war.

19 Newell. H. W., and Lidz, T. : The Toxicity of Atabrine to the Central Nervous System. Am.

J. Psychiat. 102: 805-818, May 1946.

20 Livingood, C. S., and Dieualde, F. R.: Untoward Reactions Attributable to Atabrine. J.A.M.A.

129: 1091-1093. 15 Dec. 1945.

21 Agress, C. M. : Atabrine as a Cause of Fatal Exfoliative Dermatitis and Hepatitis. J.A.M.A.

131: 14-21, 4 May 1946.

22 Schamberg, I. L. : Studies on Post-Atabrine Dermatitis. II. Permanent Anbidrosis, Anhidrotic Astbenla and Prolonged Dermatitis Following Atabrine Dermatitis. J. Invest. Dermat. 21:

279-292, November 1953.
CHAPTER XVI

Clinical Aspects of Malaria

Harold D. Levine, M.D.

To most medical officers, malaria was a wholly new experience. By and

large, they had never seen the disease before and were not likely to see it

again. Except such textbook knowledge as they might possess, they had

very little basis for comparison of its clinical features in World War II with

previous observations. Perhaps for this reason, perhaps because interest in

the bedside aspects of malaria was dwarfed by the tremendous advances made

in the field of personal and group prophylaxis against the disease, amazingly

few attempts were made to document its anamnestic features, symptomatology, and physical findings.

Another reason may underlie the dearth of clinical data on malaria during this war period. It is common experience that the clinical picture of a

disease may be modified by its treatment, particularly if the treatment is

effective. Thus, full-fledged use of digitalis, diuretics, and salt manipulations has modified the clinical characteristics of congestive heart failure.

Likewise, the employment of antibiotics has altered the symptomatology of

pneumococcal pneumonia. The same appears to have been true of malaria.

In the overwhelming majority of cases, therapy was promptly effective in

aborting the disease. Except during the very earliest phases of the war, when

dosage was not yet adequate, and in some studies of recurrent cases, or in

therapeutic malaria for neurosyphilis, in which treatment was deliberately

withheld, the classical picture was blotted out in its earliest stages. Thus,

the spontaneous pattern of a clinical attack of malaria was simply not observed in its entirety. To most physicians, therefore, malaria was a brief,

grippelike illness with fever, chills and sweats, headaches, and generalized

aches and pains.

Source material for the present review consists of a small collection of

documents, official and nonofficial, particularly the reports from those theaters of operations where malaria rates were highest; namely, the Mediterranean (formerly North African) Theater of Operations, U.S. Army, and

the South and Southwest Pacific Areas. A number of thoroughgoing studies

of relapsing malaria due to Planmodium vivax were also conducted in the

Zone of Interior at Harmon General Hospital, Longview, Tex. The author

has also drawn upon a number of publications in the medical literature and,

of necessity, from his personal experience with the disease. A convenient

baseline against which wartime clinical experiences with malaria may be

compared is a series of papers entitled "The Infection in the Intermediate

479
480 INFECTIOUS DISEASES

Host," which appeared in "A Symposium on Human Malaria" published by

the American Association for the Advancement of Science in 1941.

PREDISPOSING FACTORS

There appeared to be two factors in determining whether a clinical attack of malaria, either initial attack or relapse, would be precipitated. One

was the intrinsic or host factor; after the earlier phases of the war, this

boiled down simply to the question whether the soldier was receiving optimum suppressive doses of Atabrine (quinacrine hydrochloride). In the absence of adequate prophylaxis, a number of extrinsic factors, such as injuries,

acute illnesses, and surgical operations, appeared to be capable of upsetting

the delicate physiological balance between the micro-organism and the host.

It was common to find malaria developing on surgical, orthopedic, or general

medical wards. In the Mediterranean theater, Lt. Col. (later Col.) James B.

McLester, MC, noted, during a period when malaria transmission probably

did not occur, that malaria made its appearance in about 5 percent of patients

with atypical pneumonia, in a similar percentage of patients with infectious

hepatitis, and in about 1 percent of those with trenchfoot. 1 Other factors

that were thought to be important in activating the disease were fatigue or

exhaustion, hemorrhage, alcoholic bouts, the use of anesthetics, or exposure

to extreme or sudden changes in temperature. There seemed little doubt

that once the stage was set, any one or more of these factors could trigger a

clinical attack. Contrariwise, it must be stated that in numerous trials it

was demonstrated conclusively that even excessive physical activity was not

a cause of breakdown of Atabrine suppression ("breakthrough").

In addition to these intrinsic (host) and extrinsic (environmental) factors in the precipitation of a malarial paroxysm, there was the parasite factor. It is well known that there are certain attributes resident in the individual Plasmodium itself that must not only determine whether a paroxysm

will be inducted but what sort of clinical picture it will present. In short,

although the malarial fevers possess certain common characteristics, they are

actually a group of several distinct entities each with its peculiar attributes

and individual potentialities.2 Most descriptions of the disease available to

the writer, however, failed to distinguish between the various plasmodial

species responsible for the attack. In the text that follows, a description

referring to a definite species can be assumed by the reader to be an exception to this generalization either stated in the quoted document or personally known to the author.

1 McLester, J. B.: Relapsing Malaria. M. Bull. Mediterranean Theat. Op. 3: 111-113, April

1945.

2 Kitchen, S. F.: Symptomatology: General Considerations. In Malarlology, A Comprehensive

Survey of All Aspects of This Group of Diseases from a Global Standpoint. Philadelphia: W. B.

Saunders Co., 1949, pp. 966-994.
CLINIICAL ASPECTS OiF MALARIA 481

PRODROMAL SYMPTOMS

Especially in cases that began insidiously, it. was very difficult to draw a

dividing line between prodronial symptoms and the actual onset of aii attack

of malaria. Patients with a brisk onset. often stated that they had felt perfectly well on the preceding day. When prodronmata were described, they

lasted 2 or 3 days and were generally the usual symptoms of the frank attack

presenting in lesser intensity. The most frequent complaints were headache,

backache, weakness. and generalized aches. In a study at tlarnion General

Hospital of 435 soldiers with malaria due to P. r;ra, who were permitted

to relapse. three-fourths had prodromial symptoms.3 Most of these patients

could reliably predict the inmminence of an attack.

CLINICAL SYMPTOMS OF THE ACUTE ATTACK

Headache.-Headache, generally severe, of a pounding character, and

frontal or bitemporal in distribution, occurred in almost all cases. In some.

it was described as having a retrobulbar component. In general. this symptom outlasted the fever and other symptoms by several days. In Pl,.rimodhum

falidparun& cases, it was occasionally the harbinger of an impending cerebral

syndrome.4 In some cases there was an associated meningismus.

ChilL.-In 80 percent of the attacks observed in the study at Harmon

General Hospital, there was an acute rigor or chill; in another 8 percent,

there was at least a sensation of chilliness.

Fever.-The oreat majority of patients showed fever peaks ranging from

102' to 105' F. by mouth. Since the response to treatment was generally

prompt and convincing, the. fever was generally interrupted after one or two

peaks so that the remainder of the spontaneous febrile pattern of the attack

was not observed. In the study made by Gordon and his coworkers, well over

80 percent of patients had thus attained a normal temperature after 3 days

of treatment, and over 90 percent by 5 days after the beginning of treatment.

Although the war experience afforded some opportunity to study the detailed

morphology of the fever course in the various forms of malaria, a careful

documentation of intermittency, remittency, periodicity, regimentation, anticipation, postponement of fever peaks, continued fever, or of the fever

spikes characterized as being broad based or narrow based, could not be

found. Nor is it clear that this would have served a useful purpose.5 In

the Southwest Pacific Area, remittent quotidian fever was seen more often

3 Gordon. H. H.. Lippincott. S. W.. Marble. A.. Ball. A. L., Ellerbrook. L. D., and Glass. W. W.,

Jr.: Clinical Features of Relapsing Piasmodlum Vivax Malaria in Soldiers Evacuated from the

South Pacific Area. Arch. Int. Med. 75: 159-167. March 1945.

4 All material on malaria in the Mediterranean (formerly North African) Theater of Operations, U.S. Army. except when otherwise noted, is taken from GoIs. Harold H.: Human Malaria

in the North African and Mediterranean Theaters of Operations. U.S. Army. [Official record.]

5 Kitchen. S. F. : Falciparum Malaria. In Malariology. A Comprehensive Survey of All Aspects

of This Group of Diseases Fron, a Global Standpoint. Philadelphia: W. B. Saunders Co., 1949,

pp. 995-1016.

639243--63- 34
482 INFECTIOUS I)iEASlS

than anticipated and this apparently without regard to species ideniitication.

Ini general. initial attacks were much more likely to be characterized by continned fever and relapses by ai hectic fever.

Sweats.- Pro fuse lperspirat ion Was ,inhanicterist ic of I le overt paroxysmi.

A few observers felt that it sweat out of lproportion to the fever in the absence of tn antecedent chill was actually a helpful aid in the diagnosis of

malaria.

Splenomegaly.-At a Marine installation in ()regon,6 spleliniegaly was

noted in less than 5 percent of cases acquired in the Soiithwest Pacific Area,

even aifter 20) to 30 rl'lrudlescences. fransient sjplenonieiigaly. generally of

only mild degree, was detected in only about 3 percent immediately after acute.

attacks of iwilaria caused by P. v'uyux. Such experiences are in conformiity

with lprevioilis observations regarding splelioniiegaily in nialarii. Increase in

tile size of tie spleenll apparently depends upon the lpossession of somle degree

of immunity. It is also well known that the enlargement raipidlv diihinishes

oni cessaition of the paroxysm, particularly if interrupted by treantiment. In it

tabiulatio'l of tlie s vin llloliiS of inillaria as oblserved in the Medilu rranean

theater. based upon ta quest•olnniaire ,ent to medical officers, splenomllegaly was

reported in i ranige of front 27 to 85 percent. This wide divergence wisi attribulted to differeiices in tile thoroughness with which the exaniination was

conducted. A low incidence was, however, reported from all other theaters

and is probably reail. What enlargement took place was not striking and was

generally transient. This low percentage of palpablle spleens standls in nmarked

contrast to tile aiccelpted high incidence of this finding in seasoned ilnnmune

natives exposed presumably to the same mnalarial parasites its were these uinseasoned, noniniunine tr(xol)s.

American niedical officers who had the opportunity of working with

Australian niedical officers learned one technique of palpating spleens whiich

is worthy of repetition. "o far as this authior knows, the mnethod is virtually unknown in tlhe U nited States. It consists in having the lpatient sit ulp

in bed drooped forward over his knees. A remnarkable degree of relaxation

of the alldomiinal muscles is often thus attained. With tile examiner at. the

patient's back, tile fingers- of both of the examiner's hands are curled around

tile left lower flank of thel patient wllile the patient. takes deepl breaths.

Frequently, the palpating tingers can extend well ill) under tile rib margin.

In it nuimber of cases, the spleen can be felt. by this method and by none

other. The technique is perhaps best adapted to yoting individuals of military age.

Hepatomegaly.-In a considerable percentage of cases. the liver was palpable one or two fingerbreadtis below the right costal margin, firm, sharp,

and slightly tender. Kern and Norris found such involvement in 60 percent

6 Coggeshall, L. T. : Malaria and Fliarliasia in the Retirnling Servieenlan. Ninth Charles Franklin Craig Lecture. Am. J. Trop. Med. 25: 177-184, May 1945.
CLINICAL ASPECTS OF MALARIA 483

of 1,153 cases of malaria seen on a hospital ship.7 In the North AfricanMediterranean theater this was noted in from 5 to 20 percent of cases. In

the Southwest Pacific Area, this finding actually approached or exceeded the

frequency of splenomegaly. This may be due to the fact that slight degrees

of hepatomegaly are more readily detected than the slight degrees of splenomegaly that occur in noninmune, promptly treated soldiers. It is conceivable, although less likely, that this discrepancy is related to a predilection of the Southwest. Pacific malarial strains to liver involvement. This

observation appears to have been anticipated by the peacetime findings of

Gunther," who noted the frequent finding of tenderness in the right hypochondrium in New Guinea malaria. He designated this as gallbladder tenderness.

Lymphadenopathy.-It was the observation of the author that the most

common cause of slight to moderate degrees of generalized glandular enlargement in the Southwest Pacific Area was malaria. The pronounced grade

of enlargement characteristic, for example, of scrub typhus was never observed in malaria.

Abdominal symptoms.-IHalf of the patients complained of abdominal

pain. This was more frequent on the left than on the right side and occasionally radiated to the left lower chest. When bilateral it was generally

sharper on the left. Although this was attributed to splenomegaly, the

spleen was felt. in only a minority of these patients. In a quarter of the

patients the left side of the abdomen was tender; in some there was tenderness on the right side as well, generally in the right upper quadrant. Nausea

occurred in 59 percent, and vomiting in 36 percent of attacks, but troublesome vomiting was very infrequent. The relative role of treatment with

quinine or Atabrine on the one hand, and of the disease itself, on the other,

in the development of these symptoms was uncertain, since treatment was

started promptly in the great majority of cases. Diarrhea was not uncommon as the presenting complaint in uncomplicated malaria, regardless of type,

in tropical areas where it occurred in mild form in about 10 percent of cases.

This symptom was no more common in 1. falciparum cases but when present was more severe and at times dysenteric and associated with bloody

stools.9

Upper respiratory symptoms.-These were quite common and anmost certainly a part of the disease itself. The most common symptom was a dry,

painless cough. This was generally associated with musical rales, squeaks,

and groans throughout the lung fields, signs quite characteristic of bronchial

asthma but disappearing promptly on therapy. Coryza and bronchitis were

less frequent manifestations. Malaria was frequently associated with bronchitis, and roentgenographic examination frequently showed infiltrations inter7 Kern, R. A., and Norris, R. F.: Liver Involvement in Malaria. U.S. Nay. `M. Bull. 43: 847-

858. November 1944.

8 Gunther, C. E. M. : Practical Malaria Control. Sydney: Consolidated Press, Ltd., 1943, p. 47.

9 Hughes, S. B., and Bomford. R. R. : Clinical Features and Treatment of Malaria in British

Troops in West Africa. Brit. M.J. 1 : 69-73, 15 Jan. 1944.
484 INFECTIOUS DISEASES

preted as the result of complicating viral or bacterial lueuniioia. It would

be difficult to determine to what extent these were actually part and parc-l

of the malarial infection.

Miscellaneous symptoms.-Ilerpes labialis was seen ill a rather high percentage of cases in the Mediterranean theater. Ltivaria, generally transitory, was occasiontally seen, particularly in the earlier phases of the war

when quinile was used more frequently. Tinnitus was noted in almut a

quarter of the cases. lin most patients with this complnlaint. it was difficult

to determine the relative role of the disease or the treatmeent in its development. Cerebral synmptomns such as drowsiness, faint ing, disorientation, change

in disposition, or mneningismus were coonplaints ill a few cases of malaria due

to P. fah'kI/truni.10 The promIpt subsidence ,)f these symptoms ini malaria

caused by P. ru'tar led to the impression that they were tile result of the

associated fever per se and not of cerebral nmalaria. In the alleged irstances

of cerebral malaria due to P. vih'ar infection,1 the possibility of an undetected mixed infection including ".. flcitarum cannot be excluded.

In one exceptional experience, a number of patients with malaria preseted symptoms suggesting hyperthyroidisn1.12 These individuals showed

promninent eyes, loss of weight, sudoresis, wet palms, tachycardia, and fine

tremor of hand-s and tongue. Tile basal metabolic rate was normal in these

cases.

COMPLICATIONS OF MALARIA

In the past, involvement of every organ or organ system has been described as complicating malarial fever, particularly when caused by P. falTparum. "he have generally been ascribed to capillary infarction resulting from agglutination of tile parasites along the capillary endothelium.

Experience in Worlh War II emphasized the extreme infrequency of such

complications in adequately treated malaria and recalled the admonition of

Stratman-Thomas that "the innumerable clinical manifestations, symptoms

and sequelae which have been ascribed to malaria are unflattering demonstrations of the imagination and credulity of the human mind." '3 The following manifestations appear, however, to be fairly well documented.

1. Cerebral 'molria.-Almost without exception, malaria deaths were due

to cerebral involvement."' A clear-cut picture of just what constitutes cerebral malaria was often difficult to draW. 1 5 Empirically, the term may be

10 Talbot, D. R. : New Aspects of Malaria. J.A.M.A. 123: 192-194, 25 Sept. 1943.

11 MeGinn. S., and Carmody. J. T. B.: Cerebral Symptoms in Malaria. U.S. Nav. M. Bull. 43:

1157-1162. Iecember 1944.

12 Weeks. 1). A. : Observations on Malaria. U.S. Nay. M. Bull. 43: 1171-1177. December 1944.

13 Stratman-Thomas. Warren K. : The Infection in the Intermediate Host: Symptomatology,

Vivax Malaria. In A Symposium on Human Malaria. Washington: American Association for the

Advancement of Science, 1941, pp. 183-189.

14 (1) Russell. Paul F., West, Luther S.. and Manwell, Reginald D. : Practical Malartology.

Philadelphia: W. B. Saunders Co., 1946, p. 293. (2) Medical Department, United States Army.

Preventive Medicine in World War II. Volume VI. Communicable Diseases: Malaria. [In preparation.]

13 See footnote 11. above.
CLINICAL ASPECTS OF MALARIA 485

applied to any case exhibiting any one or more of the following findings:

Meningisnmus. convulsions, persistent delirium, or well-defined neurological

signs. Aln index of the prevalence of cerebral malaria in World War I1 may

be taken from the records of one U.S. Army general hospital in India where

in 6 months of 1943 there were 40 cerebral cases among 1,764 U.S. soldiers

and 100 cases among 4,295 Allied personnel."6 In the Mediterranean theater, when the bulk of our troops were in Italy, medical officers of approximately 25 evacuation, station, and general hospitals reported 163 cases of

cerebral malaria. Of these, 144 were recognized as caused by P. faleiparum,

and 19 were ascribed to P. vivax. There were 11 deaths due to P. falciparum

infections, and of these 8 were cases of cerebral malaria. Preliminary tabulations of individual medical records indicate that there were 57 deaths due

to malaria, all forms, originating in the Mediterranean theater during the

years 1942-45. Of these, 27 were due to P. fakiparum infections. Usually,

the symptoms made their appearance a week or so after the onset of the clinical attack of malaria, following a day or two of precoma with persistent

vomiting, increasing restlessness, mental confusion, and severe headache, but

sometimes cerebral malaria developed abruptly without warning even after

1 or 2 days of treatment. Blurring of vision or diplopia were not uncommon.

Acutely developing psychotic or psychoneurotic states were particularly

alarming.

After the onset of the syndrome, the patient might show a profound

stupor deepening into a coma; he might develop convulsive seizures 17 or

exhibit nuchal rigidity, maniacal states, or various reflex disturbances. The

temperature would rise progressively or abruptly to extremely high levels

before death. In many respects, the illness resembled meningitis, encephalitis, or severe typhus fever. The spinal fluid was generally under increased

pressure. Half of the spinal fluids examined showed an increased globulin

content and many showed cell counts ranging between 20,000 and 30,000. The

blood smear often failed to reveal malarial parasites until after repeated examination. When recovery occurred, it was generally completed, although

a few patients showed residual cranial nerve palsies, hemiplegia, paresis, or

psychosis.

2. Other involvement of the nervous 8ystem..-In the Mediterranean theater, patients were seen with peripheral neuritis involving the lower extremities. Three patients exhibited transient blanching of the optic nerve, one

facial neuritis and homolateral brachial neuritis. In one hospital in the

Southwest Pacific,18 16 patients were seen with a severe irritative neuritis

with hyperalgesia, hyperhidrosis, and increase in muscle tone with actual con16 Fitz-Hugh, T., Jr., Pepper, D. S., and Hopkins, H. U. : The Cerebral Form of Malaria. Bull.

U.S. Army M. Dept. No. 83, pp. 39-48, December 1944.

17 Simpson, W. M.. and Sageblel, J. L.: Symposium on First Year of Activities at U.S. Naval

Base Hospital- ; Cerebral Malaria. A Report of 12 Cases Encountered at U.S. Naval Base Hospital-. U.S. Nay. M. Bull. 41: 1596-1602, November 1943.

18 Harvey. A. M.: A Type of Neuritis Associated With Malarial Fever. Bull. Johns Hopkins

Hosp. 75: 225-231. October 1944.
486 INFECTIOUS DISEASES

traction occurring in bilaterally symmetrical areas, usually the forearm and

hand. Milder forms of neuritis, occurring ill 18 of 100 consecutive cases of

nmalarial fever, pelsented only subjective manifestations with transient attacks of numbness and tingling. With recurrent attacks of malarial fever,

the nervous symptoms increased. The majority of these cases were due to a

mixed infection. Distinction had to be drawn between these neuritides and

those following that almost ubiquitous tropical disease. cutaneous diphtheria.

3. Iiae'wkater fever.-This was rare. Twenty-five cases of acute hemolvtic anemia and hemoglobinuria were reported as blackwater fever from the

South Pacific Area. There were three deaths in this group, a much lower

mortality than is usual for blackwater fever. Fifteen of the twenty-five cases

occurred in Negro troops stationed on one island.19

4. Cardkar nilaria.-Functional cardiac disorders, such as irritable heart

with tachycardia, premnature beats, and systolic murmurs, were, of course, not

extremely rare in patients during malarial attacks or between relapses. But

true organic cardiac changes, such as cause death from myocardial inflammnation or capillary infarction, were extremely rare.' These generally occurred in individuals with malaria due to P. fahlpar•i•m. The author saw

two such patients who developed severe cerebral malaria in the combat area,

both cases caused by P. falcipairutm. One had auriculoventricular and intraventricular block and the other a moderately enlarged, possibly dilated heart.

The subsequent fate of these soldiers could not, be followed. Two other patients with P. fadeiparuin infection died at a nearby hospital. Both showed

agglutination of the parasites along the capillary endothelium in the myocardium.2 1 This experience led to the suspicion that microscopic coronary

occlusions might be as important a factor in fatal P. falciparium cases as

occlusion of cerebral vessels.

5. Rupture of the spleen..-This was a rare complication corresponding

with the low incidence of splenomegaly.

6. Ocular conuplicatolns.-A few cases of iridocyclitis coincided with attacks of malaria. In one patient, transient edema of the cornea occurred in

each of two attacks of malaria due to P. vh,ax in the Mediterranean theater.

7. Mledical shock.-If nothing else was done about the ancient terminology of clinical malaria, the record was set straight regarding the obsolete

designation algid malaria. The fact that this is nothing more nor less than

medical shock complicating malaria 22 should have been acknowledged long

before World War II. This reorientation is of more than academic importance for it provides the clinician with a whole group of well-recognized

19 Harper, Paul A., Butler, Fred A., Lisansky, Ephraim T., and Speck. Carlos D. : Malaria and

Epidemic Control in the South Pacific Area, 1942-44, pp. 195-207. [Official record.]

20 Sprague, H. B. : The Effects of Malaria on the Heart. Am. Heart J. 31 : 426-430, April 1946.

21 Merkel, W. C. : Plasmodium Falciparum Malaria; The Coronary and Myocardial Lesions Observed at Autopsy in Two Cases of Acute Fulminating P. Falciparum Infection. Arch. Path. 41:

290-298, March 1946.

22 Kean, B. H., and Taylor, C. E. : Medical Shock in the Pathogenesis of Algid Malaria. Am.

J. Trop. Med. 26: 209-219, March 1946.
CLINICAL ASPECTS OF MALARIA 48T

therapeutic aids for the treatment of this serious complication. The discovery of adrenal hemorrhages in Filipinos who died with this syndrome23

suggests the feasibility of steroid replarenient therapy, but whether this

would be a universal finding is not known.

CHRONIC MALARIA

All observers agreed that in the absence of other factors, such as concomitant infection or malnutrition, the classical textbook picture of chronic

nmalaria was wasting, anemia, and splenic enlargement. It was not observed

in the U.S. Army, where troops were well fed and given adequate suppressive therapy. The extraordinarily low incidence of splenomnegaly and anemia

has already been discussed. Due significance must be accorded the role of

hydration and of slight loss of weight as early adaptive processes attending

acclimatization to the Tropics-the former might suggest anemia; the latter,

wasting.24 In contrast to the native with chronic malaria, exhibiting the

characteristic triad of intermittent fever, anemia, and splenic enlargement,

the U.S. Army patients who were incapacitated between relapses presented

complaints generally falling into four categories: (1) Neurocirculatory asthenia, (2) symptoms referable to the musculoskeletal system, (3) vague

symptoms referable to the central or autonomic divisions of the nervous system, and (4) combinations of two or more of these three groups. 25

A careful study was made of a very large number of soldiers suffering

from repeated P. vivax relapses and who complained of not feeling up to

their usual health between attacks.2 6 These men described the following

symptoms: Weakness, fatigability, tension, excessive sweating, headaches,

exertional dyspnea, anorexia, palpitation, blackouts, insomnia, nervousness,

splenic pain, muscle pain, indigestion, and urinary frequency. These symptoms were always extremely difficult to evaluate. Although another group of

observers who thoroughly studied this symptom complex in 50 servicemen

conceded that malaria itself might be of prime importance in its production,27

it was their further conviction, strongly concurred in by others, that the way

in which the individual adjusted himself to his malaria and to concurrent

situational factors was more significant in the development of symptoms, in

their perpetuation, and intensification. It was the impression of most medical

office rs that these were exaggerated symptoms in men who were actually more

interested in returning to their homeland than in rehabilitation for active

23 Garcia, Euseblo Y.: Malaria in War and Peace. Manila: Grace Trading Co.. 1945, p. 49.

24 Lee. D. H. K.: The Human Body and Hot Environments; Factors Influencing Man's Reactions to Heat Stress. [Unpublished manuscript.]

25 Levine, H. D.: Medical Experiences With American Troops in the Pacific, With Remarks on

the Diagnostic Value of Sternal Puncture in Malaria and on the Innocuousness of Hookworm Infection. New England J. Med. 235: 933-938, 26 Dec. 1946.

26 See footnote 3, p. 481.

2; Tumulty, P. A., Nichols, E., Singewaid, M. L., and Lidz, T. : An Investigation of the Effects

of Recurrent Malaria; An Organic and Psychological Analysis of 50 Soldiers. Medicine 25: 17-75,

February 1946.
488 INFECTIOUS DISEASES

duty. In the majority of cases, the sym)toms obviously were strongly conditioned by such factors as exposure to combat and adv.-rse living conditions

or previous personality l)roblems. None of the patients complaining of

dyspnea on exertion presented evidence of heart disease as judged by physical

exa ninat ion. exercise tolerance tests, roentgenograp)hic examinations or electrocardiograms. A red blood cell count below 4 million was extremely rare.

Half of them had weight losses of fromn 10 to 3o pounds. But no measurable

damage or dysfunction of the organ systems could be found. These observers

condemned the practice of repeated or prolonged hospitalization for these individuals, contact with neuropsychiatric patients, or with patients about to be

returned to the United States.

RELAPSES IN MALARIA

The tendency of malaria due to P). ri'ax to recrudescence was well documented before Worl( War I1, and subspecies variability in this respect has

been recognize(d.28 Relapsing malaria caused by P. vda.r in World War II

should not, therefore have been a surprise,29 nor should tile particular character of one P. vh'ax strain as contrasted with another.30

Accurate statistics are not. available, but there can be little doubt as to

the remarkable relapsing tendencies of the P. veiaxr strains in the South and

Southwest Pacific Areas. The author first became aware of the magnitude of

this problem while on detached service with all Australian hospital. The medical officers there, only recently returned from service in the Mediterranean,

were appalled by the stubborn relapsing tendency of the New Guinea strains

of P. vhax, contrasting with the relative infrequency of relapse in the strains

to which they had become accustomed in the Middle East. That this was the

result of species specificity was subsequently confirmed in reports from Europe and the Mediterranean and in experience at Harmon General Hospital

with malaria inocula of Pacific and Mediterranean origin. With the Pacific

strains, relapses occurred in 70 percent of cases, and 75 percent of the relapses

developed within 60 (lays of completion of Atabrine therapy. In the Mediterranean strains, there was a much lower incidence of relapses (30.6 percent)

and a much longer delay (150 to 200 days) before relapse. There was other

inferential evidence that malaria caused by P. ,iva., in tile South Pacific Area

differed from the same type of malaria seen elsewhere. Of the men in that

area, 57 percent had in excess of 14 acute attacks, some as many as 40. The

relapses appeared moreover to have a greater rhythmicity and regularity

than those caused by other strains.3 ' It should be borne in mind that all the

2s Hackett, L. W. : Malaria in Europe, An Ecological Study. London: Oxford University Press,

1937.

29 Russell. P. F. : Lessons in Malariology From World War Ii. Charles Franklin Craig Lecture,

1945. Am. J. Trop. Med. 26: 5-13. January 1946.

30 Essential Technical Medical Data, European Theater of Operations, U.S. Army, for May 1944,

inclosure 17 thereto.

31 See footnote 6. p. 482.
CLINICAL ASPEC'TS 01 MALARIA 489

experience here described was derived chiefly from P. cv;,ax infections contracted by persons who had no immunity whatever to malaria .

3 2

Malaria caused by P. .fc;patiim exhibited relatively little tendency to

relapse in the Mediterranean and Southwest Pacific, and when relapse, subsequently occurred in these cases, it was only occasionally due to this same

micro-organiisin. It appears more than likely that their original infection was

actually a mixed one, 1P. f/,tdhjrtim. being the dominant organism in the first

attack, the subsequent relapses resulting from the emergence of the originally

recessive f). riax strain.3 Thus, in advance areas in the Southwest Pacific,

P. fdchptilm infections accounted for about 40 l)ercent of all attacks,3 4 while

in the rear nonnalarious areas P. fa/cipatzrm. was found in only 8 p)ercent of

cases, I1. vi',i'a, in 68 percent. Such usurpation of the dominant role in the

relapse by P. 'i•ax was well known long before the war.3 5 Quartan malaria

has long been regarded as relapsing malaria par excellence, but experience

with quartan malaria in World War I was too limited to justify more than

passing mention.

SUPPORTING EVIDENCE FROM THE LABORATORY

Parasite identification.-Most of the time during the war, the diagnosis

of malaria was made with positive support from the laboratory. The techniques principally used have been discussed elsewhere. Variable success was

reported in experiences with sternal puncture. In a number of studies.36 occasional marrow smnears were reported positive when the thick and thin blood

smears were negative. Subsequent improvement in the accuracy of routine

blood examinations for malarial plasmodia, however, dampened interest in

sternal puncture.

Blood studies.-The white bloore cell count was generally below normal,

usually in the range between 4,000 and 6,000 in the Mediterranean theater

study. This fact was frequently of diagnostic significance. In a small percentage of cases, a more marked leukopenia (less than 3,000) was recorded.

Leukocytosis was seen under three conditions; namely, in the presence of a

concomitant. or complicating bacterial infection, in some severe uncomplicated

cases, and in cerebral malaria. In the latter groups, it was apparently related

to necrosis of tissnes. Mild lymphocytosis was the rule. In a series reported

from the Mediterranean theater, 45 to 65 percent of the lymphocytes resembled

tbose observed in infectious mononucleosis.

32 lDleuaide, F. R. : Chronic Relapsing Vivax Malaria in the Army. 1942-44. [Official record.]

33 (1) Malaria in the First Marine Division While Staged in Base Section No. 4, 1943. [Official

record.] (2) Metcalf, R. J., and Ungar, J., Jr.,: Relapsing Malaria: Analysis of Cases from the

Solomons. U.S. Nay. M. Bull. 43: 859-870, November 1944.

34 Baker. M. P., Lyman, J. R., and Coons. A. H.: A Summary of Three Months' Experience

With Malaria at the 105th General Hospital, U.S. Army, Southwest Pacific Area, December 1942-

February 1943. [Official record.]

35 See footnote 28, p. 488.

36 (1) See footnote 25, p. 487. (2) Jacobson, B. M., and Russell, II. K. : Sternal Puncture in

Diagnosis of Malaria. U.S. Nay. M. Bull. 45: 429-432, September 1945.

639243--63----35
490 INFECTIOUS I)ISEASES

The reported incidence of anelnia was variable. Only one instance of

mild normocytic, normochromic anemia was found in a group of 50 wellstudied patients with malaria due to P. vhax at the 118th General Hospital

in the South Pacific. 37 This was the general experience. In the Mlediterranean theater, however, 29.5 percent of patients with malaria caused by

P. vivax had red cell counts of 4 million or less. Anemia was somewhat. more

common in malaria due to P. falc/parum., particularly during or shortly after

the paroxysm. Counts of less than 31⁄2,, million were stated to have been common in P. falciparum infections.

In a small p)ercentage of cases, the sedimentation rate was increased. In

about half of these, this finding was accounted for by some complicating infection: in the remnammider, 4t was unexplained and presumably related to the

malaria per se. Erythrocyte fragility was probably normal.

Serological tests.-The serological tests for syphilis were frequently positive for longer or shorter periods after the acute paroxysmls. The exact incidence of this finding cannot. be stated. Dawber :3 found false-positive tests iln

12.5 percent of 64 cases of malaria, generally becoming seronegative in 10

days after the last. chill. One case remained positive for 18 days. At the

1 1Sth General Hospital, 15.6 percent of 900 cases of malaria ascribed to

P. vivax were positive to Kahn tests. In the South Pacific Area, f,!-v i,,,sitive reactions were found in 51 percent by the Mazzini test, 47.5 percent by

Kahn, 33.6 percent by Kline, 20.4 percent by Kolmer. 10.A percent by Eagle,

and 5.8 percent. by the Hinton technique.39 Rosenberg 40 likewise found that

the Hinton test yielded the smallest proportion of falsely positive reactions.

He found that the strongest false reactions were obtained between 7 and 10

days after the chill and persisted for 4 to 6 weeks. He felt that persistence

of positive serology by any test beyond 6 weeks, in the absence of continued

evidence of malarial infection, should arouse the suspicion of syphilis.

The complement fixation test, for malaria in general gave unsatisfactory

results. In the Mediterranean theater, this was attributed to a faulty antigen.

The consensus furthermore was that the adrenalin provocation test (Ascoli)

was not, helpful in diagnosis.

A number of studies were made of liver function in malaria patients. A

study of 317 patients with chronic relapsing malaria, due to P. vivax at Harmon General Hospital disclosed transient disturbances of function but gave

37 See footnote 27, p. 487.

38 Dawber. T. R. : On the Importance of Malaria as a Cause of False Positive Serologic Reactions. Ann. rnt. Med. 19: 651-655, October 1943.

39 Simpson, W. M., Leake. W. H., McMahon. A., Gudex, T. V., and Rupckert, R. R.: Symposium

on First Year of Activities at U.S. Naval Base Hospital-; Experiences With Malaria at an

Advance Base in the South Pacific. Report of 4,647 Admissions at --. U.S. Nav. M. Bull. 41:

1588-1595. November 1943.

40 Rosenberg, A. A.: Effect of Malaria on Serologic Tests for Syphilis. Bull. U.S. Army M.

Dept. No. 84, pp. 74-80, January 1945.
CLINICAL ASPECTS 0O' MALARIA 491

little or no indicattion of permanent. hepatic dysfunction. 41 The. percentage

of abnormal response to tests was somewhat higher in a study conducted in

North Africa, but, this was not, limited to 1'. v;va.,e cases. In this latter group,

the liver was enlarged in 20 percent of cases.

DIFFERENTIAL DIAGNOSIS

The morbid conditions that had to be differentiated from malarial fever

were legion. They varied, of course, w hi geograpllic location. Thus. sandfly

fever (in the Mediterranean). dengue ci" scrub typhus fever (in the Pacific),

and pneumonia (in Panama )42 had to be given important consideration. The

medical school teaclhing that it is wisest in a given case to explain a symptom

complex on the basis of a single diagnosis rather tlian iimultiple diagonoses

was not justifiable in malarious areas. Malaria being almost ubiquitous, the

medical officer had to be prepared to find it as a complicated or a complicatinig disease. When the smear was positive, the decision had to be made

whether the Plasnwdium. was there as an active hidden partner or whether

this finding represented a mere parasitic relapse of little or no clinical importance. Almost. all of the patients with salmonellal infection described by

Baker and Bragdon, 43 for example, showed smears positive for malaria. A

large majority of the patients with scrub typhus fever who came to the 105th

General Hospital in the Southwest Pacific had positive smears.

A complete elaboration of the different conditions that would have to be

considered in the (lifferential diagnosis would be too formidable a. task to be

undertaken here. Such a list would certainly have to include tuberculosis,

typhoid fever, amebic and bacillary dysentery. amebic hepatitis, preicteric

infectious hepatitis, meningitis, Hodgkin's disease, subacute bacterial endocarditis, leishmaniasis, and schistosomiasis as well as the conditions that. have

just been enumerated; namely, dengue fever, sandfly fever, salmonellal infection, and scrub typhus. At times, the symptoms of a paroxysm would

simulate an acute surgical emergency, such as biliary colic, ruptured peptic

ulcer, ruptured spleen, or acute appendicitis. And here again, with an established surgical condition, a complicating malarial infection was not uncommon. At the 105th General Hospital, for example, about a fifth of the patients with malaria were battle casualties on the surgical service. Hyman

analyzed the records of 100 patients admitted to a naval base hospital in the

Pacific with a diagnosis that was subsequently clanged to malaria.44 These

41 Lippincott, S. W., Ellerbrook, L. D., Hesseibrock, W. B.. Gordon, H. H., Gottlieb, L., and

Marble, A.: Liver Function Tests In Chronic Relapsing Vivax Malaria. J. Clin. Investigation 24:

616-622, September 1945.

42 Applebaum, I. L., n nd Shrager. J.: Pneumonltis Associated With Malaria. Arch. Int. Med.

74: 155-162. September 1944.

4.1 Baker, M. P.. and Bragdon. J. H.: Septicemia Due to Salmonella Enteritidis. New England

J. Med. 237: 175-179, 7 Aug. 1947.

44 Hyman. A. S. : Clinical Masquer' 'es of Malaria; Observations in South Pacific Combat Areas.

U.S. Nay. M. Bull. 45: 287-303, August 1945.
492 INFECTIOUS DISEASES

cases fell into groups classified according to the major predominating symptom that led to the erroneous diagnoses, as follows:

Diagnoses Number

Simulated diseases of the chest ------------------------------------------ 34

With cardiac symptoms ----------------------------------------- 21

With pulmonary symptoms --------------------------------------------- 13

Diseases of the abdomen ------------------------------------------------ 26

Stomach ------------------------------------------------------- 9

Liver and gallbladder ------------------------------------------- 8

Spleen --------------------------------------------------------- 6

Appendix ------------------------------------------------------ 3

Diseases of the bones and joints .. .. .. . . ... . 21

Diseases of the head---------------- ........... .. . 12

Brain -------------------------------------------------------

Eyes .. 3------------------------------

Other--------------------------------........................ 2

Miscellaneous -------------------------- ---------------------.--------------- 7

Kidney ---.-------------------------------------------------------- 4

O t h e r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

T o ta l . . . . . . . . . . . . . . . . . . . . . . . .100

These diagnoses were made during the early days of the Solomon Islands

campaign before most of the medical officers had become familiar with the

bizarre manifestations of malaria and before an adequate schedule of Atabrine suppression had been worked out.

SUMMARY

When malaria was promptly recognized and effectively treated in the

nonimmune American soldier it was generally a brief, grippelike illness with

headache, backache, pain in the abdomen, chills or chilliness, nondescript

fever, and sweating. These patients showed very little splenomegaly, more

impressive hepatomegaly. Diarrhea and wheezing occurred in many of the

acute cases. There was very little, if any, tendency to complication. Anemia

was not a problem in P. vivax infection; in some P. falciparum cases it was

a moderate and transient phenomenon. The Pacific strains of P. vi'vax

showed an extraordinarily stubborn tendency to relapse. Disability between

relapses was largely related to prolonged tropical or combat service, to ennui

or nostalgia, or to the soldier's reaction to his illness. The mortality rate

was phenomenally low. (See p. 460.) Death was generally the result of

cerebral malaria due in most, if not all, cases to P. falciparum.
CHAPTER XVII

Treatment of Malaria

Perrin H. Long, M.D.

INTRODUCTION

An interesting commentary on the state of health of the people of the

United States at the beginning of World War II was that the majority of

physicians entering the Armed Forces had had practically no experience in

the diagnosis or treatment of malaria. To be sure, in the medical school

courses of clinical microscopy, each had studied stained slides showing malarihd parasites, or if there happened to be a patient in the ward who had

malaria inoculata, thick fresh films of blood might have been examined. Occasionally in seaports, sailors suffering from malaria were seen on the medical services, treated with quinine, and then discharged shortly after their

fever had subsided. As far as malaria inoculata was concerned, the problem

was often to keep the infection from dying out rather than to arrest it by

treatment. The average younger American physician, except in certain rural

areas in the Southern United States, hardly gave a thought to malaria and

was unconcerned about his lack of knowledge of this disease.

When it became evident in May 1940 that the Armed Forces of the

United States were going to be sharply augmented, the Surgeons General

of the Army and the Navy requested Dr. Lewis H. Weed, then Chairman of

the Division of Medical Sciences of the National Research Council, to set up

certain consultative and advisory committees. One of the earliest of the

groups formed by Dr. Weed was that which, under the chairmanship of Dr.

Henry E. Meleney, devoted itself to problems of tropical diseases. Of course,

malaria immediately became a prime subject for discussion by this group.

Out of the work of this subcommittee came the initial recommendation for

the suppression and treatment of malaria with quinine. Obviously in 1940

and during the first half of 1941, there was no positive indication that the

Axis Powers would seize Indonesia, the main source of the world's supply

of quinine. Although Atabrine (quinacrine hydrochloride) and certain other

suppressive and therapeutic agents were carefully considered, their use for

suppressive or therapeutic purposes at that time was always thought of as

secondary to the use of quinine.

The military events that occurred late in 1941 and early in 1942 brought

a rude awakening to all concerned with malaria in this country. With relatively small supplies of quinine on hand, the Japanese move into Indonesia

and Malaya, which cut off the major source of quinine, brought the Subcommittee on Tropical Diseases, National Research Council, to the recom493
494 INFicrTIoUs DISEASES

liendation tihat. tile inilitaryv forces of tile United States niust rely on Atabrine for the suppressive and tile specific therapv of malaria. At that time,

there was relatively little in the U .S. medical literature concerning the properties of At\abrine. aml very few Amierican l )hysicianis had used it or, for

that matter, even heard of it. Very little was known al)out its pharnmiacological or toxic lproperties. Schemes of therapy. either suppressive or definitive,

were based oil empirical observations or even guesswork. This was the status

of a ttairs when the Office of Scientific Research and I)evelolmient initiated

its large-scale research 1)roject on Atalbine in 1942. On)e of tihe earliest iap)-

1l)ied projects was testing the drug in normal human beings over a period of

weeks to determine its possible toxic effects when it was used for suippressive

therapy over a long period. The dosage schedule employed was 0.1 git. twice

a. week. Various social groups, such as students, reform-school inmates, and

prisoners in penal institutions, were employed as test subjects in these early

trials. One of the results of these trials was extraordinarily significant. Bint.

how significant it was, unfortunately, was not, recognized until, at least in

the North African (later Mediterranean) Theater of Operations. I.S. Army,

serious, if not periamanent, damage had been done to the minds of the militamry

relative to the use of Atabrine for the suppression of malaria. It was noted

that in the test subjects there were sharp, prostrating gastrointestinal attacks characterized by nausea, vomititing, and diarrhea following the third

(lose of the Sul)l)ressive medication. This occurred very frequently in the

student group, very much less frequently in the reformatory inmates, and

least of all in the inmates of the State prisons. It was also observed that, if

tile therapy was continued, there were very few individuals who had to discolntinue tile ktabrin'e because of gastrointestimnal disturbances following sulbsequent dloses of Atabrine. It was further noted that, if the drug was given

in dosages of 0.1 gin. per day, gastrointestinal dlistrlbances were minimal.

In the North African and Mediterranean theaters, where everything having to do with I mialaria was a joint con)iianl aml professional project between the British and Americans, and for a considerable period with the

French and Italian forces, the author was a member of the Malaria Committee of Allied Force Hleadquahrters. In .January 1943. this committee begait its discussion which led to a joint command directive regarding the use

of Atabrine for the suppression of malaria. The author, remembering the

Mist rointestinal dist urlmnces that. occurred after tile third dose in the trials

in the United States, held out for a daily suppressive dose of Atabrine. The

British and French members of the coimitittee resolutely o plosed this ttethod

of suppression. To make a long story short, the author was outvoted and,

under the operational rules of Allied Force Ileadquarters, had to accept tile

committee's decision. On 22 April 1943, suppressive therapy was begun on

a biweekly ('Monday and Thursday) basis, 0.1 gin. of Atabrine per (lose.

No troubles were encountered after the administration of the first two (loses.

The third dose was administered to all troops at the evening meal o0n Thurs-
TREATIMENT OF MALARIA 495

day, 29 April 1943. Withiin 4 or 5 hours, sharply defined toxic reactions

characterized by varying degrees of nausea, vomniting, and diarrhea made

their appearance. Curiously enough. military personnel stationed to the rear

of combat elements suffered far more than the fighting mIei. Infantry units

of the II Corps in combat in Tunisia had about 5 percent toxic reactions;

whereas, in certain hospitals and headquarters units in the rear, more than

75 percent of the personnel were affected. As one of our British colleagues

remarked the next day, "it had been a shaking experience."

Understandably, as reports of toxic reactions piled into Allied Force

Headquarters from all over the North African theater, consternation prevailed. and there was an imnediate demand that supl)ressive therapy be discontinued. Calm was eventually restored, faith in the use of Atabrine was

reaffirmed officially, and s•uppressive therapy was continued. However, as

can well be imagined, th1w ,hulage was done, and it can be said that throughout the rest of the wvar. discipline relative to suppressive therapy was poor

in many units throuirhout the theater. Then, to compound confusion, the

first great seasonal &lpidemic of infectious hepatitis occurred in American

troops beginning in August 1943, and in many quarters this epidemic was at

first thought related to the use of Atabrine for the suppression of malaria.

The author cannot determine, from the reports available to him, whether

similar incidents occurred during the initiation of suppressive therapy with

Atabrine in other theaters of operations. However, it appears that, in all

areas in which there was fighting and malaria was epidemic, the discipline

required to carry out successful campaigns for the suppression of malaria

by the use of Atabrine was difficult to enforce and the terrific toll of ineffective military personnel resulting from malarial attacks was directly

related to this lack of discipline. Command was not convinced of the value

of suppressive therapy with Atabrine and did not, except in a few areas,

take the steps necessary to make the suppressive program effective.

EXPERIENCE IN THE PACIFIC

Our military forces first felt the impact of malaria on their ability to

wage war effectively in the South Pacific Area. The experiences with malaria in that area were so rich and varied, and such careful, large-scale

studies were carried out on its nature and the suppressive and therapeutic

problems it posed, the reader is referred to other volumes in the history of

the Medical Department in World War II for statistical and other details.1

The substance of these observations is in part summarized here, for their

bearing on treatment.

1 (1) Medifeal Department, United States Army. Internal Medicine in World War II. Volume I.

Medical Consultants. Washington: U.S. Government Printing Office, 1961, pp. 603-618. (2) Medical Department, United States Army. Preventive Medicine in World War II. Volume VI. Communi-able Diseases: Malaria. [In press.]
496 INFECTIOUS DISEASES

In this as in other theaters, most medical officers early in the war had

little practical knowledge of malaria. Some few had had clinical experience,

mostly in the southeastern part of the United States, and they were disposed

to ascribe "properties to quinine that it did not possess." Such "malaria

experts" scattered through many medical units "were believed to have done

much harm, for most of them preached quinine with evangelical zeal and

blamed" everything, particularly the very difficult problem of controlling

relapsing malaria, "on the enforced use of Atabrine." Quinine, in short supply, was limited by command to cases intolerant to Atabrine, and the problem of controlling relapse was not solved until experience had taught the

proper use of Atabrine.

According to Col. Benjamin M. Baker, MC, Senior Consultant in Medicine, Office of the Surgeon, South Pacific Area, there were few cases of cerebral malaria (46), fewer still of severe anemia (14), blackwater fever (13),

and splenic rupture (6). However, based on sample tabulations of individual

medical records, there were no admissions for blackwater fever in the Central and South Pacific Areas during 1942-45. As in the Army as a whole,

there were few deaths; in this theater, only 24 were attributed directly to

malaria between 3 October 1942 and 1 September 1944. The more virulent

infections caused by Plasrodium falciparum predominated during epidemics.

Infections with the less virulent but stubbornly relapsing Plasinodhtm nvhax

appeared in increasingly higher percentages of cases when troops were removed from malarious to nonmalarious islands and suppressive Atabrine

therapy gradually withdrawn. It was apparent that Atabrine, even in suppressive dosage, cured malaria due to P. falciparunm. To this specific action

of the drug has been ascribed the low death rate and the comparatively low

incidence of malignant malaria in the Pacific areas. The most pressing concern of the U.S. Army was the very high relapse rate of vivax infections,

immobilizing whole regiments of men.

The 147th Infantry Regiment met the enemy, both human and plasmodial, in Guadalcanal (1942-43), armed against the latter with suppressive

doses of quinine for a short period, and Atabrine later. In May 1943, the

entire regiment was sent to Samoa, a nonmalarious island. Here, Atabrine

therapy was gradually withdrawn, and the men were given no further specific treatment until they developed fresh attacks, with the hope that their

malaria would "burn itself out." The actual result was the development of

chronic malaria with repeated relapses in the overwhelming majority. It

was apparent that the suppressive therapy on Guadalcanal had cured few,

if any, cases of malaria due to P. vivax. Massive therapy was also ineffective in curing latent vivax infections. Before the regiment could be returned

to active duty, suppressive medication with Atabrine had to be reinstituted.

This therapy effectively reduced the malaria rate, and the physical fitness of

the regiment was restored.
TREATMENT OF MALARIA 497

Similar results followed a similar attempt to "demalarialize" the Americal D)ivision on the Fiji Islands. Troops heavily seeded with malaria were

not well enough to return to combat after many months of "demalarialization." Many patients were evacuated to the Zone of Interior, but many remained in the theater, relapsing repeatedly. The only reasonable course was

to resume suppressive therapy with the hope, but as yet no certainty, that

continued use would materially reduce the staggering noneffective rate.

An experiment was set up on the Fiji Islands with combat units engaged in maneuvers under conditions simulating those of jungle warfare.

One group was given no suppressive therapy; the other, sufficient Atabrine

to establish the blood levels that had been found to be effective. In the control group, the relapses continued to occur at about the same rate as during

previous months; in the treated group, malaria was practically eliminated.

The cases that did develop were in men who, like some others observed previously, exhibited consistently low Atabrine blood levels.

Subsequent to this study, troops were kept on suppressive medication

whether they remained in malarious areas or were sent to nonmalarious regions for rest and recreation. First to come under the new policy was the

25th Infantry Division, which had become heavily seeded with malaria on

Guadalcanal and was now removed to malaria-free New Zealand, where suppressive therapy was continued. After Atabrine discipline was tightened,

the results were excellent.

Having proved feasible, the control of malaria by continued suppressive medication was required by military necessity. Experience had shown

that Atabrine in suitable dosage (0.1 gin. a (lay) was an effective suppressive

for most if not all primary malaria and, if continued, for recurrent attacks.

Nevertheless, many questions remained in medical minds. Some feared that

relapse was only being postponed to the day when Atabrine would finally be

withdrawn. Some thought the parasite would acquire tolerance to the drug.

Such considerations had an important bearing on plans for reemployment of

highly malarialized troops, and on treatment of troops in malarious areas.

To provide answers to many questions, a large number of men of the

147th Infantry were followed from Guadalcanal (November 1942) to Iwo

Jima (August 1945). Their medical history "included heavy exposure, light

exposure, atabrinization, de-atabrinization, long-continued suppressive medication, and terminal de-atabrinization." The observations, made on the same

experimental group and covering this not inconsiderable expanse of time,

space, and experience, appeared to justify the conclusion that long-continued

suppressive Atabrine therapy does, in fact, ultimately destroy a large amount

of infection due to P. vivax. After 17 months of continuous suppression, all

antimalarial therapy was discontinued, in the nonmalarious environment of

Iwo Jima, 20 months after the last significant exposure to infection. During the ensuing 3 months, there was only a slight increase in the malaria rate

in contrast to the violent outbreaks that had followed the initial deatabrini-
498 INFECTIOUS DISEASES

zation. It was, unfortunately, not possible to continue followup observations

beyond this 3-nionth period.

In another comprehensive study, no serious aftereffects of malaria were

found in soldiers who had been through many clinical attacks. Toxic reactions to Atabrine were not troublesome ini the South Pacific Area. Signs of

intolerance in the central nervous systemi appeared ini a small group of cases

and were carefully studied: they subsided when dosage w%%as decreased. In

comparative studies, other drugs (Plasmnochin naphthoate (pamaqiniie nalphthoate), the sulfonamides, totaquine) appeared to be generally inferior or

not, superior to Atabrine.

In the Southwest Pacific Area, important studies were carried out on

suppressive treatment, such as those in Australia by Lt. Col. (later Col.)

Garfield G. Duncan, MC, of the Anmerican Army and by Brigadier N. Hamilton Fairley of the British, and those by Lt. Col. (later Col.) Maurice C.

Pincoffs, MC, and others in New Guinea. The observations made early in

the war on that island were probably the first to demonstrate clinically that

malaria caused by P. falciparuni could be cured by Atabrine in suppressive

dosage. 2 Subsequent studies by Bang and others showed that a certain concentration of the drug in the blood was necessary for protection against clinical attacks and that equilibrium could be achieved by giving 0.1 gin. daily

for 6 weeks, or 0.3 gin. daily for 4 days, and could be maintained by continuing suppressive doses. It was shown that this treatment resulted in control

of ganietocyte carriers and this, in turn, prevented epidemic outbreaks of

malaria when troops were exposed again to infection.

EXPERIENCE IN THE INDIA-BURMA THEATER

Malaria as constituting a major medical problem in the India-Burma

theater has been presented in another volume in the history of the Medical

Department in World War 1I, from which the following summary has been

largely drawn. 3 It is obvious that in many instances information will overlap. In India, U.S. troops were exposed to malaria, most of them for the

first time, in a vast region where the incidence was something like 4,000 per

1,000 per annum in the population. An overnight journey by train was

likely to result in clinical malaria in 80 percent or more of the troops making the trip. The highest percentage of patients with malignant tertian

malaria was seen in this theater; cerebral malaria was the principal clinical

problem. Medical officers came from the 17nited States unprepared for the

multiform manifestations of the disease and were often, particularly at first,

uncertain in diagnosis. As to treatment, there was much individual experimentation. This may have been due, in part, to the proximity of the Indian

Medical Service and its methods of therapy; in part, to delays in receiving

" Baker, B. M.. and Platt, D.: The Effect of Long-Continued Suppressive Atabrine Medication

on Reiapsmes of Vivax Malaria. Tr. Am. Clin. & Climatol. A. 58: 145-152, 1946.

3 See footnote 1, p. 495.
TREATMENT OF MALARIA 499

information from the Surgeon General's Office on newer methods of treatment; and in part, perhaps, to the presence in Armny hosp)itals of highly individualistic, research-ininded medical officers.

The overall percentage of cases of malaria, classified as cerebral, in tile

three. hospitals where most of themi were seen, was 1.9 percent. At the 20th

General Hosl)ital, the incidence was 2.3 percent for all patients with malaria

and was 2.2 percent for Americans alone. At the 73d Evacuation Hospital,

during a 6-nionth period. there were .57 cases of C'erebral malaria with 27

fatalities, only 1 an American. At the 48th Evacuation Hospital, treating

chiefly Chinese soldiers, between April 1944 and March 1945, the mortality

was 43 percent, with no deaths in Americans. From September 1943 to May

1945, the 14th Evacuation Hosp)ital had 121 cases with 33 deaths, all the

fatalities occurring in Chinese patients.

P. falciparitm was recognized as the causative agent in most. cerebral

cases, some few were ascribed to P. -vvax. In the majority of all kimerican

patients with malaria, P. vvax predominated: in the majority of ('hinese,

1'. falcipetriin. predominated. Col. Francis C. Wood, MC. of the 20(h General Hospital thought that an observation made there threw light upon this.

Some Chinese patients were given no treatment for several days preparatory

to testing with a new drug, at the request of Chinese medical officers. This

was Fraxine, a preparation of unknown composition and, in the event, of no

proved value. Of these patients, those with infections due to P. virax became symptom free in 4 days without treatment; the infections with P. fa/ciparnim, did not subside during this period. It appeared probable that ('hinese soldiers infected with P. r'rax recovered spontaneously and were usually

not seen at. hospitals.

The India-Burma theater was established in October 1944 when U.S.

Army Forces, China-Burma-India, was divided into two separate theatersthe China Theater and the India-Burma Theater. What seems to have been

the first publication in the theater on the treatment of malaria appeared in

the opening issue of the Field Medical Bulletin. Headquarters, Services of

Supply, U.S. Army Forces in China-Burma-India (August 1942). This was

a summary of a pamphlet issued by the British War Office recommending

treatment different from that advised in Circular Letter No. 56, Office of the

Surgeon General, IU.S. Army, 9 June 1941, entitled "A Note on tihe Treatment and Control of Certain Tropical Diseases." In the November 1942

issue of the Field Medical Bulletin. Maj. Sydney P. Waud, MC, and Maj.

Robert S. Crew, M[C, of the 159th Station Hospital, l)resented "several

changes in the treatment of malaria," derived from the School of Tropical

Medicine, Calcutta, India. Finally, the Bulletin in its January 1943 issue

reprinted Circular Letter No. 135, Office of the Surgeon General, U.S. Army,

dated 21 October 1942 and entitled "The Treatment and Clinical Prophylaxis

of Malaria," but in the issue of February 1943, Lt. Col. Gordon S. Seagrave,
500 INFECTIOUS DISEASES

1MC. expressed doubt concerningv the efficacy of Atabrine and presented hIls

own viewis onl therapy including liquor arsenical is and nieoa rsphiela In ine.

The theater as at whole continuled to use the plani of treatmient outlined

inl Circular Letters Nos. 135) aind 33, the latter dlated[ 2 February 19)43 and

entitled -T1reatmient and C

1ont rol of Certain Tropical D iseases. Circular

Letter No. 33 was replaced 1w Circular Letter No. 153, Office of thle Surgeon

General, U.S. Army, 119 August 19)43, entitled "Tile D~rug T1reatmnent of

MXalaria. Suppressive anld ('1inical." By the end of 1943, inst allat ions in

heavily infested areas had reached their own conclusions onl thle basis of experience. Thle view expressed in it special report onl malaria inl thle annual

report of the 73d Evacuation H1osp~ital wats that all nuethoils in use there

were about equally effective inl their end results 1)ut that quinine and Atab)rine used inl combinat ion reduced temperature muore rapidly than the officially recommended therapy. At the 48th Evacuation Hospital, Lt. Col.

(later Col.) Herman A. Lawson, MC, and 'Maj. .John A. D~illon, 'MC. treated

a g-roup of Chinese patients with ai somewhat larger total dose of Atabrine

than was recommiendled, but Could1 finld no certain adlvantage. Thle experience of the theater with the treatment, described in Circular Le'tter No. 153

was summnarized1 in tile Essential Technical Medical D)ata reported to The

Surgeon General for .Jime 1944. Thle greneral ojpinionl wits that only inl very

sick painswas itncsayt uppIlemnent. At :irine with quinine. usually

given by injection. Patients with cerebral mahl via were sometimes unlable to

take oral medication. In such cases, bef t, parenteral Atabrine was available. quinine was gi veni inutravenously.

During the period coveredl by ( '1 itlar lA't ters Nos. 135, 33. anid 15:3,

which included all of 1943 andl most of the malarial s-eason of 1944. oecasional investigations were miade, particularly at the 20th Greneral Hospital,

onl the effectiveness of drug~s or comb~inations of drugs other than those recomimended, andl also on the side effects and usefulne~ss of commonly used

drugs.

The treatment of rvlapse lin benign tertian malaria with it combination of Atabrine

and M1apharsen (oxophienarsine hydrochloride) was studied by Maji. Calvin F. Kay, 31C.

itelapses occurred lin the g-roup so treated ats frequently ats in those treated with~ Atabrine alone.

Fraxine, at preparation used by Chinese medical officers and tested at their request,

proved1 of no0 vailue in malignlant tertlan malaria, and its effectiveness in benigni tertlan

malaria was extremely dloubtful in view of the apparent tendency of Chinese troops to

recover spontaneously.

A special prolblem with chinese patients was to keep them in the hospital. As soon

as they felt better they left or were taken out by their omimuminding. officers. To circumuvent this, Maj. Thomas H. Machella, MC, sought to (levise a safe and effective

method of g.iving thle total dlose of Atabrine within 24 hours. A group of 80 Chinese

patients given 0.3 gina. of Atabrine every 3 hours for eight (loses. did as well or even

better, as regards duration of fever and parasitemlia, ats compared wvith patients treated

according to Circular Letter No. 1513. Because 2 of the 80) patients showed signs of

stimulation of thle central nervous system, the dosage wit~s redluced to 0.2 gin. every 3

hours for eight dose..
TREATMENT OF MALARIA 501

An experimental study by Major Machella failed to demonstrate any effect of a

single intravenous infusion of an antimalarial (Atabrine or SN 6,911) upon the ability

of the liver to excrete bronisulphalein before, during, and after an attack of malaria.

Some patients with cerebral malaria were treated with a single intravenous infusion

of Atabrine, the dose varying from 0.6 gin. to 1.0 gin. The patients who received the

infusion too rapidly had brief psychotic episodes. Although the iiumber of cases was

small, Major Machella felt that Atabrine was at least as effective as quinine, and that

0.8 gin. Atabrine given by slow intravenous drip was an effective method of clearing the

blood of parasites.

All three drugs commonly used in the treatment of imalaria produced

react ions. Plasmnochin Ipmroved to be particularly toxic in Negroes. Many

Negro patients from units working along the Ledo-Burma road were sen at

the 73d Evacuation and 20th General Ilospitals. A severe type of hemolytic

reaction to Plasniochin occurred in approximately 30 patients. One patient

was Chinese and the rest were Negroes. All of them developedl a moderately

severe anemia; in six. the erythrocyte count fell below two million. Because

of the frequency and severity of these reactions, administration of this drug

was stopped in all hosp)itals in the Assam-Burma region, and eventually in

the theater.

Quinine had long been known to produce toxic effects. Used intravenously in cases of cerebral malaria prior to the advent of parenteral Atabrine,

it was generally considered a lifesaving procedure. At the 48th Evacuation

Hospital, however, eight Chinese patients died in convulsions shortly after

injection of quinine. Althouigh admittedly a cause and effect relationship

could not be proved, the clinical impression was so strong that at this hospital any reasonable alternative was regarded as preferable.

All the reactions commonly attributed to Atabrine were seen in this theater. including atypical lichen planus and various other skin reactions, toxic

p)sychoses, and the usual gastrointestinal disturbances. When suppressive

treatment with Atabrine was instituted in February 1945, many medical officers were still apprehensive of its supposed toxic potentialities. Many symptoms were attributed to Atabrine without good evidence of a causal relationship, others on a more plausible basis. The Air Transport Command's

division surgeon, Col. Edward A. Abbey, MC, and the chief of preventive

medicine, Maj. Edgar A. Lawrence, MC, reported on the effects of continued

doses (0.1 gm. daily) on the visual acuity of airplane pilots, concluding there

was no adverse effect except in rare, highly sensitive individuals. In these,

withdrawal of Atabrine resulted in relief of symptoms; readministration of

the drug was followed by recurrence, which in turn was relieved by cessation

of suppressive therapy.

Various nonspecific therapeutic measures were employed, particularly at the 2-th

General Hospital, with variable benefit. Transfusions of whole bhloo were thought to

be lifesaving in some cases, especially in those with pulmonary edenm. At this hospital

an initial spinal tap was considered advisable in all cases. At the 73d Evacuation
SI) INFEtCTIOU'S )ISEASES

Hospital, on the con1trary, the reduction of spinal-fluid pressure by lumb1"ar pPzwOture was

thought to be appreciably effective only hi rare cases. At Imoth hospitals intravenous

Adrenalin (epinephrlie) was considered of value in so.le cases, but Was not in routine

use hecause of untaoward reactions. Sedatives were universally uwsd for excited or convulsive patients, usually Ainytal Sodium or paraldehyde given intravenously. Various

other measures were tried without any striking benefit, These includedi oxygen therapy,

Benzedrine (racemic desoxy-nor-ephedrine), ephedrine, aminophylline by intravenous and

by lntra(,arotld iijection, a11dl injectiom or nitroglycerine into the carotid.

EXPERIENCE IN THE MEDITERRANEAN (FORMERLY NORTH

AFRICAN) THEATER OF OPERATIONS

It. Col. Harold It. Golz, 1(', 182d Station Hlospital, and Maj. Phillip B.

Bleecker, MC. 225th Station Hospital, collected and compiled extensive data

on the elpidemiology. clinical and laboratory diagnosis, clinical course, and

treatment of malaria in U.S. Army troops in countries bordering the Mediterranean. What follows is in large part taken from the final report on malaria

written by Colonel G(olz. 4

Thlroughlout recorded history. malaria played its part in the insidious

defeat of armies, and here. in this theater in World War II, it rapidly became

the foremost medical problem. The vast majority of American troops who

moved into these highly malarious regions had never been exposed to the

disease, and the great majority of medical officenr had had no exp)erience

with it. At that time. tile 1)ossibilities of drug p)rophylaxis and SUl)p)ression

were only in process of being elucidated, and mechanical protection from

infection in amphibious operations could at best be only a feeble ef'ort. Fortunately, the initial landings were made at a season when the. incidence of

primary infections was low.

The disease occurred throughout the theater, more intensively in certain

regions. In North Africa, the most highly malarious areas were in the neighborhood of Rabat and Port Lyautey in Morocco, the Constantine area in

Algeria. and the Tunis-Bizerte-Ferryville area in Tunisia. Sicily had a high

rate on the Catania plain and on the southern coastal plain. The entire eastern coastal p)lain of Corsica was highly malarious, and the malaria rate in

civilians of Sardinia was the third highest in the world. A survey of 8W2

children in Sardinia before World War II showed that 34.2 p)ercent had

positive smears, of which 51.4 percent were P. fadciparum and 43.1 percent

were P. virax.

The worst malarial areas in Italy were in the region of Salerno and

Paestum, along the Volturno and Garigliano Rivers, about the Pontine

Marshes, and around the river mouths on the eastern coast. There was little

malaria in southern France, and urban centers such as Florence were free of

malaria, although it did approach the municipal limits of Rome and Naples.

4 GolI, Harold HI.: Human Malaria In the North African and Mediterranean Theaters of Operations. U.S. Army. [Official record.]
TRFATMENT OF MALARIA -03

Incidence

Based on saipleh- tabulations of individual medical records, there were

aplproximately 81,000 cases (attacks) of known malaria in the U.S. Army in

the Mediterranean theater during 1942-45. These cases consisted of new

admissions and readmissions as well as admissions for other causes, but in

which malaria existed concurrently or developred subsequently (table 54, clh.

XIV). 'Tere were approximately 28.000 cases of FUO (fever ot Aaideterrained origin) recorded on individual nmedical reeords in the Mediterranean

theater during the war period, and of these, between 5 and 10 percent werc.

probably malaria. Assuming that 7.5 percent, or 2,100 cases, of FU('s were

malaria, this number, when added to the approximate 81.000 known malaria

cases. produced about 83.000 probable cases of malaria in the Mediterranean

theater during 1942-45. By year, this meant that there were less than 1,000

cases in 1942, about 34,000 in 1943, 40,000 in 1944, and 8,000 cases in 1945.

The data on malaria, b)y month, in the Mediterranean theater for 1942-45

are shown in table 66. The 1942-43 data are based on tabulations of individual medical records and consist of new cases admitted for malaria and new

(p1ses in which mnalaria appeared as a secondary diagnosis. The 1944-45 data

are from the statistical health reports andl are in terms of total malaria

TABLE 66.-Malaria cases I in the Mediterranean (formerly North African) Theater of Operations, U.S. Army, by month, 19412-45

iData based on tabulations of :ndividual medical records (1942-43) and statistical health reports (1944-45)]

[Rate expressetd as number of cases per annum per (;0MM average strengthI

19422 1943 1944 1945

'Month

Number Rate Number Rate Number Rate Number Rate

of cases of cases of ca&- of cases

January ----.... 517 24. 95 1,392 29. i1 759 19. 95

February - --------------- 214 10.28 2,214 46.61 j 636 15. 98

March -------------------- -------- 60 2.24 4, 498 72. 11 988 20.60

April ----------------------------- 86 2.89 4, 222 80.24 1,077 28. 23

May-------------------------------180 4.85 :3, 022 56.67 1,139 31.20

Juie ---------------------------- 1, 847 47.82 4,691 69. 75 1,002 25.81

July ----------------------------- 4, 806 112.00 4,341 81.26 639 23.67

August --------------------------- 8,516 191 50 4, 897 90.78 392 15.32

September ------------- ------- 6,047 129.78 4, 870 73.88 111 7.90

October ------------ --------------- 6, 235 1 22. 93 3, 270 60. 96 32 2. 96

November ---------- 67 8.58 2,550 53.24 2.030 38.04 21 2.41

December ........ 664 43.92 1,753 34. 85 1,235 25.48 4 .88

Total ------- 731 31.89 32,811 71.84 40, 682 61.67 6,800 20.52

I The 1942-43 data represent incidence; it consists of new eases admitted for malaria and cases in which malaria

appeared as a secondary diagnosis. The 1944-45 data are. in terms of total malaria attacks, which is comprised of cases

readmitted for malaria as well as new primary and secondary cases.

2 No troop strength present in the theater before November 1942.
504 INFECTIOUS DISEASES

attacks which include readmissions as well as new cases. The statistics enumerate the malaria attacks as they were diagnosed and reported currently

and regularly on the statistical health report and may include tentative diagnoses. Such data therefore do not tally identically with those derived from

statistical tabulations of individual medical records which are based on final

diagnoses. However, they do provide a general basis for epidemiological

description of malaria in the Mediterranean theater during World War II.

The average length of hospitalization for this disease in 1943 was a fraction

less than 17 days, representing a total of about 425,000 man-days lost during

the year or the equivalent of the effectiveness of an entire division lost f,-

a month. In 1944 the average period of hospitalization was reduced to 11.8

days but, the number of man-days lost for the year was 519,000. In the average hospital, malaria represented 4 to 5 percent of all hospital admissions.

The geographic distribution of the cases broken down into clinical types

is shown in table 67. This table shows only 22.936 cases and represents the

total experience of 32 hospitals of all types during their entire period of

operation in NATOUSA (North African Theater of Operations, U.S. Army)

to August 1944. Table 68 shows the incidence of clinical types for the remainder of 1944 and about half of 1.945, when the bulk of our troops were in Italy.

In the Sicilian campaign (9 July to 17 August 1943), the loss in fighting

effectiveness in the Allied armies was equivalent to two infantry divisions and

exceeeded the total number of battle c-asualties by 20 percent. A large number

of men also developed the disease while in training in areas of troop concentration in North Africa and were unable to participate in the invasion. The

number of troops thus affected was well over a thousand.

The malaria of Sicilian origin made its appearance in the Seventh U.S.

Army and British Eighth Army after 7 August 1943 and reached a peak a

week later. The rates for these two armies were 425.43 and 420.39, respecTABLE. 67.-Experience of 32 hospitals with malaria during the entire period of operation in

the Mediterranean (formerly North African) Theater of Operations, U.S. Army1, to August 1944,

by area

Faki- Malariae

Viiax paru it (quar- 'Mixed- Unelas- Clinical

Area (tertian) (estivo- tan) type sified malaria Total Percent

malaria autumnal) malaria malaria malaria

malaria

Africa ----- 7,068 1,221 94 15 505 983 9,886 43. 1

Italy- 7,737 507 19 5 449 1,329 10, 04CN 43.8

Sicily ..... 2,428 340 .... . 32 17 ------- 2,817 12.3

Other areas l 174 11 2 ------.------ ------- 187 .8

Total_ 17,407 2,079 115 52 971 2,312 22,936 100.0

Percent of total 75. 9 9. 1 0.5 0.2 4.2 10. 1 100. 0

SPantelleria, France, Corsica, and Sardinia.
TREATMENT OF MALARIA 505

TABLE 68.-Malaria cases discharged from all hospitals in the Mediterranean (formerly North

African) Theater of Operations, U.S. Army, from 15 September 1944 to 11 May 1945,

inclusive

Vivax Falciparum 1 Quartan Mixed or Clinical

malaria malaria malaria unclassified malaria

Period malaria Total

New Old New Ohl New Old New Old New Old

15 Sept.-27 Oct 1,541 762 76 8 1 2 63 37 112 28 2,630

28 Oct.-8 Dec ....... 1,042 824 448 5 2 __- 18 15 152 56 2,162

9 Dec.-12 Jan.... - 414 551 15 7 --------- 3 8 75 46 1,119

13Jan.-2Feb.- 185 304 4 4 ------------ 9 12 23 541

3 Feb.-2 Mar- . 190 444 1 3 1 1 1 7 22 22 692

3 Mar.-30 Mar ------------ 257 442 2 2 ----.---.- 3 4 18 25 753

31 Mar.-27 Apr ------------ 329 434 2 ---- 2 1 4 5 53 51 881

28 Apr.-ll May 256 281 1 ----- -------- 6 6 14 23 587

Total ------------ 4, 214 4,042 149 29 6 4 98 91 458 274

8,256 178 10 189 732 9,365

Percent of total ------------ 88.2 1.9 0.1 2.0 7.8 100.0

tively, although in some divisions they were much higher. The incidence in

the entire campaign would approximate 400 per 1,000 per annum. Later,

strict control measures were adopted. The rates dropped steadily, but it was

not so much the control measures that were responsible for the drop in the

malarial rates in Sicily in the fall of 1943 as it was the removal of troops

from hypermalarious areas and the fact that it was fall of the year.

Several explanatory remarks should be made in referring to table 66:

In 1943, the highest rates occurred during the summer months when they

were expected. In October 1943, when the bulk of U.S. troops were in North

Africa, there was a rise in the rate which was also expected because of the

September rains, but this rise did not appear in 1944 when the greater part

of U.S. troops were in Italy. The increase in malaria noted in 1943 cannot

be attributed to conditions in North Africa. It resulted from conditions

existing on the Salerno beachhead during September and had its origin in

the sharp increase in cases of malaria in the Fifth U.S. Army during that

period. The rates in the winter of 1943 and 1944 were relatively high during

the season when few if any primary cases occur and are explained by the

relapses of primary infections incurred during the summer and early fall of

1943. The withdrawal of Atabrinie suppressive treatment from November

1943 to May 1944 undoubtedly played an important role in these rates. In

1943, the FUO rate was twice as high as that in 1944 because, for various

reasons, the effort to make laboratory diagnoses in that year was not as great.
506 INFECTIOUS DISEASES

In the summer of 1944, the FF0 rate was neticeably high. This can be

accounted for in part by the high incidence of pappataci fever from July

through September. Many medical officers were unfamiliar with this disease

and diagnosed such cases as fever of undetermined origin.

The relatively high rate in August and September 1944, however, has

another explanation. For several months prior to the invasion of southern

France (15 August), three divisions that had been withdrawn from the Fifth

U.S. Army and assigned to the Seventh U.S. Army were staged and trained

in a malarial area near Naples. These divisions, classed as noncombat troops,

had malarial rates of 130 to 140 per 1.000 per annum while in training.

Hospitalization

Medical battalions.-Through the usual channels of evacuation, a sick

soldier reached the clearing station by way of the battalion aid station and

the collecting station. At each of these, the need for hospitalization and

treatment was evaluated. When the need was recognized, the patient was

evacuated to the next. medical echelon. Thus, he usually reached the evacuation hospital from the clearing station. At the collecting and clearing stations, facilities for making the diagnosis of malaria on other than clinical

grounds were not often available so that the patient ordinarily left the clearing station with a diagnosis of fever of undetermined origin or, occasionally,

suspected malaria, without having had specific treatment. Under exceptional

circumstances when the military requirement for manpower was pressing, a

diagnosis of clinical malaria might be made by the surgeon at the collecting

station on the basis of a recent previous attack of malaria, a typical history,

and a palpable spleen. If the soldier was only mildly ill, the surgeon might

return him to his unit with instructions to remain at rest in his tent for several

days, and standard Atabrine treatment was administered under the close

supervision of a company aidman. Although this method of management left

much to be desired, it resulted in the saving of many man-days that would

ordinarily have been lost through evacuation, hospitalization, and the process

of return to unit.

Evacuation hospitals.-This type of hospital was the first stop in the

chain of evacuation where adequate facilities existed for making a laboratory

diagnosis of malaria. These hospitals used the same diagnostic methods as

employed in the fixed hospitals of rear echelons-naniely, repeated thick

smears. (The 15th Evacuation Hospital took three thick and thin smears

for routine examination and if these were negative, a fourth was taken 2

hours after the subcutaneous injection of 0.5 cc. of Adrenalin 1: 1,000. If the

smear following Adrenalin was negative. the diagnosis of clinical malaria

was made only if there was a history of recent malaria, a typical clinical

picture, and a palpable spleen.) As a result of such careful methods of

examination, often done under highly adverse conditions. the diagnosis of

clinical malaria was not often made in evacuation hospitals.
THEATMENT )F mAiLARA 5 ()-,

Eviacuaitioni policies varied widely from time to time and wvere influenced

1v() thle anticipated need for beds, (2) the experienice of the corps, arutly,

or base sevtion surgeon, and (3) the professional intelligence of thle medical

officer who wats dlirectly respoiosible for thle adiliiifistrat ive phlases of evactiaI ion. D~uring the Sicilianl campaign of 1943. hundreds of patients suiffering

front malaria were evactiate(1 front the 11 Corps area to North Africa because

su~fficient b~eds for their care were not availab~le, owing to the fact that the

Seventh U.S. Army broke away from its p)repalred planl of p)roviding" hospitalizat ion andl (lid not c-all for all of their large evacuation hospitals until

after the campaign wvas over. In tile fall amid early winter of 1943, hundlredls

of patients ill with mialaria were evacuated to hospitals in thle Peninsular

Base Sectionl because b~eds for their care were not emnsidleredl to be available

in the Fifth V.S. Army area, although data on the bed status during that

period show that rarely after 1 November were there less than L.500) usable

beds in the Fifth U.S. Army area and that generally the figure for emplty

b~eds wits much greater. With experience. fewer and fewer malarial patients

were evacuated. MItch unniecessarv evacuation of malarial pat ienits withI a

resultant loss of manpower occurred-b-oth in forward and( in rear areas--

b~ecause many administrative officers in charge of evacuation looked umponi

lpat mellts as *bodIies" occm-Ij)YiImg slpave wit ilouit referencee to their d iseatse anid

their ability to return to their iimits prompltly.

When patienits wvere evacmited. they were Illovedl by air, rail, ship. or

ambulance to the next echelon hospital. ulsually the general hospital, although

hii certain instances they might lbe sent to a station hospital.

General hospitals.-By the time the malarial patient reached the general

hospital, d iagrmosis had usually beeni made and treat ment~ st artedl. When the

eourse of treatmenit was completed, the paut ient was cgiven such recondlit ioninig as hie miight require mind wats then returned to h is 11tuit by way of the

replacement dlepot. Most general hospitals made the diagnosis of clinical

mmalaria 01Viveyexcept jona ci rcimnstamices, alIthough they concur-red in

such a transfer diagnosis when the patient had already been undler treatment.

Wheii this dliagrnosis was mmade initially in these hmospitals, it was usually in

cases in which, although thick smnears wvere negative, the patient's condition

required prom pt t reatneien and hiis response to specific treatment wvas typical.

Undler cert ainm ci rcumst ances, general hospitals received patients directly

fromt command by way of at dispenisary. Whmeii mialaria was suispected in these

cases, every effort was exp~endled to make ai laboratory diiagnosis. At the 12th

G~eneral H~osp~ital, when the combiniation of leukopeniia, qualitative changes

ini the lymphocytes of the peripheral blood, and reticulocvtosis was found,

repeated thick smears were taken without further request from the wvard

officer.

Aniother source of adumission was in transfers from station hospitals from

which the patients were sent as pro~blenfls in disposition.
508 INFECTIOUS DISEASES

It was only ill the last half of 1944 that hospitals ill this theater reclassified soldiers to limited assignmient because of malaria. This reclassification.

made l)ut rarely, was usually applied to a combat individual who had been

relatively noneffective because of repeated hospitalizations without, however,

meeting the criteria for evacuation to the Zone of Interior. Frequently, letters

from unit medical officers requesting reclassification accomlanied the soldier

to the hospital. The purpose was to permit the combat unit to get a more

efr ý'.e replacement and to move the patient to an environment where he

Oss likely to relapse and could still be of some use to the service.

I'he theater policy for reclassification to class C (return to the United

StaLtes) for malarial patients was set forth in Circular Letter No. 21, Office

of the Surgeon. Headquarters, NATOLTSA, dated 3 April 1944. The criteria

for this classification were cachexia, repeated attacks with persistent splenomegaly, refractory anemia, repeated attacks of cerebral malaria, and blackwater fever. This policy did not envisage evacuation to the Zone of Interior

for repeated attacks per se. Approximately 1 percent of patients with malaria

eventually were sent to the United States for this cause. A review of the

records of several genend hospitals revealed the following additional causes

for C( classification:

1. Chronic cachexia with or without persistent splenomegaly and anemia

in a patient who had lost 3 months or more from duty in 1 year because of

nialaria.

2. Proved intolerance to both Atabrine and quinine.

3. Treatnment-resistant parasitemnia.

4. Psychosis following falciparum infections.

5. Repeated attacks of falc;pa(run malaria.

Station hospitals.-These hospitals were not normally in the chain of

evacuation and for the most. part received their patients directly from command by way of dispensaries, although during periods of peak evacuation,

the station hospital might supplement the bed capacity of general hospitals.

Many cases had a laboratory diagnosis made in the referring dispensary, and

when the report of the smear accompanied the patient it was accepted without verification. Other cases arrived with the diagnosis of fever of undetermined origin. Diagnostic methods then emp)loyed were the same as those

used in the general hospitals, and a diagnosis of clinical malaria was rarely

made. For example, in one station hospital, it was resorted to only seven

times in more than 800 malaria admissions, and in 6 of these cases, it was

the transfer diagnosis of patients already under specific treatment. Treatment methods and criteria for reclassification to limited assignment were the

same as those employed in general hospitals. When it was felt that a malaria

patient, should be evacuated to the Zone of Interior, he was transferred to a

general hospital for disposition.

Duration of hospitalization.,From the Machine Records Unit, Allied

Force Headquarters, it was determined that the overall average period of
TREATMENT OF MALARIA 509

hospitalization for 6,078 cases of malaria in the 8-month period between

September 1944 and May 1945 was 14.5 days. This average applied only to

cases discharged to general military duty and did not include reclassified

cases or cases disposed of by transfer to other hospitals. When calculated

for type of hospital the following averages were obtained: (1) Field and

evacuation hospitals, 10.4 days; (2) station hospitals, 13.9 days; and (3) general hospitals, 22.6 days.

Laboratory procedures.-In the early days of this theater, the diagnosis "iclinical malaria" was made more often than was necessary. Clinicians had

no hesitancy in ascribing responsibility for this to the inexperience of laboratory technicians which was undoubtedly a factor, but. clinicians should not

forget that their own unfamiliarity with the disease was as large a factor, if

not larger. After more than 2 years of rich experience with malaria, most

hospital clinicians and technicians had become thoroughly acquainted with it.

These two groups were mutually helpful in the quest for knowledge of this

(lisease. and certainly niuch credit for this happy state of affairs can be

ascribed to those officers in high echelons of the theater who waged a relentless war against the diagnosis of "clinical malaria." Subsequently, hospital

medical officers almost without exception proudly claimed that they rarely

if ever made the unsupported diagnosis and they staunchly defended their

own technicians as experts in parasite identification. And, indeed, the rank

and file of laboratory technicians in the theater had become highly efficient

parasitologists; for this, due credit must be given to the training courses for

technicians conducted by the malariologists.

A note on technique may not be amiss. All hospitals agreed that a thickdrop blood film was indispensible. In 17 of 20 hospitals visited, thick-drop

examination was routine, and several of these hospitals had dispensed with

the thin smear entirely, maintaining they could identify the species satisfactorily on the thick drop. In the other three hospitals, the thin smear was

examined first, and if negative, the thick drop was examined. The purpose

was to save time in diagnosis, but in Italy, where the ratio of P. viva.x to

P. falciparum was about 46: 1, perhaps such urgency was unwarranted.

For routine work, more than one-third of the hospitals preferred Field's stain,

prepared fresh each week, kept cold, and filtered at least twice weekly. Other hospitals

invariably used Giemsa stain in preference to Wright's stain.

Many studies were carried out in the laboratories of Army hospitals,

which have been described in detail elsewhere (p. 489). Here it may be noted,

that certain characteristics formerly though to be limited to falciparuin infections were not uncommonly found with P. vivax; in particular, double-cell

infections, double-chromatin dots, and marginal rings.

Treatment

Theater directives.-The history of the treatment of malaria in this

theater properly begins with Circular Letter No. 6, Office of the Surgeon,
510 INFECTIOUS DISEASES

Headquarters, NATOUSA. dated 10 April 1943, in which the QAP (quinineAtabrine-Plasmochin) treatment is recommended; that is, quinine 0.67 gin.

three times a day for 2 or 3 (lays to control parasiteliia, followed by Atabrine

0.1 gin. three times a day for 5 (lays followed by a 2-day rest period, and then

0.1 gin. of Plasmochin two or three times a day for 5 days. ('ircular Letter

No. 32, Office of the Surgeon, Headquarters, NATOUSA. 3 September 1943,

amended Circular Letter No. 6, eliminating Plasimuohin from the schedule andals reoiuiidiig, ine alone, 0. ' ni. thetis and also recommending, as an alternative, Atabri . . hree times

a day for 5 days. Finally. on 14 September 1943, Circular Letter No. 34.

Office of the Surgeon. Headquarters, NATOUSA, advocated the Atabrine

schedule: 0.2 gin. of the drug every 6 hours for five doses followed by 0.1

gin. three times a day for 6 days. Circular Letter No. 10, Office of the Surgeon. Headquarters, NATOUSA, dated 15 February 1944, revolninended that

for third and subsequent. relapses quinine be used in a dosage of 1.0 gin. three

times a day for 3 days and then 0.3 gm. three times a day for 10 days. Circular Letter No. 41, Office of the Surgeon, Headquarters, NATOI7SA, dated

29 July 1944, rescinded Circular Letter No. 10 in view of the fact that the

use of quinine in the therapy of relapsing malaria had shown no advantages

over the use of Atabrine.

Atabrine.-This therapeutic Atabrine dosage scheme was found to be

safe, effective, and productive of results equally as good as those obtained

with quinine. Formerly, it had been observed that. Atabrine did not effect a

temperature drop as promptly as did quinine. At that. time, it was not the

practice to administor loading doses of Atabrine during the first day or two

of treatment. This objection was largely eliminated after it was found that

the plasma concentration of the drug was a measure of its therapeutic effectiveness and that effective levels were more rapidly attained when larger doses

were given at the start. of a therapeutic regimen.

It was the experience of all the medical officers of the Mediterranean

theater that many soldiers said they were intolerant of Atabrine, but when

the drug was given in either suppressive or therapeutic doses, no such intolerance was demonstrated. Toxic reactions from therapeutic Atabrine were

extremely rare. There were probably few if any medical officers in this theater who were not finally convinced that Atabrine was at least, as effective and

safe as quinine. This attitude represented a complete reversal of opinion

within 2 years and, as such, was an eloquent testimonial to the value of the

drug. When Atabrine was introduced as a suppressant in doses of 0.2 g1n.

twice weekly 2 years before, there was such an explosive outbreak of gastrointestinal symptoms that the drug fell into some measure of disrepute. Medical officers were wary and suspicious of it, and only its continued use at the

insistence of higher authority served to dispel these fears. A few officers

still remained somewhat reluctant to accept Atabrine as the drug of choice.

They were mainly physicians who had become thoroughly indoctrinated with

the virtues of quinine when it was the only efficient antimalarial available.
TREATMENT OF MALARIA j511

The chief remaining differences of opinion regarding the effectiveness

of the two drugs were concerned with the speed of action in bringing the

temperature into the normal zone. When Atabrine was given as directed in

Circular Letter No. 34 and quinine as directed in Circular Letter No. 10,

mainy officers thought that quinine brought the temperature to normal 24 to

48 hours sooner than did Atabrine and that. in most cases patients (lid not

have another chill after quinine was started, whereas most had one additional

paroxysm after Atabrine. A smaller group of officers could observe no difference in this respect, between the two drugs, and a small minority thoug'ht, that

Atabrine produced faster results. Obviously, these differences of opinion

were largely due to the fact that they were based ulpon clinical impressions.

The only factual data on the subject were gathered by Capt. (later Maj.)

Franklin K. Paddock, MC. of the 33d General Hospital on 28 cases treated

with quinine and 24 cases treated with Atabrine, in such dosage as has been

described. His results are summarized in table 69 and show that there was

little difference between the two drugs.

TABLE 69. RTesulis of -dy of duration of fever after hlart ,f treatment in 28 quinine-treated

cases and 2.; Atabrinf-tr,attcd csJ.es of malaria

Q•uinine A tabrine

D u ration o f fever _______ A_ _ _ _ _ _ _ _

(days) Number Percent Number Percent

1 ------------------------.-------------- 14 85.7 24 100.0

2 ----------------------.----------- 21 75.0 22 91.7

3 -------------------------------- 13 46.4 7 29.2

4 ---------------------------------- - 2 7.1 2 8.3

In many hospitals, 0.4 gm. Atabrine by intramuscular injection was substituted for the initial dose of 0.2 gm. Atabrine given orally. Officers who

used this modification of the routine plan were enthusiastic over the results.

There were no toxic effects; temperatures fell to normal within 24 hours;

there was no secondary rise in temperature and no additional paroxysms;

and convalescence was quicker. Several other hospitals initiated treatment

with 0.2 gin. given intramuscularly. The results were not as good as with

the larger dose. The 118th Station Hospital gave 0.4 gin. Atabrine orally in

one dose and followed it with 0.1 gin. three times daily. Results were said to

be comparable with those obtained from the larger of the doses given intramuscularly.

Plasmochin.-The drug was dropped from the therapeutic armamentarium early because no peculiarly beneficial effect was ascribed to it and because

of the narrow margin of safety between therapeutic and toxic doses.

Quinine.-For reasons of supply, its use was limited. Patients were occasionally seen who failed to respond to quinine given orally and in whom no
INFECTIOUS DISEASES

trace of the drug could be found in the urine. In certain types of cases, it

was freely used intravenously. in all instances well diluted and given slowly.

Circular letters directed that quinine should be administered in at least 300

cc. of normal saline or glucose and saline. Reactions other than mild cinchonism were not seen. In cerebral malaria, this was tile routine method of

treatment. It was usually given in infections with t'. faledpwr)-lint wheen patients were vomiting. One hospital gave at least one dose of quinine intravenously in all fale;parilm. infections. Trhe d(ose employed was almost invariably

IJ) gr., and it wits repeated at 6- to S-hour intervals when necessary.

Sulfonamides.-()ccasionailv, a misdiagnosed case of malaria was treated

with one of tile sulfonamide drugs. It was observed that the drug, usually

sulfadiazine, (lid suppress clinical symptoms and parasitemia. A few reports

were received indicating that sulfadiazine in full therapeutic doses mIlight

possess some merit. in the treatment of .fdepar in, gninetocytentiai resistant

to Atabrine and quinine.

Sontoquine.-A limited supply of Sontoquine bisulfate and Sontoquine

naplhtholate was received in tile theater and divided between the 225th and

IS2d Station Hospitals. It was planned that each hospital should treat, equal

numbers of malaria cases with each of the two drugs and that, a third group

should be treated with Atabrine for comparison. Unfortunately. the experiments were undertaken at, a season when the malaria rate was the lowest in

theater history, and during the period of study both hospitals were moved to

other locations in Italy. Consequently, a total of only 14 cases were studied

in the, two hospitals. Of these, eight. patients received Sontoquine and six

patients received Atabrine. The( dose of all three drugs was 0.2 gin. every

6 hours for five doses and then 0.1 gin. three times a day for 6 dlays. There

was no (lifference noted between the two salts of Sontoquine and no difference

between these drugs and Atabrine. Temperatures returned to normal and

blood smearss were negrative within 48 hours in tile patients treated with Sontoquine and in all but one of the patients treated with Atabrine. This one patient. had fever and positive smears until the fifth day of treatment. No sign

or symptom of intolerance to Sontoquine was noted, and repeated blood

counts and urinalyses failed to show any ill effects whatsoever. It was

planned to continue this study.

Iron.-Routine use of iron in all cases of malaria in some hospitals was

thought to speed convalescence.

Other measures.-Intravenous glucose and saline were freely used to

combat dehydration. In rivax cases with vomiting, the fluids often seemed

to allay this symptom so that patients could retain oral therapy. One hospital reported that a single dose of morphine had a similar effect.

In patients gravely ill with falciparutm infections, repeated infusions of

plasita and whole blood were frequently employed. Several medical officers

felt that these measures were frequently lifesaving.
TREATMENT OF MALARIA 513

Treatment To Reduce Relapse Rate

Throughout tile entire history of the theater, officers were searching for

a therapeutic regimen that would reduce the relapse rate in vivax infections.

The 7th Station Hospital reported that relapse after Atabrine treatment

appeared to be considerably delayed and that recurrence frequently followed

quinine treatment within a matter of days or weeks.

Many different dosage schedules and combinations of Atabrine, quinine,

and Plasmochin were used in the various hospitals and some of these programs required weeks of hospitalization. The criticism common to all of

these studies was that they were done in only a very small series of cases;

they were not controlled, and followup studies were either inadequate or

completely lacking. It is perhaps significant that not a single officer was

found who had any faith whatsoever in any of these or other plans of treatment designed to prevent relapses. For the sake of interest and completeness,

several of these plans will be noted.

One hospital supplemented routine Atabrine or quinine treatment with a modified

Ascoli treatment plan. Adrenalin was given intravenously in graduated doses beginning with 0.01 mg. and increasing to 0.1 rag. or to tolerance. Eight patients received

this treatment daily for 15 days and four received it twice daily for 10 days.

Another hospital gave quinine intravenously with Adrenalin three times daily for 7

days. Another hospital gave 0.2 gin. Atabrine every 6 hours Intramuscularly followed

by 0.2 gin. twice daily by the same route for 6 days. The local effectts were said to

have been disagreeable.

Still another hospital gave a routine course of quinine followed by a routine course

of Atabrine followed by four weekly doses of Mapharsen. Another hospital gave a routine course of Atabrine, followed by a routine course of quinine, followed by a routine

course of Atabrine. On the first day of treatment the patient received 0.4 gin. bismuth

subsalicylate, intramuscularly, and on the 7th, 14th, and 21st days, 0.2 gui. In addition

he received 60 mag. of Mapharsen twice weekly for six doses.

In many of the above instances patients relapsed within a month or two after completion of treatment.

Capt. (later Maj.) John C. Ransmeier, MC, of the 300th General Hospital treated

three cases of relapsing vivax malaria with Fuadin (stibophen) (one with quinine as

well, two with Fuadin only) reasoning that its penetration into the cells of the reticuloendothelial system might be effective. One patient received 6 daily doses of 5 cc.

intramuscularly, another 10 cc. doses daily, and the third 10 doses of 5 cc. each at 24-

to 48-hour intervals. The patient who received quinine as well was followed for only 1

month, during which he was well. In the second patient, the temperature became normal within 48 hours and parasites disappeared from the peripheral blood within 96

hours. He relapsed on the 13th day after completing treatment. The third patient

became afebrile within 72 hours. At the conclusion of treatment parasites were absent

from the peripheral blood for only 72 hours. Clinical relapse occurred in the ninth

posttreatment day. Mild neutropenia was observed in all three cases.

As a result of experiences such as those cited, few medical officers in this

theater believed that current methods of treatment coulk do more than suppress symptoms and parasitemia in vivax malaria. In -another theater, prolonged experience suggested that Atabrine therapy not only was effective in

639243--63--36
514 INFECTIOUS )1SEAS•ES

suppressing relapsing malaria but, if continued long enough, might ultimately

cure it (p. 497). There is no indication in Colonel Golz's report that such consistently long-sustained therapy was ever carried through in the Mediterranean theater where, indeed, conditions were. lacking for such continuous

observations on identical groups of men as were possible in the Pacific area.

The desideratum was a method of treatment that would obviate relapses. The

British thought they had achieved this goal, or come near it, by their use of

Plasnmochin in conjunction with quinine. U.S. Army medical officers had

early discarded Plasmochin. finding it, of no particular merit as used by

them. and very toxic, especially in Negro troops. Our achievement was rather

in the increasingly more efficient use of Atabrine. Both lines of thought were

fruitful and, during and since World War II, have been carried to more

effective therapy and new drugs.

Results of Treatment

Mortality.-One measure of the effectiveness of treatment is the death

rate which in the Mediterranean, as in all theaters, was extraordinarily low.

In the entire history of the theater, there were approximately 62,000 definitely

diagnosed new cases of malaria in U.S. Army troops. According to individual medical records for 1942-45, there were 57 deaths due to malaria among

cases originating in the Mediterranean theater. There were 3 deaths in 1942,

40 in 1943, 13 in 1944, and 1 in 1945. After an extensive search, Colonel Golz

discovered only 11 deaths that actually occurred in the Mediterranean theater. Of 8 deaths ascribed to malaria on clinical grounds in official records for

1944, post mortem studies showed that death was due to other causes in 5

(1 Hodgkin's disease, 1 brain tumor, 1 infectious hepatitis, 1 hemorrhagic

bronchopneumonia, and 1 "cause undetermined but not malaria"). By any

calculation, the mortality was surprisingly low.

There are several reasons for this. Table 67 shows that in Italy the

incidence of infection caused by P. falciparuwn was low. Other factors were

Atabrine suppressive treatment (curing many .alciparum infections) and the

excellent distribution and the high caliber of medical care available to U.S.

troops.

Morbidity.-The malaria relapse rate was 28 percent in the Mediterranean

theater and 23 percent in the Pacific areas. These figures are gross figures in

that they have not been adjusted to take into account evacuation, death, or

transfer of cases. The figures merely reflect a ratio of readmissions to new

admissions.

Several attempts were made to assay the dimensions of the problem by

indirect means. Colonel Golz, on the basis of data shown in tables 70 and

71, concluded by one line of reasoning that, of any group of primary malaria

cases, 30.6 percent might be expected to relapse at least once, with the average

number of relapses being 2.08 for the group. He also cited Lt. Col. (later
TREIATMENT OF MALARIA 515

Col.) James B. McLester, MC, of the 17th General Hospital who, using the

same data and some of his own. made a somewhat different approach. Of a

group of cases followed from 1 to 10 months, 30.5 percent. relapsed. Over

one-half of the relapses during the first. 9 months occurred 1. the first 2

months and another quarter, in the next 2 months. Since after 6 months, the

monthly rate remained between 1 and 2 percent, it seemed probable that the

relapse rate would be found to be between 50 and 60 percent if the followup

were more complete and continued longer. Other data, more extensive numerically, derived from 27 hospitals by questionnaire by the malariologist of

NATOUSA, suggested, by several lines of reasoning, a relapse rate of about

50 to 55 percent.

TABLE 70.-- Incidence of attacks of malaria reported by 27 hospitals in the IMediterranean

(formerly North African) Theater of Operations, U.,S. Army

Primary lciaps

\urnlwr aidl Lype oe hospitals reporting Total

Number Percent Number Percent I

1 field -------------..... ....----------- 33 11.3 258 88.7 291

1 evacuation -------------------------- 1,525 83.5 301 16.5 1,826

2 convalescent --------------- --------- 55 34.0 107 66.0 162

16 station ---------- 5,467 61. 1 3,479 38.9 8,946

7 general ---------------------------- 1,492 49.6 1,516 50.4 3,008

Total --------------------------- 8,572 60.2 5,661 39.8 14,233

TABLE 71.-Incidence of relapses due to malaria reported by 18 hospitals in the Mediterranean

(formerly North African) Theater of Operations, U.S. Army

Number of relapses

Number and type of hospitals reporting Total

cases

1 2 3 4 5 6 7 8 9 10 II

I evacuation ---------------------------- 184 36 28 29 9 4 7 0 2 2 0 301

1convalescent ------------------ 14 15 14 4 3 0 1 2 0 0 0 53

10station ------------------------------- 934 496 267 137 69 32 21 15 6 3 4 1,984

6 general ----------------------------- 553 230 126 97 57 43 40 14 8 2 4 1,174

Total -------------------------- 1,6851 777~ 435 267 138 7 9 3 16 3,1

Percent of total ------------------------- 48.0 22.1 12.4 7.6 3.9 2.2 2.0 0.9 0.5 0.2 0.2 100

I Data not available from field hospitals.

Colonel McLester stressed the obstacles to statistical accuracy. In the

Mediterranean theater, the number and composition of troops were constantly

changing with the tactical situation, and the population at the time of recurrence might be very different in size from the population at the time of pri-
516 INFECTIOUS DISEASES

mary attack. Fresh troops might come in who had not previously been exposed to malaria and might have time for only one attack. Soldiers who had

had a primary attack might be evacuated, or killed, or transferred to another

theater before relapse could develop. Furthermore, in an attempted followup of patients who had been treated in the 17th General Hospital, gross errors

were found in their medical histories. Also, the record was regarded with

suspicion when a patient, known to have had an attack with P. faleiparum,

was reported as having relapse with 1. vivaax.5

Table 72 will show that the percentage of cases transferred to the Zone

of Interior is not a valid figure for the malaria question as a whole. Many

of the admissions to general hospitals were transferred from other hospitals,

and with few exceptions only general hospitals had the power to transfer

cases to the Zone of Interior.

Many of the cases found in general hospitals had been transferred there

by other hospitals specifically for Zone of Interior disposition because of repeated recurrences. Nevertheless, a study was undertaken at the 182d Station

Hospital to determine the final disposition of its malaria cases: 757 cases

were investigated, of which 437 were recurrent and 320 were primary. Of

these, 103 cases were transferred to other hospitals for reasons other than

malaria and could not be traced as to disposition. Of the remaining 654,

those who were transferred were satisfactorily traced. The result of this

study showed that 641 went to general military service, 5 went to limited

assignment, and 8 (1.22 percent) were recommended for evacuation to the

Zone of Interior by a general hospital.

TABLU 72.--Malaria patients evacuated to the Zone of Interior from the Mediterranean (formerly North African) Theater of Operations, U.S. Army, 25 hospitals reporting

Number and type of hospitals reporting Total caes Numberevacuated Percent

18 station ---------------------------------- 10,604 28 0.26

7 general ----------------------------------- - 3,185 250 7.85

Total --------------------------------- 13, 789 278 2.02

5 Although complete and accurate statistics on the Incidence of relapse are not available from

any theater, similar relapse rates for Mediterranean strains (approximately 30 percent) were found

elsewhere in this theater and also in the Zone of Interior during periods of 120 days following

treatment with various antimalarials. Relapse rates were much higher with Pacific strains during

like observation periods of 120 days, being approximately 80 percent In one study and 80 to 90 percent in another. It should be noted, however, that a very much higher percentage of relapses of

Pacific origin will fall within the 120-day period (75 percent occurring within the first 60 days in

one study). With the Mediterranean strains, there is a longer average interval to the first relapse

(150 to 200 days). Even when this is taken Into account, the estimated rate of 50 to 60 percent

remains appreciably lower for the Mediterranean strains of P. vivac.

Modifications of relapse rates by the treatment preceding the observation periods were not

such as to invalidate these calculations, except when Plasmochin was used In conjunction with

quinine. In extensive comparisons, the majority of relapses occurred within the first month after

treatment with quinine or totaqulne and within 3 months after quinacrine or chloroqulne; that Is,

well within the span of 120 days.-P. H. L.
TREATMENT OF MALARIA 517

Machine records data concerning cases sent to the Zoae of Interior are

available for the period 15 September 1944 to 6 April 1945. During this

time, 8,055 cases of malaria were disposed of and, of these, 90 cases (1.1 percent) were returned to the Zone of Interior for this cause. An additional 3#3

cases were found with a secondary diagnosis and the available records were

not clear as to which diagnosis was responsible for the evacuation. If these

two groups are combined, the total number of cases is 126 or 1.6 percent.

Case Histories

In the 13 case histories 6 which follow, examples of particular problems

-most of them exceptional, some more typical-are described briefly. Included are eight fatalities.

Skin lesions

Herpes labialis occurred in some cases, and occasionally urticaria, which

was usually transitory. Urticaria had been seen more often in the early days

of the theater, when quinine therapy was still popular. Colonel Golz reported an interesting case, summarized in case 1. Four hospitals reported

seven casis of purpura simplex, beginning shortly after or concomitantly with

the clinical onset, and clearing completely soon after the start of antimalarial

treatment; in four cases this was associated with vivax infections, in three,

with falciparum infections. One hospital reported 10 cases of erythema

multiforme.

Case 1.-In one unusual case, the maturation of each cycle of parasites was accompanied by a severe attack of generalized urticaria and angioneurotic edema of about 12

hours' duration. These attacks occurred three times at 48-hour intervals without any

sign or symptom to suggest malaria. There was no elevation of temperature. With

the fourth such attack the patient had his first chill and rise in temperature. P. vivax

was found In his blood. Atabrine treatment resulted in prompt cessation of his hives

and he had no further chill or fever. During the 4 months following his discharge

from the 182d Station Hospital he had five relapses for which he was admitted to other

hospitals, and In each relapse the same train of events occurred. He was then evacuated to the Zone of Interior.

Blackwater fever

Four cases were reported in the Mediterranean theater. Case abstracts

of two of these patients are appended, one of whom died. Available data on

the third patient were so meager as to raise the question of diagnostic accuracy. Records of the fourth were not available.

Case 2.-The soldier was admitted to the 33d General Hospital with a history of chills,

jaundice, and dark urine for 4 days. The record did not state whether he had previously had malaria. Prior to admission he had no treatment. On the day of admission

he was stuporous and icteric but malaria smears were negative and the leukocyte count

6 In another theater, however, under more favorable conditions for prolonged observations on

the same body of men, there was shown a reversal of species incidence from 55 percent P. fateparum, 24 percent P. vivax during an epidemic In a malarious environment, to zero percent P. Jakfparum, 99 percent P. vivam, after the troops were removed to a nonmalarious environment.-P. H. L.
518 INFECTIOUS I)ISEASES

was 4,700. On the second hospital day trophozoites of 1'. falciparurn were found in the

blood. The urine was negative except for a trace of albumin. On the second and third

days fie was given 2.7 gin. of quinine orally and 1.3 gin. intravenously. On the third

day the red blood cell count was 4,330,000, tile hemoglobin 13.0 gin., and the leukocyte

count 5,300. On the fourth day the urine became reddish brown in color, showed 3 -+-

albumin and was positive to test for occult blood. The red blood (cell count had dropped

to 3,060,000 and the hemoglobin to 11.5 gin. per 100 cc. Trophozoites of P. falciparum

were still present in the blood. The blood nonprotein nitrogen was 37.5 mg. percent

and the icteric index, 9 units. Quinine treatment was stopped; Atabrine, given orally,

was started cautiously; and the patient was given a transfusion of 500 cc. of whole

blood. On the fifth day lie was much improved; the urine was negative; the red blood

cell count, 3,780,000; the hemoglobin, 12.0 gin. per 100 cc.; and gametocytes of P. falciparum were present on blood smear. The Atabrine dosage was then increased. Thereafter the course on full doses of Atabrine was uneventful. The urine remained normal

although the anemia persisted at a level of about 3,500,0M0 red cells per cu. mm. Gametocytes of P. falciparum were found on the smear daily until the day after Atabrine was

stopped.

Case 3.-A 32-year-old soldier was admitted to a station hospital in August 1943 coniplaining of chills, fever, and general malaise for 4 days. lie stated that he had had

malaria several years previously in the United States. He also stated that he had been

taking Atabrine in suppressive doses regularly. Physical examination revealed nothing

of note. Blood smear was positive for P. falciparum. He was given 10 gr. of quinine

three times daily by mouth. On the second day his general condition had deteriorated

and quinine was increased to four times daily. Physical and X-ray signs of bronchopneumonia developed on the third day. On the fourth day the urine became dark brown

and gave a strongly positive test for blood. The hemoglobin fell from 13.0 gin. in the

morning to 10.5 gin. in the afternoon. The blood nonprotein nitrogen began to rise.

He was given a transfusion of whole blood and an intravenous infusion of sodium bicarbonate solution. This treatment was repeated on the fifth day. The course, however,

had been progressively unfavorable and he died on the fifth hospital day with a clinical

diagnosis of blackwater fever. Autopsy confirmed the cause of death as malaria.

Vague symptomatology

Every hospital representative interviewed in this theater reported occasiomally seeing patients who complained of vagrue symptoms of fatigue, headache, and malaise; whose temperatures remained perfectly normal, and whose

blood smears were positive for vivax trophozoites. Asymptomatic carriers of

jalciparim, gametocytes were relatively more comnon. Not infrequently met

were cases of proved malaria with recent histories of one or more hospitalizations for fever of undetermined origin, with spontaneous remission. It is

highly probable that these previous febrile episodes were due to malarial

activity.

Case 4.-A soldier without a previous history of malaria was admitted to a station

hospital with the admitting diagnosis from his dispensary as "Vague complaints-nervous." The hospital history indicated that he had had a poor appetite, general malaise,

and chilly sensations at night for it week. During the first 24 hours in the hospital his

temperature remained normal and he showed what were interpreted as signs of an

anxiety neur,'is. On the evening of the second (lay in the hospital, the patient had a

chill, his teii.jerature rose sharply and he became irrational, confused, and restless.

Examination of the blood showed a marked anemia, leukocytosis of 14,000 and a heavy

infestation of the red blood cells with P. falciparum. In spite of 5 gr. of quinine intra-
TREATMENT OF MALARIA 519

venously every G) hours and four whole blood transfusions of 500 cc. each, his condition

gradually deteriorated]. Hle lapsed into coma on the third hospital day and died on

the fifth.

Fever

In approximately 75 percent of r'h'ax infections, the typical intermittent

temperature graph with quotidian or tertian paroxysms was seen. The relatively high percentage of remittent fever (25 percent) may be ascribed to the

prompt institution of specific treitnient. The majority of .falcparulm infections exhibited remittent fever without frank paroxysms.

Some cases were without fever through all or a large part of their clinical course.

Case 5.-A soldier was admitted to a station hospital with a history of having had

chills and fever, nausea and vomiting for a week. On admission jaundice was observed

and the liver was palpated three fingerbreadths below the costal margin. He was afebrile and malaria was not suspected. Two days after admission the patient became

stuporous. His red blood cell count %:i 2,700,000, his leukocyte count 40,000, blood

nonprotein nitrogen 99 mg. percent, and Ihis blood smear was positive for P. falciparum.

Despite vigorous treatment with oral and parenteral quinine, the patient died on the

third hospital day, having remained afebrile throughout.

Liver and spleen

Hepatolnegaly of mild degree was associated with malaria in about 15

or 20 percent of cases. Minimal scleral icterus was seen in less than 5 percent

and was thought to be an expression of the blood destructive process that accompanies malaria. Definite jaundice was occasionally seen concurrently with

malaria and was thought to be due to complicating infectious hepatitis. Definite jaundice due to malaria did occur in blackwater fever and moribund

cases. The term "malarial hepatitis" was freely and glibly used in this

theater, but no evidence was adduced to show that such a condition existed.

Pathologists found no parenchymal lesion; liver function tests showed only

transitory changes, and enlargement of the liver was usually only transitory.

The spleen was often found palpably enlarged during the second week

of the acute attack. It was usually soft and tender in the acute stages, and

was firm and not tender in the chronic stages. Reports from various hospitals

in this theater varied widely as to the incidence of palpable spleens. The

acute splenic tumor usually subsided rapidly after antimalarial therapy.

Persistent enlargement usually signified a chronic latent infection; many of

the cases that had frequent relapses had a chronic splenomegaly. In one

case, a ruptured spleen was found at autopsy.

Case 6.-A soldier was admitted to a station hospital in a moribund condition. He

was reported to have fainted shortly before admission and on recovering consciousness

complained of substernal pain and vomiting. He denied any injury. In the emergency

room he showed extreme pallor, air hunger, and restlessness. His pulse was imperceptible. The abdomen was not distended nor tender. A blood smear showed 4 percent

parasitization of the red cells with P. riraxr. l'lasina was administered as an emergency

measure, but the patient ceased breathing while the plasma was being given. At autopsy

the peritoneal cavity was found to be filled with blood and a 4 cmr. tear was noted in
520l'() INFECTIOUS DISEASES

tilt' Aheen,. The pathe mhI i gi1 tiagnii sis was spheiolllehn kly Idate to HiraWr ilife*ti 4n, and

sponiitllitatin s rlpilt ure of tihe splhete.

Gastrointestinal symptoms

\'omit1ing. ovcurring ill about 20 percent of ,<ewr infections, was usually

not severe and was asscviated only with the paroxysis: ill .fl/.cpU1 infections, it tended to be more severe and persistent and wias one of the frequent

:iiicat ions of the cerebral svndronie.

Abdominal painl was verv coi1iltioti. Most frequent was an achy pain

high ill the left uipper quadhralnt, sometines radiating to the left lower chest

anl oft en aggravated by respnirat'ory excursions. Infrequent cases were seen

simulating acute surgical emergencies. Two in which laparotomy was performed are described:

Case 7.--A soldier was admijtted to an evitcuation hospital with a history suggestive

of a ruptured al)domuhinal vIscilS. There was boardlike rigidity of the abdominal muscles,

zanid the leukocyte count was 14.4)N(. Exploratory laparotltiy revealed niothlilg ahMiorila 1. SnbsMuently 1. fohipttrumn was discoverel in the peripheral bloohl. Antimalarial

therapy produced complete recovery.

Case 8.,A soldier wias admitted to a station hospital with at diagnosis of acute appendicitis. having exiwrIenced 24 hours previously the onset of generalized cratuping ahdo(1a11al pain, which subsequently localized In the right lower quadrant. There was

nausea but no vomiting or distur-antce of bowel habit. There was no history of Malaria.

Tile temperature wits 102.80 F. and the leukocyte count 5,.MM). Marked tenderness was

notetl in the right lower quadrant on direct palpation and oil rectal examinatlon. Eimergency appendectomy was performed Nut a nornial appendix was removed. The postoperative course for 2 weeks was (olnplicated by intermittent fever of 1MY0 or lII2* F.

exhibiting a tertian periodicity. (On one occasion Ite had a chill and a temperature

rise to 1050 F.) Repeated malaria smears were negative. On the 19th postoperative

day 11. vivax was found. Antinmhalarial therapy resulted iii disappearaiwe of aill signs

and symptomis.

Generalized aching or cramping abdomiinal pain was occasionally I comiplaint, especially in patients with diarrhea. It was usually of mild (legree,

occasionally more severe, and occurred inl about 10 percent of infections with

P3./t1X. In malignant terti malaria. diarrhea was not nmre connmmon but

wais often more severe, at times dysenteric. The stools in such cases sometimes

contained red blood cells but never pus, parasites, or pathogenic bacteria. A

brief description of a fatal case follows.

Case 9.-A 24-year-old soldier was admitted to a station hospital in October 1943

couinlaiiinig of severe diarrhea of 5 (lays' duration. The diarrhea was tceompanied by

severe abdontinal cramps and grossly bloody stools. Tie had had one chill prior to ad(]-

mission. There was no previous history of nmalaria but the soldier had fought through

the Sicilian (2lmpaign several months previously. On examination he was found to be

in shock. The pulse was almost imperceptible, blood pressure was 70 systolic andC (1)

diastolic, and temperature 970 F. The abdonen was rigid, leukocyte count was 25,00M

and the red'41 blood cell count was below :1 million. The stools c.ontained dark blood and

blood smears were positive for P. fhlciparunl. The surgical consultalnt felt that there

waits o inldication for surgical intervention. Oin the first hospital day lie was giveln 10

gr. (of quiinne tit rivenoull-y. at transfusion of olle liter of citraited blood and aplliretllly

aldeqitlate aim1ollults of physiological silline solution1 inltravelnosly. (Oril qulllnine t lieraloy
TREATMENT OF MALARIA 521

was started. On the second day he was markedly improved. Diarrhea and vomiting

ceasedi temperature rtse to 101' F. and the systolic blood pressure to 110. Oralt quinine

three times daily was continued. On the third day lie suddenly went into a state of

peripheral circulatory collapse and promptly died. Autopsy showed an extensive hemorrhagic enterocolitis. Malaria parasites were found in sections of the intestinal tract

and the heart showed numerous areas of focal necrosis. No notable changes were found

in the brain.

The cerebral syndrome

Of the 57 deaths due to malaria in the Mediterranean theater during

1942-45 (p. 514), 14 were ascribed to viva.x malaria, 27 to falciparum. malaria,

and 16 to "other or unclassified malaria" (the "other malaria" excluding

quartan malaria and mixed malaria infections). In the 11 deaths reported

by Colonel Golz, 10 were due to malignant tertian mnalaria, and of these, 8

were caused by the cerebral form of the disease. All eight cases illustrated

the grave danger attendant upon failure, for whatever cause, to initiate vigorous treatment early.

Case 10.-A soldier was admitted to aul evacuation hospital with a history of c-hills and

fever for 4 (lays. There was no past history of nmalaria. On the (lay before admiissidon

he had a temperature of 104.4° F. with pain in the left upper quadrant, and smears were

positive for P. falciparum. He was given 0.2 gui. of Atabrine every 6 hours orally. On

admission his temperature was 98.8' F. and his general condition seemed to be fair.

Blood counts showed a marked anemia and smears showed all stages of P. falciparum.

Spinal fluid was negative except for increased pressure. On the second hospital (lay lie

suddenly became stuporous, psychotic, and could not be aroused. There was only a

slight pupillary reaction and his neck was rigid. On this day the patient received a

total of 3.3 gin. of quinine intravenously. In spite of this he developed tonic convulsions

and (tied. Blood quinine level was 7.1 mg. per liter.

Case 11.-A 45-year-old soldier was admitted to a station hospital in the spring of

1943 in a marked state of mental confusion and delirium. Because of his mental state

no history could be oitained. Persistent vomiting was present. Red blood cell count

was 2,000,000 and leukocyte count 12,000. Diagnosis was made on the second day with

the identification of P. faliparunt in the peripheral blood. Ten grain- of quinine wereý

given orally three times daily. However, vomiting persisted. On the fourth day 10 gr.

of quinine intravenously every 8 hours was instituted, and the patient received this

medication four times. He was also given two whole blood transfusions. He lapsed

into coma in spite of this treatment and died on the fifth day. Autopsy report was not

available.

Case 12.-A soldier was admitted to a station hospital in a comatose state. Signs of

lobar pneumonia were present. There was marked anemia, and blood smears were positive for P. falciparum. In spite of treatment with sulfadiazine, intravenous quinine,

whole blood transfusions, and oxygen, the patient died on the third hospital (lay. Death

was ascribed clinically to cerebral malaria. Autopsy showed lobar pneumonia and numerous malaria parasites in the brain, heart, andu muscles.

The incidence of this ill-defined syndrome varied widely among the

hospital representatives questioned although none declared it to be common.

Restricted to cases showing one or more of such signs as coma, meningismus,

convulsions, persistent delirium, and well-defined neurological signs, 144 cases

were reported due to P. falciparum and 19 due to P. vivax. This did not

6.39•243'-63-¢- 3•7
522 lxFE~CTI'r DIS FlSE~~S

represent total theater experienice. since it was not possible to Surlvey all1 of

the hospitals in the theater.

Of the eight deaths in this t heater tite to cerebral malaria. all wvere

fadauainfections. The. moderni coucept of the pat. )logical ph : ysiol ogVof cerebral malaria permits a reasolialble dobuit as to its occdurrence Ini 0110.11

infections. In only 1 of the W9 cases so reported was the record availab~le

for analysis, and in this case the accuracy of the diagnosis was quest ioniable.

A summary follows.

Case 13.-The lpatient became ill (; October 1944 with nausea ani some vomniting.

Began "slhaking." No further coherent story could be elicited. Temperature was 970 F.,

pulse 104, and respiration 24. There were no abnorinal findlings. The battallon surgeon

who sent the patient to the station hospital oin 7 October, suspected malaria. Temperature was 100.20 F. ait timne of onset.

The patient wits seinicomatose, on 8 October 1944. Lumblar puncture wag done on

the samne day. Pressuire was elevated. The first tube contained red ce-lls: the se'ondl

was crystal clear. There were 84 cells, 301 lNlyinorphonuclears, andl 58 lymph)locytes.

Tfle examining medical officer was not certain that the patient had meningitis. Lyinphocytic choriomieningitis or encephalitis wias (considered. The( patient had four generalized

convulsions on It O ctober and was transferred on that (late !in deep (01111 to at general

hospital wvith the diagnosis of epilepsy. Oni admnission considerable inotor unrest wits

noted ibut 11o movenments of right side. Exalmintijton Was (difficult but did show bilateral

ankle- clonus and Babinski's anid O ppenheimn's signs. Abdominal reflexes were absent.

Right sidle of face did not imove as well as left ; slight internal squint, right eye. Plendular nystagmus, on looking ahead. changed to dlefinite slow vestibular variety on looking

to right. Conjugate movements of eyes were preservedl; pupils dilated, reacted poorly

to light ; fundi normal. Patient gave no response to painful stimuli. Definite meningitis neck with direct Brudzinski's sign andl bilateral Kernig's sign. Temperature was

102.20 F., pulse 96;, respiration 22, and blood pressure 126 systolic and 8A) diastolic.

The picture was that of an acuite nieningoencephahitis. How many of the focal signs

were due to the illness per se and how many at product of thme postconvulsive state could

not then he determined.

Spinal puncture yielded clear fluid ; 280 n1111. of water pressure; normnal dynamnics;

4 white blood cells (lymphocytes) ; sugar, 100 imug. percent: chlorides, 73:3 mug. percent;

globulin, nmegative. Total protein, 22 ing. percent. Kahnm negative. (;old curve, 1.111,-

(0(K,0W~. Subsequent smevar, culture, and pelli1cle studies were negative.

12 Octobe~r 1944 : Temperature dropped to normal. Patient responded to questions

but was confused much of the time. Neurological signs persisted.

13 October 19441: Spinal fluid examination showed: 260 mim. of water p~ressure;

clear; pressure dropped to 70 mm. of water after removal of 30 cc. of fluid: 5 white

blood cells (lymphocytes) ; sugar, (;2 nugr. percent (simultaneous blood sugar. 84 mug.

percent)-, chlorides, 759 mug. percent ; globulin,. negative; total protein, 24 ing. percent.

Smear and subsequent culture, negative. Generalized convuilsion ; then .Jacksonian tit of

right sidle. "Status" aborted with intravenous Amnytal Sodium.

14 October 1944 : Suspect right homonymnous heinianopsia (transient). Periods of

delirium and hallucinations. Afebrile.

146 October 1944: Two attacks of furor (equivalents). Was being given luminal

(phenobarbi tal ). Bromidiies added.

17 October 1944 : Today patient has left homonymous hemianopsia. No astereognosis. Soine tendlency toward pres~ervation. Meningeal signs persist.
TREATMENT OF MALARIA 523

18 October to 23 October 1944: Essentially the same. Some confusion. Ilemianopsla (left) persists.

24 October 1944: Temperature to 101.80 F. Malaria smear positive for tertian

parasites.

25 October 1944: Temperature rose to 103.40 F. during morning. Second slide positive for malaria (P. vivar). Quinine sulfate, 15 gr., three times a day by mouth started.

Four previous smears had been negative for malaria and he had been afebrile for

10 days when the micro-organism was found. White blood counts: 7 October, 12,350

(neutrophils, 80 percent; lymphocytes, 20 percent), 8 October, 5,300 (neutrophils, 74 percent; lymphocytes, 26 percent), 11 October, 11,500 (neutrophlls, 64 percent; lymphocytes,

36 percent).

Serology: Kahn, positive, 11 October. Kahn and Wassermann, negative, 17 October.

All spinal Kahns negative. Blood bromide, 75 mig. percent, 25 October 1944.

Spinal puncture on 25 October: Pressure 200 mm. of water; 2 white blood cells

(lymphocytes) ; sugar, 56 mg. percent; chlorides, 685 rng. percent. Total protein, 26 mg.

percent. Gold curve, 1,111,000,000.

Course: Afebrile on 26 October 1944, ard since. Cleared mentally. All neurological

signs cleared up except the homonymous field defect which was still present when he

was transferred.

Regardless of some diagnostic confusion, all medical officers in the theater acquired a wholehearted respect for the cerebral manifestations of the

disease. The grave prognosis of the frank cerebral syndrome and the serious

implications of persistent vomiting in faleiparum infections were quickly

learned, and this was responsible for the early institution of vigorous therapy

in such cases.

Cachexia

As with cerebral malaria, the incidence varied widely as reported by the

various hospitals because of lack of uniformity in the criteria for diagnosis.

When the discussion was limited to chronic, truly cachectic states, 12 hospitals reported a total of only 26 cases. It is probable that the theater experience did not greatly exceed this figure. Many medical officers noted that

the American soldier stood repeated attacks of vivax malaria remarkably

well, and a study in the South Pacific confirmed their impression.

From the reports cited, it can be seen that in all theaters of operations

in which command and medical officers found malaria a major problem their

experiences were very similar, and the stages of their education in dealing

with this disease were painfully alike. Rarely has the old adage, "Experience is a hard teacher" been so well illustrated in the annals of medicomilitary history. The same prejudices, the same mistakes, the same fumblings,

and the same slow correction of errors in tactical and medical thinking mark

the evolution toward solution of the problem of malaria as exhibited in the

reports of the consultants in medicine. Lack of foresight, on the one hand,

caught us with scant supplies of quinine; on the other hand, enterprise and

ingenuity found ways to improve upon quinine. Under the pressures of war,

we learned the chapter on malaria and expanded the section on chemother-
524 INFECTIOUS I)ISEASES

apy. Military medicine, like war itself and the events that lead to war, is

full of such ironies; of failures to do something relatively simple that would

save much trouble, and then doing something prodigious under the most trying circumstances; in other words, of the Iillman capacity for getting ourselves into the most dreadful difficulties, and thein, by summoning great vigor,

intelligence, and fortitude, gettinig outrselves out again. The great wars of

our times might be in general so described. The question for the future is

how long the human race can take its victories by hairsbreadth; whether, as

the wheel spins, we shall always come out on top.
CHAPTER XVIII

Clinical Trials of Antimalarial Drugs

Harry Most, M.D.

Extensive military operations in various highly malarious regions during the Second World War stimulated intensive research in the chemotherapy of malaria. Interruption of the normal supplies of quinine from the

Far East made it necessary, while conserving existing supplies, to reevaluate

the efficiency of Atabrine (quinacrine hydrochloride) and other agents with

known antimalarial properties and to widen the search for new drugs for the

treatment, suppression, and possible cure of malaria.

Numerous investigations were carried out by civilian, military, and public health research groups under contract of the Office of Scientific Research

and Development, Committee on Medical Research of the National Research

Council, and integrated by the Board for the Coordination of Malarial

Studies.' Approximately 15,000 compounds were studied, and the more

promising were given detailed pharmacological and toxicological examinat ion prior to testing in human beings. Important contributions to the knowledge of chemotherapy of malaria resulted from this comprehensive program.

Quinacrine proved as good as quinine in most, and superior in some, aspects

of treatment. New agents were found thac proved superior both to quinacrine and quinine. In addition, other drugs which apparently produce definitive cure of malaria were later found.

The principal purpose of this chapter is :. review briefly some of the

clinical drug trials made during World War I1 in relation to their military

application in the management of malaria. A note is added oin some of these

studies as continued, still under the auspices of the U.S. Army, and brought

to significant conclusions in the iniiiediate postwar period (p. 594).

PENICILLIN

The occurrence of acute attacks of malaria in military patients who were

given large amounts of penicillin for surgical or other infections suggested

very early in experience with this antibiotic that it would have no vlIue in

the treatment of malaria. Failures to terminate acute attacks with penicillin in amounts of 460,000 to several million units were reported. The imI A Joint Body Composed of Representatives of the Office of Scientific Research and Development, the Army, the Navy, the U.S. Public Health Service, and the National Research Council, vole.

I-VII. [Official record.]

525
526 INFECTIOM1.4 DISEAXSIl

pression was further confirmned in the treatnment of "'-.urosyphilis with penicillin and in the treatment of fever induced by malarial infection (transmitted

by Plhisnodiuml vi*va.r and f'la-nwdium ituthlriate).2 Of the patients who had

remissions of fever, the larger percentage (31 percent of 147 patients) had

had no penicillin during therapeutic malaria; the smaller percentage (13

percent of 46 patients) were given 30,000 units every 3 hours for 190 doses,

beginning the day after a rise in temperature to 1030 F. Again, 15 patients

were inoculated with the McCoy strain of P. rihax and studied under various

schemes of treatment with penicillin. Each patient received 3 million units.3

This therapy did not reduce the fever, after the cycle of activity, or affect

the degree of parasitemia; it (lid not prevent, postpone, or alter the nature

of the attack (chart 26). Penicillinl had evidently no place in the prevention, treatment, or suppression of malaria.

HEAVY METALS

Arsenicals.-Arsenated benzine compounds (arsphenamine, neoarsphenamine, and oxophenarsine hydrochloride (Mapharsen)) commonly used in the

treatment of syphilis have for a long time been known to possess antimalarial

properties in varying degrees. Studies made before and during World

War II 4 showed that they were ineffective against infections caused by P.

malriade and P. falciparum. Given intravenously, intramuscularly, or orally,

arsenicals were found to possess definite activity in terminating the paroxysms and parasitemia of malaria due to P. vi'vax, particularly in bloodinduced infections; in naturally acquired malaria ascribed to P. vivax, they

proved inferior to quinacrine, quinine, and other drugs as regards control of

fever, parasitemia, and the interval to relapse. It was found that their intensive use is not without danger, that they offer no practical advantage over

more effective drugs, and finally that arsenicals administered alone or in

conjunction with quinacrine or bismuth do not affect the natural relapse rate

of this disease.

2 Personal communication, Maj. Harry H. Gordon, MC, Chief of Communicable Diseases, Harmon

General Hospital, Longview, Tex., to the author.

:1 Hindle. J. A., Rose, A. S., Trevett, L. D., and Prout, C. : The Effect of Penicillin on Inoculation Malaria: A Negative Report. New England J. Med. 232: 133-136, 1 Feb. 1945.

4 (1) Werner, H.: Das Ehrlich-Hata Mittel 606 bet Malaria. Deutsche med. Wchnschr. 36

(Pt. 21 : 1792-1794, 29 Sept. 1910. (2) Curd, F. H. S.: The Activity of Drugs in the Malaria of

Man, Monkeys, and Birds. Ann. Trop. Med. 37: 115-143, September 1943. (3) Goldman, D.: The

Use of Mapharsen In the Treatment of Malaria. Am. J.M. Bc. 196: 502-509, October 1938. (4)

Morrison, W. H., and Hill, E. R.: Use of Mapharsen in Relapsing Tertian Malaria. [Official record.]

(5) Kay. C. F.: Failure of Mapharsen as an Adjuvant to Atabrine in the Treatment of Relapsing

Tertian Malaria. J.A.M.A. 127: 984, 14 Apr. 1945. (6) Spector, S., Haviland, J. W., and Cogglesball. L. T.: The Ineffectiveness of Intensive Mapharsen, Bismuth, and Carbarsone as Curative Drugs

for Chronic Malaria. Am. J. Trop. Med. 25: 463-467, November 1945. (7) Bispham, William N.:

Malaria: Its Diagnosis, Treatment and Prophylaxis. Baltimore: Williams & Wilkins Co., 1944.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 527

CHART "26.-Penicillin studies in three patients 1 tith vivax mnalaria

TEMPERATURE

0*.

o ULATION IOI WITH VIVAX MALARIAANTIMALARIAL DRUG

100

tS

61

370 6,900

PARASITE COUNT 0 0 0 - 200 2,1600 8.200 I i i I i

I i I I I i I

PENICILLIN j 3.000,000 UNITS IN 10 DAYS

I I I I

101

1O2 INOCULATION WITH VIVAX MALARIA

lOg

9.

96

PARASITE COUNT 35 45 ,5

3- 450 5,400

PENICILLIN 3,000,000 UNITS IN 10 DAYS IIIIi

106

104 -W. F.

102 INOCULATION WITH VIVAX MALARIA

100

98

96

7,300

PARASITE COUNT I + + 1,470 1 9.000 I l I I

I 1 I I

PENICILLIN 3.0OjO00O UNITS IN 10 DAYS

I i I 4 I

1 2 3 4 5 6 7 S 9 10 1 12 13, f4.15 16 IT IS 19 20 21 22 232425

DAYS

1 Patient M.R. received penicillin after the development of parasitemia and fever. Patient MY'.

received penicillin several days before the inoculation of malaria. Patient W.F. received penicillin

on or about the same day as the malarial Inoculation.
528 INFECTIOUS DISEASES

Bismuth compounds.-In one study ' reported during World War II, it

was shown that prolonged courses of bismuth subsalicylate in conjunction

with intensive Mapharsen therapy did not reduce the relapse rate in naturally acquired vivax malaria of Pacific origin. Bismuth compounds have

some limited value in therapeutic management through their ability to establish tertian periodicity 6 in patients with induced viwx malaria who have

daily or irregular paroxysms, by interrupting, although not terminating, the

infection.

Antimony compounds.-These components have been shown to have antimalarial properties 7 both in vivax 8 and jalciparum 9 infections, but practical application was not found for them in the treatment of vivax malaria of

Pacific origin. They have been provocative in precipitating clinical attacks

of falciparumn or vivax malaria in patients under treatment for kala-azar or

schistosomiasis. It is of interest, too, that relapses of vivax malaria have

occurred in nonendemic areas in patients who had previously received one

or more intensive courses of trivalent compounds (stibophen (Fuadin) or

tartar emetic) for schistosomiasis japonica, or pentavalent compounds (stibamine glucoside (Neostam) and/or ethylstibamine (Neostibosan)) for kalaazar. The prolonged administration of tartar emetic (30 days or more) in

therapeutic amounts (1.8 to 2.25 gm.) in many cases is moderately toxic.

SULFONAMIDES

Shortly after the introduction of the sulfonamides in the chemotherapy

of infections, they were found to possess antimalarial activity of varying

degree. Although data from many studies 10 indicated their limitations, addi5 See footnote 4 (6), p. 526.

6 Young. M. D., McIendon. S. B., and Smarr, R. G.: The Selective Action of Thiobismol on

Induced Malaria. J.A.M.A. 122: 492-494, 19 June 1943.

7 Schmidt, Hans, and Peter, F. M.: Advances In the Therapeutics of Antimony. Leipzig: Georg

Thleme, 1938, pp. 80-82.

8 Cole, H. N., DeOreo. G. A., Driver, J. R., Johnson. H. H.. and Schwartz. W. F.: Use of Bismuth Injections to Manage Course of Therapeutic Malaria. J.A.M.A. 115: 422-427, 10 Aug. 1940.

9 (1) De Nunno, R.: Azione del tartaro stiblato sui gametociti del plasmodium vivax e del p1. falciparum. Ricerche sperimentalL. Riforma med. 54: 1599-1601, 22 Oct. 1938. (2) De Nunno, R.:

La stimolazlone antimoniale del s.r.e. come meszo terapeutico mella malaria estivo-autumnale chininoplasmochina-atebrin resistente. Nota preventiva. Riforma med. 51 : 1087-1093, 20 July 1935.

10 (1) Niven, J. C.: Sulphanilamide (Frontosll) in the Treatment of Malaria. Bull. Inst. M.

Research, Federated Malay States (no. 4), pp. 1-27, 1938. (2) Niven. J. C.: Sulphanilamide In the

Treatment of Malaria. Tr. Roy. Soc. Trop. Med. & Hyg. 32: 413-418, November 1938. (3) Yamamato, K.: Sulfanilimide in Malaria. Japanese J. Dermat. & Urol. 46: 78, 20 Oct. 1939. (4)

Chopra, R. N.. Das Gupta, B. M., Sen. B., and Hayter, R. T. M.: Prontouil In Indian Strains of

Malaria. Indian M. Gaz. 74: 321-324, June 1939. (5) De Leon, A. D.: El paludismo y su Tratamiento Intra-venoso por las Sulfanilimidas. Medicina, M~xico 20: 551, 10 Nov. 1940. (6) Chopra,

R. N., Hayter, R. T. M., and Sen, B.: M. & B. 693 In Indian Strains of Malaria. Indian M. Gaz.

74: 658-660, November 1939. (7) Coggeshall, L. T.. Maler, J., and Best, C. A.: Effectiveness of

2 New Types of Chemotherapeutic Agents in Malaria. J.A.M.A. 117: 1077-1081. 27 Sept. 1941.

(8) Johnson, C. E., Jr.: Status of Sulfonamide Therapy in Malaria. Am. J.M. Sc. 206: 327-336,

September 1943. (9) Schwartz, L., Furst, W., and Flippin, H. F. : Sulfathlazole as an Antimalarial.

Am. J. Hyg. Sect. C 34: 160-162, November 1941.
CLINICAL TRIALS OF ANTIMALAItlAIL DRUGS 529

tional trials were undertaken to determine their supprlessive and clinical value

in malaria of war origin. Observations showed quite definitely that sulfonamides do not affect the relapse rate of vivax malaria, and successful termination of acute attacks was achieved only with large doses, which not

infrequently resulted in sulfonamide toxicity. Fever and parasitemia were

not controlled promptly, and relapses occurred early following treatment.

In short, sulfonamides were inferior to quinine or quinacrine in terminating

acute attacks. They were found to be more effective in malaria caused by

P. falciparum. In a study from West Africa, four out of six sulfonamide

compounds exerted a definite effect on fever and parasitemia, but all of them

were considered inferior to quinine and quinacrine in the treatment of .falciparum infections.

It was observed that sufonainides used in the treatment of bacterial

infections may suppress parasitemia due to P. falciparum or P. vivax and so

delay the diagnosis of malaria in patients currently or recently under treatment for pneumonia or other infections."'

Field studies were conducted in various theaters. It had previously

been shown that plasma levels of 4 mg. percent or higher maintained for 28

days after the inoculation of trophozoites of P. falciparurm prevented the

subsequent development of this infection but failed to suppress experimentally induced infections with P. vivax. In a series of brilliantly conceived

and executed experiments by Australian research teams on the chemotherapeutic, suppressive, and prophylactic activity of various drugs, it was demonstrated that daily doses of 1 gm. of sulfamerazine, sulfadiazine, or sulfamethazine would effectively suppress falciparum malaria but would prove

ineffective against infections with P. viax.'ý

The practical application of sulfamerazine as a suppressive agent in various field studies is summarized in table 73. These observations show that

sulfamerazine in daily doses of 0.5 gmn. was not a causal prophylactic, that

cyanosis and other manifestations of toxicity were not uncommon, that more

clinical attacks occurred during suppression with sulfamerazine than with

quinacrine and that they occurred sooner after discontinuance of the drug,

and that sulfamerazine exhibited a high degree of suppressive activity but

was inferior to 0.6 gm. quinacrine weekly.

Thus, the sulfonamides at most have only limited if any value in the

practical treatment or suppression of malaria during war or in civilian life

if quinine, quinacrine, or equally effective agents are available.

11 Page, S. G., Jr., and McCall, J. V., Jr.: Delay in Diagnosing Malaria After Sulfadlazlne

Therapy; Two Case Reports. South. M.J. 39: 728-731, September 1946.

12 Fairley, N. H.: Chemotherapeutic Suppression and Prophylaxis in Malaria; An Experimental

Investigation Undertaken by Medical Research Teams in Australia. Tr. Roy. Soc. Trop. Med. &

Hyg. 38: 311-365, May 1945.
530 INFECTIOUS DISEASES

TABLE 73.--rperimaental field tests with sulfamerazine, Atabrine, and sulfapyrazile

I Days' Num-l I

of I Davs I ler I Number of Number of Total malaria IDuration

Drug Dosage expo-I of of blreak- infections caseS of sure drug sul- throughs I followup jects

l'anama I

1f3 riaxr ill rirax

Sulfaznerazine --- 0.5 gm. daily-- 32 42 111 2 'iral" 4jlfeltipartm .1 Ilaiparum

Atahrne 0.4 gm. weekly- 32 42 109 0 2 n 1

l i Iirw.r 30 days.

Southwest Pacific Area 2

Sulfamerazine-... 0.5gm. daily. 44 54 99 1 fa1"3 2 pa " 3614 darum

Do --........ ' 1.0gm. daily_-_ 44 54 12 3 mixed I 57 days.

Atabrine ------ 0.6 gin. weekly. 44 54 107 I 0 25 rirax 25 riracr

Southwest l'acific Area 3

301+17 Viax i5 

Sulfamerazine 0.5 gm. daily. 33 on 100 2 6 8 2faciparum

Ata- 1I mixed

brine. '0 days.

Atabrine --------- 0.4 gm. weekly. 33 42 114 10 23 31 9fakiparum

17 mixed

India

Sulfamerazine -.-- 0.5 gin. daily_-- 31 39 -m00 14 14 4 days.

Atabrine --------- 0.4 gm. weekly- 31 39 2W0 9 9 Do.

West Africa

Sulfapyrazine ----- 0.5 gm. daily --- ------------- 140 4 ----------

Atabrine --------- 0.4 gm. weekly -.-------- 140 24 ----------

I In the control group for the experimental field tests conducted by Col. Wesley C. Cox, MC, in Panama, 281 subjects

were kept under rigid malaria control and discipline. There were four cases of malaria and all suffered breakthroughs

caused by rivaz Infections. None suffered infections following suppressive treatment. Duration of followup after therapy

was 30 days.

the field tests conducted by Col. Maurice C. Pincoffs, MC, in the Southwest Pacific Area, SIn there were 51 subjects

who had been exposed to malaria for 44 days and had received a malaria suppressive for 54 days. There were 32 cases

of malaria of which 17 suffered breakthroughs. There were eight breakthroughs due to rirax infections, eight tofalciparum

infections, and one mixed infection. Eight suffered infections after suppressive treatment, five were Vrraz Infections, two

a/ciparum infections, and one mixed infection.

3 Tests conducted by Col. Earl Maxwell, MC.

4 Tests conducted by R. N. Chopra.

3 Tests conducted by Brigadier G. M. FLndlay.
ri.I N 1 A I t. I~ A L 41. A ViiMA NI..LAII I. I iII,:

lu elivi 4' I; I ~: 41 44'* I it I4: f: lil 11A:4.rf;i

(hIN(IHON\ AL.KALID~lS

W ith1( i 41(41&4 lt - Il4l the' n r.li (d,'I the lit' .l'1 'I 1'i4' 1'4 ( '4444 '114'11111c4''.col

Iiit'li 4)4 "Ih4e 4 ch'5 1 6ce4t~ iii ll O W I: 1 1 401IIV I () ' Ii' Vt41it' fl l - 1 t lV s I (1 I rl V1

1)'4 CM i: i 1 444drv liii li i vlo I list' v I (-I 4s 14~ 1 ;1 I h3s -'t'4'l r414 Hi 1 44 If incli Itul n I I it'" k 

ako11)4i4 : h ilI (:tlihlt ill4- Iit' Il t')\\ 144th!il I44( 1-1 slt, t'5si441 A k II d \vi"i;ii MIiit Ii.t

nii1 0 ':I M -oM4(f42.lll w o ir IIiv \\([il Il ý.-rl1fc i
532 INFECL'TIOUS IDISEASES

Acute attacks

It had been shown that plasma concentrations of quinine of 4.5 Ing. per

liter (dosage range 0.12 to 1.8 gin. daily) were effective in suppressing and

in terminating acute attacks of vivax malaria. Plasma levels of 5.5 mg.

per liter suppressed and terminated acute attacks of faledparumn malaria. 14

Nevertheless, in a field-type experiment with New Guinea strains, daily (loses

of 0.6 gin. failed to prevent attacks of faleiparum nmalaria, and 0.3 gin. daily

was incapable of preventing vivax attacks. When the latter (lose was increased to 0.6 gin., complete suppression was achieved iii solne cases of infection with P. 'vivax but not in others. By contrast, daily doses of 0.1 gin.

of quinacrine were completely effective in suppressing infections with either

agent.

In West Africa, daily suppressive (doses of 0.3 gin. quinine were associated with a malaria rate of 651 per 1,000 in a group of 1.180 men, with 4

cases of blackwater fever. In another group of 96 men given 0.3 gin. of

quinine daily, 70 developed clinical malaria while on this regimen and 7 more

while being transferred to quinacrine. On the other hand, in 752 men on

relatively small doses of quinacrine (0.4 gm. weekly), the rate was 450 per

1,000 with only ! case of blackwater fever. This definite discrepancy in

attack rate would doubtless have been larger if they had been given what

was subsequently found to be the optimum dosage of quinacrine (0.7 gm.

weekly).

Relapses

Clinical studies in this country were undertaken 1 to determine the effectiveness of maximum doses of quinine in terminating acute attacks of

relapsing vu'ax malaria of Pacific origin. The following results were reported in a comparative study of a group of 100 patients treated with 28.35

gin. of quinine during 14 days and a control group of 150 patients treated

with 2.8 gin. of quinacrine during 7 days: The mean level of quinine in the

plasma (luring treatment was 7.3 lng. per liter, well above the demonstrated

effective range. Both groups had blood-smear examinations twice weekly

after completion of treatment and were observed for 120 days for clinical or

parasitemic relapse.

Special considerations

Control of parasitemia.-As shown in chart 27, quinacrine proved significantly superior to quinine in rapidly clearing the blood of malarial parasites, in some patients within 12 hours of the first dose. At 24 hours, 26

14 Bi-Monthly Progress Report No. 12. Committee on Medical Research, Office of Scientific Research and Development, 1 Sept. 1943, subject: Malarial Chemotherapy, Contract No. OEMcmr-112.

15 (1) Most. H., and Hayi in, J. M., Jr.: Relative Efficiency of Quinacrine (Atabrine) and

Quinine In Treatment of Acute Attacks of Vivax Malaria. Am. J.M. Sc. 211 : 320-324, March 1946.

(2) Gordon, H. 11., Christianson, H. B., and Llppincott, S. W. : A Comparison of Quinine and

Quinacrine in the Treatment of the Clinical Attacks of Vivax Malaria. South. M.J. 39: 6:1-634.

August 1946.
CLINICAL TRIALS OF ANTIMALARIAl, DRUGS 533

percent of those treated with quinacrine and only 7 percent of those given

quinine were free of parasites, as were 77 percent and 44 percent, respectively, at 48 hours. At. 72 hours, only 4 percent of patients treated with

quinacrine still showed parasites, and all were clear at 96 hours; almost onefourth of the patients treated with quinine still had parasitemia at 72 hours,

and ini a few this persisted as long as 132 hours.

CIIART 27.-Rate of disappearanec of par,.iitcs during trcatmet of 497 acutc attucks of

vivax malaria with quinacrine hydrochloride or quinine

[Rate expressed as percentage of patients with negative smears]

PERCEINT

0

20

%0 %'' QUININE,

40

60

so QUINACRINE HYDROCHLORIDE .

1001 - - - - -

0 24 4 29 2 3

HOURS AFTER FIRST DOSE OF DRUG

I Total dose: 28.35 gm.: duration : 14 days (100 patients).

" Total dose: 2.8 gin. : duration : 7 days (397 patients).

Control of fever.-The idea frequently advanced that quinine should be

used during the first few days of an acute attack because of its superiority

in controlling fever quickly was not borne out in this study. Quinine was

not significantly more effective in this respect in relapses and was in fact

less effective in patients with delayed primary attacks, of whom 32 percent

had fever on the second or third day after beginning treatment with quinine,

as compared to 16 percent with quinacrine.

Control of other symptoms.-It is difficult to evaluate, in relation to

therapy, data on such symptoms as headache, backache, nausea, malaise, and

weakness, which usually occur in an attack of malaria. Statistically, there

was little difference in the duration of these symptoms under treatment with

one or the other drug, although clinically one had the impression that such

symptoms, particularly weakness and anorexia, were more promptly controlled with quinacrine.
534 INFECTIOUS I)ISEASES

Toxicity.-LPersistent vomniting ass(sciated with the malarial attack was

controlled by withholding fluids and food by mouth and by giving intravenous glucose prior to the administration of quinacrine. Given several

hours of freedom from vomiting, this symptom was not brought on again

by the drug.

Gastrointestinal disturbances controlled as described were not aggravated

bIv quinine. Patients with eczeniatold or exfoliative dermiatitis and malaria

had no activation of the skin process attributable to quinine. One patient,

who proved to be hypersensitive to the (hr' acute thrombopenic

purpura and severe angioneurotic e(leia of i iie first day of treatment. Such reactions, although not unknown, were admittedly rare. A

fairly high proportion of patients treated with quinine, however. comphlaine(d

of severe and annoying tinnitus and fullness in the ears or head. In many

cases, this seemed to retard full recovery from the symptoms of an acute

attack.

No major toxic manifestations were seen during treatment with quinaCrine. Patients who alleged previous intolerance to the drug displayed none

when it was given to them in colored capsules without their knowledge of

the contents. In this series, signs and symptoms referable to the central

nervous system were not encountered in relation to quinacrine therapy. Two

patients with severe eczeinatoid dernmatitis and acute nmalaria who were not

having specific anitimalarial treatment had flareups of the skin process, and

many others with the two conditions suffered no ill effects from treatment

with quinacrine.

Relapse rate and interval to relapse.-Approximately 80 percent of IPacific infections relapsed within the observation period of 120 days, whether

treated with quinacrine or quinine, but there was a striking difference in the

leng-th of the interval to relapse. In short, the mean interval following

treatment with quinine was 22 (lays as compared with 53 days following

treatment with quinacrine (chart 28). Quinacrine thus effected a longer

interval to relapse by at least a month. reducing to a minimum the n]umber

of relapses occurring within 30 days of treatment and in 30 percent of cases

prolonging the interval to more than 60 days.

Falciparum infections

Single intravenous injections of as much as 1.2 gm. of quinine failed to

terminate acute attacks caused by P. ftlcipairum, in 5 out of 10 patients,

while intravenous injection of single doses of 0.4 to 1.0 gin. of quinacrine

terminated attacks due to P. fa~lc>paiinn in 49 out of 50 cases at the 20th

General Hospital, India-Burma theater. The relative merits of parenteral

quinine and quinacrine in fulminating facdiparum infections are diseussed in

the section on quinacrine. Maximum (loses of quinine have been shown to

produce more minor and mnjor toxic manifestations than therapeutic amounts

of quinacrine. Aside from cinchonism, quinine used in 10,00() cases of ma-
CLINICAL TRIALS OF ANTIMALARIAL I)RUGS 535

CHART 28.-Relapse rates and intervals to relapse following treatment, by days, with

quinacrine hydrochloride or quinine of 250 acute attacks of vivax malaria of Pacific origin

[Cumulative relapse rate. periveut of piatients treated]

PERCEENT

100

QUININE, • -. . '

soo

4OQUIRACRINE NYOROCHLORIDE'

0_____________________ I I

0 I0 20 30 40 50 60 70 SO 90 100 I10 120 130 140

DAYS FOLLOWING COMPLETION OF TREATMENT

I Total dose: 28.35 gin.: duration: 14 days (100 patients).

2 Total dose: 2.8 gm.; duration: 7 days (150 patients).

laria was associated with an incidence of purpura in 5 percent, with 2 deaths,

whereas no case of purpura occurred in 2,500 cases treated with quinacrine

in Panama.16 Fatal bullous erythema following 1.95 gmn. and severe dermatitis after 15 gm. of oral quinine were reported in two patients in India. In

addition, gluteal abscesses from intramuscular quinine and convulsions followed by death during or shortly after intravenous quinine occurred in eight

patients.17

Summary of comparative studies

There remained little question, ther-fore, after consideration of the data

presented, that quinine is a relatively inferior drug in the treatment of acute

attacks of vivax malaria or in the suppression of infections with P. vivax or

P. falciparulm in nonimmune military personnel. Its early use in the Pacific

combat areas resulted in numerous "breakthroughs" of falciparum and vivax

malaria during suppression and in early and repeated relapses of the latter.

Fortunately, quinacrine was available in adequate amounts, and its establishment as the standard drug resulted in effective suppression and satisfactory control of clinical attacks.

16 Shrager, J., and Kean, B. H. : Ptrpura as a Complication of Malaria. Am. J.M. Sc. 212:

54-59. July 1946.

17 Essential Technical Medical Data, India-Burma Theater. for June 1945.
536 INFECTIOUS DISEASES

Totaquine

Totaquilie (containing not less than 7 percent nor inore than. 12 percent

of anhydrous quinine and not less than 70 percent nor more than 80 percent

of total anhydrous crystallizable cinchona alkaloids) was studied at several

general hospitals in the Zone of Interior and overseas. Relatively large

amounts were available and more could be obtained for civilian or military

use. The antimalarial qualities of all the cinchona alkaloids it contained, if

additive, could result in substantial saving in quinine and other alkaloids.

In a study carried out at Kennedy General Hospital, Memphis, Tenn.,

in July 1944, totaquine proved as effective as quinine in terminating acute

attacks of malaria due to P. viva.x of Pacific origin, but it more frequently

produced epigastric distress, blurred vision, dizziness, and severe vomiting.

Similar findings were reported in a study at Bushnell General Hospital,

Brigham City, Utah. In addition to the patients treated for 5 days, 53 were

maintained on suppressive doses (0.6 gm. daily) for 55 days. Of these, 13

(about 25 percent) "broke through" with clinical malaria. Of the treated

patients, 60 percent relapsed; the average interval to relapse was 34 days

after suppressive treatment with totaquine.

At the 31st Station Hospital in New Caledonia, a study of patients in

groups of 80 treated with totaquine, quinine, or quinacrine, for relapsing

malaria of Pacific origin, again showed not much difference as to control of

parasitemia. fever, and other symptoms.18 Again nausea, vomiting, vertigo,

and blurred vision were observed with totaquine and in some cases were

severe. Relapses began within 1 week after completion of treatment with

totaquine or quinine, reaching their peak in 2 weeks, whereas relapses after

quinacrine did not begin until 3 weeks after completion of treatment and

reached their peak at 6 weeks. Similar findings were reported from two

Army hospitals in another theater.

In sunmmary, these studies indicate that totaquine is as efficient as quinine

in terminating acute attacks of malaria, but is more toxic. Moreover, like

quinine, totaquine is less effective than quinacrine in controlling fever and

parasitemia and in shortening the intervals between relapses.

These factors, in addition to its being inefficient as a suppressive, variable in alkaloid content, and difficult to standardize, would preclude the use

of totaquine on a wide scale for military purposes. It could, however, have

a useful role in the treatment of malaria in highly innmune individuals in

wholn small amounts of any antinmalarial agent. are effective in terminating

periods of clinical activity. A considerable advantage in the use of totaquine

in areas where it is locally available would be the relatively low cost and

ease of preparation, permitting the use of low grade barks of poor quinine

content.

Is Green, R. A.: Totaqulne in the Treatenwt of Malaria. Bull. U.S. Army M. Dept. No. 84,

pp. 51-57, January 1945.
CLINICAl, TRIAL 0F ANTIMALARIAL IRI'IGX .537

Other Cinchona Alkaloids

I)ihydroquinine, miiore eoninionly known as hydr(liquinine, offered ain interesting possibility because it not only could be totally synthesized but could

be. obtained in 95 to 100 percent yield from the hydrogenation of quinine.

If the higher therapeutic activity of dihydroquinine claimed for it in studies

of malaria in birds could be demonstrated in man, a useful substitute for

quinine might be available synthetically, or the effective stores of quinine

could be increased from 15 to 20 percent by converting the latter to (dihydroquinine. However, clinical tests in the Pacific with total daily doses of 0.3

to 1.8 gin. for 6 days in relapsing vhvax malaria failed to show any greater

therapeutic activity of dihydroquinine over quinine. One patient complained

of blurred vision after a total of 0.6 gn., and three other men receiving 0.3

gin. three times daily complained of vertigo (two patients) and weakness in

the legs (one patient). Dihydroquinine therefore offered no advantage over

quinine.

The ant inmalarial activity of quinidine, cinchonine, and cinchonidine have

been known for a long time, and their ability in terminating clinical attacks

of malaria was demonstrated many years ago.10 Quinidine as an antimalarial

was not explored extensively because of its potential cardiac toxicity, nor

were ,inchonine and cinchonidine, individually representing small fractions

of the total cinchona alkaloids. Development of chemical methods20 for

estimating plasma levels of these alkaloids made it possible to evaluale their

relative antimalarial activity in man. It was shown that plasma levels of

0.1 and 0.5 mg. per liter for cinchonine and 2.5 and 3.0 mg. per liter for cinchonidine for clinical control of acute attacks of malaria were effective against

v;vax and falcdparum infections, respectively, and that these levels were attainedi with daily doses of 2.0 to 3.0 gm. of cinchonine and 1.0 to 3.0 gin. of

cinchonidine. The effective levels of quinine are 4.0 mg. for rhax infections

and 5.0 mng. for falcipc'i"i, infections, although some of the latter may not

be controlled with levels as 3⁄4igh as 10 mg. per liter. Total daily amounts of

1.5 gm. of quinine (0.65 every 8 ho. r-) will provide levels of 7.0 to 12.9 mg.

per liter (average 10.3), which are adequate to control most infections. Although it may appear that cinchonine and cinchonidine are more effective

than quinine by virtue of activity a- lower plasma levels, it must be recognized that such levels are obtained only with two to four times the amounts

of these drugs in comparison w:th quinine. Consequently, no practical advantage could be derived from the individual use of cinchonine or cinchonidine

in the routine termination of attacks of malaria since they would ultimately

have to be derived from cinchona itself. No clinical studies with cinchonine

or cinchonidine were undertaken in the Army. However, it was concluded

1,J Nelson, E. E. : •inchona and Its Alkaloids in the Treatment of Malaria. A Symposium on

Human Malaria. (Pub. No. 15.) Washington: American Association for the Advancement of Science. 1941, pp. 255-260.

2) Bi-Monthly Progress Report No. 11, Committee on Medical Research. Office of Scientific Research and Development, 2 July 1943, subject: M. alarial Chemotherapy, Contract No. OEMcnir-l12.
538 INFECTIOUS DISEASES

from civilian studies that they were less toxic than quinine, l)articularly with

respect to symptoms attributable to the special senses, and that these drugs

singly or in combination, as in totaquine, should be approximately equivalent

to quinine in antiunalarial act- vity.

Summary of Studies

Studies with cinchona alkaloids during the war were therefore of definite

practical value. It was demonstrated that totaquine and its component alkaloids were as effective as quinine but more toxic, that the cinchona alkaloids

were inferior to quinacrine in both suppression and termination of acute

attacks of malaria, and that the loss of quinine was accordingly not a serious

military problem. A rational method of assay of antimalarial properties of

drugs was developed and the efficiency of the various cinchona alkaloids reevaluated. No conclusive studies on the relative efficiency of parenteral quinine and quinacrine in the treatment of cerebral malaria were reported. and

this problem still requires investigation before a final estimate can be made

of the role quinine should play in the therapy of malaria.

QUINACRINE HYDROCHLORIDE (ATABRINE) 21

The extensive prewar literature dealing with the antimalarial properties

and toxicity of quinacrine has been adequately reviewed. 22 Following the

introduction of this drug in 1931, it became apparent that the originally advocated dosage schedule of 0.1 gm. three times daily for 5 days was in many

cases, particularly iiL severe falciparum infections, inadequate for prompt and

effective control of fever, symptoms, and parasitemia. There were numerous

revisions in treatment plans, but there was no rational pharmacological basis

for defining what dosage and treatment schedules were best. for terminating

acute attacks or for suppression. The relative efficiency of quinacrine versus

quinine had not becit established, and it was questionable whether we would

be able to produce adequate amounts of effective antimalarial drugs. Numerous studies were conducted in many laboratories and hospitals in the various

theaters. It is the purpose of this section to review briefly basic clinical and

other observations hat establishv%, 4[p, ,acrine as a highly effective and satisfactory antimalarial during the wvat

In 1941, American chemistý -,,'.,.-,ed in completely synthesizing quinacrine. Chemical, pharmacological, and clinical investigations sponsored by

the National Rese:irc. Council established the identity of the German and

American drugs and found no appreciable difference between them as regards

side reactions. Rumors that the American preparation was not identical

with the German drug could be definitely dismissed. Finally, tremendously

increased production assured an adequate supply at least for military use at

first and later for civilian and lend-lease purposes.

21 Formula : 3-Chloro-7-iiiethoxy-9-(1-methyI-4-diethy itinino-butylaniino) a1cridine dihydrochloride.

22 See footnote 4 (7), 1). 526.
CLINIAl. TRIALS OF ANTIMALAIIAI. DRUGS 539

General Properties

Practical. highly sensitive, and accurate chemical methods for the estiilation of quillacrine concentrations in the blood and tissues made it possible

to study its physiological disposition in the human body. 3 It was shown

that:

* * * Atabrine Is almost completely absorbed in the gastrointestinal tract and renal

excretion accounts for very little of the daily (lose. It may be concluded from these

facts and the fact that its plasma concentration becomes stabilized after several (lays of

drug administration at constant dosage, that it is disposed of by the body mainly by

processes which result in its degradation. It follows, then, that the major factors which

will relate drug administration and plasma drug concentration are those which condition the processes of distribution and degradation in the body.

* * * It was found that the concentration of the drug In plasma, erythrocytes, and

leukocytes is in the order of 1, to 1, to 100-200.

* * * Studies * * * in experimental animals indicated that the drug may achieve

ýoncentrations in the liver and spleen as high as 10,000-20,000 times those currently

observed in the plasma. Localization in other tissues was found to be less extensive,

but highly significant. An extension of these distribution studies to the human [subject]

* * * demonstrated that a major portion of the administered Atabrine is localized in the

tissues of the body, leaving little in the plasma to exert a chemotherapeutic effect. It

is in consequence of this that unless large initial doses of the drug are given the initial plasma drug concentrations are invariably low. However, the extensive localization,

together with the low rates of degradation and renal excretion, lead to a low rate of

decline of the plasma Atabrine concentration, and consequently a low rate of loss of the

protection conferred by Atabrine, subsequent to the termination of drug administration.

It was apparent that a rational regilnen of quinacrine theral)y would

have to l)e designed along the commonly accepted principles of chemotherapy;

namely, the administration of sufficient drug when the diagnosis of malaria

is made, or when exposure to malaria is anticipated, to obtain the desired

l)lasma concentration, followed by the serial administration of small doses

to maintain it.

The next step was to determine the plasma levels of quinacrine that

would be effective in the prompt control of symptoms, fever, and parasitemia

associated with acute attacks of vivax and falciparum infections. Infections

with various strains of P. iivax and P. falciparunt. transmitted by mosquitoes

or introduced by blood, were established in volunteers and paretics, and different alnounts of quinacrine in different treatment schedules were used to

produce various plasma concentrations. It was found that if quinacrine concentrations of 30 ýLg. per liter or more were maintained for 4 days in vivax

infections there was complete termination of clinical activity and parasitemia.

Levels between 10 and 30 ug. per liter produced temporary or partial effects,

23I (1) Brodie, B. B., and Udenfriend, S.: The Estimation of Atabrine in Biological Fluids and

Tissues. J. Biol. Chem. 151: 299-317, November 1943. (2) Mackie, Thomas T., Hunter, George

W., [II, and Worth, C. Brooke: Manual of Tropical Medicine. Philadelphia: W. B. Saunders Co.,

1945, pp. 675-677. (3) Shannon, J. A., Earle, D. P., Jr., Brodie, B. B., Taggart, J. V., and Berliner,

R. W. : The Pharmacological Basis for the Rational Use of Atabrine in the Treatment of Malaria.

J. Pharmacol. & Exper. Therap. 81 : 307-330, August 1944.
540 INFECTIOUS DISEASES

and levels below 10 jig. per liter l)roduced little or no effect when maintained

for 4 days. Infections with P. fv/epartim required approximately 50 jLg. per

liter maintained for 6 days for termination of clinical activity and parasitem ia.

With the treatment schedule for luinlacrine commonly used before 1943

(0.1 gin. three times daily for 5 days), very low concentrations in the plasma

were achieved during the first 2 or 3 (lays of therapy because of the extensive

localization of the drug in tissues. If such dosage is continued for a period

of days, the plasma levels will rise progressively, as more and more drug

accumulates in the tissues, until ultimately they reach sufficient height to

terminate the attack. The delay in the initial effect of quinacrine in such

a dosage schedule had lett to the belief that quinacrine therapy should be

preceded by a 2- to 3-day course of quinine. Actually, such a cour.se is undesirable because 24 hours or less after the last dose the plasma level of quinine

is no longer effective. If parasitemia is still present, as it often is in cases

so treated. there will be a reactivation of the disease during the next few days

(of treatment with 0.1 gmi. quinacrine three times a day) until the plasma

quinacrine level in this schedule becomes effective.

If. on the other hand. total doses of 0.8 to 1.0 gin. of quinacrine are given

orally during the first 24 hours of therapy, or by a combination of parenteral

and oral routes, high effective plasma concentrations are quickly established

and easily maintained by the serial administration of 0.1 gin. three times daily

for 6 days. These considerations led to the adoption by the U.S. Arimy of a

standard course of quinacrine therapy consisting of 2.8 gin. durilig (lays

(1.0 gin. the first 24 hours and 0.3 g.m. daily for 6 more days).24

Clinical Use

In acute attacks&-Clinical experience in this country and overseas proved

conclusively the efficiency of such a regimen in terminating acute attacks of

malaria due to P. ri-alx and P. faheiparum. It was found 25 that 2.8 gi. of

quinacrine administered as recommended in Circular Letter No. 153, Office

of the Surgeon General, 19 August 1943, brought about cessation of fever

within 24 hours in approximately 90 percent of cases of vivax malaria and

in the remainder within 48 to 72 hours; approximately 80 percent of patients

had negative smears within 48 hours and almost 100 percent at 96 hours.

Relapses after treatment with quinacrine occurred in an average of 53 days,

in contrast to 24 days and the many short-term relapses following treatment

with quinine. In the treatment of acute attacks, there were no toxic maniifestations similar to those induced by prolonged intensive treatment with

quinine.

24 Circular Letter No. 15.. Office of the Surgeon General, U.S. Army, 19 Aug. 1943, subject:

The Drug Treatment of Malaria. Suppressive and Clinical.

25 See footnote 15, p. 532.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 541

In 291 patients, plasina levels were determined during and after 412

attacks of tviax malaria acquired in the South Pacifice. 6 The average daily

levels from the second to the eighth days of treatment with quinacrine were

41 to 52 jig. per liter. Tlw average increase in level 2 to 4 hours after a dose

of 0.1 gin. on the second to seventh day was 6.8 to 11.3 j~g. per liter above the

corresponding fasting level. The average level 4 weeks after completion of

2.8 gin. of quinacrine therapy was 8 tig. per liter. It was found that this

regimen produced plasma levels of 45 lig. per liter within 24 hours after treatment was begun and that all symptoms and parasitemia were abolished within

72 hours in almost 100 percent of the patients. No correlation was observed

between plasma levels and the occurrence or spacing of relapses.

The question arose whether plasma levels would be affected by such factors as jungle climnate, fatigue, combat, and diarrhea. It was shown overseas

that diarrhea or dysentery did not influence the pattern of the quinacrine

plasnma levels during therapy. In this country under simulated jungle conditions, and ,also overseas, it was shown that high temperatures, humidity, and

fatigue did not adversely affect the absorption or stabilization of quinacrine

in the plasma.

Quinacrine was found to be effective also in the treatment of delayed

primary vivax malaria appearing after discontinuance of quinacrine suppression.2 7 The continued use of this drug does not produce strains of parasites

that are resistant to its action. It was noted that fever and sometimes parasitemia were not so promptly controlled in primary attacks as in relapses,

although quinacrine was superior to quinine in both types of attack, and the

rate of disappearance of parasites from the blood in a relapse was dependent

on the degree of initial parasitemia rather than on the plasma level of quinacrine. This observation has no practical importance, however, since most

patients are free of fever and symptoms before parasites have disappeared

completely from the blood, and regardless of initial parasite density almost

all patients have negative smears within 96 hours after the initiation of an

adequate schedule of quinacrine therapy.

Attempts to enhance the response to treatment by increasing the initial

or the total dose were made in several oversea installations. However, 2.8 gn.

in 3 days, or 3.5 to 4.8 gin. in a week, proved no more effective in controlling

the acute attack or affecting subsequent relapse rates than the standard schedule of 2.8 gin. in 7 days. In the control of relapses, short courses of treatment

(1.2 gin. in 16 hours or 1.4 gin. in 12 to 16 hours) were effective in terminating

acute attacks but, if not followed immediately by suppressive doses, might be

succeeded by early relapse or in a malarious area by new infection because

of the rapid fall of concentration in the plasma below protective levels. One26Ellerbrook, L. D., Llppincott, S. W., Cateno. C. F., Gordon, H. B., and Marble, A.: Plasma

Quinacrine Concentration in Treatment of Plasmodlum Vivax Malaria Acquired In the South Pacific.

Arch. int. Med. 76: 352-357. November-December 1945.

27 London, I. M., Kane, C. A., Schroeder, E. F., and Most. H. : The Delayed Primary Attnek

of Viva% Malaria. New England J. Med. 235: 406-410, 19 Sept. 1946.
•'42 INFk'CTI( US DISEASES

day treatment courses or less have only a slight advantage in insuring the

administration of adequate amounts of drug in a short time. and little is

gained in reduction of nursing care since patients with acute malaria are

usually sick for several (lays. Moreover, unrecognized or severe falcilpamim

infections may not be controlled with this amount of medication. A false

sense of security may cause carelessness in observation of patients.

A short course totaling 2.2 gni. in 3 days (1.0 gin. on the first day, then

0.6 gin. daily for 2 days) was found, in this country, as effective as 2.8 gtn.

in 7 (lays in ternminating acute attacks of vira, malaria, with a similar

spacing of the intervals to relapse. Many patients were symptom free in

3 (lays, and in some cases the period of hospitalization coulh be reduced.

Relapse of previously treated falharunm infections, rarely seen in this country, would not constitute a hazard in 3-day treatment of vihaax relapses here.

Total (loses in excess of 2.8 gin. or in periods of less than 7 days are not

advocated except possibly in fulminating falciparuni infections, since nothing

is gained by excessive dosage and there is more risk of toxic reactions.

In falciparum infections.-The clinical studies discussed thus far have

been concerned principally with vihax infections. It has been noted )Ihat

experimentally induced fakeiparunv infections were effectively controlled with

quinacrine plasma levels in the range of 40 to 50 Ig. per liter. Plasma levels

in that order are quite uniformly attained by initial doses of 1.0 gin. of quinacrine administered during the first day of treatment by the oral or combined

oral and parenteral routes. It was to be expected, then, that standard quinacrine treatment would prove effective in the control of the majority of infections with P. falciparum.

In a report from India 28 summarizing the treatment of over 5.000 cases of malaria

of which more than two-thirds were due to P. falciparum. it was stated that quinacrine

was as effective as quinine in terminating them. This is of parrieular significance since

early in that theater's experience the dosage of quinacrine was 0.1 gin. three times a (Jay

for 5 to 7 days. Undoubtedly, higher doses on the first day would have produced even

more satisfactory results. In fact, 50 patients so treated responded promptly and were

afebrile by the third day.

By contrast, patients treated with quinine for the first 2 days had a reactivation of

fever on the third day when quinine was discontinued. It was stated that in this study

the patients treated with quinacrine remained febrile a little longer than those treated

initially with quinine, but the former had considerably less nausea and vomiting and no

tinnitus or deafness. Treatment with quinine was associated with the development of

blackwater fever in two patients. One patient developed a fatal diffuse bullous erythema

after 1.95 gui. of quinine and another developed an extensive dermatitis after 15 gin.

Extensive experience In West Africa and in various Pacific islands where the nmajority of initial attacks of malaria were due to P. falciparumn demonstrated the efficiency

of standard quinacrine therapy in terminating uncomplicated attacks. In general, its

value in the more severe forms of malaria is attested by the remarkably low death rate

from this disease during the war in conjunction with the widespread use of quinacrine.

Fulminating cerebral malaria was fortunately not common in most theaters.

2s Ware, R. E., Bremn, T. R., and Crane, N. F.: Experiences With Malaria in India. [Official

record.]
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 543

In India, of over 6,000 cases of malaria in native or foreign troops there were 140

cases of the cerebral form, or an incidence of about 2 percent (if falcipEarum infections.-9

The death rate in American troops with cerebral malaria was 5 percent and in Chinese

and other personnel, 33 percent. Quinacrine alone was said to have cured several cases.

In another report,3o it was stated that 1 death occurred in 8 patients with cerebral

malaria treated with quinacrine intramuscularly, and 31 deaths occurred in 61 patients

treated with quinine parenterally. In the latter group, eight patients had convulsions

and died shortly after intravenous injection of quinine. Of five additional patients

treated with a single infusion of quinacrine (0.8 to 1.0 gin.) for ceretbral malaria, one

died; this patient had also received more than 1.0 gin. of quinine intravenously.3' In

the four patients who recovered, parasitemia was controlled within 48 hours. The serum

quinacrine levels 24 hours after the infusion was given varied from 100 to 3'20 #sg. per

liter. The mortality for cerebral malaria in a series of 146 patients in the Southwest

Pacific treated with quinine parenterally was 37 percent and was 21 percent for 19

patients treated with quinacrine.

Parenteral quinacrine treatment thus gave definite evidence of effectiveness in some cases of cer•bral malaria. No comparative studies in sufficient

numbers were reported on which to base definite conclusions with regard to

the relative efficiency of quinacrine and quinine in severe cases with cerebral

involvement. The surgeon in the India-Burnia theater stated:

My conclusions as to the relative merits of parenteral quinine and Atabrine (in

cerebral malaria) are that I am not certain that either possesses a distinct advantage

over the other. Atabrine may have a slight advantage in that (1) it is probably less

toxic, (2) its effect persists longer, and (3) it can be given intramuscularly. All data

we possess indicate that when given in adequate amounts, it is at least as effective as

quinine, and may be more effective. Moreover, if a rapid and prolonged effect is desired

0.8 gin. in a slow intravenous drip (over 4 hours) clears the blood of parasites as rapidly as any other method and a parasiticidal concentration remains in the blood for at

least 5 days.3 2

Intramuscular injections of quinacrine were found useful in vivax and

falciparum infections with severe vomiting as a means of attaining high

plasma levels promptly. For example, single doses of 0.4 gm. given intramuscularly result in levels of 168, 327, 297, 155, 89, 60, 45, 37, and 20 gg. per

liter at 5, 15, 30, 60 minutes and 2, 3, 5, 8, and 24 hours, respectively, after

injection. Serial injections of 0.2 gm. at intervals of 4 to 8 hours for 24 hours

or more can be expected to maintain high effective levels until oral medication can be instituted.

Following a single intramuscular dose of 0.2 gm. of quinacrine, it was

shown 33 that the number of motile parasites with finely dispersed pigment

,%as reduced and the number of nonmotile parasites with clumped pigment

was increased. Three hours after the injection when the plasma level of

29 Fitz-Hugh, T., Jr., Pepper, D. S., and Hopkins, H. U. : The Cerebral Form of Malaria. Bull.

U.S. Army M. Dept. No. 83, pp. 39-48, December 1944.

30 See footnote 17, p. 535. 31 Blumgart, Herrman L., and Pike, George M.: History of Internal Medicine In India-Burma

Theater. [Official record.]

32 See footnote 17, p. 535.

33 Trager, W., Bang, F. B.. and Hairston, N. G. : Relation of Plasma Level of Atabrine to Morphology and Motility of Plasmodium Vivax. Proc. Soc. Exper. Biol. & Med. 60: 257-258, November

1945.
544 INFECTIOUS DISEASES

quinacrine was falling rapidly the ratio of motile to noninotile parasites

returned to normal, and since the total parasite count did not change it was

suggested the parasites had recovered after temporary dainage. Similar

changes during the first 3 hours after quinine at levels of 6 to 10 ixg. per

liter were noted. These observations emphasize the necessity for the continued serial administration of antinialarial agents in sufficient amounts and at

properly spaced intervals so that adequate levels would be maintained sufficiently long to terminate clinical activity and parasitenxia.

The value of single intravenous infusions of quinacrine in falciparum

infections was studied at the 20th General Hospital.

Doses of 0.4 gin., 0.6 gin., and 0.8 gin. in 1,000 cc. of fluid were given intravenously

to groups of 10 patients on each dosage schedule, and 1.0 gin. in a single infusion was

given to each of 20 patients. The acute attack was terminated in all but one patient

(given 0.4 gin.) without further treatment. The duration of fever in the various groups

was 8 to 64 hours (average 27.2 hours) and smears became negative in from 1 to 3 days

(average 2.2 days). Of the 30 patients treated with 0.8 or 1.0 gin., 19 were observed

for a month or more after treatment and 4 relapsed within 3 to 5 weeks. Of the 20

patients who received 0.4 or 0.6 gin., 9 were followed for a month or more and 8 of the 9

relapsed within 10 to 23 days after termination of the attack by intravenous quinacrine.

Three patients had brief periods of vomiting shortly after the infusion; one patient

had a generalized convulsion: a fifth patient developed an acute state of exhilaration

and excitement lasting 5 hours. Two patients with moderately severe cerebral malaria

treated with 1.0 gin. of quinacrine intravenously responded well, being out of stupor in

18 hours. Twenty control patients treated for acute attacks of jalciparum malaria with

quinacrine by mouth all responded well although parasitemia and fever persisted in

them a little longer than in the groups treated intravenously. In a comparison of the

relative efficiency of single intravenous doses of quinine and quinacrine, it was reported

that of 10 patients treated for acute falciparum malaria with 1.2 gin. of quinine In an

Infusion of 1,000 cc., the attack was terminated in only 5. The remainder continued

to have high fever for 60 to 132 hours after treatment and required additional therapy.

Three relapses occurred in the successfully treated group 6, 9, and 13 days, respectively,

after infusion. Three patients who received single doses of 2.0 gin. of quinine in an

infusion developed signs and symptoms of shock. It should be pointed out that these

doses of quinine (1.2 and 2.0 gin.) are in the toxic range for this drug and are rarely

if ever resorted to therapeutically. Further, a comparison of single doses of quinine

and quinacrine does not take into account the rapid excretion of quinine. A more

practical estimation would have been the serial administration of nontoxic amounts of

quinine intravenously.

From these observations, it is apparent that although quinacrine given

intravenously effectively terminates attacks of falciparum malaria such a

procedure is not without danger and has little advantage over oral treatment

in most cases. In cerebral malaria, comparably high effective plasma levels

may be reached as quickly by serial intramuscular injections without the

dangers inherent in intravenous therapy. Relapses, which occurred at short

intervals after single doses of 0.8 or 1.0 gin. of quinacrine injected intravenously, are very common in falciparum infections after 2.8 gin. given in 7

days by mouth. Finally, the prompt response from intravenous quinacrine

reported in Chinese patients with a high degree of immunity may not be
CLINICAL TRIALS OF ANTIMALlARIAL DRUGS 545

duplicated ill nonininune white Ainerican troops. The question of parenteral

quinacrine versus quinine therapy remained unsettled.

In suppression.-The dosage of quinacrine for suppressive purposes recoinlnended before World War II was based on evidence derived from malaria

rates in various parts of the world, I)opulated, for the most part, by immune

natives. Daily doses of 0.05 gin. of quinacrine were considered inferior to a

daily (lose of quinine, but 0.4 gui. of quinacrine weekly in two divided doses

was considered more effective than daily doses of quinine in suppressing cliniical malaria.3 4 Although numerous reports indicated varying success in the

suppression of malaria with this divided dose of quinacrine, it was not known

when we entered the war how effective such a schedule would be in nonimmune troops in highly malarious zones and under combat conditions.

Studies of the course of plasma levels resulting from 0.4 gin. and 0.6 gin.

of quinacrine weekly as well as from larger anmounts were conducted in England on volunteers, and in the United States on medical students 35 and at a

military installation. Of 230 white soldiers observed in active training at

Fort Knox, Ky., 100 men received 0.4 gin. of quinacrine weekly and another

100 received 0.6 gm. weekly. Thirty volunteers subjected to conditions simulating jungle climate were given 1.2 gin. during the first week and 0.6 gin.

weekly for the next 11 weeks. It was shown that, with constant regimens,

the plasma concentrations differed widely in individuals but that the group

plasma level at any time was a function of the daily dose, the preexisting

level, and the interval since the last dose. The group mean level rose progressively for 4 to 8 weeks to reach an equilibrium, which then remained substantially constant. The equilibrium level for the group given 0.4 gm. weekly

was 1.2 l&g. per liter, and was 17 for the group on 0.6 gin. weekly. It was

shown that a hot., humid environment did not influence the group equilibrium

level and that suppressive therapy under such environmental conditions did

not affect the rate of acclimatization and performance of the men. The time

for reaching equilibrium levels could be reduced from 5 to 6 weeks to 1 week

by administering high initial doses for a short period (0.2 gm. daily for 5 to

6 successive days). Similar results and conclusions were reported from studies in England and civilian installations in the United States.

It was obvious that such plasma levels would give little or no protection

during the first 4 to 6 weeks, or until maximum equilibrium was attained

with these doses. Furthermore, marked variations in individual levels meant

that the smaller weekly dosage (0.4 mg.) would frequently fail to protect

significant numbers of men, especially if occasional doses were omitted. It

was clearly necessary to give a large initial or priming dose before or when

troops entered malarious zones in order to give immediate protection and

34 The Treatment of Malaria; Study of Synthetic Drugs, as Compared With Quinine, In the

Therapeutics and Prophylaxis of Malaria. Fourth General Report of the Malaria Commission,

League of Nations, Bull. Health Organ. 6: 895, December 1937.

35 Minutes. Subcommittee on the Coordination of Malarial Studies, 3 June 1943, National Research Council. Bulletin on Malaria Research. pp. 99-105.

639243'-63-- 38
546 INFECTIOUS DISEASES

prevent clinical "breakthroughs."' Tliese data were collected during the early

months of 1943. Shortly thereafter, these conclusions were translated in

terms of the specific recommendations for suppression of malaria contained

in Circular Letter No. 153 (p. 540).

In the ineantime, numerous rel)orts from overseas had been received

which documented the development of the clinical disease in large numbers

of troops shortly after their arrival in malarious areas and clearly demonstrated the value of priming (loses and the superiority of from 0.6 to 0.7 gin.

quinacrine weekly over 0.4 gin. for sup)pression. Valuable information was

obtained on "breakthroughs" during suppression with 0.4 and 0.6 gin. weekly

and the relation of such failures to plasma levels and quinacrine discipline.

Brief reference to a few field experiences to elucidate some of the factors

associated v. t ii poor and successful suppression follows.

The Americal Division, which was on New Caledonia from March to October 1942,

was moved to Guadalcanal during October, November, and December, where it remained

until March 1943.36 The men were forced to live and fight in hypermalarious areas

with little to no field control and no mosquito repellent. Quinacrine, 0.4 gin. weekly,

was prescribed but the extent of its use was not known. The malaria rates on Guadalcanal were as high as 2,500 per 1,000 per annum. The ratio of falcipatrum to virax

infections was 3 to 1. Following removal of these troops to the Fiji Islands and mass

treatment ending on 10 June 1943, the rates in August and October were still 4,220 and

2,948 per 1,000 per annum, respectively. In September, 613 men were placed on suppressive doses of quinacrine of 0.4 to 0.6 gin. per week. The malaria rate in this group

fell from 219 per 1,000 peý month to 23. In November, the Division was placed on 0.4

gin. weekly and this dosage was increased to 0.6 gin. on 12 December. The malaria

rate fell from 2,948 per 1,000 per annum to 80 and after 2 months' combat in Bougainville the rate in March 1944 was only 97.1. The experience in this division showed that

early suppressive doses of 0.4 gin. weekly were inadequate to control malaria in combat

although a moderate degree of satisfactory suppression was obtained in a nonnmalarious

area under fairly good disciplinary conditions. On the other hand, 0.6 gin. of quinacrine proved highly efkective both in malarious areas and in regions free from malaria

(chart 29). Another example was the 43d Division, which had also been on 0.4 gin.

weekly with a high incidence of malaria. Half the division was taken off suppression

and had a malaria rate of 2,000 per 1,000 per annum. The other h:,!f was placed on

0.6 gin. weekly and their rate fell to 236 per 1,000 per annum. Again, a naval construction battalion of 840 men, on a suppressive regimen of 0.4 gin. weekly, arrived on

Guadalcanal on 12 December 1942.37 During the first 5 weeks, 1"23 men were down with

malaria, about 95 percent of which was due to P. falciparum. In the same report it

was stated that two combat infantry outfits on 0.4 gin. weekly entered a highly mialarious area and within 2 weeks malaria was occurring at the rate of 40 to 60 cases a day,

most of them caused by P. falciparurn.

Although the great majority of initial infections in the Pacific islands

were caused by P. falciparum, subsequent relapses were principally caused by

P. via4. When adequate amounts of quinacrine were used in termination

of the ai tack of falc;,paru-m malaria and when suppressive medication of 0.1

36 Essential Teehnical Medical Data, South Pacific Area, for April 1944.

3- Lewis, R. A. : The Suppression of Malaria. [Official record.]
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 547

CHART 29.-Malaria rates in, an infantry regiment under various schedules of suppression with quinacrine hydrochloridc, by wceck

[Rale expressed is number of attacks per linnumltI petr 1,100) avt.rage strength]

RATE

9,000

8,000 - PRIMARY ADMISSIONS

7,000

READMISSIONS

6,000

5,000

4,000

3,000

2,000-

4,000-

0

MAY JUNE JULY AUG. SEPT. OCT. NOV. DEC. JAN.

1943 1944

nn. daily was continued. /'tc;p(tmwn malaria rarely ocetirred on discontinuance of suppression.

In the Australian studies that have been referred to,38 It was conclusively shown

in volunteers infected with P. falciparum (New Guinea strain) transmitted by mosquitoes that, if 0.1 gin. of quinacrine were administered during the period of infection

and for 23 days after the last infective bite, clinical mnalaria did not occur during suppression or after its termination. Actual cure was demonstrated by subinoculation of

200 cc. of blood into other volunteers. If subinoculation was done on the 9th to 11th

days after infection, malaria developed in the recipients, indicating that quinacrine was

not a causal prophylactic but effected a cure by permanently destroying the erythrocytic parasites after their appearance in the blood. Similar studies in England and in

this country with other strains of P. falciparaim also demonstrated the curative action

of quinacrine suppression in such infections. In the Australian experiments along the

same lines with P. vivax, there was shown complete clinical suppression during therapy

but no curative effect, for all the volunteers developed vivax malaria at varying intervals after quinacrine was discontinued.

The practical inferences from these observations were that effective

plasma equilibrium having been established, quinacrine administered in doses

38 See footnote 12, p. 529.
548 INFfCTIOU' S DISEASES

of 0.1 gui. daily without interruption would effectively suppress both fakiparunm and vivax malaria and that, if suppression were continued for about

3 weeks in troops leaving the malarious area, falcdparum malaria would not

develop. Vivax relapses would occur later and could be effectively terminated with quinacrine or delayed indefinitely if necessary by continued suppression. These results were seen in many studies overseas and in this country.

In one experiment, for example, 107 volunteers were taken to a highly malarious

area in New Guinea where they were exposed to infection for 44 days. Initial priming

doses were followed by 0.1 gin. of quinacrine daily administered 6 days a week during

the period of exposure and for 10 days thereafter. No case of malaria developed during the period of suppression, whereas of 44 men who acted as controls and received no

medication, 32 developed malaria (in 9 caused by P. falciparum). Subsequent to the

discontinuance of suppressive therapy 25 cases of malaria due to P. vivax developed.

No case of malaria caused by P. falciparum developed in the group receiving quinacrine

either during or after suppressive treatment. This field study showed definitely the

value of quinacrine in absolutely preventing clinical malaria due to P. vivax and P. falciparum during adequate suppression and the curative as well as suppressive action of

quinacrine in falciparum infections.

In general, the plan of suppression with doses of 0.1 gin. daily was widely

used with excellent results. In one oversea area, it was suggested that troops

on patrol or in combat may fail to take occasional doses. Studies with single

doses of 0.4 or 0.5 gm. twice a week carried out in the field showed that such

a schedule would provide adequate protection and insure affective levels all

the time.39 This modified plan was not generally adopted but could be used

under circumstances precluding regular daily suppressive medication.

By continuing quinacrine therapy for suppression following termination

of acute attacks of vivax infections, it was possible to maintain effective fighting strength in combat units highly seeded with malaria. In this country,

continued suppression for 3 months or more reduced the number of hospital

admissions for relapses without interrupting training or rehabilitation programs. At one hospital in the United States, for example, 79 men treated

with 2.8 gin. of quinacrine in 7 days for acute attacks of vivax malaria of

Pacific origin were maintained on 0.1 gin. daily for 150 days after termination

of the acute attack. No parasitemina or clinical attack occurred during the

5 months of suppression. In a similar sized group, also treated for acute

attacks but not subsequently placed on suppressive therapy, 80 percent relapsed during the first 120 days' observation after treatment. The group

given effective prote!'tion during 5 months by continued therapy was not

thereby protected against subsequent relapse, for 82 percent relapsed during

the 120-day period of observation after discontinuance of suppression (chart

30).

39 Duncan. G. G.: Qulnacrine Hlydrochioride as a Malaria-Suppressive Agent for Combat Troops.

War Med. 8: 305-318, November-lh.cDmber 1945.
CLINICAL TRIALS OF ANTIMALARIAl, DRUGS 549

CHART 30.-Distribution of relapses i4 two groups of patients after treatment for acute

attacks of vivax malaria of Pacific origin

[Percent of patients with acute attacks]

PERCENT

60

GROUP A

40

ATABRINE (0.1 GM. DAILY)

30-

20 RELAPSES

10 NO ATTACKS

so

GROUP a

40

NO SUPPRESSIVE MEDICATION

30

20 RELAPSES OBSERVATION TERMINATED

10 -

0 30 60 90 120 ISO ISO 210 240 270

INTERVAL TO RELAPSE FROM COMPLETION OF TREATMENT. DAYS

The subject of "breakthroughs" or clinical attacks during suppression

received attention at many oversea installations. In India, six patients supposedly taking 0.1 gin. of quinacrine a day were admitted to the 20th General

Hospital and found to have plasma levels of 6, 7, 8, 12, 12, and 14 Pg. per

liter, respectively. In every case, it was possible to show that the individual

was able to absorb quinacrine normally, the reason for the low levels being

failure to take the prescribed dose daily. In the Southwest Pacific, 80 percent of 116 men who had attacks while on suppression were found to have

levels of less than 10, whereas only 25 percent of another group of 853 men

had similarly low levels. Seventy-five officers having attacks while supposedly

taking 0.1 gm. quinacrine daily were found to have low plasma levels and

admitted not taking the drug regularly. On the other hand, four men with

acute attacks were found to have levels of from 16 to 30 Jg. per liter when

admitted. It is possible that self-administered medication for beginning

symptoms may account for apparently adequate levels in some "breakthroughs." In a division in the Southwest Pacific, the average level for 1,021

men on suppression for a year or more was 13 lsg. per liter and varied from

an average of 5 in men who "broke through" to an average of over 20 in

companies with good discipline.40

40 Schaffer, A. J., and Lewis, R. A.: Atabrine Studies In the Field. I. Relation of Serum Atabrine Level to Breakthrough of Previously Contracted Vivax Malaria. Bull. Johns Hopkins Hoap.

78: 265-281, May 1946.
550 INFECTIOUS DISEASES

Toxicity

Effects of prolonged administration

Toxic reactions, principally related to the gastrointestinal tract and

nervous system, associated with the ingestion of quinacrine or its parenteral

use had been reported before World War I1. In an analysis of toxic reactions

observed in 49,681 patients to whom quinacrine had been administered before

1941, it was concluded that neurogenic symptoms (headache, mental depression, delirium, psychoses, convulsions) occurred rarely (less than 1 per 1,000)

and that gastrointestinal symptoms (nausea, vomiting, diarrhea) were uncommon and of little significance and were frequently related to the concomitant administration of other drugs. More serious reactions were poorly documented and could not be unequivocably related to quinacrine.

Following our entry into the war and the extensive use of quinacrine

over prolonged periods for suppression and frequently for termination of

acute attacks with larger amounts of drug than were previously used for

either purpose, great interest was stimulated in the potential acute or chronic

toxic effects of such medication. No attempt will be made in this section to

review the voluminous studies made with various experimental animals.

Brief reference will be made to observations on the effects of quinacrine not

previously reported or to findings that were of significance during World

War II.

Liver and kidneys.-Studies of hippuric acid synthesis, serum phosphatase, urea clearance, and liver biopsies (10 cases) performed on 101 men who

had been on suppression from 8 to 36 months revealed no abnormalities.

Similar negative findings resulted from detailed examinations of liver and

kidney function of 43 Oxford University undergraduates who took 0.1 gin. of

quinacrine daily over a period of 9 to 12 months.

Studies to discover subclinical hepatic damage in white and Negro American troops who had been taking 0.6 gin. quinacrine weekly for 18 to 24

months were done on various groups of 50 men. The icteric index, urinary

urobilinogen, sulfobromophthalein excretion, fibrinogen, galactose tolerance,

and cephalin-cholesterol flocculation tests failed to detect any evidence of

subclinical hepatic dysfunction. 41 On the other hand, there were a few reports of varying degrees of liver disease believed related to quinacrine ingestion.

Four vase.s of hepatic dysfunction (two subctlinical and two severe hepatitis, one of

whi'h ended fatally) believed related to quinacrine were reported from an oversea

theater. An interesting feature in these eases was the association of corneal edema,

manifested by blurred vision. In three of the patients corneal edema became less marked

after discontinuance of quinacrine and was aggravated by its readministration. Impaired liver function did not become apparent until 3 to 6 months after the initial episode of visual disturbance. The observers of these patients felt that corneal edeema and

41 Gottfri•ed. S. 1'.. and ILevine, A. C. : Liver Function Studies on Soldiers Under Prolonged

Atabrine Administration. J. Lab. & CliIn. Med. 30 : 853-s55. Octciber 1945.
-CLINICAL TRIALS OF ANTIMALARIAL DRUGS 551

,punctate erosions of the surface epithelium were due to quinacrine, that this was a rare

manifestation of quinacrine toxicity, and that its occurrence may be followed by liver

.disease.

In a large series of Chinese patients receiving quinacrine for suppression or treatment of malaria there were 5 with severe hepatitis and exfoliative dermatitis, 3 of whom

died of this complication (incidence 1 in 2,000-3,000 Chinese).-' The rash present in

each case appeared as early as the 2d day and as late as the 10th day of medication

and consisted of a scarlatiniform, maculopapular, dry, scaling eruption beginning on the

face and involving the entire body. Conjunctivitis and exfoliation of the tongue were

observed. Jaundice, which appeared several days after the rash, was accompanied by a

high ("septic") fever, leukocytosis, proteinuria, and hilirubinuria. The liver was large

and tender at first but shrank rapidly. Mental clouding was prominent and death followed in coma in the third to fifth week of the disease. At autopsy there was gross

and microscopic evidence of severe hepatitis or necrosis of the liver. It was concluded

that quinacrine in previously sensitized individuals was responsible for both the hepatitis and the severe dermatitis.

Aplastic anemia.-A small number of cases of aplastic anemia with and

without atypical lichen planus had been reported from the Pacific area,

and this was thought to be possibly ascribable to quinacrine. In an attempt

to determine whether prolonged use of quinacrine was responsible for the

production of pathological changes in the body, the Army Institute of Pathology (now the Armed Forces Institute of Pathology), Washington, D.C., instructed laboratory officers to furnish data of quinacrine ingestion with all

autopsy protocols, regardless of the cause of death. For some time, nothing

of significance was observed. Later, it became apparent that aplastic anemia

was the cause of death in a disproportionately large number of cases represented by autopsy material sent from the South and Southwest Pacific Areas

where an extensive regimen of quinacrine suppression was in force. Fiftyseven cases of aplastic anemia were the basis of a report 43 on the possible

relation of this disease and quinacrine. The incidence of aplastic anemia per

100,000 men varied little (0.1 to 0.3) from 1942 to 1945 in the continental

United States and all foreign theaters, exclusive of the South and Southwest

Pacific Areas and the China-Burma-India theater, where it rose from zero in

1942 to a, peak of 2.84 per 100,000 during the last 6 months of 1944. Quinacrine was the common drug in at least 47 cases, 9 others being excluded because of the possible role of arsenic, irradiation, or sulfonamides in the production of the aplastic state. In the group treated principally with quinacrine, the drug had been taken for a period of from I to 34 months; in the

majority, from 4 to 9 months. Large doses were specifically reported in six

cases. Four patients had increased the daily dose. to 0.2 gm. for a period of

from 3 weeks to 8 months; one patient took 20 to 30 tablets during 4 days

before onset of symptoms and another was said to have ingested "massive

doses" for 3 weeks before he became sick. Hepatitis was present in 10 cases

42 Arress, C. M.: Atabrine as a Cause of Fatal Exfoliative Derinatitis and Hepatitis. J.A.M.A.

131: 14-21. 4 May 1946.

430istr, R. P.: Aphastic Anmnlia in Soldiers Trreated With Atabrine (Quinacrine). Ani. J.M.

S.. 212: 211-224, Aigwst 194(;.
552 INFECTIOUS D)ISEASES

and the "'quinacrine derniatit is complex" in 25. 'n'e liver iesions In five cases

were indist il n) ishable froiii epidemic, bepit it is. Cerebral heniorrhage was

thle immnediate cause of (lentil in 10 cases. Trie bone marrow in till1 cases was

badly dlepleted of norinal hieniatopojet ic elemnents, often almost totally So

without evidence of ext rainteul lary hemiatopoiesis. Occasionally, the influx

of lymphocytes, pl asniocytes, and hist iocytes attained such Iproport ions that

at. first glance the fundamental hypoplastic state was not apparent. One mail

who received 65 transfusions andl lived 10 mionthis had extensive secondary

fibrosis of the marrow cavity. Clinically. the onset was gradlial in mlost

cases, and Innrpuric mnanifestationis were comlimmonily seenl early. In m1anly

cases, the red ulood cell count cotildl be imaintainedl at fairly goodI levels by

repeated transfusions, lbut. tile white cells and p~latelets reniailled uniformly

depressed. In 20 cases, the '"quinacrine dermnatitis compllex* l~reedled tile

anemia.Although this form of poss5ible qilinacrine toxicity ha~s poe aa

in thle. great majority of cases, recovery hias been repor~tedl.4

Asymptomatic changes in the skin.- -Cha iiges ill tile skin andl~ nuicotis

membranes resulting from the proloinged a(Imininist rat ion of qui nacri ne wvere

the subject of numerous rep~orts. They varied f roni asymiptoniati pc~iginent arv

changes to severe and (lisabling fornms of dermnatitis.

The yellow discolorationi of the skini associated with quinacrine ingestion

was a common finding in tile miajority of muen onl prolonged suppression. The

intensity of thte discoloration. whlich is uuot a toxic manifestation of drug ingestion but rathier. an expression of its dleposition ill the skin, variedl with

dlurationl andl dlosagre of suppression, exp~osure tosunligwht, andomlxin

being most mairked ill subjects with (lark skin and hair.

Attempts were made to correlate thle degree of fluorescence produced by quinacrine

in the skin and plasma levels with tile use of a dernofiluorometer. A high deg-ree of

correlation of induced palmar skin fluorescence with mean plasma levels was found In

33 volunteers on 0.2 gin. daily for 1 week and 0.1 gtu. daily for 3 weeks. The peak of

fluorescence in tile skin was reached in 4 to 5 week.,; after initial (dosage aild (decreased

slowly over a 12-week periodl after the dIruig was dliscontinued. It was believed that this

instrumnent might be useful in the field in determiningn. whether quinacrine suppression

discipline was effective.

Quinacrine discoloration of the selera, as observed in a smnall numlber of

individuals, was (lescribedl 5 as. consisting of yellowish pigmientation. most

marked around the limbus i1l tile part of the sciera, exposed in tile palpebral

fissure, and fading towardl the fornices. Onl thle. other ]land, inl jaundlice. the

pigmentation is most marked in the fornices toward the, equator of tile gflobe

andl fading towardl the limbus.

Ochronosis-like pigmentation of nmucous mnembranes, skin, and cartilage

was described in miany individluals onl quinacrine suppression. In a dental

4-4 Most. H.. and Hlayman. J. ',%.. Jr. : Recov..ry Pronm 5'vtore Hypopiastic Anemia Associated

With Atypical Lichen Piannis. Bull. U.S. Army 31. Dlept. 5: 339-342, March 1946.

45 Hlayman, J. '.%., Jr. : Atabrine Pigmentationi of the. Isclera. Bull. U.S. Army M. Dept. No. 82,

pp. 1241-121, November 1944.
CLINIC AL. TRIALS OF ANTIMALAItIAI IRtUGS 553

survey of 1,000 men in the Philippine Islands, 300 showed bluish-purple pigmentation of the hard palate. The color varied from a light blue purple to

intense blue black involving from 1 cin. to the entire palate.4 6 In another

report,4 the incidence in 500 men in the Southwest Pacific Area was 31 percent. The majority of the men with pigmentation of the palate had been oil

quilnacrine suppression for at least 7 months. The nature of the pigment

based on staining reactions of biopsy sections was considered to be hemosiderin. A detailed study of a small number of patients showed the ochronosislike pigment, to be distributed in the skin, hard palate, nail beds, the cartilages

of the nose, ears, epiglottis, and trachea, the conjunctivae and corneoscleral

imnbus. Phenol and alkaptonuria were excluded as causative factors. Surveys at Harmon General Hospital, Longview, Tex., and Moore General Ilospital, Swannanoa, N.C., likewise demonstrated an incidence of 15 to 30 percent, of asymptomatic pigmentation as described above in patients who had

been on prolonged quinacrine suppression overseas.

Atabrine dermatitis complex.-More significant changes in the skin were

reported from overseas as causing disability and frequently serious prolonged

illness. For security reasons and in order to maintain the morale of quinacrine suppression, the data accumulated were not made generally available

at first. It was necessary in the beginning to collect information on the incidence of these reactions and to evaluate fully the relation of quinacrine to

them. The possibility of substituting another suppressive agent for quinacrine had to be considered if this cutaneous complex proved to be widespread

or if unfounded rumors as to its incidence and severity threatened a breakdown in discipline. Fortunately, this did not occur nor was it found that

the incidence of the Atabrine dermatitis complex was very great. The following paragraphs from a report entitled "Evaluation of the Untoward Reactions Attributable to Atabrine" prepared by the Medical Consultants Division

of the Surgeon General's Office 48 summarize the vast amount of clinical and

other data collected overseas and in this country:

Medical officers in the Southwest Pacific Area called attention, in the latter part of

1943, to a characteristic cutaneous syndrome which was occurring in soldiers who had

been evacuated from New Guinea and adjacent islands. Lt. Col. Charles L. Schmitt,

MC, and Maj. (later Lt. Col.) Thomas W. Nisbet, MC, derniatologists stationed with genera' hospitals in that area, were the first to submit to The Surgeon General official reports in which they described the disease and its probable etiology. Later, similar cases

were reported from all other theaters where suppressive atabrine medication was in

general use as a control measure for malaria. This syndrome has been observed most

frequently in New Guinea and adjacent islands and in Assam and northern Burma; in

other areas only small numbers of cases have occurred.

46 Summer. S. : An Oral Manifestation of the Use of Atabrine. [Official record.]

47 Lippard. V. W.. and Kauer, G. L., Jr.: Pigmentation of the Palate and Subungual Tissues

Associated With Suppressive Quinacrine Hydroehloride Therapy. Am. J. Trop. Med. 25: 469-471,

November 1945.

4sEvaluation of thei Untoward Reactions Attributable to Atabrine. Bull. U..-Ariny M. Dept. 4:

653-659. D ecemuber 1945.

639243-'63-39
554 INFECTIOUS DISEASES

This skin disease which has acquired the name atypical lichen planus is characterized by various * * * types of lesions. * * * Almost all patients have both violaceous,

hypertrophic lichenoid plaques and some form of cutaneous eczematoid reaction. During the course of the disease, a considerable number of these patients have acute, "explosive" generalized exacerbations, manifested by oozing eczematoid dermatitis having a

predilection for the flexors, groins, axillae, extremities, and neck. Such exacerbations

resemble exfoliative dermatitis * * * which is as severe as the cases of primary exfoliative dermatitis described below. The seriousness of such a state and the need for expert

management of these patients cannot be overemphasized.

Usually the disease Is characterized by the onset of localized violaceous or erythematous eczematoid plaques * * * followed by generalization of the lesions with subsequent appearance of the lichenoid plaques and mucous membrane lesions. * * * Any

part of the cutaneous surface may be involved, but there is a predilection for the lower

legs, forearms, dorsal surface of hands and feet, face, buttocks, lower anterior surface of

the neck, genitalia, mucous membranes of the mouth, eyes, and eyelids. Residual effects

and lesions which develop later in the course of the disease include: atrophy; hyperpigmentation (melanin) and depigmentation; diffuse follicular accentuation over the

upper back, shoulders, and extremities; changes in the nails; moth-eaten, patchy alopecia; and marked disturbance in sweating function.

* * * A characteristic type of eczematoid dermatitis which also has occurred in individuals taking suppressive Atabrine * * * is characterized by bilateral, symmetrical,

violaceous-tinged, vesicular, eczematoid and oozing plaques involving the hands, arms,

feet, legs, and sometimes other parts of the body. Secondary pyogenic infection is common. The nail bed and skin of the nail folds are usually involved, frequently resulting

in exfoliation of the nails without true suppurative paronychia. With experience, on

clinical grounds, one can in most cases distinguish between this eruption and other forms

of eczematoid dermatitis. Tentatively the term "symmetrical eczematoid dermatitis" has

been used * * *

It does not seem advisable to make a sharp distinction between the so-called atypical

lichen planus and the symmetrical eczematoid dermatitis syndrome. From a broad point

of view, it seems that all of these patients have either a lichenoid cutaneous reaction or

an eczematoid cutaneous reaction or a combination * * *. A small percentage of the

total group have lichenoid lesions alone; a larger group have a combination of lichenoid

and eczematoid lesions; and a still larger group have eczematoid lesions that are not

accompanied by lichenoid lesions.

* * * reports of general Army experience * * * indicate that Atabrine is the essential etiological factor. The mechanisms resulting in the lichenoid reaction and the eczematoid reaction are probably different. For example, it was observed in a carefully

controlled series of cases at Moore General Hospital that the time interval preceding

exacerbations of eczematoid lesions is much shorter than with the lichenoid lesions.

The fact that the incidence has been so very much higher in New Guinea and adjacent

islands and in Assam and northern Burma suggests that climatic or geographic factors

may play a contributory role in the etiology. There is evidence that various forms of

cutaneous trauma may contribute to the onset and localization of the lesions, particularly the eczematoid phase of the eruption. The sequence of events in many cases suggests that individuals taking suppressive Atabrine have a tendency to acquire chronic

eczematoid dermatitis on contact with external allergens (such as certain jungle plants

and trees) rather than self-limited contact dermatitis which is the usual course * * *

It appears that cutaneous reactions are more frequent in individuals who have been

taking Atabrine in dosages above the recommended suppressive amount (0.7 gin. per

week). It should be emphasized that the incidence of these cutaneous diseases has

been relatively low, even in New Guinea, and, from the military point of view, has not

been an important handicap.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 555

Since available evidence indicates that we are dealing with one complex, it is suggested that it would be best to group these cutaneous reactions attributed to Atabrine

under one heading "Atabrine dermatitis complex" and classify the various manifestations as follows: (1) lichenold dermatitis; (2) lichenoid and eczematoid dermatitis

(both including cases heretofore referred to as "atypical lichen planus") ; (3) eczematold dermatitis (including cases heretofore referred to as "symmetrical eczematoid dermatitis") ; (4) exfoliative dermatitis secondary to (1), (2), or (3).

The treatment of these conditions depends for the most part on early recognition

of the trouble and discontinuation of Atabrine. In many instances, it is difficult to decide whether or not a given case of eczematoid dermatitis is due to Atabrine. It is

necessary to study such cases carefully, with careful observation after withdrawal of

Atabrine and possibly cautious trial readministration of the drug (do not attempt readministration of Atabrine to a patient who has had exfoliative dermatitis or a severe

generalized eczematoid exacerbation). * * * When possible, such patients should be seen

by a competent dermatologist, and every effort should be made to rule out other etiological factors. Parenteral administration of penicillin is indicated in patients with secondary pyogenic infection. Local treatment should be bland and nonirritating, and should

consist of preparations such as 1: 9,000 potassium permanganate soaks, Burow's solution

soaks, 5 percent aqueous solution of tannic acid spray for oozing intertriginous sites,

and application of borated cold cream if a grease is indicated. Preparations such as

salicylic acid ointment, tincture of iodine, and sulfonamide ointments should not be used.

Arsenicals and bismuth have been tried in some cases without affecting the course significantly; they should not be used. Superficial X-ray therapy, if indicated, should be

used only under the direc.tion of a competent dermatologist and in small (loses itnot

more than 75 r and not to exceed a total of more than 375 r to 450 r). At least some

of these patients have some degree of light sensitivity. Therefore, exposure to sunlight

should be avoided and ultraviolet light therapy should not be used. All patients should

be studied from the general medical standpoint, including studies of blood, serum proteins, and liver function. Therapeutic agents such as plasma, liver extract, multiple

vitamins, and intravenous glucose should be used when indicated.

The prognosis varies from individual to individual. In general it is excellent, especially if the patient is hospitalized early in the course of the disease * * *. The lichenoid

lesions involute slowly, but they do not tend to recur; the eczematoid phase of the eruption may involute rapidly, but it tends to recur and is respoasible for the prolonged

disability which occurs in some cases. In general, recovery is a matter of weeks and

months. Residual hyperpigmentation, depigmentation, and atrophy at the sites of lesions

become less pronounced as time goes on and the hypohidrosis which occurs in many

patients also improves spontaneously. The course is usually prolonged in all cases of

exfoliative dermatitis because of frequent exacerbations. It should be noted that these

patients have not been followed for a sufficient length of time to make final statements

in regard to the prognosis of these cutaneous reactions.

Another major type of cutaneous reaction which has been attributed to Atabrine is

primary exfoliative dermatitis, not secondary to the lichenoid-eczematoid syndrome. This

is characterized by acute fulminating exfoliative dermatitis, demonstrably associated

with true hypersensitivity to Atabrine. It is in every respect similar to exfoliative dermatitis due to other agents such as arsenicals. This type of cutaneous reaction * * *

is believed to be associated with Atabrine, much less commonly with quinine. Hypersensitivity of this degree may constitute a dangerous state in either instance.

Acute reactions to short-term administration

The l)rincilpai toxic imanifestations froll therapeutic miounts of quina -

trhie usually eil)loved in terminating a;cute attacks of malaria or from smilall
556 IN'l~l':c'rF I JUS DISEASES

initial doses early in suppression are related mnainly to the skiii, gastrointestinal tract, and central nervous system.

Skin.-Acute reactions in the skiti related to hyperseiisitivity or reactivaat of eezemnatoid dermatitis following small amounts of quinacrine have

been discussed. In addition, urticaria and pruritus have been described as

an uncommnon toxic manifestation of quinacrine ingestion. In a report 49

from India, 12 cases of pruritus and urticaria, particularly of the palmns, were

described in the course of quinacrine suppression. In 2 patients, symptomns

began within 3 days after suppressive medication was started and, in the

other 10 patients, within 2 to 3 weeks. The symptoms subsided in three patients while they were still on the drug and in nine within 4 days after the

drug was discontinued. Six patients had no recurrence when quinacrine was

readlnilistered, and, in tile three who had a recurrence, symlptomns disappeared

with continued medication.

Gastrointestinal tract.-Giastrointest iMal .ymptomns (nausea and vomiting) are rarely encountered with quinacrine during therapeutic termination

of acute attacks of malaria. Frequently, these symptoms when present are

due to malaria rather than to ingestion of the drug. The administration of

quinacrine in colored capsules to patients who stated they could not take it

because of gastrointestinal symptoms completely forestalled the development

of such symptoms. 50 Likewise, giving the drug after meals or with sweetened

fluids during an attack of malaria reduced the incidence of nausea. Nausea,

vomiting, and diarrhea were reported in large numbers of men on initial suppressive doses of 0.2 gin. twice weekly in some series and not at all in others.

Symptoms usually disappeared after three or four doses and occurred only

infrequently in the 0.1 gin. daily schedule. Psychological factors, field sanitary conditions, and other reasons were held mainly responsible for gastrointestinal symptoms. The consensus was that these reactions were never severe

and almost invariably disappeared if the drug was continued. 51

Central nervous system.-Before World War II, mental disturbances

were reported as occurring in approximately 1 to 2 of every 1,000 cases of

malaria treated with quinacrine orally or intramuscularly, and various aberrations of the central nervous system attributed to quinacrine were reported

in a number of cases during the war.

In 7,604 patients treated with quinacrine in a period of 7 months at an

overs-ea general hospital, 35 cases of toxic psychosis were observed. 52 Total

doses of 2.1 gm. quinacrine in a week were routine. The greatest number of

reactions occurred within 6 days of completion of therapy, although one was

observed after only 0.9 gnm. had been given and one developed as late as 12

days after therapy. There were two main types of onset. The most frequent

49 Essential Technical Medical Data, India-Burma Theater, for August 1945, inclosure 3 thereto.

50 See footnote 15 (1), p. 532.

51 The Drug Suppressive Treatment of Malaria. Bull. U.S. Army Al. Dept. No. 73, pp. 29-34,

February 1944.

%- Gaskill, H. S., and Fitz-Hugh, T.. Jr.: Toxic Psychoses Following Atabrine. Bull. U.S. Army

M. Dept. No. 86, pp. 63-69, March 1945.
CLINICAL TRIA.LS OF ANTIMIALARIALI IAft'-; 557

(65 percent) was marked by excitation, hallucinations, and delusions. '1he

other (35 percent) began with retardation, disorientation, and amnesia for

recent events together with confabulation. No constant physical or laboratory

findings were obtained. The course of the psychosis was benign in most

instances. Sixteen patients were subsequently (after 16 to 210 days) retested

with quinacrine and only one showed any untoward reaction, consisting of

mild excitement which cleared within 24 hours. There was no evidence that

the men who developed toxic quinacrine psychoses were unstable p)sychologically. Two patients who did not recover developed typical schizophrenic

reactions. There was no eIdence of latent psychosis in the previous behavior

of these two patients. Treatment consisted of restraint, sedation, supervision.

and nursing care. The authors believed that the psychoses represented a

quinacrine sensitivity reaction following which there was an unreactive

period.

In another report from overseas,53 28 cases of quinacrine psychosis were

observed in the Americal Division. The degree of malarial infection and

the great number of relapses treated in this division would indicate the incidence of this reaction to be extremely low. Two patients gave a history of

previous psychotic reactions to quinacrine, and in two additional patients it

was believed that schizophrenia was induced by the drug. Only one case

was noted during the standard course of 2.8 gIn. of quinacrine in 7 days.

The remainder developed during or after larger total doses, 18 patients receiving more than 3 gin. Confusion was the prominent clinical feature of

the psychosis in 27 p)atients. Hallucinations occurred in eight cases. Recovery was complete within 10 days in 16 patients. By the use of the Koh's

block test, these authors showed that there was evidence of confusion in 7 of

31 patients treated with 4.5 gin. quinacrine during 9 days, while no such

changes could be demonstrated in 27 patients treated with 2.1 gm. in 7 days.

Additional cases of quinacrine psychosis were reported from various installations overseas and in the United States, but their incidence was an insignificant fraction of the total number of psychoses that occurred in the U.S. Army.

Convulsions were reported in six patients treated with "massive" amounts

of quinacrine orally 54 and in two who were treated intravenously. The convulsions occurred during treatment or on the following day, with unconsciousness for 5 to 15 minutes followed by confusion. Within 24 hours, these

patients were all mentally clear. Plasma levels determined in three cases

were from 180 to 280 pg. per liter. Studies were stimulated by observation of

high plasma levels with parenteral quinacrine therapy and by reports in the

literature before World War II 55 of mental changes associated with parenteral medication. A group of 13 volunteers were given 0.9 gm. of quinacrine

531Newell. H. W.. and Lidz, T. : The Toxicity of Atabrine to the Central Nervous System.

I. Toxic Psychoses. Am. J. Psychiat. 102: 805-818, May 1946.

54 Newell, H. W., and Lidz, T. : The Toxicity of Atabrine to the Central Nervous System.

II. Convulsions. Am. J. Psychlat. 102: 805-818, May 1946.

" See footnote 34, p. 545.
558 INFECTIOUS DISEASES

daily for 7 days. Peak plasma levels were from 156 to 420 with a mean of

286 /Ag. per liter. No symptoms or signs related to the nervous system were

observed. Elect roencephalographic studies revealed only small and inconsistent changes not characteristic of those observed in convulsive disorders of

the brain. In another study, five normal subjects were given sufficient quinacrine by mouth during 7 to 10 days to produce plasma levels in excess of

100 ug. per liter. In all cases, there was evidence of marked psychologic

stimulation (motor acceleration, restlessness, sleeplessness, and increased capacity for work), and the electroencephalogram showed a significant shift

toward faster frequencies. These manifestations appeared by the third day

and persisted for 6 to 8 days after the drug was discontinued. uie authors

considered the data convincing evidence that quinacrine acted as a cortical

stimulant.

Summary of Studies

An experimental approach to the chemotherapy of malaria led to a rational use of quinacrine for effective treatment of attacks and for suppression. The development of chemical methods for estimating quinacrine in

biological fluids and tissues resulted in a better understanding of the limitations of treatment and suppressive schedules in use before and early in

World War II. Clinical and field studies carried out on a large scale demonstrated that quinacrine if properly used was superior to totaquine or its

component alkaloids for treatment or suppression of malaria due to P. vitax

or P. falciparumn. Quinacrine produced more prompt control of fever, symptonis, and parasitemia; was less toxic; and provided a longer interval to

relapse than quinine, sulfonamides, or heavy metals. Quinacrine was shown

to induce definitive cure in falviparum infections and to provide effective

suppression of relapsing malaria when priming initial doses were followed by

daily doses of 0.1 gm. Failures in suppression (breakthroughs) were shown

mainly due to poor discipline and failure to take the drug. Parenteral use

of quinacrine was found effective in severe falciparum infections, but no conclusive comparative study was reported between quinine and quinacrine given

parenterally. Toxic reactions known before the war were encountered, these

consisting of minor gastrointestinal symptoms and toxic psychoses. In addition, prolonged quinacrine ingestion produced edema of the cornea in some

cases, and in a large number of cases, the following reactions were described:

(1) Ochronosis-like pigmentation of skin, mucous membranes, and cartilage

(possibly with hepatitis), (2) urticaria and, more significantly, a dermatitis

complex (atypical lichen planus and/or eczematoid dermatitis), and (3)

aplastic anemia. It was only shown that long-continued suppression produced these reactions in only a small proportion of men taking the drug and

that on the whole no significant disturbances in organ function resulted. The

proper use of quinacrine made possible effective i.iilitary operations in highly

malarious areas.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 559

4-AMINOQUINOLINE COMPOUNDS

The background for the elaboration and study of this group of compounds is reviewed in a report on investigations of potentially antimalarial

drugs in the laboratories of the I. G. Farben Werke in Elberfeld, Germany.

Following the discovery, in 1924, of Plasmochin (a trade name for pamaquine

naphthoate, an 8-aminoquinoline) interest was centered on the possibilities of

quinoline derivatives. A total of 314 acridine derivatives were prepared, but

none was found to be more active than quinacrine. In 1929, work with the

4-aminoquinoline compounds was begun, and in 1934 a compound as effective

as quinacrine was discovered and furnished the impetus for the preparation

of numerous derivatives during the years following. Although this information was not available to us during World War II, it is of interest that

two reports appeared in the French literature which discussed very generally

the antimalarial properties of Sontochin (SN 6,911), one of the 4-aminoquinoline drugs prepared in Germany.

This drug became available in North Africa during the Second World

War, and its chemical identity was established. It was subsequently synthesized and made available to the U.S. Army for experimental and clinical

testing. A brief discussion of the antimalarial properties of Sontochin is

presented, to be followed in turn by brief discussions of several other derivatives prepared in this country, particularly SN 7,618 or Chloroquine

Diphosphate, which proved to be the most effective. The proper uses of

Plasmochin, rediscovered during the war, will be discussed in due course.

Sontochin (SN 6,911) 56

General properties

Absorption of the bisulfate of SN 6,911 is essentially complete whereas

only about 80 percent of the binaphthoate is absorbed. Following its absorption, the drug is extensively localized in the tissues. About 25 percent

of the daily dose is excreted; about 75 percent is degraded. The plasma level

falls approximately 25 percent per day. Daily doses of 0.3 gin. of base result in mean plasma levels of 160 tg. per liter (range 66 to 292). Therapeutic effects in vivax infections, that is, control of fever and parasitemia without recurrence within 14 days, are obtained with mean plasma levels above

80 ,g. per liter for 4 days and, in falciparum infections, with levels of 110

to 200 jug. per liter for 6 days. A therapeutic schedule consisting of 0.9 gm.

on the first day and 0.3 gm. daily for 3 additional days produces plasma levels of from 125 to 193 tg. per liter for 4 days and is effective in terminating

induced vivax and falciparurn infections.

5Formula: 3-Methyl-7-chloro-4-(4-diethylamino-l-methy lbutylamlno) quinoline bisulfate or binaphthoate.
560 INFECTIOUS DISEASES

Clinical testing

Acute attacks.-The relative efficiency of SN 6,911 and quinacrine in

the treatment of acute attacks of vhax malaria of Pacific and Mediterranean

origin was studied at Harmon General Hospital. A total of 99 patients

were treated with 3.2 gin. of SN 6,911 base during 7 days. There was prompt

control of fever and symptoms (86 to 100 percent fever free on the second

day), but, not, signmificantly more so than with quinacrine, and parasites disappeared from the blood at approximately the same rate with either drug.

Of 75 patients followed for at least 60 days after completion of treatment,

49 (about 65 percent) relapsed; the interval to relapse was snorter, 27 percent occurring in the first 5 weeks after treatment with SN 6,911, compared

with only 7 percent in the same interval after treatment with quinacrine. In

this study, no advantage of SN 6,911 over quinacrine was found.

From similar observations in studies carried out at various U.S. naval

installations, similar conclusions were drawn. Single doses of 1.0 gmn. SN

6,911 were found effective in terminating acute attacks of vivax malaria of

Pacific origin in 45 patients. Parasitemia was controlled within 36 hours,

and usually no further paroxysms occurred. Relapses were observed in as

little as 24 days after therapy. Toxic symptoms or signs were not encountered.

No extensive studies on treatment with SN 6,911 for malaria caused by

P. falcdpairum were carried out in the field. In India. it was shown that a

single infusion of 0.64 gin. of SN 6.911 in 1,000 cc. of saline given intravenously during 2 to 3 hours was effective in terminating acute attacks of

fadciparumn malaria. Twenty Chinese soldiers were so treated, and within 1

to 4 days (average 2.5 days) blood smears became negative. Fever was controlled in 12 to 80 hours (average 41 hours). The response was comparable

to that observed in 20 patients who were given 0.6 gm. of quinacrine intravenously although the latter became fever free on the average of 12 hours

sooner than those treated with SN 6,911. In the United States, it was shown

that 0.9 gim. of SN 6.911 administered for 1 day followed by 0.3 gm. daily

for 6 days effected definitive cure in induced .faleiparum infections.

Suppression.-Studies with SN 6,911 were carried out in Australia on

volunteers infected by mosquitoes with the New Guinea strains of P. vivax

and P. falciparum, the method of approach being the same as previously described. Volunteers who received "build-up" doses of SN 6,911 of 0.2 gm.

twice daily for 4 days before exposure to infection and then had 0.1 or 0.2

gin. daily during the period of exposure and for 23 days after the last infective bite had smears completely parasite free (except one patient who

had one parasite on 1 day only), and they had no attacks of malaria. Following discontinuance of suppressive medication, all volunteers infected with

P. vivax developed acute attacks (average 27 days), but none of those infected with P. falciparum developed malaria within 92 days after discontinuance of the drug. In the latter group, cure was demonstrated by failure to
C'LINI•AI 'ril.lS OF ANTIMAI.AIt.AI, 1)!{1 ,5 561

produce imialaria ini recipients who were given 2 00 co. of blood from tile test

subjects. No innnuinitv was demionstrated since subsequently it was possible

to induce malaria in the same subjects with the same strain of fi/tdtpartini,

parasites. Subinoculation of blood from subjects treated with SN 6.911. on

the eighth and ninth days after reinfection with 1. falciparanum produced

imialaria in the recil)ients. These studies therefore showed that SN 6.911

was curative in .falc/cp.ruit infections through its effect on the parasites after

they reached the peripheral blood.

In an experiment of simulated tield type, volunteers were heavily exposed

to infection for 58 days while suippressive doses of 0.1 gin. SN 6.911 were

given daily: this dosage was continued for 28 ,lays after tile last infective

bite. In addition, the men were subjected to extreme exercise, cold. and

adrenalin injections. During the period of exposure and continued stippression, no parasiteinia or clinical malaria occurred. After the drug was

stopped, malaria developed in all volunteers infected with IP. ril.ax and in

none of those infected with P. falcdparunm. Control studies with similar

doses of quinacrine gave identical results.

Toxicity

No toxic manifestations related to SN 6,911 were reported from these

studies in which more than 200 patients were given 4.2 gin. of drug during 7

days' treatment for acute attacks of ib;ra(x malaria. There were no toxic

signs or symptoms in subjects who received 0.1 or 0.2 gin. daily for suppression for several weeks or months nor were, any noted in subjects who received

0.4 gill. daily for 20 or more days. No skin discoloration was observed.

Convulsions occurred during the administration of SN 6.911 in three

patients with general paresis and malaria. Acute confusional psychosis was

observed in two additional patients with plasma concentrations over 400 ftg.

per liter. One patient who had 1.5 gm. of SN 6,911 intravenously after a

preliminary full therapeutic course of quinacrine developed a convulsion.

The drug was given in a 2.5 percent saline solution, injected at tile rate of

1 cc. per minute. Plasma levels in the order of 1,000 ttg. per liter at the

end of tile injection and levels above 200 jig. 24 hours later were observed in

other patients who received similar amounts of SN 6,911 intravenously.

Experience with SN 6,911 was not sufficiently prolonged or extensive to

permit the accumulation of data with regard to more chronic toxic manifestations of the nature reported from prolonged quinacrine administration.

However, it is of interest that stimulation of the central nervous system was

demonstrated in subjects with high plasma levels of SN 6.911.

Summary

SN 6,911 was found to be as effective as quinacrine, except for the briefer

interval between relapses after cessation of treatment, but was in no way

superior to quinacrine. except that it did not discolor the skin. It might

have proved a useful sul)stitute had there been a serious breakdown in the
562 INFECTIOUS DISEASES

use of quinacrine because of alleged or proved toxicity. These studies stimulated further syntheses and alterations of various 4-amino acid compounds

which ultimately resulted in a drug that was, in fact, superior to quinacrine.

This was SN 7,618, or Chloroquine Diphosphate.

Chloroquine Diphosphate (SN 7,618)5"

An intensive 2-year study was made of this drug in man and in experimental animals. Its pharmacology was studied in fairly extensive experiments with mice, rats, dogs, monkeys, and man. Extensive studies were made

on its prophylactic activity against domestic strains and Southwest Pacific

strains of vivax malaria, on its curative activity against sporozoite-induced

infections when administered alone and in combination with other compounds, and on its suppressive activity. Large-scale in ,estigations of its

use in terminating the acute attack and for suppression were carried out in

military installations. Most of these studies were made in comparison with

quinine.

General properties

Absorption of SN 7,618 from the gastrointestinal tract is complete or

nearly complete, and somewhat more rapid than absorption of quinacrine.

Like quinacrine, SN 7,618 is metabolized in the body. Only 10 to 20 percent

is excreted unchanged in the urine; this fraction can be increased by acidification of the urine, decreased by alkalinization. On any given dosage schedule there are substantially higher concentrations of SN 7,618 in the plasma,

since there is less localization in the tissues than there is with quinacrine.

The pattern of distribution is in general similar. SN 7,618 is concentrated in

nucleated cells (also in leukocytes); the liver, spleen, kidneys, and lungs

contain from 200 to 500 times the amount in the plasma, while the brain and

spinal cord contain no more than 10 to 25 times the plasma concentration.

The marked localization of this drug in the organs, together with the

slow rate of excretion and degradation, necessitate a priming dose if the

desired concentration in the plasma is to be rapidly reached and maintained.

As with quinacrine, these factors result in slow disappearance of the drug

from the body when it is discontinued; its concentration in the body fluids

generally falls about 60 percent per week when administration stops.

Antimalarial activity

SN 7,618 proved more active than quinacrine in all of the avian malarias

in which it was tested. In Pla8modium cathemerium both in the canary and

in the duck it is 3.5 times as active as quinacrine, 5 to 13 times as active

against Plasmodium gallinaceum and 2.5 times as active in PlRamodium

lophurae in the duck. Like quinacrine, it does not produce permanent cures

in any of these infections, nor is either drug prophylactic in sporozoite57 Formula: 7-Chloro-4-(4-diethylamino-I-methylbutylamlno) quinollne diphosphate.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 563

induced cathemerium malaria in the canary or gallinaceum malaria in the

chick.

SN 7,618 is highly active against -throcytic forms of P. vivax and

P. fcaciparum. It does not prevent i , in vivax malaria even in doses

many times those required to terminate an acute attack, nor will it prevent

the establishment of a vivax infection when administered as a prophylactic.

It is highly effective as a suppressive agent and in the termination of the

acute attack, significantly lengthening the interval between treatment and

relapse beyond that observed with quinacrine or quinine. In falciparum malaria it has been shown to suppress the acute attack and to effect complete

cure of the infection. Studies of the antimalarial activity of SN 7,618 against

well-standardized strains of P. vivax and P. falciparum have shown it to be

approximately three times that of quinacrine. In well-tolerated therapeutic

doses a great majority of patients will be afebrile within 24 hours and the

remainder within 48 hours. Thick smears for parasites will generally be

negative at 48 to 72 hours.

Mean plasma levels in the range of 10 tg. per liter have been shown to

be effective in treating attacks of induced vivax malaria. Initial oral doses

of as little as 100 mg. followed by daily doses of 85 mg. for 4 days produce

plasma levels above the therapeutic range and result in termination of the

attack. The therapeutic level for terminating attacks due to P. falciparum

are in the range of 20 Ig. per liter and such levels and clinical effects have

been produced with initial doses of as little as 150 to 300 mg. followed by

daily doses of approximately the same amount for 4 to 6 days. It is evident

from these observations that the antimalarial activity of SN 7,618 is significantly greater than quinacrine both on the basis of oral dosage and plasma

drug concentration.

Clinical testing

SN 7,618 has been given to more than 1,000 patients with acute attacks

of vivax malaria of domestic, Pacific, and Mediterranean origin. The clinical

testing of this drug in vivax malaria of war origin was carried out principally at Harmon and Moore General Hospitals, designated as specialized

treatment centers in the United States for the study of tropical diseases.

Other studies in the U.S. Army with SN 7,618 were carried out overseas.

In addition, clinical and toxicologic investigations were conducted at various

naval, Federal, and civilian installations in this country and abroad as well

as by investigators of Allied Nations.

The observations on the use of SN 7,618 in the treatment of vivax malaria

reported from Moore General Hospital, 58 summarized in the following paragraphs, are representative of other reported studies.

58 Most, H., London, I. M., Kane, C. A., Lavietes, P. H., Schroeder, E. F., and Hayman, J. M.,

Jr.: Chloroquine for Treatment of Acute Attacks of Vivax Malaria. J.A.M.A. 131: 963-967, 20

July 1946.
564 INFECTIOUS DISEASES

STUDY AT A SPECIALTY CENTER

Material and methods.-The patients were military lpersonnel who had

acquired vivaa infections in the Pacific area or Mediterranean theater. All

phases of the disease, first attacks as well as early and late relapses, were

represented by significant numbers of men. Approximately 50 to 75 patients

were included in each of the five treatment plans.

All patients with an acute clinical attack were admitted to two specialstudy wards for observation and therapy with SN 7,618. No patient was

treated unless his blood smear was positive for malaria parasites and his

tenlperature over 1000 F. Cases were selected only with respect to the geographic origin and age of the disease, to ensure adequate representation on

each treatment schedule.

All treatment was begun on the morning following the onset of the current attack.

Parasite counts were done twice daily and continued until negative for 3 consecutive

days. The plasma levels of SN 7.618 were ascertained frequently during and after treatment to determine the pattern of accumulation, stabilization, anti disappearance of the

drug from the plasma. Temperatures were taken every 4 hours during treatment and

every 15 minutes during a paroxysm. The clinical response was followed during daily

rounds. All signs and symptoms possibly related to malaria or to treatment with SN

7.618 were recorded. In addition, clinical and laboratory observations were directed

specifically to recognizing possible toxic manifestations. All drugs were administered by

a medical officer.

Following completion of treatment and study on the wards, the patients

were transferred to a convalescent area on the hospital grounds for observation until relapse or for 120 days from the last day of treatment.

During this interval smears were examined twice weekly. In the event of parasitemia the temperature was recorded three times daily and smears made every day. A

temperature rise of over 1000 F. by mouth associated with a positive smear was considered a relapse, and the patient was readmitted to a ward for further observation and

treatment. Approximately 80 percent of the relapsed cases were direct admissions from

the convalescent area following paroxysms with temperatures of from 1030 to 1050 F.

The other 20 percent were admitted as a result of temperature observations made during

Interval parasitemia. Of the latter group at least one-half developed paroxysms shortly

after admission to the ward. No patient was treated without coincident fever and

parasitemia.

Treatment plans.-Protocols for treatment schedules were furnished by

the Office of the Surgeon General. Representative treatment schedules which

have been found most satisfactory are presented in table 74. (Tablets of

0.1 gm. and 0.3 gin. of SN 7,618 59 were available and were used singly or in

combination to supply the proper individual dose.)

Other treatment plans consisting of the administration of a total of 0.8

gin. during 7 days and 1.5 gm. during 3 days were also studied.

59 The dosage, wherever It appears In this chapter, Is in terms of base. This drug was not

commercially available at the time these studies were made. and the tablets were specially prepared.-H.M.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 565

TABLz 74.-Representatire treatment schedules for chloroquine

Schedule Hour I)o-zge (grams)

Plan A:

1st day ---------------------------.--------- 8 a.m ---------.... 0.4

12 in-- ---------- ---- -0.3

5 p .m ------------ 0.3

Total ------------------------------------.------------------ 1.0

Plan B:1

1st day ---------------------------------------- 8 a.m ------------ 0.3

12 in -------. -.. .. .- 0.3

2d day ---------------------------------------- 8 a.m ------------ 0.3

3dday ----------------------------------------- 8a.m_ 0.3

4th day ....----------------------------------- 8a. ------------- 0.3

Total ..--------------------------------------------------------- 1.5

Plan C:

1st day -------------------------------------- 8 a.m ------------- 0.4

12 m ---------------- - 0.2

5p.m -------------- 0.2

2d day --------------------------------------- 8 a.m - 0.2

3d day ---------------------------------------- 8 a.m- - 0.2

4th day ------------------------------------- 8 a.m --------------- 0.2

5th day ------------------------------------- 8a.m------------- 0.2

6th day --------------------------------------. 8.am.-------------- -0.2

7th day ------------------------------------ - 8 a.m_-------------- _0.2

Total -------------------------------------.-------------------- 2.0

SThis schedule advocated for routine use.

Results.-These results are as follows:

1. Control of parasitemia.-The rate of disappearance of parasites from

the peripheral blood during the administration of SN 7,618 in comparison

with quinine and quinacrine are shown in chart 31. It may be seen that the

peripheral blood becomes free of parasites more rapidly with SN 7,618 (plans

A, B, and C) than with either of the other drugs, the difference being more

marked between SN 7,618 and quinine than between SN 7,618 and quinacrine.

The superiority of SN 7,618 was manifest in vivax malaria of Mediterranean

or Pacific origin in first attacks as well as in relapses occurring at any stage

of the disease.

2. Control of fever.-In a total of 244 attacks treated with SN 7,618

according to plans A, B, and C, only 5 patients or 2.1 percent had fever (temperature of 100' F. or more) the day after treatment was begun or subsequently. By contrast, treatment with quinine in 184 attacks and with quinacrine in 391 attacks was associated with fever on the second day or later in
566 INFECTIOUS DISEASES

CHART 31.-Comparative rate of disappearaice of parasites from peripheral blood during

treatment of vivax malaria with quinine (172 attacks), quinacrine hydrochloride

(397 attacks), and chloroquine (298 attacks)

[Percent of patients with negative smears]

PERCENT

0

\o , So,, ,, 40 - " QUININiE

\ " . •

40-

QUIWACRINE HYDROOMLONIDE

60QUNN

so 'LOROUINE ..

fool0 24 46 72 96 120 IS2

HOURS AFTER FIRST DOSE OF DRUG

8.7 and 8.0 percent. respectively, of patients treated. The superiority of

SN 7,618 in this respect is manifest in infections of both Mediterranean and

Pacific origin, regardless of the initial parasite density, and in Pacific infections regardless of whether the attack is the very first or a relapse at any

stage of the disease. In delayed primary attacks the proportion of patients

who have fever on the second day after treatment with SN 7,618 is begun is

higher than in patients treated in relapse. This is also true even to a greater

extent for delayed primary attacks treated with quinine or quinacrine, shown

in chart 32.

3. Control of symptoms.-It is difficult to evaluate comparative effects

of quinine, quinacrine, and SN 7,618 in controlling symptoms which are

usually present for a few days in a treated attack of malaria. However.

clinical impressions based on treatment of more than 1,000 acute attacks of

vhyaw malaria and supported by a more detailed statistical analysis, indicate

that SN 7,618 is at least as good as quinine or quinacrine in the control of

all symptoms, and is superior to one or the other in the control of some

symptoms.

Headache and backache are relieved more rapidly with SN 7,618 or quinine than with quinacrine. Quinine is more effective than quinacrine in the

control of generalized aching, but is not significantly better than SN 7,618.

Weakness, dizziness, and lightheadedness disappear more rapidly with SN

7,618 or quinacrine than with quinine. Nausea persists longer in patients

treated with quinine than in those treated with SN 7,618 or Atabrine. The

effect of each of these drugs on the duration of vomiting, abdominal pain, and

abdominal tenderness is essentially the same.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 567

CHAuT ,32.-('omparatir'e efflcieney of quinine, quinacrine hydrochloride, and chloroquine

in controlling fever during treatment of delayed primary attacks of relapses of

vivax malaria

[Percent of patients with fever on second day or later]

PERCENT

40

30 DELAYED PRIMARY ATTACKS

20

RELAPSES

10

01

QUINI NEE QUINAGRINE CHLOROQUINE HYDROCHLORIDE

4. Effect on interval to relapse.--Quinine, quinacrine, and SN 7,618

do not materially influence the ultimate relapse rate following treatment of

the acute attack. Apparently the ultimate relapse rate in large groups is not

affected by the age of the disease, the number of previous attacks, total amount

of drug, or duration of treatment. More than 500 patients treated for acute

attacks of vivax malaria of Pacific and Mediterranean origin were followed

to relapse, or for a minimum of 120 days. The relapse rates following treatment with quinine, quinacrine, or SN 7,618 were from 75 to 85 percent for

Pacific infections and approximately 35 percent for Mediterranean infections.

The cumulative relapse rates following treatment of acute attacks of vivax

malaria of Pacific origin are shown in chart 33. At 120 days, 85, 80, and 70

percent of patients treated with quinine, quinacrine, and SN 7,618, respectively, had relapses.

The interval to relapse, however, and the distribution of the relapses that

occurred during the first 2 months after treatment are strikingly different for

the three drugs. These differences are presented in chart 34.

During the first month after treatment, 54 percent of the patients treated with

quinine relapsed, 9 percent relapsed after quinacrine, and none relapsed after SN 7,618.

At 40 days, relapses following SN 7,618 begin to occur, but these represent less than 1

percent of treated patients, whereas 67 and 28 percent relapsed at 40 days after treatment with quinine and quinacrine, respectively. At 50 days, 72, 40, and 11 percent of

the patients relapsed after quinine, quinacrine, and SN 7,618, respectively.

In terms of the total number of relapses that occur within 120 days, the percentages of patients who relapsed within 50 days were 85, 50, and 16 percent, respectively,

for quinine, quinacrine, and SN 7,618. Thus, of the total relapses that occur within 120

days, more than three-fourths of them will take place In the first 50 days after quinine,
568 INFECTIOUS DISEASES

while during the same time after quinacrine only one-half, and after SN 7,618 only onesixth will occur. The median interval to relapse following treatment with quinine is

24 days, with quinacrine, 504) days, and with SN 7,618, 61 days.

CHART 33.-Cumulative rates of relapses during a minimum of 120 days followilly treatment of acute attacks of vivax malaria with quinine (76 patients), quimeriine

hydrochloride (118 patients), anud chloroquine (156 patients)

[Cumulhtive relapse rate. per'ent of patieuts treated]

PERCENT

00

s o Q u i n i n e,.

40o"

20/ HLOROQUINE

0 10 20 30 40 50 60 70 00 90 100 110 120

DAYS FOLLOWING COMPLETION OF TREATMENT

Since none of these drugs produces a complete cure of malaria, the drug

of choice on the basis of interval to relapse is the one that gives the longest

mean interval, the greatest median interval for a large group of patients, and

the smallest number of short-term relapses. The data presented show that

the interval to relapse after treatment with SN 7,618 will be on the average

at least 5 weeks longer than after quinine and about 2 weeks longer than after

quinacrine. Only a negligible number of patients treated with SN 7,618 will

relapse during the first 50 days after treatment. Accordingly, SN 7,618 not

only controls symptoms, fever, and parasitemia promptly but, in addition.

confers freedom from another attack for a period of approximately 2 months.

Plasma levels.-Blood was drawn at such times as to determine the rate

of accumulation, stabilization, and disappearance of SN 7,618 from the plasma

during and after treatment with various dosage regimens. The values obtained during and after treatment on schedules A, B, and C are presented in

chart 35.

The minimal plasma concentration of SN 7,618 that is effective in terminating an acute attack has been shown to be in the range of 10 ,g. per liter.

The levels observed during and after treatment on plans A, B, or C are well

above this range.

No correlation has been found between variations observed in levels obtained in single individuals receiving the same amount of drug and their

interval to relapse or to the first parasitemia after completion of treatment.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 569

CHART 34.-Comparison of distribution of relapxes oceurringa during the first 60 days after

treatment of acute aittaeks of vivax malaria of Piscific origin with quiniuc.

quina1crine hyidrochloride', antd l.Iloroq int

[('unmulative relapse rate, percent of patlonts treated]

PERCENT

100 QUINACRIKNE HYOROCMLORIVE

SO CNLOROOUIN I

QUININE

40

20-

04

1-20 21-30 31-40 41-50 51-60

DAYS TO RELAPSE FOLLOWING COMPLETION OF TREATMENT

Summary.-The data presented in the study on the relative efficiency of

quinine, quinacrine, and SN 7,618 are summarized and presented for reference

in table 75.

TABLE 75.-Relatire efficiency of quinine, quinacrine hydrochloride, and chloroquine in trealment of acute attacks of vivax malaria

Effhfiency ;wtors Quinine Quinacrine Chloroquine

hydrochloride (SN 7,618)

Total amount of drug --------------- grams-. 28.35 2.8 1 1.0, 1.5, 2. 0

Duration of treatment ---------------- days-- 14 7 1 1,4,7

Rate of parasite clearance --------------------- - + + ±+ 4 + +

Control of fever:

Delayed primary attacks 2 .................. - + + + + + +

Relapses- 3--------------------------------- + + + + ++++

Interval to relapse:

Median ---------------------------- days- 24 50 61

Relapses:

First 50 days ------------------- percent-- 85 50 16

Total, 120 days ------------------ do .... 90 82 75

Control of symptoms ------------------------- + + + ++ + + ± ±

Toxicity ------------------------------------. 4 + + + +

'Plans A, B, and C. See table 74.

2 Infections of Pacific origin.

3 Infections of Mediterranean or of Pacific origin.

4 Cincbonism.

5 Eezematold reactions in patients sensitive to quinacrine hydrochloride.

6 Slight, transitory pruritus; rare erythema or urticaria.
57-0 INFECTIOUS DISEASES

From this study it was concluded that SN 7,618 is a highly effective, safe

ant inmalarial drug which is sul)erior to quinine and quinacrine in the treatment

of acute attacks of v;',ax malaria. Routine treatment was recommended as

follows:

One tab'et (0.3 gm.) of SN 7,618 is administered when the diagnosis of

vi'ax malaria is established by a positive blood smear. This amount of drug

(0.3 gni.) is repeated 4 hours after the first dose. One tablet (0.3 gin.) is then

given on each of the following three mornings. The total dose is 5 tablets,

totaling 1.5 gi. of SN 7,618 administered during 4 days.

CH.,ART 35.-AAverage plasmna levels of ehloroquine (176 patilints) during and after tr'atment under plans A, B, and C

INCROGRAMS PER LITER

250

I20

PLANLBe

I\.~LA GPaNJ

0

2 3 4 5 .1 r 9 10 11 2 13 .4 .5 16 7 '8 q 20 21

DAYS

I Total dose: 1.0 g'm.; duration: 1 day.

2 Total dose: 1.5 gin.; duration: 4 days.

3 Total dose: 2.0 gm. ; duration : 7 days.

NoTE.--ln all schedules, the mean plasma levels during treatment are from 7 to 20 times above

the required therapeutic level. Note also the persistence of thm, drug long after termination of

treatment.

OTHER STUDIES OF FIVAX INFECTIONS

Treatment plans with SN 7,618 in which total (loses of 1.0 gi. in 1 (lay.

0.8 gin. in 6 days, 2.0 gm. in 6 days, and 1.2 gn. in 3 klays were studied at

Harmon General Hospital. The results reported from a total of 235 attacks

treated on the above schedules were essentially the &,lme as those reported

from the Moore General Hospital. Treatment of primary attacks of Pacific

origin or relapses of Pacific or Mediterranean vi'a.x malaria with SN 7,618

resulted in prompt control of symptoms. Parasitemia and fever disappeared

more promptly than with quinacrine, and the interval to relapse was greater
LINICAL TRIALS OF ANTIMALARIAL I)ADRUGS 571

ian with the latter except in the patients who had a total of only 0.8 gin.

SN 7,618 during 6 days. It was felt that SN 7,618 was superior to other

itimalarial agents previously studied at that installation (quinine, quina-

-ine, and SN 6,911).

A single dose of 1.0 gin. SN 7,618 ,-.as administered to each of 50 patients

ith acute attacks of 'vivax malaria at a U.S. naval installation. There was

rompt subsidence of fever, and parasites disappeared in all cases within 36

urs. The interval to relapse from this single-dose schedule was longer

kan that following the standard quinacrine course. At another naval instaltion, more than 100 patients were treated with SN 7,618 for acute attacks of

'vatx malaria of Pacific origin. The majority received 1.0 gin. within a

?riod of 16 to 24 hours. Control of symptoms and fever was more prompt

ian was observed in patients treated with quinacrine, and parasites disapmared from the blood in most cases within 48 hours. Short-term relapses.

iat is, less than 40 days, did not occur after treatment with SN 7,618, in

mntrast to a significant number of relapses in less than 40 days after treatent with quinacrine.

SN 7,618 was used clinically to terminate acute attacks of vivaX, malaria

various oversea areas. In India, 26 American military patients with acute

V'uX infections were treated with 0.9 gin. during the first 24 hours followed

r a single dose of 0.3 gin. on each of the 2 successive days (total 1.5 gin. in

days). The average duration of fever was 24.1 hours and parasiteinia 1.5

tys. In Peru, more than 300 natives were treated for acute attacks of vvaxa.

1ciparunz, and mixed malaria with relatively small doses of SN 7,618 (0.75

n. on the first day and 0.25 gin. on the second day; total 1.0 gm. in 2 days).

i 70 cases carefully studied, blood smears were positive in only 17 and 5 at

t and 48 hours, respectively, after the initiation of therapy. The clinical

ýsponse to treatment was considered good in the majority of patients. It was

)ted the falciparunm infections responded more slowly than those due to • i2vax.

STUDIES OF FALC'PARUM INFECTIONS

SN 7,618 did not have any extensive clinical trial in the treatment of

Iciparum infections, particularly the fulminating variety with cerebral

volvement. Preliminary studies in this country with injections of domestic

rains of P. falciparum indicated that plasma concentrations of 20 pg. of

-ug per liter maintained for 4 to 6 days resulted in the control of fever and

Lrasitemia without recurrence of symptoms or signs of infection for 14 days

Imore. Such relatively low plasma levels are easily obtained with initial

)ses of 200 mg. and maintained with daily doses of 100 mg. In actual prac-

:e, the oral dosage schedules of 0.6 to 1.0 gin. during the first 24 hours folwed by daily doses of 0.2 to 0.3 gin. result. in plasma levels of 5 to 10 times

at required to terminate falciparnm activity. It is probable therefore that

S7,618 would prove effective in terminating most infections with P.

1c;J)(lrum.
572 INFECTIOUS DISEASES

At the 20th General Hospital in the India-Burma theater, 10 Chinese

soldiers with acute falciparum malaria were treated with 1.5 gin. of SN 7,618

during 3 days. Clinical response was satisfactory in all patients. The average duration of fever (102' to 105' F. at onset) was 34 hours after the first

dose (range 8 to 64 hours), and blood smears became negative within 3 days.

In another report from the same hospital, similar results were recorded in

eight American soldiers with acute falciparum malaria treated with SN 7,618

(total 1.5 gin. during 3 days). The average duration of fever (102.40 to

104.80 F. at onset) was 28.4 hours after the first dose, and blood smears were

free of parasites within 1 to 3 days.

In the Peru study of more than 300 acute attacks of malaria (many

P. falciparum or mixed vivax-jalciparum) treated with a total of 1.0 gmn. of

SN 7,618 during 2 days, 17 infections with P. falciparum and 7 mixed cases

were closely followed; the response to treatment was considered rapid or good.

There were no treatment failures. Fever and parasitemia were quickly controlled. In general, the rapidity of disappearance of parasites and the clinial response to treatment varied with the severity of the infection. It should

be borne in mind that the total duration of treatment and total doses of drug

employed were no optimum and that the satisfactory response was observed

in highly immune natives who are not comparable with nonimmune American

troops.

Unfortunately, no parenteral SN 7,618 was available, and no opportunity

was afforded for comparing the relative efficiency of SN 7,618 and parenteral

quinine or quinacrine in the treatment of fulminating falciparwum infections

complicated by severe vomiting or involvement of the central nervous system.

STUDIES OF SUPPRESSION

The suppressive efficacy of SN 7,618 and the mode of its action against

vivax and falciparnrm infections were investigated in Australia in the manner

of similar studies of quinine, quinacrine, and SN 6,911.60 New Guinea strains

of P. vivax and P. falciparum were employed. The "build-up" doses of

SN 7,618 were 0.2 gm. twice daily for 4 days. Subsequently, the daily dosage

was 0.1 gm. continucd for 23 days after the last exposure to infective mosquitoes. None of the volunteers infected with P. vivax or P. falciparmm developed clinical malaria or microscopically detectable parasitemia during the

period of suppression. However, subinoculation of 200 cc. of blood to other

volunteers 9 or 10 days after infection produced malaria in the recipients.

This proved that the test subjects were infected and demonstrated that the

action of SN 7,618 was not prophylactic and that its suppressive action against

the parasites was exerted after their appearance in the blood. Following

discontinuance of medication, all volunteers infected with P. vivax developed

malaria within 40 to 60 days, but no falciparum malaria developed during a

60 See footnote 12, p. 529.
CLINICAL TRIALS OF ANTIMALAIIIAL DRIUGS 57:3

period of 81 days in the men infected with 1'. falciparuwu. SN 7,618 was thus

shown to be equally as effective as quinacrine or SN 6,911 in suppressing both

vivax and falciparum infections and in curing the latter.

Anticipating the practical application of SN 7,618 as a suppressive agent,

one must consider the persistence of this drug in the body and the fact that

relatively low plasma levels (10 ýg. per liter) have pronounced antimalarial

activity. It was shown that the administration of 0.3 gin. of SN 7,618 in

single doses once a week resulted in the maintenance of mean levels above

10 ,g. per liter in the majority of more than 50 subjects who remained on this

suppressive schedule for 4 to 8 weeks.

Suppressive schedules of single weekly doses of SN 7,618 were studied,

in this country, in patients with recurrent vivax malaria of Pacific origin.

Ninety-four men who previously were having frequent relapses were p)lace-(

on 0.3 gm. weekly for approximately 3 months. During the period of suppression, only one man had a positive blood smear on one occasion. During

the last 10 days of suppression, 75 men were placed on an extremely rugged

test of physical endurance, consisting of daily hikes of 5 to 15 miles over very

rough terrain, forced marches, and rifle drill. In this period, six men developed transient parasitemia. No clinical attacks occurred during suppression, including the period of exercise. It was calculated on the basis of the

number of attacks these men had had in 3 months prior to suppression that at

least 75 relapses should have occurred if no suppressive therapy had been

taken. It was thus shown that SN 7,618 given once a week was completely

effective in suppressing clinical malaria in a group with a high index of relapse and parasitemia (positive smears in 84 percent in the 5-week period

prior to suppression).

At Moore General Hospital, more than 100 patients who had had an

attack of vivax malaria within the previous 3 months were placed on 0.3 gm.

SN 7,618 once a week for 8 to 16 weeks. More than half of these patients

had tuberculosis. During the period of suppression, no parasitemia and no

clinical malaria occurred. The patients, especially those with tuberculosis,

were reluctant to discontinue their weekly dose of SN 7,618 because they felt

reassured that they would not have malaria while they were taking the drug.

In a series of more than 200 men treated with 1.0 gin. of SN 7,618 in 1 day

for acute attacks of vivax malaria of Pacific origin, the shortest interval to

relapse was 33 days. It was therefore believed that successful suppression

could be accomplished by the administration of 1.0 gm. in 1 day at monthly

intervals. Accordingly, 35 men recently treated for an acute attack with

1.0 gin. of SN 7,618 in 1 day were advised to take 1.0 gm. within 1 day every

4 to 6 weeks. They were observed from 60 to 162 days while on this schedule

of self-medication. In this period, the expected number of relapses was calculated to be 24, but only 8 occurred. It is possible that, if medication had

been supervised and administered regularly once a month rather than at. irreg-
574 INFECTIOUS DISEASES

ular intervals up to 6 weeks, more effective or complete suppression might

have been produced. Thus, SN 7.618 is not only effective as a sup)pressive with

weekly doses of 0.3 gin. but it is possible that satisfactory suppression may

result from larger doses at greater intervals.

Studies on suppression with SN 7,618 were made in various areas overseas: In Peru, in more than 1,200 adults and children (natives) ; in India. in

school children, in coolies, and in colored troops; and in the Philippines. in

American soldiers during, unfortunately, a time when there was practically

no transmission of malaria. Militarv deactivation of units prevented coml)letion of the last investigation as l)reviously planned. In all these studies, the

results were good, but such observations in natives, or in American troops

during p)eriods of nontransinission. offered no conclusive evidence that complete suppression under combat conditions in highly malarious areas would

result front the administration to troops of a weekly dose of 0.3 gin. of

SN 7,618.

The experiments in Australia, the observations on the control of parasitemia overseas, and the suppression of relapses in this country indicate, however, that SN 7,618 in weekly suppressive doses should prove effective under

combat conditions. The apparent advantage of SN 7,618 as a suppressive

agent lies in the ease of administering it in the form of one tablet once a week,

the absence of the yellowish discoloration of the skin resulting from the prolonged use of quinacrine, and its tolerability.

Toxicity

Extensive studies of the acute and chronic toxicity of SN 7,618 were

conducted in animals prior to its clinical application in man. Observations

were made on the tolerability and toxicity of varying amounts of drug administered to human volunteers, often for prolonged periods. Finally, data collected on possible toxic signs or symptoms during the administration of therapeutic or suppressive amounts of SN 7,618 in several thousand individuals

furnished the backg'round for the following statement approved by the Board

of Coordination of Malarial Studies:

There is little difference In the toxicity of SN 7,618 and that of quinacrine in experimental animals. The acute toxicity of both drugs given orally is about the samne in

the rat and monkey. The acute toxicity of intravenous SN 7,618 is greater than that

of quinacrine In the dog. Short-term chronic toxicity tests in the mouse show the two

drugs are about equally toxic. In such tests carried out in the rat and the monkey for

periods not exceeding 30 days, SN 7,618 is slightly more toxic titan quinacrine. In

longer term studies with the rat and monkey extending up to 120 days, the drugs are

about equally toxic or, if anything, SN 7,618 is slightly less toxic than quinacrine.

In man, the symptoms that have been observed following doses of SN 7,618 adequate for treatment of the acute attack include mild and transient headache, visual

disturbances, pruritus, and gastrointestinal complaints. In chronic toxicity studies in

man using a dose (0.5 gm. weekly) In excess of that necessary for adequate suppression.

no serious symptoms and no impairment of health have been observed In 31 subjects

over a period of 11 months of consecutive drug administration. In studying the record
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 575

of 2,675 individuals who have received SN 7.618, every symptom that has been observed

has been recorded in an effort to bring out even minimal toxic manifestations. In a

small number of instances, usually with dosages higher than necessary for either treatment or suppression, individual subjects have refused to continue drug administration

because of unpleasant symptoms; none of these manifestations has been constitutionally

serious and all have been readily reversible. Unlike quinacrine, SN 7,618 does not discolor the skin.

Statements on toxicity in various reports concerned with the therapeutic

or suppressive use of SN 7,618 will be briefly cited.

In a treatment study 81 in which 3W5 patients with acute attacks of vivax malaria

were given total doses of 0.8 to 2.0 gin. of SN 7,618 during a period of 1 to 7 days, no

major toxic manifestations were encountered clinically or in numerous laboratory Investigations. It was not necessary to interrupt or discontinue treatment in a single case.

Occasionally, there was mild nausea if the drug was taken in the fasti~ag state. No

visual disturbances were noted. Particular effort was made to detect cutaneous symptoms or signs that might be attributed to SN 7,618, and special questioning elicited information that would rarely have been volunteered. Of the 284 patients treated with

SN 7,618, 56 complained of pruritus during the course of drug administration. The

pruritus was accasionally generalized but more often localized, particularly to the palms

and soles, and in the great majority it was transitory and very mild. Of the 56 patients

who developed pruritus, 50 had no coincident skin eruptions. Seven patients, or only

2.4 percent of the total number treated, developed erythema, urticaria, or a mild papular eruption. No similar emphasis was placed on skin symptoms in patients treated with

quinine or quinacrine and it Is likely that the reported incidence in association with

SN 7,618 therapy is disproportionately high. In this study, the administration of SN

7,618 to patients with eczematoid dermatitis or the eczematoid-lichen-planus complex due

to quinacrine did not result in exacerbation of the underlying skin condition in any case.

In another series of 236 patients treated with similar total doses of SN 7,618 the

incidence of pruritus was 7 percent but urticaria or rash occurred only in 3 cases.

Visual disturbances were not encountered. Gastrointestinal symptoms were negligible.

Visual disturbances, that is, blurred vision and difficulty in shifting

fixation from near to distant objects, have been described in volunteers on

daily doses of 0.5 gin. SN 7,618 and in patients treated for acute attacks of

vivax malaria with 3.2 gin. These symptoms are undoubtedly of importance

in evaluating the toxicity of SN 7,618 since they originate in the central

nervous system. It must be pointed out, however, that symptoms or signs

have not occurred in almost 1,000 patients treated with total doses of less than

2.0 gin. or with suppressive doses of not more than 0.3 to 0.5 gin. per week.

The amounts of SN 7,618 reported to have produced visual disturbances are

in the order of 10 times that required for adequate suppression and 2 to 4

times the required dose for termination of an acute attack.

In the field studies of suppression that have been cited, based on several thousand

subjects, no striking toxicity is noted, and the incidence of gastrointestinal or other

symptoms requiring the discontinuance of the drug is remarkably low. Detailed investigations of the effects of SN 7,618 suppression on various organ functions were carried

out at Randolph Field, San Antonio, Tex. Doses of 0.5 gin. weekly and twice weekly

"m See footnote 58, p. 563.
576 INFiCt "'ll 1"S D•lSF.ASl•I

were given for 4 weeks. No significant effVTts on physic.al titiiss, on psychlogi.hal pelrformante at grotnd level and at 18.00)0 feet, on vision (ias indicated by scotopic vision.

visual fields, or near-polnt acconmuodation), on auditory acuity, on heart aits Indiicated

by electrocardiograms i, or on ability to retain balance while Iblindfoldeul. were ohiserved.

Observations on the prolonged administration of SN 7,618 were mlla'd ill colisciet'll

tious objectors. Forty men given 0.3 gin. daily for 77 days and then 0.5 gin. weiekly for

12 weeks showed no serious toxic reactions. 1leadache and difficulty in quickly fixing

on distant objects occurred in this group on very large doses. Visual symptoms persisted in only 2 men of 31 who remained on the drug for 9 months. Bleaching of the

hair at the rot~s was observed in live blonde subjects while they were receiving 0.3 gin.

of SN 7,618 daily. The color of the hair returned to normal when the drug was discontinued. One patient given SN 7,018, 0.5 gin. weekly, for 8 months developed an eruption resembling lichen planus which persisted during the subsequent administration of

tile drug and began to subside 2 weeks after Its discontinuance.

The last observation is of extreme importance in that it suggests the possibility

that the prolonged administration of SN 7,618 in large doses may result in tile derinatilis complex (eezematoid dermatitis and/or lichen planus) described with quinacrine

suppression. In tills connection It is of interest that of 30 patients with atypical lichen

phntius who were placed on suppression doses of SN 7,618 in the Indila-Burlla theater

40I.3 gin. weekly), one suffered an actual tlareup of the dermatitis descrilbed as a mild

ac.-h, eczematold reaction which caine on after one dose and disappeared within 2 (lays.

It must be remelibered that patients with eczematoid dermatitis may react to many

drugs. At Moore General Hospital more than 50 patients with atypical lichen planus

and a like number with eczenatoid skin conditions were given SN 7,618 for termination

of aciute attacks of malaria. There was no exacerbation In the skin disease in these

cases, and in a group of patients with lichen planus who continued on suppressive therapy of 0.3. git. weekly up to 3 months, no change was noted in the lichenold lesions

other thati continued regression.

The toxic manifestations of SN 7,618 may be summarized briefly. Little

to no toxicity was encountered with therapeutic (1.0 to 2.0 gin.) or suppressive (0.3 gin. weekly) doses of SN 7.6,18. Minor toxic symptoils consisted of

occasional gastrointestinal complaints and pruritus in a small number of subjects. Following large doses for thel'rapy 01' Sllp)V5siol, visual disirliamices

occurred, and in one case atypical lichen planus developed after suppressive

imedication for S months (0.. gin. weekly). In general. it wits felt by 1mmost

observers that SN 7,618 in recommended doses was a safe drug.

Summary

Clinical experience with SN 7,618 proved this drug to be a highly eWfective antimalarial agent, superior to quinacrine, quinine. and SN 6,911. It

excels quinacrine and quinine in more prompt. control of fever, symp)toms, and

parasitemia, in a shorter course of treatment, in a longer interval to relapse.

in the abolition of short-term relapses, and in freedom from major toxic

reactions. Given in single weekly doses, SN 7.618 is able to provide effective

suppression against. viv'ha and falhipartim, infections and to cure the latter.

SN 7,618 does not discolor the skin. Unfortunately. no assay of its value in

fulminating falcipanim infections was possible. Experience has shown SN

7,618 to be a safe drug.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 577

Oxychloroquine (SN 8,137) 62

General properties and antimalarial activity

The absorption, degradation, distribution, and antimalarial properties of

SN 8,137 are essentially similar to SN 7,618 although it appears to have less

antimalarial activity in oral dosage. The greater persistence of SN 7,618 in

the body is reflected in the smaller weekly dose required of this drug than

of SN 8,137 for comparable suppressive effects. The latter appears to be less

toxic, but this advantage may be offset by the larger doses necessary for

equivalent suppressive action.

The estimated "critical" plasma levels of SN 8,137 necessary for terminating clinical activity and parasitemia due to P. vivax and P. falciparum

have been shown to be approximately 17 and 19 [Lg. per liter, respectively.

In induced experimental malaria, total doses of 0.3 gim. for vivax infections

and 0.6 gm. for falciparum infections have given the mean plasma levels in

the order of 25 to 50 gg. per liter in the falciparum infections and 17 to 31

pg. per liter in the vivax infections. It is apparent therefore that relatively

greater doses and higher plasma levels are required for equivalent antimalarial activity than with SN 7,618. Single weekly doses of 0.25 gm. of SN

8,137 for 4 weeks were found effective in suppressing vivax (domestic strain)

infections transmitted by mosquitoes, whereas weekly doses of 0.125 gm. were

ineffective.

No toxicity was reported in 16 volunteers who were given SN 8,137 daily

for 6 weeks. The dosage in the sixth week was 600 mg. daily and the total

dosage per man during the entire period was 12.2 gmn. or an average of 0.3

gm. daily for 42 days. Headache, anorexia, and visual disturbances occurred

with moderate frequency in subjects receiving similar amounts of SN 7,618,

particularly if the plasma levels were above 275 jg. per liter.

Clinical testing

SN 8,137 had only limited clinical application in the treatment of malaria in the U.S. Army. At Harmon General Hospital, 63 patients with

acute attacks of vivax malaria were treated with total doses of 2.0 gm. in 3

days (1.0 gint. on the first day and 0.5 gin. on each of the next 2 days). A

greater number of patients treated with SN 8,137 had fever on the second

day of treatment than had groups treated with SN 6,911, SN 7,618, or quinacrine. Parasite clearance was not as rapid during the first 24 hours of treatment as with quinacrine or SN 7,618, although more rapid than with quinine

or SN 6,911. In the next 48 hours, the parasite clearance rate was about the

same for SN 8,137 as for the other 4-aminoquinolines as well as quinacrine.

Toxic symptoms with SN 8,137 in this study appeared more frequently than

with the other synthetic drugs used. There was nausea, vomiting, anorexia,

wFormula: 7-Chloro-4-(3-dlethylamino-2-hydroxypropylamlne) qulnoline diphosphate.

639243T-63-----40
578 INFECTIOUS DISEASES

and abdominal cramps in a total of four patients, diarrhea in five patients,

pruritus ini four patients, urticaria and a rash in two patients, and dizziness

in four patients.

Although the patients were not retained for determination of the interval to relapse, six patients did relapse within 31 to 39 days after completion

of treatment. It appears from this small amount of data that SN 8,137 is

inferior to SN 7,618 in its poorer control of fever, slower parasite clearance,

shorter interval to relapse, and greater toxicity.

Summary

SN 8,137 has not been studied as extensively as other 4-aminoquinoline

compounds. Despite the fact that it appears to have considerable antimalarial activity, although less than SN 7,618, it is doubtful if it offers any

advantage over the latter. In the treatment of acute attacks, SN 8,137 proved

to be inferior and more toxic than SN 7,618. As a suppressive agent, SN

8,137 may possibly have some value because of its apparent tolerability in

relatively large doses. On the other hand, its rapid disappearance from the

body compared to SN 7,618 may require doses of an order to offset its alleged

tolerability.

Summary of Studies

As a result of extensive clinical and pharmacological studies with these

drugs, compounds were found that could be substituted, if necessary, for

quinacrine without sacrificing any of the advantages of the latter in the

treatment or suppression of malaria. In addition, one of the derivatives of

this group of drugs (SN 7,618 or chloroquine) proved superior to quinacrine

and other drugs both for treatment and suppression. The 4-aminoquinolines

were found to cure falciparum infections and to be effective as suppressive

agents in single weekly doses. They do not discolor the skin and may be

taken for prolonged periods without apparent severe toxicity. The relapse

rate in vivaa, infections is not materially influenced by treatment with these

drugs, although with SN 7,618 there is a significant prolongation of the interval to relapse and a reduction in the number of short-interval relapses

after treatment. Treatment schedules of 1 to 4 days are practical in acute

attacks of vivax malaria. Extensive field studies of falciparum infections

were not carried out, and this phase of the treatment of malaria requires

further investigation. The occurrence of atypical lichen planus during the

prolonged administration of SN 7,618 suggests the possibility of the significant development of this syndrome if chloroquine were to be used as widely

as quinacrine. The careful and complete clinical and pharmacological studies

carried out with these drugs have added much to knowledge of the chemotherapy of malaria.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 579

8-AMINOQUINOLINE COMPOUNDS

Pamaquine (Plasmochin Naphthoate)"

Historicai review

The first promising synthetic antimalarial drug was introduced in Germany in 1924, by Schulemann and his coworkers at Lkverkusen. The schizonticidal and gametocidal properties of Plasmochin in experimental hosts and

in man were such as to represent a major advance in the chemotherapy of

malaria. It was hoped that as a result of continued chemical and pharmacological investigations a less toxic and more curative compound would be

found. Actually, as will be demonstrated in this section, Plasmochin if properly used produces definitive cure in infections with strains of P. v/vaw that

have a high index of repeated relapse after all other forms of treatment.

The drug-testing program in Germany continued during World War II and

resulted in the synthesis and testing of more than 200 of these 8-aminoquinoline compounds. In the United States, similar activity was directed in a

search for an 8-aminoquinoline drug that would be superior to Plasmochin,

be less toxic, and might be a true causal prophylactic or curative agent in

the prevention, suppression, and treatment of malaria. As a result of these

studies, a reevaluation of Plasmochin led to its rational and successful use in

curing relapsing vivax infections and to the discovery of several compounds

that are considered less toxic and in other respects superior to Plasmochin.

Certain prewar studies on the clinical application of Plasmochin, reviewed at

Moore General Hospital,64 will be described briefly. In addition, clinical

studies made during the war that led to the successful use of Plasmochin as

a curative agent will be discussed.

Acute attacks of malaria are more effectively and safely terminated by

the use of quinine, quinacrine, or the more recently introduced 4-aminoquinoline compounds than by Plasmochin alone. In recent years, Plasmochin

has been used almost entirely as an adjunct to other antimalarial therapy

because of its ability to eradicate gametocytes of P. falciparum with small

amounts of the drug in a matter of a few days. This practice is of questionable value as a control measure in areas where malaria is endemic. There

is evidence, however, that simultaneous administration of Plasmochin and

quinine daily for 2 weeks or more is highly effective in reducing relapse rates

in vivax malaria during an observation period of 2 to 6 months. This is in

sharp contrast to curative failure or high relapse rates in malaria caused by

Pacific strains of P. vivax after treatment with quinine, quinacrine, or

4-aminoquinoline compounds.

63Formula (pamaquine naphthoate): methylene-bis-f-hydroxynaphthoate of 6-methoxy-8-(1-

methyl-4-diethylamino) butylaminoquinoline.

64Most, H., Kane, C. A., Lavietes, P. H., London, I. M., Schroeder, E. F., and Hayman, J. M.,

Jr.: Combined Quinine-Plasmochin Treatment of Vivax Malaria; Effect on Relapse Rate. Am. J.M.

Bc. 212: 550-560, November 1946.
580 INFECTIOUS DISEASES

Prewar studies.-Sinton and Bird,6` in 1928. reported from India on

86 patients given Plasniochin alone or Plasnmiohin and quinine together for

an attack of vzvaz malaria and observed for 2 to 4 months after treatment.

Occasionally, patients failed to complete treatment because of toxic reactions

or disappearance from observation. The percentage of relapses was calculated on this basis. Twenty-nine patients were given 0.08/gn. of Phasmochin

(probably Plasmochin naphthoate) on 17 treatment days during a period of

39 days as suggested by the German manufacturers of the drug. The relapse

rate (luring the period of observation was 36 percent. Twenty-two patients

were given 0.08 gin. on as many consecutive days as possible for 28 treatment days with interruptions only for toxic manifestations, the average

treatment period being 36 days with a range from 28 to 53 (lays. The relapse

rate in this group was 23 percent. Fifteen patients were given 0.10 gin.

Plasmochin phls- 1.25 gin. quinine sulfate on 17 treatment days during a

39-day course of treatment. The relapse rate (luring 2 to 4 months was 20

percent. Finally. a group of 20 patients received these same daily amounts

of both drugs for 28 days as continuously as possible during an average

treatment period of .37 days. None relapsed during the period of observation.

The relapse rate for the 51 patients who received Plasmochin alone was 30

percent and for the 35 patients who received Plasmochin and quinine together, 8.5 percent. Thus. of the total number of 86 patients- who received

Plasmochin for 17 to 28 days. the relapse rate as given by the authors was

21 percent. This percentage includes 6 patients who were lost to followup

studies or who did not complete the full course of treatment and were

counted as failures; the failure rate actually observed in 80 men during a

period of 2 to 4 months after treatment was 16 percent. In contrast to this

finding, the relapse rate for 111 men treated with quinine alone and similarly

observed was 77 percent. There is little question that in this study combined

quinine-Plasmochin treatment very substantially reduced the incidence of

relapse during 2 to 4 months after treatment.

In 1930, Sinton and his coworkers 6 reported two additional groups of

patients on combined quinine-Plasmochin treatment for acute attacks of

vivax malaria. Seventeen were given, daily, Plasmochin, 0.06 gin., and quinine sulfate, 1.25 gin., from 4 to 21 days. None of them had a clinical or

parasitemic relapse during 2 months after treatment, when the experiment

was terminated. An additional 44 patients received Plasmochin, 0.04 gm.,

and quinine, 1.25 gin., daily for 21 days. Three patients relapsed, making a

total failure rate of 6 percent for 554 men who had Plasmochin for 14 or

more days in contrast to a relapse rate of 42 percent for 38 patients who

were treated with quinine alone.

6i Sinton, J. A.. and Bird. W.: Studies in Malaria, With Special Reference to Treatment.

Part IX. Plasmoquine in the Treatment of Malaria. Indian J.M. Res. 16: 159-177, July 1928. 66 Sinton, J. A.. Smith, S.. and Pottinger, D.: Studies in Malaria. With Special Reference to

Treatment. Part XII. Further Researches into the Treatment of Chronic Benign Tertian Malaria

With Plasmoiiulne and Quinine. Indian J.M. Res. 17: 793-814, January 1930.
CLINICAL TRIALS OF ANT[MALARIAL ID)RUGS 581

In 1932, Jarvis 7 reported 8.0 percent relapses during a 2 to 4 months'

period of observation of 75 patients who received Plasmochin, 0.03 gin., and

quinine, 1.3 gim., daily for 21 days. Manifold 68 reported a study of some

3,000 Indian and British troops treated for acute attacks of vivax malaria

with Plasmochin, 0.04 gin., and quinine, 1.3 gin., daily for 21 consecutive

day-z. Of these, 98 percent were able to complete the full course of treatment. Analysis of readmission records for 5 months after treatment showed

the relapse rate for the whole group was 5.2 percent in contrast to a wide

experience of rates from 42 to 77 percent after treatment with quinine alone.

"Vartime studies.-In 1945, Kelleher and Thompson6 9 reported obserSmade during the war on the effects of combined quinine-Plasmochin

,dent of vivax malaria of Mediterranean origin. Of 100 patients with

,ed primary attacks treated with 4.6 gin. of quinacrine during 12 days,

,ercent relapsed during an observation period of 5 months. Of 76 patients

with delayed primary attacks treated for 10 days with Plasmochin base,

0.03 gim., and quinine 2.0 g-m., daily, only 14, or 18 percent, relapsed. The

relapse rate for 650 men treated with quinacrine as above for later relapses

and followed for 5 months was 34 percent, whereas the relapse rate for 584

men treated for later attacks with combined quinine-Plasmochin was 10 percent. In American experience, the relapse rate in 120 days for Mediterranean

vivax malaria (150 patients) treated with quinacrine or quinine was 32 percent. There can be no question about the significance of the reduced relapse

rate in this British report.

Thus far, references have been cited which indicated that combined

quinine-Plasmochin given for at least 10 days, the amounts of Plasmochin

base being at least 0.03 gm. a day, is highly effective in reducing the relapse

incidence of viva'x malaria during an observation period of 2 to 5 months.

Small amounts of Plasmochin or short-term schedules are definitely of no

value in vivax malaria of Pacific origin, and experiences with such schedules

are generally unconvincing. Dieuaide,70 in reviewing relapses following various schedules of treatment in the Pacific area, cites 83 percent within 16

weeks for 185 men who had had two courses of quinacrine hydrochloride for

acute attacks of vivax malaria and 78 percent for 136 patients who had had

two consecutive courses of treatment consisting of quinacrine (0.1 gm. three

times daily for 7 days), followed by Plasmochin naphthoate (0.02 gm. three

times daily for 5 days), after which both were repeated. Thus, Plasmochin

for 5 days and repeated a week later was not effective in reducing the relapse

rate as compared with quinine or various schedules of quinacrine mentioned

67 Jarvis, 0. D.: Further Researches into the Treatment of Chronic Benign Tertian Malaria

With Plasmoquine and Quinine. Indian J.M. Res. 20: 627-631, October 1932.

66 Manifold, J. A.: Report on a Trial of Plasmoquine and Quinine in the Treatment of Benign

Tertian Malaria. J. Roy. Army M. Corps 56: 321, May; 410, June 1931.

69 Kelleher, M. F. H., and Thompson, K. : Treatment of Malaria. Lancet 2: 217, 18 Aug. 1945.

70 Dieuaide, R.: Clinical Malaria in Wartime. War Med. 7: 7-11, January 1945.
582 INFECTIOUS DISEASES

by Dieuaide. In the Bullet;n of the US. Army Medietl Departnuent,71 relapse

rates are compared for various groups of patients treated in this country for

acute attacks of v'iraa malaria of Pacific origin and followed for at least 90

days afterward. Of these, 176 patients were given quinacrine or totaquinlo

alone, and 57 percent relapsed: 299 patients received 0.01 gnn. Plasmochin

base three timnes daily for 3 days after quinacrine or totaquine and quinacrine, and the combined relapse rate in all these Plasnlochin groups was 56

percent. Here, again, is good evidence that Plasnmochin for 3 (lays after

other antimalarial therapy is not effective in influencing the relapse rate of

Pacific ih'a.r malaria. On the other hand, Geizkow and ('allender,7 2 in

1938, reported from Pananma that this almount of Plasniochin (0.01 gni. three

times a day for 3 days) in addition to 2.4 gmi. of quinacrine, during 4 (lays,

given to 128 patients resulted in a relapse rate of 9.4 percent in 6 mionths

comlpared to 45.6 percent in 215 patients who received quinacrine alone. This

report is based on analysis of patient malaria registers. From India, Bird 13

reported 30.9 percent relapses in 152 patients treated with Plasmochin, 0.01

gin. three times a day for 5 days, following 5 to 7 (lays of quinacriue, and a

relapse rate of 46.3 percent. for 201 patients who received the same anmount

of Plasinochin after 7 days of quinine.

Summary.-The evidence that has been cited indicates quite definitely

that simudtaneous quinine-Plasinochin treatment for 14 days or more of vivax

malaria of Indian or Mediterranean origin resulted in a very significant reduction in relapse rates during periods of observation of from 2 to 6 months

and that. Plasmochin for 3 to 5 days after quinine, totaquine, or Atabrine is

of no benefit in reducing relapses in vivax malaria of Pacific origin. In this

connection, it should be borne in mind that the majority of relapses occur

within a month after quinine or totaquine treatment and within 3 months

after quinacrine or the 4-aminoquinoline drugs. Short-term courses of Plasmochin (3 to 5 days) are of doubtful value in reducing relapse rates in vivaz

malaria of Indian origin, and the reported beneficial effect of 3 days of Plasmochin after quinacrine in reducing relapses in vivax malaria of Panamanian

origin remains unconfirmed.

Study at a specialty center

The following report from Moore General Hospital, a specialty center

for tropical diseases, deals with the effect on subsequent relapse of sinultaneous combined quinine-Plasmochin treatment for 14 days in vivax malaria of

Pacific origin, which had not previously been studied.

-1 Treatment of Relapses of Vivax Malaria. Bull. U.S. Army M. Dept. No. 89, pp. 21-22, June

1945.

-2 Gentzkow, C. J., and Callender, G. R.: Malaria in the Panama Canal Department, United

States Army. I1. Results of Treatment With Quinine, Atabrine, and Plasmocbin. Am. J. Hyg. 28:

174-189, September 1938.

"7 Bird. W.: Atebrin and Plasmoquine in Treatment of Benign Tertlan Malaria. J. Mal. Inst.

India 5: 395, 1944.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 583

Material and methods.-The protocol described here was furnished by

the Office of the Surgeon General. Seventy-two white patients with acute

attacks of vivax malaria of Pacific origin having fever and positive smears

were admitted to a special treatment and study ward. No attempt at selection

of patients was made. All drugs were administered by a medical officer. On

the first day, quinine sulfate, 1.0 gin., and Plasmochin naphthoate, 0.02 gin.

(0.01 gin. base), were given together at 8-hour intervals. On days 2 to 14

inclusive, quinine sulfate, 0.65 gin., and Plasniochin naphthoate, 0.02 gin.,

were given together at 8-hour intervals. The total amount administered during the treatment period of 14 days was 28.35 gin. of quinine sulfate and 0.84

gin. of Plasmochin naphthoate. A control group of 75 patients with acute

attacks of vivax malaria of Pacific origin were treated with a total of 28.35

gin. of quinine alone on the same schedule. Temperatures were recorded

every 4 hours. Parasite counts were done twice daily until negative for 3

consecutive days. Hemoglobin, methemoglobin, and total white blood count

determinations were made daily. (Hemoglobin and methemoglobin were

determined colorimetrically as cyamethemoglobin.) Each patient was examined at least once daily by a medical officer, and special attention was paid

to possible manifestations of Plasmochin toxicity. On the day after completion of treatment on the ward, the patients were transferred to a convalescent

area for further observation. The duration of observation was until relapse

or for a minimum of 120 days. During this interval, smears were examined

twice weekly. In the event of parasitemia, temperature observations were

made every 4 hours and parasite counts were done daily. A temperature of

1000 F. or more by mouth in association with a positive smear was considered

a clinical relapse.

Results.-The cumulative clinical relapse rates during 120 days' observation after treatment of acute attacks with quinine, quinacrine, and combined quinine-Plasmochin are shown in chart 36. The total failures after

treatment are summarized in table 76.

1. Quinine.-Seventy-five patients with acute attacks of vivax malaria of

Pacific origin were treated with 28.35 gin. of quinine sulfate during 14 days.

Sixty-two patients or 82.6 percent had a clinical relapse within 120 days.

Five patients who did not relapse had, at one time or another during their

period of observation, a positive smear without fever or symptoms. Thus,

quinine failed to eradicate the infection in 67 or 89.3 percent of patients

treated and observed for 120 days.

2. Quinacrine hydrochloride (Atabrine).-Sixty-nine patients with

acute attacks of vivax malaria of Pacific origin were treated with 2.8 gin. of

quinacrine during 7 days. Fifty-six patients or 81.2 percent had clinical

relapses within 120 days after completion of treatment. An additional two

patients who did not relapse had, at one time or another during their period

of observation, positive smears without fever or symptoms. Thus, within
584 INFECTIOUS DISEASES

CHART 36.-Relapae rates and intervals to relapse after treatment of acute attacks of

vivwx malaria of Pacific origin with rarious drugs

[Cumulative relapse rate, percent of patients treated]

PERCENT

soO

000

QUININE

go-X OUINAGRINE , -"

HYOROCHLORIOE ,

. / " CNLOROOUINaE

40

20

.0 1

0 10 20 30 40 50 60 70 40 90 100 100 120

DAYS FOLLOWING COMP0ETION OF TREATMENT

120 days following quinacrine, 84.1 percent of treated patients exhibited evidence that they were not cured of the infection.

3. Chloroquine diphosphate ($N 7,618).,Eighty-two patients with

acute attacks of Pacific vivax malaria were treated with 1.5 to 2.0 gm. of

SN 7,618 from 4 to 7 days. Sixty-two or 75.6 percent had a clinical relapse

within 120 days after completion of treatment. Four additional patients

developed asymptomatic parasitemia without clinical relapse during the 120-

TABLE• 76.-Results of treatment in four groups of patients administered antimalarial drugs

for acute attacks of vivax malaria ,.r Pacific origin

I)ura* Aver- clinical Parasitemnic Total failures 3

Num- tion of age A verage relapses i relapse,. I

Drug her of D)osage treat- number prior . .

patient, Warnms) ment ofpre- activity'

(days) vious (months) Num-I Per- Num- Per- Num- Perrelapses ber cent ier , Cent her cent

Quinine --------------- 75 A. 35 14 3.8 9..1 62 82.6 5 7 67 9.3

Quinacrine ------- 69 2.8 7 4.4 7.8i ,56 '81.2 2 2.9 58 84.1

Chloroquine ----------- 8V 1.5-2.0 4-7 5. 1 10.7 62 775.6 4 4.9 66 80.3 0 70 22 35 5 14 &02 10.6 3 4.2 0 5 6.9 8 120dp a .............................. yschin 0.840

I Clinical recurrence with fever, symptoms, and p eretive blood smear, observed within 120 dats after treatment.

2 Positive smear only, without fever or symptoms and not followed by clinical relapse during 120 days' observation

after treatment.

d Clinical relapses plus parasitema relapses during 1l20 days after treatment.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 585

day period of observation. In other words, a total of 66 patients or 80.5

percent of the whole number treated represent treatment failures in that they

suffered clinical or parasitemic relapses while under observation after treatment with SN 7,618.

4. Combined quinine-Plasmochin.-Seventy -two white patients with

acute attacks of vivax malaria of Pacific origin were treated with Plasmiochin

and quinine as described under "Material and Methods." Three clinical relapses occurred within 120 days after completion of treatment, a clinical

relapse rate of 4.2 percent. Five additional patients showed parasitemia but

had neither fever nor symptoms during the observation period. Thus, of 72

Pacific infections treated, there were altogether only o failures, making a total

failure rate of 11.1 percent for the 120 days.

Toxicity

Clinical experience.-Numerous references can be found in the liý •rature

dealing with toxic manifestations of Plasmochin of varying type and severity.

Most frequently reported are gastrointestinal complaints, that is, mild to

severe epigastric pain or soreness, anorexia, abdominal cramps, nausea, vomiting, and diarrhea; cyanosis; dyspnea and changes in pulse, in blood pressure

and in electrocardiograms; changes in the blood varying from mild anemia

to severe or fatal hemolytic crisis or agranulocytosis; vague muscular aches

and pains and weakness; and symptoms referable to the central nervous

system, principally headache, dizziness, "nervousness," psychosis, and coma.

The incidence of severe toxic reactions varies from 1 to 10 percent in different

series reported. The lhemolytic reaction is the most serious manifestation of

Plasmochin intoxication and may vary from mild progressive anemia to a

sudden fatal hemolytic crisis associated with shock, severe anemia, jaundice,

hemoglobinuria, and azotemia. This reaction may come on early after relatively small amounts of drug but also may occur at any time during the

administration of Plasmochin. Weakness and dark urine are the most common symptoms at onset. During the acute episode the erythrocyte sedimentation rate accelerates; the white blood cell count and hemoglobin diminish.

Race, diet, climate, and the prior administration of other drugs have all been

suggested as factors that may be responsible for initiating a hemolytic reaction. Evidence will be reviewed regarding the possible relation of race to

predisposition. The degree of methemoglobinemia in many individuals is

probably related to the dose of drug. Gastrointestinal symptoms are most

common during the fourth and fifth days of therapy and X-ray studies during this time have revealed gastric hyperperistalsis and intestinal spasm.

There follows a brief summary of the incidence of toxic experiences repiled

in relatively large groups.

Manifold, in a 1931 report 74 dealing with the results of treatment of

vivax malaria in India with quinine, 1.25 gm., and Plasmochin, 0.04 gin.,

74 See footnote 68, p. 581.

639243Y-63---41
586 INFECTIOUS DISEASES

given together daily for 21 days, noted toxic symptoms or signs occurring

in 21 percent of 1.298 British soldiers and in 10 percent of 1,915 Indians

treated. Epigastric pain or other gastrointestinal symptoms were complaints

in 15 percent of the British and in 8 percent of the Indian patients. Cyanosis

was observed in 4 percent of the British cases but was not accurately determined in the Indians because of the color of their skin. Jaundice was observed in only three patients, and in one of these, an Indian, death followed

as a result of a severe hemolytic reaction. In Manifold's opinion, the majority

of the symptoms were mild. He also emphasized that, of 480 British patients

personally treated, the full course of 21 days of Plasmochin was completed

without interruption by all but 2 patients. He further stated that 98 to 99

percent of the patients in the entire series of more than 3,000 cases completed

a full course of treatment.

West and Henderson, 75 in 1944, reported an incidence of 2.85 percent

Plasmochin toxicity in 846 patients treated for falciparinm infections in

Africa with quinine, 2.0 gin. daily for 3 days, quinacrine, 0.3 gin. daily for

5 days, no treatment for 2 days, then Plasmochin base, 0.03 gin. daily for 5

days. Twenty-two of the twenty-four patients with toxic signs had primary

falciparum infections, and the other two had had malaria and had been

treated with Plasmochin previously. Four patients were hospitalized after

being given 0.66 gin. of Plasmochin base, and the mean total toxic dose was

0.119 gin. Jaundice was the most common finding and was observed in 20

patients, the mean icteric index being 27.6. Twenty patients had abdominal

pain. Headache, weakness, and dizziness occurred in 16, 14, and 11 patients,

respectively. Two patients were psychotic and one in coma. There was

anemia in 19 patients, and in 1 the red cell count was 1.4 million per cubic

millimeter, the average being 2.88 million per cubic millimeter. The white

cell counts varied from 4.5 to 20.8 and averaged 10.2 thousand per cubic

millimeter. All patients except one were ambulatory during the period of

Plasmochin therapy. Unfortunately, the race of the patients or the ratio

of black to white in the population sample reported is not stated in this paper.

The color of the skin is of particular interest, as Swantz and Bayliss 76

in 1945 reported moderately severe hemolytic toxic reactions in nine Negrt.es

who had received Plasmochin in the course of treatment for malaria. These

reactions were encountered during a period in which approximately 3,000

cases of malaria were treated. The amount or duration of Plasmochin treatment is not stated. As to race, the authors say only that the majority of

their malarial patients were white. The absence of a single hemolytic reaction

in the 'whites treated and the occurrence of nine cases of severe intoxication

in the Negroes suggest some predisposition to Plasmochin hemolytic reactions in Negroes. In studies summarized by Shannon, 6 hemolytic reactions

"75 West, J. B., and Henderson, A. B.: Plasmochin Intoxication. Bull. U.S. Army M. Dept.

No. 82. pp. 87-99, November 1944.

76 Swantz, H. E., and Bayliss, M.: Hemoglobinuria; Report of Ten Cases of Its Occurrence in

Negroes During Convalescence From Malaria. War Med. 7: 104-107, February 1945.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 587

(5 Negroes and 1 Chinese) were observed among 71 pigmented patients, an

incidence of 8.4 percent, but none in 35 white patients who received 0.03 gm.

Plasmochin base for from 2 to 14 days. All reactions occurred during the

third to fifth days of Plasmochin therapy and were characterized by weakness, dark urine, and icterus at onset.

Hardgrove and Applebaum," in 1945, reported from Panama an incidence of 10.13 percent hemolytic reactions in 4,361 laborers who were giver.

a routine mass treatment for suppression of malaria, the treatment consisting

of quinacrine, 0.1 gm. three times daily for 5 consecutive days, no medication

for the next 2 days, and then Plasmochin base, 0.01 gm. three times daily,

for 5 consecutive days. In 8.12 percent of the whole treated group, the reactions were sufli'iently severe to require hospitalization. Three-fourths of

these patients were admitted during a 48-hour period corresponding to the

last day of Plasmochin treatment and the da. following; only 21 toxic reactions occurred following less than 0.10 gin. of Alasmochin base. The principal

complaints and findings were abdominal pain, dark urine, anorexia, jaundice,

headache, nausea, and vomiting; abdominal tenderness, enlarged liver, pallor,

cyanosis, low grade fever, hemoglobinuria, bilirubinemia, anemia, and leukocytosis. Treatment was essentially blood transfusion, intravenous glucose

solution, and sodium bicarbonate by mouth. There were no deaths. It should

be noted that in this series of patients a large proportion (not precisely

stated) were not of the white race; also that the Plasmochin was administered to the men while they were working.

Kelleher and Thompson 78 in their study of 660 British soldiers who were

treated for acute attacks of vivax malaria with quinine, 2.0 gm., and Plasmochin base, 0.03 gm., daily for 10 consecutive days encountered practically no

severe toxic manifestations. Of 295 patients personally treated by the

authors, in only 3 was therapy interrupted because of toxicity. Other medical

officers participating in the study, having less experience with Plasmochin,

interrupted therapy in 2 to 4 percent of 365 subjects. No serious reactions

were encountered.

It is evident from this brief survey of the literature that toxic experiences

with Plasmochin vary considerably in their incidence and severity. Large

groups of patients have been given 0.03 gin. of Plasmochin base for 10 to 21

days with practically no toxicity. On the other hand, serious hemolytic

reactions have been reported when the drug was given for only 3 to 5 days.

There is evidence that hemolytic reactions occur more frequently in patients

who are not of the white race. Some investigators believe that toxic manifestations are more common in patients who have recently received quinacrine. Although it is true that the levels of Plasmochin in the plasma are

very much higher in patients who have recently had quinacrine than in

patients who have not, it has not been established that high plasma levels and

1 THardgrove, M., and Applebaum, I. L.: Plasmochin Toxicity; Analysis of 258 Cases. Ann.

Int. Med. 25: 103-112, July 1946.

78 See footnotes 69, p. 581.
588 INFECTIOUS DISEASES

toxicitv are related. It seems probable that taking Plasmochin while working may be a factor in producing serious reactions.

The writer (II.M.) and his coworkers administered Plasmochin naphthoate inl doses of 0.02 gin. three times daily at S-hour intervals for 14 days to

100 white patients. No major toxic manifestations were observed, and all

patients were able to complete the full course of therapy.

Forty percent of the patients had some form of complaint referred to

the gastrointestinal tract and probably related to Plasmochin. These symptoms usually began from the third to the fifth day and lasted from 1 to 7

days; they consisted principally of abdominal cramps or abdominal soreness

which were rarely severe.

Cyanosis was observed on the 11th day of treatment. in one patient who

had a methemoglobin value of 12 percent. Ninety percent of the patients

showed methemoglobinemia above normal values at some time during treatment with amounts ranging from 1.0 to 12 percent (average 2.3 percent) of

total hemoglobin.

In 16 percent of the patients who were given Plasmochin for 14 days,

there was a fall in total hemoglobin of from 11 to 20 percent during the second

week of treatment which we considered related to the drug. An equal number

of patients had an average fall in hemoglobin of 15.3 percent during the first

5 days. In the latter group, this fall in hemoglobin was apparently due to

active malaria rather than to Plasmochin therapy since it occurred in the

first few days of the acute attack and reversed itself with continued treatment.

Severe anemia did not occur, and no hemolytic crisis was observed.

The effect of Plasmochin on the white blood cell count was to produce

leukocytosis in a significant number of men (15 percent. with counts above

10,000 per cubic millimeter) during the second week of treatment and leukopenia (24 percent with counts below 5,000 per cubic millimeter) during the

first week after discontinuance of the drug. Subsequent counts 2 weeks after

treatment were all normal.

In our experience, the toxic manifestations related to the administration

of Plasmochin were not severe or serious and should not detract from the

value of the drug if proper care is taken in recognizing potentially serious

signs of toxicity.

Recommendations for therapeutic use.--It is suggested that patients

given Plasmochin as described in this chapter be hospitalized during treatment and observed frequently to recognize early severe hemolysis, should it

occur. Treatment with Plasmochin should be limited to white patients.

Hemoglobin determinations should be done daily and complete blood counts

at least twice aweek. Cyanosis alone is not an indication for discontinuance

of therapy. A fall in total hemoglobin of more than 20 percent in any one

day should be regarded with suspicion; if followed by a further decline in

the amount of total hemoglobin on the next day, Plasmochin treatment should

stop. One cannot anticipate sudden hemolysis by any laboratory method,
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 589

but symptoms of severe weakness and dark urine during the first 5 days of

therapy should be investigated with this possibility in mind. Fluids, blood,

and alkalies by vein are indicated if a severe reaction should occur. Abdominal cramps occur most frequently during the first week of treatment and if

severe may be controlled with atropine. The usual symptoms of cinchonism,

namely, tinnitus, fullness in the head and ears, and headache, were encountered in varying severity in the first week of treatment in the majority of

patients. These symptoms gradually subsided in the second week and caused

no interruption of therapy. During the first 2 to 5 days of the acute attack

of malaria, most patients should remain in bed. For the remainder of the

2-week period of treatment in the hospital, the patients may be ambulant on

the ward but should not be permitted vigorous exercise nor be given overnight passes. Each dose of drug must be personally administered by a nurse

or physician, and each patient should be seen at least twice daily. Patients

with anemia, severely malnourished, or in poor physical condition should not

be treated with Plasmochin.

Discussion

The clinical relapse rate of only 4 percent and a total failure of 11.1

percent following combined treatment with quinine and Plasmochin is very

striking. In our experience, the clinical relapse in 10 groups of at least 50

patients each has varied from 65 to 85 percent, with total failure rates after

treatment of from 75 to 90 percent for all groups except the group treated

with quinine-Plasmochin as here reported.

Analysis of more than 1,000 attacks of vivax malaria treated and observed at Moore General Hospital for 120 days indicated that within this

period of observation the relapse rate for any given attack is not significantly

influenced by the number of previous attacks, by the age of the disease (table

76), or by the amount or duration of treatment with quinine or quinacrine.

It is unlikely that these factors can account for the wide discrepancy in the

observed results. One must also consider what the probability may be of

late relapses occurring in the quinine-Plasmochin group after the 120 days'

period of observation. The median interval to clinical relapse following

treatment with quinine or totaquine is 24 (lays and following quinacrine or

4-anminoquinoline drugs, 50 to 65 days. Within 120 days, 80 to 90 percent of

all patients treated for an acute attack of v;iax malaria of Pacific origin with

currently used antinmialarial drugs will have interval parasitem ia without fever

or syml)toms or will actually relapse clinically. We know that a relatively

small percentage of failures do occur after 120 days. It, is unlikely that

absolutely no definitive cures follow treatment with quinine or (l1uinacrine,

but even if this were so, the maximum ummber of failuIres that could possibly

occur after 120 days' observation would 1e only 10 to 20 I)ercent of treated

patients. The median interval to failure (parasitemic and clinical) in the

relapses that actually were observed in the quinine-Plasmochin group was

34 (lays coml)ared to 36 days for the quinine controls. In other words, when
590 INFECTIOUS DISEASES

quinine-Plasmochin failed it did so in the same interval after treatment as

did quinine alone. Subsequently, we observed 20 percent of the Plasmochin

group for at least 180 (lays after treatment and no failures after 120 days

had occurred. Unless Plasmochin alters the biology of vivax malaria in man

so that very late failures will occur in the majority of treated patients, it is

our opinion that the freedom from parasitemia or clinical relapse for 120

days in 90 percent of our treated patients represents definitive cure for at least

80 percent of men so treated.

Analysis of our Plasmochin relapses gives us no clue to a possible explanation for failure. The average mean plasma levels of quinine and Plasmochin are in the same order and range in the failures as in the whole group

treated as well as for the patients in whom 120-day cures were observed.

There was one failure in nine delayed primary attacks treated. As regards

the average age of the disease and the average number of previous attacks,

the other seven failures were comparable to the patients in whom treatment

was successful.

Clinical use.-Four-month cures in 90 percent of patients treated with

combined quinine-Plasmochin raised the question of the general application

of this form of treatment for vivax malaria. In infections of Mediterranean

origin, the relatively low clinical relapse rate of 30 percent within 120 days

for v;rax malaria following treatment. with quinacrine or quinine makes it

questionable whether routine Plasmochin treatment is indicated in such

infections, especially in the second year of the disease. Certain individuals,

however, with vivax malaria of Mediterranean origin relapse frequently and

at short intervals after treatment during the first year of the disease particularly if quinine is used to terminate the acute attack. In these cases,

combined quinine-Plasmochin treatment should be consideied.

Since 120-day failure rates after treatment of attacks of Pacific Viva.

malaria may be as high as 90 percent, more serious consideration should be

given to the use of combined quinine-Plasmochin in this type of infection.

Even though there is only a 10 to 20 percent chance that a patient treated

with quinine or quinacrine for his first attack will have no subsequent attack

in 120 days, it seems worthwhile to take this chance for that attack and possibly for the next one or two relapses. However, the occurrence of repeated

attacks, at short intervals, for example, 3 to 6 attacks during the first 6 months

of the disease or repeated attacks later in the disease, is in our opinion an

indication for the use of combined quinine-Plasmochin therapy. The coexistence of other diseases precluding the use of quinacrine therapeutically

or for suppression (quinacrine sensitivity and/or exfoliative or eczematoid

dermatitis or atypical lichen planus) is another indication for the use of

combined quinine-Plasmochin. Likewise, patients who relapse frequently

at intervals of a month or less after quinine and who cannot take quinacrine

can be treated with Plasmochin, as outlined. Finally, patients whose convalescence from other diseases is interrupted or delayed by repeated attacks
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 591

of malaria should be considered candidates for combined quinine-Plasmochin

therapy. Each case must be considered individually and the probability of

cure weighed against potential toxicity and a 2 weeks' course of hospital

treatment with Plasmochin, compared with a short, safe course of treatment

with other antimalarial drugs and the high possibility of failure.

Appreciating the potential dangers of Plasmochin, one is nevertheless

impressed by the complete absence of severe or serious toxicity in a series of

100 consecutive white patients who were given 0.06 gm. Plasmochin naphthoate daily for 14 days. The fact that the patients were all white, closely

observed in the hospital, and in good physical condition may be factors in

the absence of toxicity.

Further study.-Following completion of the study just described, 30

additional white patients with acute attacks of vivax malaria of Pacific origin

had, in addition to quinine, quinacrine, or SN 7,618, received Plasmochin for

14 days. Information was now available on relapse rates during 120 to 180

days' observation after treatment for more than 100 cases of vihvax malaria.

The observed relapse rate for the group was 4 percent and the total failure

rate less than 10 percent. There can be little question about the curative

value of Plasmochin.

It is interesting that, in a group of 10 men who received Plasmochin for

14 days after 2.2 gon. of quinacrine had been given to terminate the attack,

only one relapse occurred during 120 to 180 days' subsequent observation. No

relapse occurred in a similar period of observation in another 10 men who

received, during the first 4 days of treatment with Plasmochin, a total of 1.4

gm. of SN 7,618 in addition to the Plasmochin, which was given for a total

of 14 days. It seems that successful treatment with Plasmochin may be

accomplished after the acute attack is terminated with quinacrine or SN 7,618,

or by giving either of these drugs simultaneously with Plasmochin for a few

days until the acute attack has been terminated and then continuing Plasmochin until it has been given for 14 consecutive days.

It is noteworthy that of the 100 cases successfully treated with Plasmochin there were 20 patients with primary attacks and 19 with only one prior

attack. There were only 2 failures in this group of 39 men, or a failure rate

of 5 percent. The severity of infection acquired naturally may vary considerably, but all evidence suggests that the age of the disease or severity of

infection is of secondary importance in determining the end results of Plasmochin therapy. Likewise, no correlation has been found between Plasmochin

plasma levels and success or failure of treatment. On the other hand, total

dose and duration of treatment appear to be crucial factors. For example, in

a group of 10 men who received combined quinine-Plasmochin treatment for

only 10 instead of 14 days, 6 relapses occurred.79 Similar failures were reported in treatment of primary attacks or relapses if the total dose of Plasmochin was 0.42 instead of 0.84 gin. during 14 days.

79 Most, H.: Unpublished data.
592 INFECTIOUS DISEASES

Summary

The clinical studies on the effect of Plasmochin inl definitively terminating

vtrvaa infections are of the utmost importance in the chemotheraply of malaria.

As a result of these carefully controlled experiments, Plasmochin or similar

drugs were established with a definite place in the management of relapsing

vivax malaria. The original observation by James so that Plasinochin given

in adequate amounts before, during, and after sporozoite infections resulted

in cure of vh',ar malaria has been clinically applied. Similar results with

domestic and foreign strains of P. vivax in protective and therapeutic tests

have been reported in the United States. Treatment of primary attacks or

relapses resulted in cures in the great majority of cases in which total (loses

of Plasmochin of 0.84 gin. were given with quinine or other drugs for 14

days.8 1

Extension of these studies has been made with other 8-aminoquinoline

compounds. At least one of these, SN 13,276 or pentaquine, has great promise.

No clinical studies with this drug were made in the U.S. Army during World

War II. However, it has been shown by civilian and Federal research agencies that it will produce a tgreater number of cures than Plasmochin in primary attacks and relapses of vivax infections transmitted by mosquitoes as

well as in protective tests. It has also been shown that it may be less toxic.

Summary of Studies

Protective tests and clinical trials conclusively demonstrated the curative

properties of this class of compounds. A reevaluation of Plasmochin resulted

in the demonstration that if this drug is administered with quinine or other

drugs for 14 days vivax malaria will be cured in 80 to 90 percent of naturally acquired clinical disease. In contrast, relapse will be forestalled in

only 10 to 20 percent of vivax infections after treatment with quinine, quinacrine, or the 4-aminoquinolines. The feasibility and safety of administering

0.84 gm. of Plasmochin to white patients was shown, with only minor toxicity

occurring. Plasmochin, which has had its "ups and downs" in the story of

the treatment of malaria, was shown to have a definite and important position

in the management of relapsing vivax malaria. As a result of detailed studies

of the 8-aminoquinoline compounds, new members of this group have been

found which may be so superior to Plasmochin as to end the search for a

curative antimalarial drug.

SUMMARY

The magnitude of the malaria problem during World War II can be

appreciated only if it is realized that the war was fought in areas where the

disease is endemic and that about a half million cases developed in the U.S.

80 James, S. P., Nlchol, W. D.. and Shute, P. G.: On the Prevention of Malaria With Plasmoquine. Lancet 2: 341-342, 15 Aug. 1931. 31 See footnote 64, p. 579.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 593

Army. At the beginning of the war, there was great anxiety with regard to

the loss of our sources of quinine, and there was some question concerning

the efficacy of quinacrine as a suppressive and therapeutic agent. Our scientific resources were beautifully organized in a search for better antimalarial

drugs. Fundamental studies and a rational approach to the problem led to

a clear understanding of the optimum methods of using quinine and quinatrine. Newly developed methods made it possible to compare the relative

efficiency of various drugs. It was shown that certain sulfonamides could

be substituted in extreme emergencies as suppressive agents. Heavy metals

on the whole offered little promise. Antibiotics were of no value.

Quinacrine was shown to be superior to quinine for all purposes except

possibly for the treatment of fulminant infections with P. falcipartim. The

toxicity of quinacrine was extensively studied; hitherto undescribed reactions, in particular the eczematoid-lichen-planus-dermatitis complex, and

aplastic anemia were encountered in a small percentage of cases. In proper

dosage, quinacrine was more effective than quinine in terminating acute attacks and in curing those caused by P. falciparum, while the proper use of

quinacrine for suppression made possible successful military campaigns in

highly malarious areas. Mortality from malaria during World War II was

negligible principally because of effective treatment and suppression of clinical malaria.

In the search for new drugs, the 4- and 8-aminoquinolines were widely

studied. Several (SN 6,911 and SN 8,137) were as effective as quinacrine

and if necessary might have been substituted for it. In addition, one was

found (SN 7,618 or chloroquine) that was superior to quinacrine. It does

not discolor the skin; it could apparently be given with safety over a long

time and would produce satisfactory suppression by single weekly doses.

These drugs also cure falciparum infections. No studies were available on

their value in fulminating falciparum infections in comparison with quinine

or quinacrine.

Finally, the curative properties of the 8-aminoquinoline compounds were

demonstrated. Plasmochin was reestablished as a drug of great value in the

treatment of relapsing vivax malaria in conjunction with quinine, and new

compounds were found (SN 13,276 or pentaquine) which may have fulfilled

the search for a generally curative antimalarial agent. The final step in

progress to the ideal therapeutic will be an agent that is truly chemoprophylactic. Such a drug may be found, which will be safe when taken over long

periods and will completely prevent the development of infection.

This is how the matter stood when World War II ended. The momentum

of these studies carried over into investigations continued during the postwar

years 1946-54. These investigations were for the most part under the auspices of the U.S. Army. A note is appended on this work, as it ties together

the whole and brings it to more sharply defined conclusions. This addendum
594 INFECTIOUS DISEASES

on postwar research is drawn from a review prepared by Dr. L. H. Schmidt

and Dr. G. Robert Coatney.82

Postwar Research

At the close of hostilities, it was evident that much work remained to be

done with intent (1) to evaluate known but inadequately assessed suppressive

and therapeutic agents and (2) to develop new curative drugs. Many investigators who during the war had taken part in the research programs of the

Office of Scientific Research and Development (OSRD) retained their interest in the chemotherapy of malaria. It seemed to them that this unfinished

business could best be completed within a similar pattern of cooperative

effort.

Accordingly, the fruitful period from 1946 to 1954, inclusive, saw investigations in large part conducted with the active participation and support of

the armed services. A Malaria Study Section, under the U.S. Public Health

Service, recommended grants-in-aid to interested scientific workers at various

institutions. They, together with parasitologists and clinical investigators

in the Section on Chemotherapy, Laboratory of Tropical Diseases, National

Institutes of Health, agreed to coordinate their activities to achieve specified

objectives. A joint group known as Investigators in Malaria Chemotherapy

met frequently from October 1946 through 1948 to assess progress and plan

new activities.

Investigations under OSRD had established the value of quinacrine. Of

the compounds that gave promise in preliminary tests or of having even

superior qualities, only one, chloroquine, had been tested sufficiently to be

recommended for general use. Two other compounds, amodiaquin and oxychloroquine, belonging to the same chemical group, the 4-aminoquinolines,

seemed to merit further trial, as did the 4-quinoline-methanols and a small

number of naphthoquinones. In addition, there were the biguanides, particularly chlorguanide, made available to OSRD investigators through the scientific liaison between Great Britain and the United States.

It had been recognized also, during the latter years of the wartime

studies, that certain prewar work by the British had shown that the old German drug pamaquine (Plasmochin) possessed a property not common to

other antimalarial drugs; namely, its ability to cure naturally acquired 'Vivax

malaria. This recognition led to confirmatory observations and subsequently

to a large program involving synthesis, pharmacological study, and clinical

evaluation of the 8-aminoquinolines, a program which dominated the last

year of OSRD activities in this field. At the end of the war, this effort had

led to the development of at least one compound, pentaquine (SN 13,276),

believed to be superior to pamaquine.

82 Schmidt, L. H., and Coatney, G. R.: Review of Investigations in Malaria Chemotherapy

(U.S.A.) 1946 to 1954. Am. J. Trop. Med. 4: 208-216, March 1955.
CLINICAL TRIALS OF ANTIMALARIAL DRUGS 595

In the first of the cooperative postwar studies, the naphthoquinones were

found to have only a low level of therapeutic effectiveness and gave no evidence, in man or monkey, of prophylactic or curative properties. Of the

4-quinoline-methanols, three compounds were shown to possess no significant

advantages over quinine in the treatment of vivax malaria. The fourth produced phenomenal lengthening of the relapse interval, but this was associated

with the development of photosensitivity. Accordingly, work on all of these

compounds was abandoned. In the 4-aminoquinoline group, continued investigation on the long-term suppressive activity of chloroquine, and on the

short-term suppressive and therapeutic properties of amodiaquin, showed

that these drugs possess similarly high therapeutic and suppressive activity.

The effectiveness and tolerability of chloroquine given intramuscularly, and

its effectiveness in single doses given orally, were amply demonstrated.

Chlorguanide, the biguanide that had shown considerable promise in

preliminary clinical evaluation by British, Australian, and OSRD investigators, was now thoroughly studied in man and experimental animals. Longterm administration was found to be safe. In the body, the drug was degraded extensively to products that, like the parent drug, exhibited activity

against simian malaria. Although, as shown by British investigators, otte

compound was formed that was more active than the parent compound

against avian malaria, subsequent work by other British investigators showed

that this metabolic product was no more active than the parent drug against

infections with P. falciparum. In therapeutic and suppressive studies, chlorguanide exhibited a high degree of activity against infections with P. vivax,

but it was definitely slower than chloroquine in reducing fever and parasitemia. It was further shown that each of the species of avian, simian, and

human plasmodia studied acquired a high order of resistance to the drug

when exposed to suboptimal doses and that the resistant characteristic of the

simian plasmodium could be transmitted unaltered through the mosquito.

When produced in sporozite-induced infections, resistance was a property of

the erythrocytic parasites only. Infections with chlorguanide-resistant strains

responded normally to drugs such as quinine, quinacrine, and the 4-aminoquinolines. Field study in Guatemala confirmed the superiority of chloroquine for suppression in a systematic comparison with chlorguanide.

These various studies had thus established the therapeutic potentialities

of both chloroquine and amodiaquin and demonstrated that either drug was

superior to chlorguanide in the general management of malaria in man. The

work of consolidation was in general complete.

The major new effort of the Investigators in Malaria Chemotherapy was

directed toward development of a generally useful drug that would not merely

suppress but would cure the relapsing malaria caused by P. vivax. This

attempt, centered about work on the 8-aminoquinolines, during 1946 and 1947

followed the pattern of the last year of the OSRD program. This involved

synthesis of various congeners of pamaquine (Plasmochin), testing for tox-
596 INFECTIOUS DISEASES

icity in monkeys, and finally testing of compounds free of neuronal toxicity

against vh, ax infections in human volunteers. In addition, efforts were made

to define more precisely the activity of pentaquine and the more effective

ways of using it.

In 194S, this pattern of work was changed as the result of a demonstration by Schmidt and his colleagues at. the Christ. Hospital Institute of Medical

Research, Cincinnati, Ohio. They showed that infections with P/la.&nodium

cynonmolgi in the rhesus monkey were the biological and chemotherapeutic

counterparts of infections in man with Southwest Pacific strains of P. via..

with essentially complete parallelism in response both to qualitative and to

quantitative aspects of drug activity. For the first time, it was possible to

carry out toxicological and, particularly, therapeutic studies in an experimental animal with reasonable expectation that the results could be translated in terms of malaria in man.

Collaborating groups of chemists at. Columbia University, New York,

N.Y., University of Maryland, College Park, 31d., and University of Notre

Dame, Notre Dame, Ind., synthesized 42 new 8-aminoquinoline derivatives

and remade older analogs in quantities sufficient for simian and human

studies. Toxicological and curative therapeutic studies were carried out on

all of these compounds in monkeys at the Christ Hospital Institute, and 18

of the compounds were selected for human trial at the University of Chicago,

Chicago, Ill. Both in man and in monkey, four compounds emerged with

properties superior to pamaquine. These were pentaquine and isopentaquine,

which had been developed in 1946 and 1947, respectively, primaquine (SN

13,272), and SN 3,883. The last two compounds. with terminal primary

amino groups on the side chain, had been prepared during the OSRD program but were subjected to study in man only after investigations at the

Christ Hospital Institute had focused attention upon the high tolerability

of this class of compounds and their unusual activity against the early and

late exo-erythrocytic stages of P. cynomolgi.

Between 1948 and 1950, considerable study was also given to the mechanisms for enhancing the effectiveness of known agents. Two observations that

proved of practical significance were made at the Christ Hospital Institute

and later conlirmed in principle in the human subject at the University of

Chicago. These observations were (1) quinine had no specific enhancing effect

on the curative activities of 8-aminoquinolines such as pentaquine, isopentaquine, and primaquine, and (2) that these drugs could cure and in some cases

prevent malaria infections when given alone. It followed that the sole contribution of quinine was the control of erythrocytic infection. This contribution explains the therapeutic effectiveness of Plasmochin combined with

quinine; it could be made as well by chloroquine or any other schizonticidal

drug, or could be dispensed with if the 8-aminoquinoline were administered,

in established infections, in the interval between relapses. This finding

formed the basis for the "interim primaquine" regimens which allegedly have
CLINICAL TRIALS OF ANTIMALAMIIAL DRUGS 597

been responsible for the reduced incidence of malaria among troops returning

from Korea in 1952 and 1953.

Late in 1950, it was decided to concentrate the cooperative studies upon

the relative merits and best use of the four compounds that seemed most

promising, pentaquine, isopentaquine, primaquine, and SN 3,883. Evaluation

of these drugs in curing established infections with P. vivax in voi inteers was

in part made the responsibility of a group of investigators headed by Dr. Alf

S. Alving at the University of Chicago. A second clinical testing facility was

established at the U.S. Penitentiary, Atlanta, Ga., under the direction of Dr.

(Coatney.

In the meantime, the appearance of numerous cases of acute malaria

among military I)er.)lnel returning from Korea demanded more immediate

solutions. At a meeting called by The Surgeon General, Department of the

Army, on 3 July 1951, it was decided to focus attention upon primaquine and

particularly to investigate (1) its effectiveness in eradicating established infections in returnees from Korea and (2) the feasibility of administering 15 mug.

daily for 14 days to all servicemen returning from Korea by ship.

The overall safety of this dosage schedule for military men on full duty

was demonstrated in a preliminary investigation, involving 1,000 U.S. Army

personnel, carried out at Fort Benning, Ga., and Fort Knox, Ky. Beginning

on 18 September 1951 with a group of servicemen returning by ship from

Korea, the administration of 15 mg. of primaquine daily for 14 days was

adopted as a general procedure pending more precise data from the controlled studies underway in the United States. Collateral studies at the

University of Chicago showed that daily doses of 30 mg. of primaquine were

tolerated by Caucasians; in Negroes, such doses evoked intravascular hemolysis in 5 percent.

Data from the controlled studies on prisoner volunteers, available in

January 1952, showed the superiority of primaquine over pentaquine, isopentaquine, and SN 3,833 as a curative drug. The results obtained in active infections with P. vivax in returnees from Korea showed the high order of curative

effectiveness of primaquine and its superiority over pamaquine (Plasmochin).

The effectiveness of interim treatment with primaquine was demonstrated in

selected returnees. This composite information, together with toxicological

data obtained by study of prisoner volunteers, provided a solid basis for the

adoption of interim treatment with primaquine for the cure of vivax malaria

of Korean origin. This procedure was eventually applied to all military personnel returning by ship from Korea and has been associated with the virtual

elimination of malaria among them.

Late in 1950, interest was aroused in a new type of antimalarial drug

which had been produced in the Wellcome Research Laboratories, New York,

as a by-product of investigations on purines and pyrimidines as carcinolytic

agents. Attention centered on pyrimethamine (2, 4-diamino-5-p-chlorophenyl-6-ethylpyrimidine, I)araprim). Extensive studies were carried out oin its
598 INFECTIOUS DISEASES

pharmacology in man and lower animals, on its activity against avian and

simian malarias, and agrainst infections with P. vihax and P. faleiparum.

Therapeutic studies in both lower animals and man showed that the compound had higher activity against erythrocytic parasites than any known

antiniha lial dru11g. It. was slower, however, th an c1h1oroqui ne in controlling

active simian and human infections. It was active against the ,xo-erytlhrocytic stages of all species of malarial parasites studied. It was able to effect

suppressive cure in a high proportion of infections with P. vivax. Resistance

to pyrimethamine developed rapidly during inadequate treatment of ervthrocytic infections with avian, simian, and human plasmodia. In cynomo~qi and

vivax malarias, the resistance characteristic could be transferred unchanged

through the mosquito. Pharmacological studies in the monkey demonstrated

that repeated administration of pyrimethamine produced signific• nt deleterious changes in the bone marrow, kidney, and adrenal cortex. Tolerability

studies in man attested to the safety of the currently recommended doses of

pyrimethamine but showed that, at a sevenfold increase in dosage, changes

occurred in the bone marrow similar to those exhibited by the monkey.

The capacity of pyrimethamine to function as a suppressive cure strongly

recommended its use by U.S. armed services. On the other hand, its potential

for inducing resistant strains and its slowness of action in treatment of acute

attacks were disadvantages not possessed by chloroquine.

In conclusion, one sees that during the period from 1946 to 1954, inclusive,

there were marked developments in the chemotherapy of malaria. The position of chloroquine and amodiaquin in the suppression and treatment of vivax

and falciparum malarias and in the cure of the latter was established firmly.

The usefulness and limitations of chlorguanide were defined with reasonable

certainty. A generally useful drug for the cure of relapsing infections with

P. vivax was developed in primaquine, and the value of this agent was proved

in both laboratory and field investigations. Finally, a new compound, pyrimethamine, possessing interesting possibilities as a suppressive antimalarial

drug, was introduced. The ultimate significance of these developments for

worldwide control of malaria remains to be appraised. It seems likely, however, that satisfactory measures are now at hand for suppression, treatment,

and cure of all human malarias. This remarkably favorable position of malaria therapy is in marked contrast to the uncertainty of the pre-World War

II period. It is a tribute to all who took part in the OSRD and postwar

malaria researches.
INDEX

AAF. See Army Air Forces. Admissions, for-Continued

AAF Regional Hospital, Mitchel Field, 237 chronic bronchitis, 43

AAF Regional Station Hospital No. 1, 233 encephalitis, 84

Abatssia, 157 lung abscess, 46

AaBEY, Col. EDWARaD A., 501 malaria, 450, 460

Abdominal pain, in- pneumonia, 27, 32

cutaneous diphtheria, 303 primary atypical pneumonia, 20-21, 23, 27

malaria, 483, 520 pulmonary emphyseŽma, 48

pancreatitis, 36 rheumatic fever, 229

Abdominal reflexes, in Japanese B encepha spontaneous pneumothorax, 373

litis, 88 types of Vincent's infection, 5

Abdominal symptoms, in malaria, 483 See also Hospital admissions.

Abscess(es): Adrenal cortex, degeneration of, in fulmibrain, 100 nating bacteremia, 250

gluteal, 535 Adrenal glands:

in ,treptococcal infections, 6 in epidemic typhus:

lung, 45-46 involvement of, 216

skin, 220 pathology of, 170

Acetylkalicylic acid, 76, 438 tuberculosis of, 367

Aches: Adrenalin, effect of, on suppressive action of

generalized: Atabrine, 470

in dengue, 72, 76 Adrenals, hemorrhage into, in fulminating

in Fort Bragg fever, 437 ineningococcal bacteremia, 252-253,

in malaria, 479, 481 255-256, 270-271

in meningococcal infections, 253 Adriatic Sea, 53

in sandfly fever, 56 Aedes aegypti, 442, 445

muscular, in Q fever, 106 breeding places of, 62, 63, 64, 69

vague, in malaria, 518 dengue vector, 59, 61

Acidosis, diabetic, 259 flight range of, 64

Acute respiratory diseases, 2-42 Aedes albopictus, 445

comparison of morbidity and mortality of, breeding places of, 69

in World Wars I and II, 1 dengue vector, 59

mode of transmission of, 1 flight range of, 64

See also Respiratory tract, diseases. Aedes atlanticus, 442

Adenitis, suppurative, in cutaneous diph- Aedee canadensie, 442

theria, 295 Aedes hebrideus, dengue vector, 59

Adenopathy, in dengue, 74 Aedes mosquitoes:

Adjutant General, The, 433 breeding index of, 64-65

Administrative memorandum. See Direc- breeding places of, 64, 68

tives. Aedes scutellaris, 59, 66

Admission rates, for- Aedes scuiellaris hebride-us, 62

common respiratory infection, 8 Aedes vexans, 442

infections due to Vincent's organisms, 5 Aegean Sea, 53

primary atypical pneumonia, 20-21, 23 Aero-otitis, 1

tuberculosis, 330, 335, 336, 353-354 Aerosols, in control of infection, 6

Admissions, for- Africa, 82

acute articular rheumatism, 225 Age, factor of, inbacterial pneumonia, 27 infee.,ous mononucleosis, 39

bronchiectasis, 45 malignant diseases of the lungs, 48

599
600 INFECTIOUS DISEASES

Age, factor of, in-Continued Amebiasis, deaths due to, 243

murine typhus, 222 Amebic dysentery, 491

poliomyelitis, 92, 95 Amebic hepatitis, 491

scrub typhus, 119 Americal Division, 280, 451, 557

susceptibility to influenza, 10 "demalarialization" in, 497

tuberculosis, 400, 401, 402 malaria in, 458

typhus fever, 220 See also Military units.

Agent(s), causative, of- American Association for the Advancement

Brill's disease, 201 of Science, 480

cerebral malaria, 499 American Civil War, 225, 329, 330

common cold, 3 American Medical Association, Council on

epidemic typhus, i43 Pharmacy and Chemistry of, 265

influenza, 10-11 American Red Cross, 344

murine typhus, 204, 205 American Zone, of occupied Germany, 397,

sandfly fever, 52 398, 399

Agranulocytosis, 200, 263 Amigen, for typhus patient, 153

Air, disinfection of, in control of infection, 6 ANDERSON, Dr. C. RussELL, 136, 195n, 201

Air Force Base Unit, 1306th, 453 ANDREWES, Dr. C. H., 22

Air Surgeon, 227 investigator of epidemic influenza, 10

Air Transport Command, 501 Anemia, 496

1306th Air Force Base Unit of, 453 aplastic, 551-552

Air transportation, for tuberculous patients, in blackwater fever, 486

342, 379, 380, 381 in malaria, 487, 490, 501, 508

Airborne Engineer Company. 900th, 452 Anesthetics, factor of, in activating malaria,

Airborne infection, methods for reduction of, 480

6 Anorexia:

Airfields. See Army airfields, effect of, on suppressive action of-AtaAirplane spraying, of DDT, in mosquito brine, 470

control, 67, 69 in dengue, 72

Aitape, 121, 123 in Q fever, 106

Alaska: in sandfly fever, 56

outbreaks of influenza in, 13 Antibiotics, 1-2

tuberculosis in, 365 broad-spectrum, 109, 139, 269

Alaskan Department, tuberculosis in, 365 in bacterial pneumonia, 27, 31, 32

Albuminocytological dissociation, 300 in epidemic typhus, 194--195

Albuminuria: in malaria, 525

in epidemic typhus, 217 in meningococcal infections, 266-269

in murine typhus, 222 in scrub typhus. 136

Alcoholic bouts, factor of, in activating See also specific names.

malaria, 480 Antimalarial drugs, clinical trial of, 525-598

Algeria, 49, 50, 53, 453, 502 cinchona alkaloids, 531-538

Algid malaria, 486 4-aminoquinoline compounds, 559-578

Algiers, 50 8-aminoquinoiine compounds, 579-592

Alkaloids, cinchona. See Cinchona alkaloids, heavy metals, 526-528

ALLEN, Maj. ARTHUR C., 132, 133, 169, 171 penicillin, 525-526

Allergic disorders, 9 quinacrine hydrochloride, 538-558

Allied Force Headquarters, Mediterranean sulfonamides, 528-530

theater, 495 Antimony compounds, in malaria, 528

Machine Records Unit of, 508 Antitoxin, meningococcal, 265-266

Malaria Committee of, 494 Anuria, in meningococcemia, 253, 262. 263

ALVING, Dr. ALF S., 597 Anxiety, in rabies, 101

Ambulation, for rheumatic fever patients, APC capsule, 6

233 Aphasia, in Japanese B encephalitis, 88
INDEX 601

Aplastic anemia, factor of Atabrine in, 551-- Army Institute of Pathology, 90, 132, 169,

552 251, 252, 302, 551

APPLEBAUM, I. L., 587 Army Medical Center, 133, 179, 417, 437

Arbeitsdienst, 395 Army Medical Department Research and

Archives of Pathology, 172 Graduate School, 138

Arctic Circle, 396 Army Medical Research and Development

ARLING, Dr. P. A., 266 Board. 384

ARMERUST, C. A., Jr., 119 Army Medical School, 184, 195

Armed Forces Institute of Pathology, 90, Army Medical Service Graduate School. 447

132,169,171,251,252, 258, 270, 302, 551 Army regulations, pertaining toArmy: tuberculosis, 375, 387, 388. 406 British First, 49 venereal diseases, 413, 429

British Second, 154 see also Directives.

British Eighth, 453, 504 Army Service Forces, 29, 343, 354

First U.S., 353 circulars of, pertaining to tuberculosis,

Fisth Fifth U.S., U.S., 351 3 387, 394. See also Directives, pertain- 51, 104, 354, 506, 507 igt ueclss

French, 330 ing to tuberculosis.

ereanc 1,3130 general hospitals designated as rheumatic

Germ , 51, 3121, 316, 3fever convalescent centers by, 233

Sinth U.S., 121, 1,46 Army Specialized Training Program, 13 Seventh U.S., 51, 155, 453, 504, 506, 507 AryVtiaySevc,9 Army Veterinary Service, 95

Army Air Force Technical School, 11, 29, 30 ARONSON, J. D., 370

epidemic of influenza at, 12-13 Arrhythmia, in rheumatic fever, 231

Army Air Forces, 228, 334, 354, 379 Arsenicals:

regional hospitals of, 233, 237 in malaria, 526

designated as rheumatic fever con- in syphilis, 418, 419

valescent centers, 233 Arsphenamine, 424

rheumatic fever control program of, 227, in malaria, 526

237, 238 Arthralgia:

tuberculosis in, 343-344 in murine typhus, 221

Army Air Forces Letter 25--7. 29 Apr. 1944, in rheumatic fever, 235

233, 236 Arthritis:

Army airfields: disability discharge due to, 339

Boca Raton, 39 in rheumatic fever, 231

Chanute, 101, 226 of hip, complicating dengue, 75

Scott, 20, 226 Arthropodborne virus encephalitides, 79-91

Seymour Johnson, 46 experience with, during World War II,

Truax, 20 83-91

Army Epidemiological Board, 6, 13, 80, 86, incidence of, 83

237, 238, 283 military history of, 80-83

commissions of, on- Artificially cultivated influenza vaccine,

acute respiratory diseases, 3, 4, 11, 18, immunity with, 11, 13

19, 20, 105 ASHBURN, P. M., 59

airborne infections, 227 Aspirin therapy, in Q fever, 107

hemolytic streptococcal infections, 226, Assam, 127, 281, 312, 452

227 Asthenia:

measles and mumps, 34-35 in Q fever, 107

neurotropic virus diseases, 76, 86, 443 in sandfly fever, 57

pneumonia, 28, 29 neurocirculatory. See Neurocirculatory

Army Ground Forces, 228, 343 asthenia.

Officers' Training Center of, 341 Asthma, 43-44

redistribution station of, 346 management of, 43

Army Group, 21st, 154 Asthmatics, fitness of, for duty, 43
602 INFECTIOUS DISEASES

Atabrine, 115, 452, 465, 493, 494, 510-511, Atlantic, colds contracted during crossing of,

529, 583 6, 15

blood levels of, 468, 473-476, 497 ATLAS, L. T., 3

clinical use of: Atropinization, in mumps, 38

in falciparum malaria, 542-545 Attack rates, for malaria, 454, 455, 456, 457,

in vivax malaria, 540-542 458

concentration of, in blood, 473-476 Atypical lesions of diphtheritic infection, 287-

dosage of, 465, 467, 471, 473, 476, 497, 288

545-549 See also Diphtheritic lesions.

schedules for, 466, 494 Atypical Pneumonia Board, European theaeffect of- ter, 21, 22

adrenalin on suppressive action of, 470 Atypical pneumonia, primary, 16-26

prolonged administration of, 550-556 reporting of, 20, 23

withdrawal of, 468-469 See also Primary atypical pneumonia.

effectiveness of: Auckland, 279

compared with quinine, 511 Aureomycin, effectiveness of, inunder combat conditions, 466, 469 bacteremia, 269

experimental field tests with, 530 Q fever, 109

general properties of, 539 meningitis, 269, 273

in falciparum infections, 469, 470. 496, scrub typhus, 139

498, 542-544 Australia, 8, 10, 42, 95, 103, 108, 111, 123,

in vivax infections, 469, 470, 472, 540-542, 360, 466, 470, 498, 560, 572, 574

543 outbreak of dengue in, 60-61

intramuscular injection of, 511, 543 Australian Armed Forces, in New Guinea,

oral administration of, 511 112

plasma concentration of, 510 Australian General Hospital, 2/9th, 113

research on. 494 Austria, 84

short-term administration of, reactions'to, Autopsy findings, in scrub typhus, 115, 116

555-558 Auxiliary Surgical Group, 1st, 341

superiority of, to quinine, 525 Avertin, 102

toxicity of, 466, 495, 498, 550-558 Axis Powers, 493

undesirable effects of, 476-477 AYCOCK, Col. GEoRoGE F., 382, 384

untoward reactions attributable to, 553- Azotemia:

555 associated with typhus fever, 152, 220

See also Quinacrine hydrochloride, in murine typhus, 222

Atabrine dermatitis complex, 553-555

Atabrine suppressive therapy, 494 Babinski's sign, 88

continuation of, during rehabilitation pe- Bacillary dysentery, 243, 491

riods, 469, 471 Backache:

contribution of, to troop effectiveness, 477 in acute attack of malaria, 481

discipline in relation to, 495 in murine typhus, 221

early failure of, 466-468 Back pain, severe, in poliomyelitis, 94, 97

effect of, on parasite species, 469-470 Bacteremia, 27, 244, 260

effect of physical activity upon, 480 diagnosis of, 261

effects of withdrawal of, 468-469 fulminant meningococcal, 244-246, 249-

institution of, 501 256

long-term clinical experience with, 471-472 antiserum in, 239

principles of regimen of, 539 rash in, 245-246

result of, 476 symptoms, 244-245

study on, 466 treatment of, 271-273

toxic reactions to, 495 with adrenal hemorrhage, 252-253

Atelectasis, in Q fever, 107 without adrenal hemorrhage, 249-252

Athens, 51, 105 transition from, to meningitis, 248-249
INDEX 603

Bacteria: Bedding, oiling of, to reduce airborne inassociated with Corynebacterium diphthe- fection, 6

riae, in cutaneous lesions, 292 BEDSON, Sir SAM PHILLIPS, 22

relationship of, to virus in common cold, 3 BELL, E. J., 156

Bacterial pneumonia, 26-32 Belsen Concentration Camp, 349

admissions for, 27 epidemic of typhus fever in, 154, 168

complicating typhus, 220, 222 BENGTSON, I. A., 135, 183, 190

deaths due to, 243 BENNETT, B. L., 138, 179n, 190, 208, 210

effect of- BENSTED, H. J., 296, 297, 312

antibiotics on, 31 Benzine compounds, arsenated, in malaria,

sulfonamides on, 31 526

epidemics of, 29 Benzoic acid, 196

in continental United States, 28-31 Benzyl benzoate, for scabies, 432

in European theater, 31 Berlin, 51, 102, 397, 398, 399

in Mediterranean theater, 32 BERMAN, B. B., 322

in oversea theaters, 31-32 BERNHARD. W. G., 261

incidence of, 29, 31 BERRY, J. F., 134

introduction, 26-28 BERRY, M. G., 124

See also Pneumonia. Besangon, 346

Bacteriological media, for recovery of Beta hemolytic streptococcus, sulfonamideCorynebaclerium diphtheriae, 294-295 resistant strains of, 28

Bacteriological studies, of diphtheria, 280 BEYER, Maj. EMIL C., 53

Bad Berka. 353 Bhamo, 129

BADGER, Col. THEODORE L., 340, 343, 345, Biak, 66, 125, 282, 298, 307

347, 349 outbreak of scrub typhus on, 121-122

BAGNALL, 324 Bicol Peninsula, 126

Baguio, 126 BIRD, W., 580, 582

BAIN, 324 Bismarck Archipelago, 120, 359

BAKER, Col. BENJAMIN M., 280, 496 Bismuth compounds:

BAKER, M. P., 491 in malaria, 528

"Balkan grippe," 25, 105, 106 in syphilis, 418

Balkans, 143 Biting habitsBALL, D., 303 of Aedes scutellaris, 66

BANCROFT, T. L., 59 of Phlebotomus papatasii, 53

Bandicoots, reservoir of Q fever, 108 Bizerte. 24, 49, 354, 453, 502

BANG, 498 Black Sea, 52

Barr6, J. A., 301 Blackouts, in relapsing vivax malaria, 487

Bat-transmitted rabies, 102 BLAND, Lt. Col. EDWARD F., 125n, 151, 152

Battalion aid station, in chain of evacuation, Blankenhain, 353

506 BLEECKER, Maj. PHILLIP B., 502

Battalions. See Military units. Blockley, 393

Battle of Saipan, 279 Battle of Sicily, 50 Blood:

Battle ofSiy, 586 concentration of Atabrine in, 473-476

BAYLISS, M., 586 concentration of sulfadiazinp in, 262

BAYNE-JONES, STANHOPE, 144, 145, 154, 205 cultures of, in meningococcal infections,

BEARCROFT, W. G. C., 188 261

Bed rest, in treatment of- effect of loss of, on suppressive action of

cutaneous diphtheria, 305 Atabrine, 470

rheumatic fever, 232, 233 examination of, for malarial plasmodia,

scrub typhus, 131 489

spontaneous pneumothorax, 47 studies of, in diagnosis of malaria, 489-490

tuberculosis, 342 whole, in treatment of malaria, 512
604 INFECTIOUS DISEASES

Blood picture, in- Breeding index, of Aedes mosquitoes, 64-65

dengue, 74 Breeding places:

epidemic typhus, 217 of Aedes mosquitoes. 64, 68

Japanese B encephalitis, 89 of sandflies. 53

Blackwater fever, 470, 496, 508. 517, 532 BRILL, NATHAN. 201

in malaria, 486 Brill's disease. 201-204. 220

B LAKE, Dr. FRANCIS G., 116, 117, 11 S, 119 clinical picture of. 202

BLANC, Dr. GEOROEs, 59n, 210 diagnosis of, 202-204

Blood smears: epidemiology of, 202

parasites in, 476 historical note on. 201-202

thick, 507 incidence of, 202

Blood urea nitrogen, in epidemic typhus, Brisbane, 61

217, 220 British Army, 106, 298

Bloodstr-' 1n1eningococci in, 244, 249 cutaneous diphtheria in, 281

Board Ae Coordination of Malarial diphtheria in, 276, 279

St ,25, 574 British civilian population, influenza in, 15

Board o,. Investigation and Control of British Eighth Army, 453, 504

Influenza and Other Epidemic Dis- British experience, with poliomyelitis, 94

eases in the Army, S0, 105, 226, 283, 443 British First Army, 49

Boca Raton Armiy Air Field, 39 British Isles, 22, 344, 368

Body lice, epidemic typhus transmitted by, British military forces, tuberculosis in, 399-

143 403

Body temperature. See Fever. British Second Army, 154

Bombay, 26, 135 British War Office, 499

B6ne, 49 British West Indies, 208

Bones, tuberculosis of, 358, 367, 383 Bronchi, tuberculosis of, 369

Bougainville, 112, 126, 451 Bronchiectasis, 44-45

Bovine tuberculosis, factor of, in nonpulmo- differential diagnosis with tuberculosis, 362

nary tuberculosis, 367 Bronchitis, 1, 2, 18, 26, 483

BowDoIN. Dr. CHARLFS D.. 443 chronic, 42-44

Brachial neuritis, homolateral, in malaria, Bronchogenic carcinoma, 48

485 Bronchopneunmonia, 1, 17, 33, 146-147

BRADL•y, B., 59 See also Pneumonia.

Bradycardia, 76 BRONSoN, L. If., 300

in dengue, 74, 75 BRUNS, Col. EARL If., 382

in Japanese B encephalitis, 89 Bruns General Hospital, 380, 384, 386-387

in sandfly fever, 57 census of tuberculous patients in, 386

in scrub typhus, 127 designation of, as specialty center for

BRAGDON, J. H., 491 tuberculosis, 381, 386

Brain: morale in, 386

abscess of. 100 orientation department, for tuberculous

due to Neisseria intracellhdaris, 258 patients, 389

in meningitis, 258 See also Hospitals, general.

involvement of, in- Brushy Creek fever. See Fort Bragg fever.

epidemic typhus, 216 Buchenwald concentration camp, 349, 353

Japanese B encephalitis, 90 Bulletin of the U.S. Army Medical Departmurine typhus. 222 ment, 283, 374, 428, 582

reactions in, in epidemic and scrub typhus, Bureau of State Services, U.S. Public Health

170 Service, 405

Breakthrough, of malaria: Bureau of Tuberculosis, Department of

during suppressive treatment, 546, 549 Health, New York City, 406

with quinine, 535 Burma, 111, 112, 127, 128, 129, 279, 451

with totaquine. 536 cutaneous diphtheria in, 281-282
INDEX 605

BURNET, investigator of epidemic influenza, Carrier rate:

10 for hemolytic streptococcus, 33

BURNETr, Capt. HARRY W., Jr., 341 for nasopharyngeal diphtheria, 313

BUSHNELL, Col. GEORGE E., 331, 332 Carriers:

BYLON, DAVID, 59 in diphtheria, 292

BYRON, R. A., 118 in malaria, 476

Casablanca, 354

C-47's, use of, in spraying for mosquito Case histories:

control, 69 epidemic typhus, 147-151, 158, 159-162,

Cachexia, 508, 523-524 165, 166

Caesar's campaigns, malaria in, 449 Fort Bragg fever, 439-440

Cairo, 94, 135 malaria, 517-523

Cairo Fever Hospital, Egypt, 145, 157, 159, meningitis, 247, 248

193 meningococcal infections, 256

Calcutta, 70, 499 meningococcemia, 246, 247, 248, 249, 250,

CALLENDER, G. R., 582 251

Calvados, 393 murine typhus, 212

CAMERON, J. D. S., 297, 312 Caserta, 53, 56, 108

Camp fever. See Epidemic typhus. CASEY, A. V., 118

CAMPINOPPETROS, Dr. J., 59n, 105 CASTANEDA, 202

Camps. See Military installations. Catania, 453

Campsites, clearing of, as preventive meas- Catarrhal fever, in South Pacific Area, 9

ure against scrub typhus, 122 CAUGHEY, J. E., 94

Canada, 82, 95 Causative agent(s), ofCanadian Army: Brill's disease, 201

tuberculosis in, 403-405 cerebral malaria, 499

western equine encephalomyclitis in, 82-83 epidemic typhus, 143

Canadian General Hospital No. 14, 324 influenza, 10-11

Canal Zone, outbreaks of influenza in, 13 murine typhus, 204, 205

Cape Gloucester, 120, 123 sandfly fever, 52

Captured prisoners of war: CELLI, A., 449

diphtheria in, 278, 315 Cellulitis, peritonsillar, 4, 7

medical treatment of, 392-393 Centers for treatment of tuberculosis, desigpolyneuritis in, 283 nation of general hospitals as, 381, 382

tuberculosis in, 393-396 See also Hospital centers.

Carbon dioxide, serum content of, in typhus Central America, 366

fever, 152 Central nervous system:

Carcinoma, bronchogenic, 48 effect of Atabrine on, 556-558

Cardiac malaria, 486 intolerance of, to Atabrine, 498

Cardiovascular disease, disability discharge involvement of, indue to, 339 epidemic typhus, 216, 220

Cardiovascular involvement, in epidemic Japanese B encephalitis, SS

typhus, 146 malaria, 485-486, 487

Carditis: mumps, 38

associated with rheumatic fever, 231, 236 syphilis, 100

complicating cutaneous diphtheria, 288, Central Pacific Area, 453, 454, 460, 496

302-303 Cephalin flocculation reaction, in monoCare of tuberculous patients, 359 nucleosis, 39

at Bruns General Hospital, 386 Cerebral malaria, 130, 470, 484-485, 496,

at Fitzsimons General Hospital, 385 508, 521-523, 543

at Moore General Hospital, 387 causative agent in, 499

Caribbean Defense Command, infectious death due to, 484, 499

mononucleosis in, 40 development of, 485
606 INFECTIOUS DISEASES

Cerebral malaria-Continuetd China-Burma-India theater, 99, 364-365

in India-Burma theater, 498, 499 453, 454, 455, 458, 460

incidence of, 499 common respiratory infection in, 8

intramuscular injections of quinacrine in, cutaneous diphtheria in, 276

544 dengue in, 70-71

prevalence of, 485 influenza in, 16

temperature in, 485 malaria in, 452

Cerebrospinal fluid: primary atypical pneumonia in, 26

concentration of sulfadiazine in, 262 tuberculosis in. 364-365

culture of, in meningococcal infections, Chinese troops:

260, 261 scrub typhus in, 127-128

meningococci in, 267 tuberculosis in. 364

Certificate of disability for discharge, 237, Chinese unit, 22d Chinese Division, 127

381,383, 434 Chloral hydrate, 192

See also Disability separations. Chloramphenicol, 139, 269, 273

Cervical lymphadenitis, effect of sulfadiazine Chlorguanide, 595

on, 6 Chlorides, serum content of:

Chain of evacuation: in epidemic typhus, 217

evacuation hospitals in, 506-507 in typhus fever, 152

general hospitals in, 507-508 Chloromycetin, 139

medical battalions in, 506 Chloroquine diphosphate, 562-563, 584-585

station hospitals in, 508 absorption, 562

Chancroid, 430-431 antimalarial activity of, 562-563

diagnosis of, 430 clinical testing of, 563

treatment of, 431 dosage schedule for, 570

Chanute Field. 101, 226 effect of, on relapsing malaria, 567-568

Chemical Warfare Service. 69 effective plasma concentrations of, 563, 568

Chemotherapeutic agents, in common cold, 3 general properties of, 562

Chemotherapy: in falciparum malaria, 563, 571-572

in common upper respiratory infections, 9 in vivax malaria, 563, 564, 570-571

in epidemic typhus, 195-200 relative efficiency of. 569

in gonorrhea, 411, 412 representative treatment schedules for, 565

in scrub typhus, 136-137 studies on suppressive efficacy of, 572-576

of malaria, research in: study of, at specialty center:

during World War II, 525-594 materials for, 564

postwar, 594-598 methods of, 564

Chest pain: results of, 565-568

in Fort Bragg Fever, 437 treatment schedules for. 564

in Q fever, 106, 107 superiority of, over quinacrine, 563

Chief consultants: toxicity of, 574-576

in medicine, 293, 321 Chlortetracycline, effectiveness of, inin tuberculosis, 349, 350 bacteremia, 269

Chill, in- Q fever, 109

dengue fever, 72 meningitis, 269, 273

Fort Bragg fever, 437 scrub typhus, 139

meningococcal infections, 245, 253 Christ Hospital Institute of Medical Remalaria, 481 search, 596

Chilliness, in- Chronic bronchitis, 42-44

Fort Bragg fever, 437 admissions for, 43

Q fever, 106 cough in, 42

sandfly fever, 56 factor of climate in, 42

scrub typhus, 111 management of, 42-43

China. 70, 86, 143, 451 Chronic malaria. See Malaria.
INDEX 607

Chronic sinusitis, 1 Clinical course, of-Continued

Cinchona alkaloids: primary atypical pneumonia, 19, 21, 25

cinchonidine, 537 Q fever, 107-108

cinchonine, 537 sandfly fever, 56-57

comparison of, with Atabrine, 538 Clinical experience, withdihydroquinine, 537 Atabrine suppressive therapy, 471-472

quinidine, 537 epidemic typhus, 145-169

quinine, 531-535 scrub typhus, 112-132

totaquine, 536 Clinical featuresCinchonidine: of Japanese B encephalitis, 88

antimalarial activity of, 537 of Q fever, 106-108

comparison of, with quinine, 537 Clinical findingsCinchonine: in murine typhus, 208

antimalarial activity of, 537 in sandfly fever, 51

comparison of, with quinine, 537 Clinical information, on rheumatic fever, 230

Cinchonism, 512, 534 Clinical manifestations, of dengue, 71-76

Circular letters. See Directives, pertaining "Clinical malaria," diagnosis of, 509

to specific subject. Clinical patternCirculars. See Directives, pertaining to of common respiratory diseases, 4

specific subject. of measles, 32

Circulatory failure, peripheral, in fulminant Clinical picture, ofmeningococcal bacteremia, 271-272 Brill's disease, 202

Civil War, American, 225, 329, 330 common upper respiratory infections, 3

Salaria during, 450 exudative pharyngitis, 4

*,ercular diseases in Union Ar;nny during, poliomyelitis, 94

rheumatic fever, 229-231 S•ilian populations: scrub typhus, 112, 113, 118, 128

dengue epidemics in, 63 Clinical research, vaccine studies, 138, 139

diphtheria in, 278, 310-312 Clinical study, of scrub typhus, 116

transmitted by military populations, Clinical symptoms, of malaria, 481-484

315-319 Clinical trials, of antimalarial drugs, 525-598

influenza in, 15 postwar research in, 594-598

Japanese B encephalitis in, 86-89 Clothing:

malaria in, 502 DDT dusted, for protection against lice,

in India, 498 201

measles in, 34 impregnation of, as preventive measure

pneumonia in, 33 against scrub typhus, 122, 127

tuberculosis in, 375 COATNEY, Dr. G. RoBERT, 594, 597

western equine encephalomyelitis in, 82 Coccidioidomycosis, 1, 47, 439

Classical signs, of scrub typhus, 130 complicating tuberculosis, 383

Clearing station, in chain of evacuation, 506 differential diagnosis with tuberculosis, 362

CLELAND, J. B., 59 Codeine, 76, 438

Climate: Codeine therapy, in Q fever, 107

effect of, on tuberculosis, 359 Cogon grass, 126

factor of, in respiratory diseases, 7, 42 Cold, effect of, on suppressive action of

Clinical aspects, of malaria, 479-492 Atabrine, 470

Clinical attack of malaria, predisposing Cold hemagglutination, in primary atypical

factors in, 480 Cdemouiation, in pi

Clinical characteristics-- pneumonia, 19, 22, 23

of epidemic typhus, 143 Colds. See Common cold.

of scrub typhus, 111 Collapse therapy, in tuberculosis. See

Clinical course, of- Pneumothorax.

dengue, 75 Collecting station, in chain of evacuation,

influenza, 15 506
608 INFECTIOUS DISEASES

Columbia University, 596 Complement fixation test, in-Continued

Combat, factor of, in diphtheritic lesions, typhus, 157, 181

286, 312 Complications, ofCombat troops, malaria in: common cold, 3

rates, 465, 466, 468 cutaneous diphtheria, 288, 298-303

suppressive therapy for, 471 dengue, 75-76

Commissions, of Army Epidemiological malaria, 484-487

Board: mumps, 35-37

on acute respiratory diseases, 3, 4, 11, 18, rheumatic fever, 234-235

19, 20, 105 scrub typhus, 118-119, 131

on airborne infections, 227 tuberculosis, 383

on hemolytic streptococcal infections, 226, CoMrrE, 143

227 Concentration camps:

on measles and mumps, 34-35 epidemic typhus in, 154-155

on neurotropic virus diseases, 76, 86, 443 tuberculosis in, 349-353

on pneumonia, 28, 29 Conjunctivitis:

Committees. of National Research Council: meningococcal, 259, 260

on medical research, 525 mild, associated with scrub typhus, 127

on medicine, 420 CONNoR, Maj. CHARLES A. R., 237

Common cold, 2 CONSEIU, 143

complications of, 3 Constantine. 453, 502

convalescence after, 4 Consultant in Infectious Diseases, in Euroincubation period of, 3 pean theater, 14

mode of transmission of, 1 Consultant in Medicine, inseriousness of. in infants, 3 China-Burma-India theater, 364

treatment of, 9 Mediterranean theater, 8

viruses of, 3 Office of the Surgeon General, 30

Common upper respiratory infection, 2-9 Sixth Service Command, 29

admissio-i rate for, 8 Sixth U.S. Army, 466

definition of term of, 2 Consultant in Tuberculosis, Office of the

in continental United States, 5-6 Surgeon General, 389, 398, 406

in oversea theaters, 6-9 Consumption. See Tuberculosis.

incidence of, 5, 6-9 Contact-tracing program, for tuberculosis,

introduction, 2-5 356-357

noneffectiveness due to, 5-6 Contagion, of nonpulmonary tuberculosis,

treatment of, 9 368

See also Respiratory tract, diseases. Continental United States. See Zone of

Communicability, of- Interior.

infectious mononucleosis, 39 Control:

measles, 32 of diphtheria, 278

mumpr a l pof prim ary atypical pneum rheumatic fever, program for, 237-238 onia, 20, 24Co v l s e c ,at r

rubella, 41 Convalescence, afterCommunicable diseases. See specific diag- common cold, 4

noses. dengue, 72, 75

Complement fixation test, in- Japanese B encephalitis, 89

Brill's disease, 203 primary atypical pneumonia, 21

epidemic typhus, 183-188 Q fever, 107-108

results of, 184, 185 scrub typhus, 123-125, 131

Japanese B encephalitis, 83, 86, 89 Convalescent centers for rheumatic fever,

lymphocytic choriomeningitis, 100, 101 hospitals designated as, 233

malaria, 490 Convulsion (s) :

scrub typhus, 134-135 Atabrine as factor in, 557
INDEX 609

Convulsion(s)-Continued Crowding of troops, effect of, on incidence

complication of quinine therapy, 501 offollowing intravenous injections of quinine, meningococcal infections, 241

535 mumps, 37

in cerebral malaria, 485 respiratory diseases, 7

in scrub typhus, 131 Cuba, 450

Cooperative Clinical Studies Group, 418 Culex mosquitoes, 82, 122

CORBITT, Maj. AusTIN J., 116, 125n Culesx quinquefasciatus, 442

Cornea: CULLINAN, E. R., 56

edema of, in malaria, 486 Culture medium(s):

ulceration of, in meningitis, 259 agar, 294

Corning fritted glass filter, 445 Lffler's, 275, 294

Corps, 11-49, 103, 495, 507 Tellurite, 295

Corps area. See Service command. Cultures, Corynebacterium diphLheriae in,

Corps of Engineers, 359 293,294

Corsica, 24, 53, 105, 453, 502

Cortisone, 271, 272 Cutaneous diphtheria, 275-327

associated with nasopharyngeal diphtheria, Cory21bacterium diphtheriae, 8, 32, 2759329, 312-315

281, 287, 288, 289, 290, 292, 293-294, carditis in, 288, 302-303 295, 296 clinical findings associated with, 295 in skin lesions, 279 complications of, 288, 298-303

Corynebacterium hemolyvicum, 319-320 cost of, to the Army, 307-308

Corynebacterium pyogenes, 292 diagnosis of, 288 Coryzna, Coryza, 483 483 methods of, 293-295 directive on, 283

in Fort Bragg fever, 437dietvon28 Cough, in-F factors favorable for spread of, 312 bronchiectasis, 45 in South Pacific Area, 279-280 chronic bronchitis, 42 incidence of, 275-278, 297-298 epidemic typhus, 216 information concerning, 279-283 Fort Bragg fever, 437 lesions of: malaria, 483 bacteriology of, 288-293 murine typhus, 221,222 factors in healing of, 306 Q feve 10 , morphology of, 288-293 fever, 106 multiplicity of, 286

tuberculosis, 354 mcoogns f 8

Council on Pharmacy and Chemistry, micro-organism of, 281

American Medical Association, 265 military problem of, 275-279

Counseling, in care of tuberculous patients, neuritis complicating, 299-302

389-390 problems for investigation of, 325-326 Schick reaction in, 296-297

Course. See Clinical course. treatme of, n 304-307

Cox, H. R., 156 treatment of, 304-307

Cox vaccine, 156 antitoxin in, 301-302

field trial of, 157 bed rest in, 305

Coxsackie virus, 100 penicillin in, 305-306

CRAIG, C. F., 59 surgical measures in, 306

CRAIGIE, J., 156, 183 See also Extracutaneous diphtheria.

Craigie vaccine, 168, 183 Cutaneous lesion(s):

Cranial nerve palsies, residual of cerebral moist dressings in treatment of, 305

malaria, 485 of epidemic typhus, histology of, 169-170

Cranial nerves, paralysis of, in meningococcal role of, in spread of diphtheria, 308-310

meningitis, 258 surgical measures for excision of, 306

Cnzw, Maj. RowERT S., 499 Cutaneous manifestations, of meningococCriteria, for evacuation to Zone of Interior, cemia, 246, 248

508 Cutaneous smears, meningococci in, 261

639243--63--2
610 INFECTIOUS DISEASES

Cyanosis, 529 Delirium, inCzechoslovakia, 84 cerebral malaria, 485

epidemic typhus, 216

Dachau Concentration Camp, 180, 197, 2290, meningitis, 270

349, 350 Delousing measures, in epidemic typhus, 201

epidemic of typhus in, 155 DELP, M. H., 300, 303

D'AGATI, V. C., 255 "Demalariazation," results of, 496, 497

DAITZ, Maj. BERNARD D., 389 Dengue, 50, 59-78, 82

Dakar, 211, 212 adenopathy in, 74

D'ALONZO, C. A., 250 as differential diagnosis in malaria, 491

DA ROCHA-LIMA, 143, 156 clinical manifestations of, 71-76

DAVIS, Maj. WILLIAM A., 154, 168n complications of, 75-76

Davis-Monthan Field, 233 convalescence, 72, 75

DAWEER, T. R., 490 course of, 75

DAwsoN, Dr. M. HENRY, 226 diagnosis of, 72, 76 differential diagnosis of, 76

Days lost from duty. See Noneffectiveness. eidemics ofg61,i62-f, 70

epidemics of, 61, 62-66, 70-71

Deafness: incidence of, 60, 63, 65, 67, 68, 70

in epidemic typhus, 216 investigations of, 76-78

in murine typhus, 221 military importance of, 59, 70, 76

residual of scrub typhus, 124 mode of transmission of, 59

Deatabrinization, 497 noneffectiveness due to, 65

Death(s), due to- onset of, 72

amebiasis, 243 outbreaks of, 60-71

bacillary dysentery, 243 physical signs of, 74-75

bronchitis, 1 rash in, 72

bronchopneumonia, I symptoms of, 72, 74-75

cerebral malaria, 484, 489 treatment of, 76

diphtheria, 243, 276, 277 vectors of, 59, 61

encephalitis, 83, 85 DEOME, K. B., 105

endocarditis, 225 Department of Health, New York City,

infectious hepatitis, 243 Bureau of Tuberculosis of, 406

influenza, 1, 10 Dermatitis, exfoliative, associated with AtaJapanese B encephalitis, 89 brine suppressive therapy, 477

lobar pneumonia, 1, 243 Dermatophytosis, noneffectiveness due to, 37

lung abscess, 46 Desert sore. See Cutaneous diphtheria.

malaria, 243, 450, 460-462, 514 DES. MArrHEWs, Lt. Col. EDWARD, 15, 24,

measles, 1, 32, 35 25

meningitis, 7 Deutsche Militdrarzt, 316

meningococcal infections, 242, 243, 251 Diabetes, complicating tuberculosis, 383

mumps, 36 Diabetic acidosis, 259

pericarditis, 225 Diagnosis, ofpoliomyelitis, 243 Brill's disease, 202-204

primary atypical pneumonia. 21, 243 chancroid, 430

rabies, 101 cutaneous diphtheria, 293-295

rheumatic fever, 231, 232 dengue, 72, 76

rheumatism, 225 diphtheria, 278

scrub typhus, 114, 119, 120, 128, 243 encephalitis, 83

tuberculosis, 243, 354, 360, 375-377 epidemic typhus, 179-192

DDT, 58, 67, 69, 10t gonorrhea, 410, 412

use of, against vector of epidemic typhus, infectious mononucleosis, 39

201 influenza, 16

DELAY, P. D., 105 lymphocytic chorioi. Angitis, 100
INDEX 611

Diagnosis, of-Continued Diphtheria-Continued

malaria, 482, 489-491, 509 nasopharyngeal, 280, 281, 282

meningococcal infections, 260-261 associated with cutaneous, 312-315

pancreatitis, 36 carrier rate of, 313

poliomyelitis, 94, 97-98 penicillin in, 321-325

primary atypical pneumonia, 20, 21-22 pharyngeal, 275, 297, 299

Q fever, 103, 104 summary, 326-327

rubella, 41 transmission of, from military to civilian

sandfly fever, 49, 50, 51, 56-57 populations, 315-319

scrub typhus, 113, 125. 133-136 See also Cutaneous diphtheria.

tuberculosis, 358-359, 361, 362, 364 Diphtheria antitoxin, 295

Diagnostic aids: Diphtheria carriers, penicillin in treatment

in epidemic typhus, 179--192 of, 322

in murine typhus, 213-215 Diphtheritic lesions:

Diagnostic test for typhus, development of, healing of, 284

179 morphology of, 284-288

Diarrhea: in relation to bacteriology of, 288-293

in suppressive malaria therapy, 466, 495, multiplicity of, 286 556 Schick reactions of individuals with, 296

severity of, in falciparum malaria, 483 Diphtheritic neuritis. See Neuritis.

Diet: Diphtheritic paronychias, 287

in epidemic typhus, 153, 192 Diphtheritic polyneuritis. See Polyneuritis.

for tuberculous patients, 379 Diphtheroids, 294, 297

otuberCol. patients, 28379 581,Diplopia, in cerebral malaria, 485

DIKUAInE, Col. FRANCIS R., 283, 581. 582 Directives, pertaining toDigitalis, 479 diphtheria:

Dihydroquinine: Circular Letter No. 69, Office of the

comparison of, with quinine, 537 Chief Surgeon, European theater, 28

in vivax malaria, 537 Sept. 1945, 278

DILLON, Maj. JOHN A., 500 Medical Circular Letter No. 5, HeadDimethyl phthalate, clothing impregnated quarters, USAFSPA, 20 Oct. 1943,

with, 122, 127 279

DIMOND, E. G., 303 Medical Circular Letter No. 14, Headquarters, USAFSPA, 5 Jan. 1944, 279

D)INGLE, 1)r. JOHN I,, 3, 18, 240n TB MED 143, February 1945, 283

Diphtheria, 279-319 Technical Bulletin No. 17, Office of the

complications of, 298-303 Chief Surgeon, USAFFE, 23 Oct.

diphtheritic neuritis, 299-302 1944,282

incidence of, 298-299, 305 discharge of patients to Veterans' Addeaths due to, 243, 276, 277 ministration:

directives on, 278, 279, 282, 283. See also War Department Circular No. 109, 26

Directives, pertaining to diphtheria. Apr. 1943, 383

epidemics of, 317 establishment of specialized centers:

faucial, 298 Circular No. 456, Army Service Forces,

immunization in, 278-279 29 Dec. 1945, 387

in combat units, 279, 280, 304, 312, 313, Japanese B encephalitis:

314 TB MED 181, July 1945, 86

in German prisoners of war, 278, 315 TB MED 181, 6 Apr. 1947, 88

in oversea theaters, 279-282 lymphocytic choriomeningitis:

in the Tropics, 310-312 Circular Letter No. 107, 21 Oct. 1941,

in Zone of Interior, 282-283 100, 101

incidence of, 275-278 Circular Letter No. 74, 19 Mar. 1943,

myocarditis in, 302 100, 101

nasal, 275 TB MED 212, 16 Jan. 1946, 100, 101
612 INFECTI'OUS DISEASES

Directives, pertaining to-Continued D)irectives, pertaining to-Continued

malaria: purchase of milk-Continued

Circular Letter No. 6, Office of the Circular No. 72, Headquarters, EuroSurgeon, NATOUSA, 10 Apr. 1943, pean theater, 10 Nov. 1942, 368

509, 510 rheumatic fever:

Circular Letter No. 10, Office of the AAF Letter 25-7, 29 Apr. 1944, 233, 236

Surgeon, NATOUSA, 15 Feb. 1944, Circular Letter No. 144, Office of the

510, 511 Surgeon General, U.S. Army, 7 Aug.

Circular Letter No. 21, Office of the 1943. 236

Surgeon, NATOUSA, 3 Apr. 1944,508 TB MEl) 97, 29 Sept. 1944, 232, 236

Circular Letter No. 32, Office of the TB MED 112, 1 Nov. 1944, 227

Surgeon, NATOUSA, 3 Sept. 1943, scrub typhus:

510 Technical Memorandum No. 10, HeadCireklar L.etter No. 33, Office of the quarters, USAFFE, 29 Aug. 1944, 124

Surgeon General, U.S. Army, 2 Feb. streptococcal infections:

1943, 500 1943500Circular Letter No. 16, Office of tihe

Circular Letter No. 34, Office of the Curgette No. 1, Oi of the

Surgeon, NATOUSA, 14 Sept. 1943, 7-8

510, 511 TB ME) 112, 1 Nov. 1944, 227

Circular Letter No. 41, Office of the TBomelv

Surgeon, NATOUSA, 29 July 1944, sulfonamides:

510 Circular Letter No. 170, of the0ffice 

Circular Letter No. 56, Office of the Surgeon General, U.S. Army, 30

Surgeon General, U.S. Army, 9 June Sept. 1943, 242

1941, 465, 499 tuberculosis:

Circular Letter No. 135, Office of the AR 40-1080, 31 Dec. 1934 and 10 Dec.

Surgeon General, U.S. Army, 21 Oct. 1943, 406

1942, 499, 500 AR 615-361, 14 May 1947, 375, 388

Circular Letter No. 153, Office of the Circular Letter No. 100, Office of the

Surgeon General, U.S. Army, 19 Aug. Chief Surgeon, European theater, 25

1943, 500, 540, 546 July 1944, 342

meningococcal infections: Circular Letter No. 102, Office of the

Circular Letter No. 170, Office of the Chief Surgeon, European theater, 4

Surgeon General, U.S. Army, 30 Aug. 1944, 342

Sept. 1943, 242, 261, 269 Circular Letter No. 10, Port Surgeon,

TB MED 9, 12 Feb. 1944, 266 New York Port of Embarkation, 26

neurotropic virus diseases: Mar. 1945, 378, 379

Circular Letter No. 74, Office of the Circular No. 40, Headquarters, EuroSurgeon General, U.S. Army, 19 Mar. pean theater, 5 Sept. 1942, 368

1943, 79, 100 Circular No. 41, Office of the Surgeon,

Circular Letter No. 107, Office of the NATOUSA, 29 July 1944, 356

Surgeon General, U.S. Army, 21 Oct. Circular No. 72, Headquarters, Euro1941, 100 pean theater, 10 Nov. 1942, 368

TB MED 181, 1945 and 1947, 86, 88 Circular No. 342, Army Service Forces,

TB MED 212, 16 Jan. 1946, 79, 100, 101 14 Oct. 1944, 394

penicillin: Circular No. 456, Army Service Forces,

Administrative Memorandum No. 151, 29 Dec. 1945, 387

Office of the Chief Surgeon, European TB MED 71, 28 July 1944, 370

theater, 27 Nov. 1944, 321 TB MED 221, 29 Apr. 1946, 388

pleurisy with effusion: TB MED 222, 16 May 1946, 389

TB MED 71, 28 July 1944, 370 War Department Circular No. 313, 24

purchase of milk: July 1944, 406

Circular No. 40, Headquarters, Euro- War Department Prisoner of War

pean theater, 5 Sept. 1942, 368 Circular No. 11, 8 Feb. 1944, 393
INDEX 613

Directives, pertaining to-Conitinued Disability separations, due to--Continued

venereal diseases: tuberculosis, 329, 332, 334-339

AR 40-235, 30 Dec. 1924, 429 Discharge rate, for tuberculosis, 338-339

AR 40-235, 11 Oct. 1939, 413 Disease(s):

Circular Letter No. 18, Office of the deaths from, 1

Surgeon General, U.S. Army, 10 disability separations for, 332, 339

Mar. 1941, 409, 410, 411, 412, 413, miteborne, 111-142

418, 419 of military importance, 59, 70, 76

Circular Letter No. 32, Office of the of respiratory traft, 1-48

Surgeon General, U.S. Army, 1 Feb. Disorientation:

1943, 414 in falciparum malaria, 484

Circular Letter No. 74, Office of the in Japanese B encephalitis, 88

Surgeon General, U.S. Army, 25 Discipline, in relation to Atabrine suppresJuly 1942, 412, 413, 419, 427 sive therapy, 495

Circular Letter No. 86, Office of the Disposition, change in, in falciparunm maSurgeon General, U.S. Army, IS laria, 484

Aug. 1942, 412 D)isposition, of patients:

Circular Letter No. 93, Office of the after rheumatic fever, 233, 236-237

Surgeon General, U.S. Army, 30 Apr. with asthma, 43-44

1943, 427 witai malaria, 516

Circula. Letter No. 97, Office of the with scrub typhus. 123-125

Surgeon General, U.S. Army, 12 May with sandfly fever, 53-55

1943, 413 with tuberculosis, 341-342, 355-356

Circular Letter No. 129, Office of the Ditiresis, spontaneous, in .crub typhus, 131

Surgeon General, U.S. Army, 22 Division of Medical Sciences, National ReJuly 1943, 413, 416 search Council, 94, 136, 493

Circular Letter No. 195, Office of the Committee on Pathology of, 171

Surgeon General, U.S. Army, 1 Dec. Office of Medical Information of, 374

1943, 409 Division of Virus and Rickettsial Diseases,

Circular No. 2, Office of the Surgeon Medical Department Professional Service

General. U.S. Army, 13 Dec. 1910, 428 Schools, 179, 180, 184

Circular No. 3, Office of the Surgeon Divisions. See Military units.

General, U.S. Army, 3 June 1911, 428 Dizziness:

TB MED 3, 11 Jan. 1944, 429 associated with dengue, 72

TB MED 9, 12 Feb. 1944, 415 following totaquine treatment, 536

TB MED 16, 6 Mar. 1944, 415 Dobodura, 113, 116, 120

TB MED 48, 31 May 1944, 427 DoEBR, R., 52

TB MED 96, 21 Sept. 1944, 415 DORLAND, Brigadier, of British Army, "98

TB MED 106, 11 Oct. 1944, 425 Dorsetshire, 23

TB MED 157, April 1945, 430 Dosage, of Atabrine, for effective suppressive

TB MED 196, 20 Aug. 1945, 416 therapy, 466-467, 473-476, 497, 498, 545-

TB MED 198, 20 Aug. 1945. 425 549

War Department General Orders No. DOWLING, H. F., 263

6, 13 Feb. 1923, 429

Disability 

Disailit Feb.1923, de Dressings, moist, for cutaneous diphtheria separaLtions, due to-- lsos 0

asthma, 44 Dlesions, 305

bronchiectasis, 45 Drinker respirator, 98

cardiovascular disease, 339 Drowsiness, in falciparurn malaria, 484

diseases of the ear, 339 Drugs, antimalarial:

duodenal ulcer, 339 Atabrine. See Atabrine; Quinacrine hymeningococcal infection, 270 drochloride.

rheumatic fever, 236, 237 chlorguanide, 595

sandfly fever, 55 chloroquine diphosphate, 562-563. 584-585

spontanetous pneumothorax, 47 clinical trials of, 525-598
614 INFECTIOUS DISEASES

Drugs, antimalarial-Continued 8-aminoquinoline compounds-Continued

effectiveness of, 500-501, 532, 536, 541, summary, 582, 592

542, 543, 548, 560, 563, 573, 574 toxicity, 585-589

Fraxine, 499 clinical experience, 585-588

oxychloroquine, 577-578 wartime studies, 581-582

pentaquine, 592, 594 Elberfeld, 559

Plasmochin naphthoate, 501, 511, 579-592 El tabardillo (Spanish). See Epidemic

primethamine, 598 typhus.

quinine, 493, 496, 501, 511-512, 531-535 Embaba Hospital, 157

Sontochin, 559-562 Emirau, 451

Sontoquine, 512 Emperor FREDERICK 1, 449

totaquine, 536 Emphysema, pulmonary, 48

toxic reactions of, 501, 536, 550-558, 561, Empyenia, in lobar pneumonia, 31

574-576, 585-589 Enanthem, of dengue, 72

Ducrey bacillus, 430 Encephalitis, 22

DUDLEY, S. F., 292n, 296, 298 complement fixation test in, 83, 89

DUMAS, J., 59 deaths due to, 83, 85

DUNCAN, Col. GARFIELD G., 466, 498 diagnosis of, 83

Duodenal ulcer, disability discharge due to, epidemics of, 81, 82

339 Japanese B. See Japanese B encephalitis.

DURIEUX, 212 lethargica, 80, 89

Dust, factor of- neutralization test in, 83, 89

in asthma, 43 resemblance of cerebral malaria to, 485

in Q fever, 105, 108, 109 Russian spring-summer, 79, 82

DYER, R. E., 108, 204 St. Louis, 79, 81, 88

Dyspnea, in- Venezuelan, 79

cutaneous diphtheria, 303 Encephalomyelitis, equine, 79, 80, 82, 88

epidemic typhus, 216 Endemic areasrelapsing vivax malaria, 487 of Japanese B encephalitis, 86

of Q fever, 108

Eagle test, for malaria, 490 Endemic typhus, 204-215

Ear, diseases of, disability discharge due to, See also Murine typhus.

339 EndemicityEast Anglia, 15, 41 of murine typhus, 209

Eastern equine encephalomyelitis, 79, 82 of sandfly fever, 49

Echo virus, 100 Endocarditis:

ECKE, R. S., 157, 159, 197 bacterial, 491

Ecthyma. See Cutaneous diphtheria, death due to, 225

Efate, 451 Enemy military units:

Egypt, 94, 180, 220, 275, 318 Afrika Corps, 313, 316

epidemic typhus in, 145 15th Panzer Division, 316

Egyptian Government, Ministry of Public 21st Panzer Division, 316

Health of, 145-146, 157 England, 7, 9, 15, 16, 17, 23, 38, 42, 344, 349

8-aminoquinoline compounds, 579-592 influenza epidemics in, 14

discussion, 589-591 Enlistment stations, 331

clinical use, 590-591 Enterocolitis, tuberculous, 383

further study, 591 Environmental factors, in precipitation of

historical review, 579-582 malarial paroxysm, 480

prewar studies, 580-581 Epidemic(s), ofrecommendations for therapeutic use, dengue:

588-589 in Australia, 60-61

study at a specialty center, 582-585 in China-Burma-India theater, 70-71

vaý.rial and methods, 583 in Hawaiian Islands, 63-65

results, 583-585 in New Caledonia, 63
INDEX 615

Epidemic(s), of-Continued Epidemic typhus-Continued

dengue-Continued epidemiology of, 143-144

in New Guinea, 65-68 histology of cutaneous lesion of, 169-170

in New Hebrides, 62-63 historical role of, 143

in Philippine Islands, 65-68 immunization in, 156, 163, 164

in Saipan, 68-70 in concentration camps, 154-155, 161)

diphtheria, 317 in Egypt, 145

encephalitis, 81, 82 in French North Africa, 145

epidemic typhus: in Iran, 145

conditions predisposing to, 144 incidence of, 146

in civilian populations, 145, 155 lesion of, 152

in concentration camps, 154-155, 169 metabolic studies of, 152

in Italy, 154 mode of transmission of, 143

infectious hepatitis, 495 morbidity, 156

infectious mononucleosis, 40 neutralizing antibody test in, 189-190, 191

influenza, 9-10, 11, 12, 14 pathological physiology of, 151

meningococcal meningitis, 239 pathology of, 169-172

mumps, 37 prophylaxis, 201

pneumonia, 29 protective measures against, 156

poliomyelitis, 93, 96-97 rickettsiae of, 143

Q fever, 103-106 serological findings in, 186, 187

in Greece, 105-106 severity of, 146

rheumatic fever, 227 summary, 215-223

sandfly fever, 50, 56 clinical picture, 215-217

scarlet fever, 226 diagnosis, 217

scrub typhus, 120, 121 immunity, 220

streptococcal infections, 227 natural course, 220

typhus fever, 143 prophylaxis, 221

Epidemic influenza, 10, 11, 14 relapse, 220

See also Influenza. therapy, 221

Epidemic parotitis. See Mumps. symptoms of, 146

Epidemic typhus, 143-201 treatment of, 192-201

antibodies, 179, 180, 184, 185, 186, 190 antibiotics, 194-195

Brill's disease following, 201-204 chemotherapy, 195-200

case histories, 147-151, 158, 159-162, 165, serotherapy, 192-194

166 supportive therapy, 192

causative agent of, 143 vaccine:

clinical characteristics of, 143 Cox (U.S. Army), 156-167, 187

clinical experience with, 145-169 Craigie (British Army), 168

in nonvaccinated individuals, 145-155 Epidemiological study, of scrub typhus, 119

in vaccinated individuals, 156-169 Epidemiology, ofcomplications of, 220 Brill's disease, 202

diagnosis of: Fort Bragg fever, 442

complement fixation tests with rick- murine typhus, 204-205

ettsial antigens in, 183-188 Q fever, 108-109

laboratory aids in, 179-192 rheumatic fever, 228-229

neutralizing antibody test in, 189-190, sandfly fever, 53-55

191 tuberculosis, 356-357

rickettsial agglutination in, 188-189 typhus fever, 143-144

strain isolation and identification in, Epidermophyton, 280

190-192 Epigastric distress, symptom of totaquine

Weil-Felix test in, 179-183 treatment, 536

dietary management of patients with, 153 Epinephrine, effect of, on suppressive action

epidemics of, 144, 145, 154-155 of Atabrine, 470
616 INFECTIOf•"S 1lSEASES

Equine encephaloniyelitis: Evacuation:

eastern, 79, 82 for polioinyelitis, 98

western, 79, 80, 82, 88 methods of, 357

Eritrva 95 of tuberculous patients, 360, 362, 364

ERKENPLCK, Col. VERNON J., 268 general principles of, 378-:381

Eruptive fever. See Scrub typhus, policy for, 342

Erythema multiforme, 247 Evacuation hospitals:

in malaria, 517 cases of cerebral malaria in, 485

Erythema nodosum, 438 Chinese patients treated in, 499, 500

Eschar: in chain of evacuation, 506-507

of cutaneous diphtheria, 284 malaria patients in, 506

of scrub typhus, 111, 113, 115, 117, 126 evacuation policies for, 507

Espiritu Santo, 62, 279, 280, 451 period of hospitalization for, 508-509

Essential Technical Medical Data reports, role of, in processing liberated prisoners,

51, 5WO 350-353

Etiological agent, of-- See also Hospitals, evacuation. dengue,i59 EVANS. E. C., 118

infections mononucleosis, 39 EVANS, K. L., 208

Japanese B encephalitis, 86 Examination(s), at induction:

Japranee B encphysical, 45, 331

malaria, 45roentgenographic, 2, 45, 331,334

Etiology: Exanthem:

of Fort Bragg fever, 443 of deng,

sandfly fever, 52-53 of epidemic typhus, 143

ETOUSA (European Theater of Operations, Exanthematous typhus. See Epidemic

U.S. Army). See European theater. typhus.

Europe, 84, 95, 450 Exercise tolerance tests, in scrub Lyphus, 123

European theater, 91, 99, 102, 410 Exertion, factor of, in asthma, 43

bacterial pneumonia in, 31 Exhaustion, factor of, in activating malaria,

chief consultant in medicine in, 293 480

diphtheria in, 275, 276 Extracutaneous diphtheria, 297-298

infectious mononucleosis in, 41 autoinfection of nasopharynx from skin,

influenza in, 14-15 298

malaria in, 453 incidence, 297-298

measles in, 35 Extrapulmonary tuberculosis, 367-370

meningitis in, 241 areas of involvement of, 367

plan for management of venereal diseases incidence of, 369

in, 425 Eye, diseases of, disability discharge due to,

primary atypical pneumonia in, 21-23 339

respiratory diseases in, 7, 15

rheumatic fever in, 229 Facial neuritis, in malaria, 485

senior consultant in infectious diseases in, Facilities:

14 diagnostic:

shortage of X-ray film in, 391 laboratory, 361, 506

syphilis in, 422-423, 425 X-ray, 361

tuberculosis in, 339-353 for reconditioning programs, 235

disposition of patients with, 341-342 for study of typhus fever, 145

hospital admissions, 340 Fainting, in falciparum malaria, 484

in Army Air Forces personnel, 343-344 FAIRLEY, Brigadier N. HAMILTON, 498

in concentration camps, 349-353 Falciparum infections, studies of chloroquine

in nurses, 342-343 diphosphate in, 571-572

in recovered prisoners of war, 344-349, Falciparum gametocytemia, resistant to

391,392 Atabrine and quinine, sulfadiazine in

incidence rates, 339-341 treatment of, 512
INDEX 617

Falciparunm malaria: Fever, in-Continued

acute attacks of, 534, 540 meningococcal infections, 253

quinine hydrochloride in, 542-545 poliomyelitis, 94

quinine in, 532 Q fever, 104

Sontochin in, 560 rheumatic fever, 231

Atabrine in, 496, 498, 542-545 scrub typhus, 111, 113, 127

cerebral symptoms in, 484 Feverishness, in sandfly fever, 56

chloroquine diphosphate in, 563, 571-574 Fever of undetermined origin, 49, 50, 60, 459

deaths due to, 461 incidei-:e of, 53-55, 503

effect of sulfonamides upon, 528-529 Fever therapy centers, general hospitals

factor of antimony compounds in precipi- designated as, 412

tating clinical attacks of, 528 Fibrosis, pulmonary, 47-48

headache in, 481 Field artillery. See Military units.

intravenous injection of quinacrine in, 544 Field hospitals, malaria patients in, period

oxychloroquine in, 577 of hospitalization for, 508-509

Plasmochin naphthoate in, 586 See also Hospitals, field.

quinine in, 532, 534 Field Medical Bulletin, 499

See also Malaria. Field's stain, in diagnosis of malaria, 509

Far East, 154, 525 Fi~vre boutonneuse, 109

tuberculosis in, 366-367 Fifth U.S. Army, 104, 354, 506, 507

Fatality. See Death(s). incidence of sandfly fever in, 51

Fatigability, in relapsing vi'ax malaria, 487 Fiji Islands, 63, 452, 497

Fatigue: FINLAND, M., 23

in activating malaria, 480 Finschhafen, 112, 122, 282, 309

in Q fever, 103 First Service Command, 396

Faucial diphtheria, 298 First U.S. Army, 353

Faucial pillars, swelling of, in nonstrepto- First World War. See World War I.

coccal exudative pharyngitis, 7 FISHBERG, M., 372

Febricula, 55 Fitzsimons General Hospital, 382-386

Feet, defects of, disability discharge due to, activity of339 during 1942, 382-383

FELIX, A., 179 during 1943, 383

FERRY, N. S., 265 during 1944, 383-384

Ferryville, 49, 453, 502 during 1945, 385

Fever(s): during war period, 385-386

blackwater, 470, 486, 496, 508, 517-518, census of tuberculous patients at, 385

532 designation of, as specialty center for

catarrhal, 9 tuberculosis, 381

control of, 533, 565-566 discharge from, 385

Fort Bragg, 437-448 morale at, 385

pappataci, 506 retirement from, 385

prolonged, of infectious mononucleosis, 39 Section for Research on Minimal TubercuQ, 103-109 losis of, 379-380, 384

rheumatic, 225-238 tuberculous captured prisoners of war

sandfly, 49-58 treated at, 394

scarlet, 1, 226, 228, 231 See also Hospitals, general.

Fever, in- Fleaborne murine typhus. See Murine

Brill's disease, 202 typhus.

common cold, 3, 4 Fleas, in transmission of murine typhus, 204

dengue, 72 FLECK, S., 278n, 316

epidemic typhus, 143 Fleckfieber (German). See Epidemic tyFort Bragg fever, 437 phus.

malaria, 481, 500, 519, 529, 533 FLETCHER, W., 133

639243'--63----43
618 INFECTIOUS DISEASES

FLEXNER, S., 239 Fuadin, 432

Flight ranges, of Aedes mosquitoes, 64 Fulminant meningococcal bacteremia, 249-

Floors: 256

oiling of, to reduce airborne infections, 6 case history, 253-254

sanding of, as preventive measure against clinical course, 253

scrub typhus, 122 Waterhouse-Friderichsen syndrome in,

Florence, 103, 104, 105, 502 249, 251, 252, 254-256, 260

Fluid balance: with adrenal hemorrhage, 252-253

in meningitis, 269 with peripheral circulatot. failure, treatin typhus fever, 192 ment of, 271-272

Focus: without adrenal hemorrhage, 249-252

of scrub typhus, 123, 126, 127 FULTON, F., 138

of typhus fever, 143, 204, 205 F.U.O. See Fever of undetermined origin.

Fontainebleau, 341 Fiirsorgestelle, 397

Foodborne streptococcal infection, 8 Furunculosis, in epidemic typhus, 147

FORBES, J. G., 312

Formosa, 81, 86, 111 GALL, E. A., 36n, 37

FORRESTER, J. S., 128 Gallipoli, 318

Fort Bragg fever, 437-448 Gametocytes:

case reports, 439-440 action of Atabrine upon, 476

differential diagnosis in, 441-442 carriers of, 476, 498

epidemiological aspects of, 442 GAMMON, Dr. GEORGE D., 283, 300

etiology of, 443 Gangrene, in epidemic typhus, 147, 155

experiments of, 445 Gargliano River, 502

incubation period in, 442, 444 "Garigha" sores. See Cutaneous diphtheria.

leukopunia in, 438 Gastric ulcer, disability discharge due to,

onset of, 437 339

rash in, 438 Gastrointestinal symptoms, in malaria, 520-

recognition of, as new disease, 437-440 521

special investigation of, 443-446 Gastrointestinal tract:

symptoms of, 437 effect of Atabrine on, 501, 556

Forts. See Military installations, effect of quinine on, 534

4-aminoquinoline compounds, 559-578 GAULD, Lt. Col. Ross L., 104, 210n

chloroquine diphosphate, 562-576 General hospitals:

oxychloroquine, 577-578 in chain of evacuation, 507-508

Sontochin, 559-562 in Zone of Interior:

Fourth Service Command Laboratory, 260 antimalarial drug studies in, 536

Fox, Brig. Gen. LEON A., 135 cutaneous diphtheria studies in, 282-

Fractions, of penicillin, 426 283

France, 102, 138, 302, 341. 346, 393, 502 malaria patients in, 485

FRANCtS, Dr. THOMAS, Jr., 12 period of hospitalization for, 508-509

investigator of epidemic influenza, 10 treatment of, 507-508

Frankfurt, 398 tubewrculous patients in, 381-388

FRANZ, K., 52 See also Hospitals, general.

Fraxine, 499 Geneva Convention, 395, 396

Frei test, in diagnosis of lymphogranuloma Genitourinary tract:

venereum, 431 diseases of, disability discharge dte to, 339

FRENCH, Lt. Col. ADAM J., 96 tuberculosis of, 358, 383

French Army, 330 GENTrZKOW, C. J., 582

French Morocco, 151, 354 Geographic distribution, of scrub typhus,

French North Africa, epidemic typhus in, 111, 112

145 Gerbilles, 136

French West Africa, 211-212 Gerbillus gerbillus, 135, 192

Friedldnder's bacillus, 27 Gerbillus pyraniddun, 135, 192
INDEX 619

GERHARD, 143 GRExFP, D., 194, 195, 196, 197

German Army: Grottaglie Air Base, 106

diphtheria in, 316 See also Army airfields.

sandfly fever in, 51 GRow, Col. JOHN B., 382

German measles. See Rubella. Guadalcanal, 359, 360, 451, 452, 468, 469,

German military units. See Enemy military 496, 497

units. Guadalcanal campaign, 280

German prisoners of war, 315 Guam, 86

See also Captured prisoners of war. Guatemala, 595

German Sanititsdienst, 396 GITILLAIN, G., 301

Germany, 102, 154, 155, 180, 278, 302, 433, Guinea pigs, in isolation of typhus fever

559, 579 organisms, 191-192

diphtheria in civilian populations in, 316 GUNTHER, C. E. M., 112, 113, 483

G.I. Bill of Rights, 390

Giddiness, residual of scrub typhus, 124 HAAGEN, E., 189, 190

Giemsa stain, in diagnosis of malaria, 509 Haffkine Institute, 135

GILDEMEISTER, E., 189, 190 Halifax, 240

GILLIAM, A. G., 193 HALL, M. W., 59

GILYARD, Maj. RICHARD T., 102 HALLMANN, 51

Gimbaru, 87 HAMILTON, H. L., 190, 195

Glands: Hamilton Field, 380

adrenal, 216 HAMMAN, L., 47

lymph, 39 Hammer Field, 233

parotid, 35 HAMMON, Dr. WILLIAM McD., 82, 87

Glucosulfone sodium, 382 Hankow, 70

Gluteal abscesses, 535 HARDGROVE, M., 587

Glycols, in air disinfection, 6 Harvard University, 39

Glycosuria, spontaneous, in meningococcal HASHIMOTO, HAKUJU, IlI

meningitis, 259 HASHINGER, E. H., 300

GOCHENOUR, W. S., Jr., 447 Hassin chifusu (Japanese). See Epidemic

GOLDBERG, B., 332 typhus.

GOLDBERGER, 201 HAVENS, 204

GOLZ, Lt. Col. HAROLD H., 502, 514, 521 Hawaii, 213, 364

Gonococcal infections, noneffectiveness due outbreak of dengue in, 63-65

to, 37 outbreaks of influenza in, 13

Gonorrhea, 410-418 Hawaiian Islands, 6.3-65, 363, 364

directives on, 413, 414 HAYMAKER, W., 90

fever therapy for, 412, 413 Headache, inmanagement of, 410, 411, 412 Brill's disease, 202

sulfonamide-resistant, 412, 413 dengue, 72, 76

test for cure of, 411 epidemic typhus, 143

treatment of: malaria, 481, 487

chemotherapy in, 411, 412 meningococcal bacteremia, 245, 253

on duty status, 413-414 murine typhus, 221, 222

penicillin in, 414-418 poliomyelitis, 97

Goodenough Island, 112, 120 Q fever, 106

GORDON, H. H., 481 sandfly fever, 56

GORDON, CoL JOHN E., 21, 102 scrub typhus, 111

Grifelfing, 302 Healing of diphtheritic lesions, 284

Granuloma inguinale, 432 Health Organization, League of Nations, 429

Great Britain, 102, 349 Heanza Shima, 86

Greece, 25, 103, 108, 180 Heart disease, valvular, chronic, complicaoutbreak of Q fever in, 105-106 tion of rheumatic fever, 234

Green Island, 451 Heatstroke, 252
620 INFECTIOUS DISEASES

Hemagglutination, cold, in atypical pneu- Hospital ships, for evacuation of tuberculous

monia, 19, 22, 23 patients, 357, 378

Hematuria, in meningococcemnia, 262, 263, Hospitalization:

269 period of, for--

Hemiplegia, residual of cerebral malaria, 485 dengue, 75

Hemolytic streptococcus, 4, 28, 32, 226 malaria, 504, 506-509

beta, 8, 13, 275 sandfily fever, 57

carrier rate, 33 for tuberculosis, 359

group A, 226, 259 in Zone of Interior, 378-390

in common respiratory infection, 2 Hospitals, evacuation:

Hemophilas ducreyi, 430 2d, 41

Heinophilus infuenzae, 3, 7, 27, 32 14th, 499

in common upper respiratory infection, 7 15th, 357

Hemorrhage, in adrenal glands, 270 30th, 120, 268

Hemorrhagic nephritis, complicating dengue, 48th, 365, 499, 500, 501

75 59th, 155, 165

HENDERSON, A. B., 586 73d, 499, 500, 501

Henley-on-Thames, 393 77th, 49

Hepatic dysfunction, in malaria, 491 92d, 122

Hepatitis, 7, 16 116th, 155

infectious, 57, 68, 103, 345, 491 127th, 350

epidemic of, 495 Hospitals, field:

factor of, in activating malaria, 480 15th, 103, 104

noneffectiveness due to, 37 26th, 458

Hepatomegaly, in malaria, 482-483, 519 77th, 345

Herpes labialis, in malaria, 484, 517 Hospitals, general:

Herpes simplex, in meningococcemia, 246 named:

Herpes zoster, in meningococcemia, 246, 258 Baxter, 282, 301

HzRRELL, W. E., 415 Birmingham, 229, 233, 236

HERRICK, W. W., 239, 244 Brooke, 97

HERTIG, Maj. MARSHALL, 53 Bruns, 380, 381, 384, 394

HILLMAN, Brig. Gen. CHARLES, 93, 95 Bushnell, 536

Hinton test, for malaria, 490 Fitzsimons, 45, 347, 380, 381

Historical note, on- Foster, 229, 233, 236

Brill's disease, 201-202 Glennan, 394, 395

malaria, 449-451 Harmon, 282, 293, 296, 304, 306, 309,

meningococcal infections, 239-240 479, 481, 488, 490, 553, 560, 563, 570,

HrrcHENs, A. P., 59 577

HODEs, H. L., 86 Kennedy, 536

HoDGEs, J. J., 266 Letterman, 48, 283, 309, 360, 391

Hodgkin's disease, 491 Moore, 282, 292, 296, 304, 553, 563, 570,

Hollandia, 66, 121, 282 573, 579, 582, 589

HOLMAN, D. V., 259 Percy Jones, 45

Honolulu, 63 Sternberg, 93

Hospital admissions, for- Torney, 229, 233, 237

malaria, 503 Walter Reed, 417, 446

meningococcal infections, 239, 241 numbered:

rheumatic fever, 227 6th, 151, 354, 355

scrub typhus, 116, 122, 128 7th, 23

spontaneous pneumothorax, 47, 373-374 9th, 282, 298

tuberculosis, 329, 334, 340, 354, 364, 367 12th, 507

typhus fever, 146 13th, 282, 309

Hospital Center, 814th, 138 17th, 354, 515, 516
INDEX 621

Hospitals, general-Continued Iceland, 341

numbered-Continued I. G. Farben Werke, 559

20th, 127, 128, 137, 281, 295, 299, 300, Immune military personnel, totaquine for

302, 309, 313, 452, 4.99, 501, 534, 544, treatment of malaria in, 536

549, 572 Immunity, to24th, 24, 354 influenza, 11, 13, 14

30th, 38 lobar pneumonia, 31

33d, 511 measles, 32

38th, 94 poliomyelitis, 93. 95

39th, 279, 280, 287, 307, 308 sandfly fever, 55-56

46th, 346, 349 scrub typhus, 138-139

54th, 282, 307 Immunization:

64th, 354 in diphtheria, 278-279

69th, 281, 297, 299, 313 in lobar pneumonia, 30

106th, 123, 282, 491 in measles, 34

118th, 490 in scrub typhus, 137-138

327th, 393 schedule of, in typhus fever, 156

8274th (Provisional), 393 Incidence, ofHospitals, station: allergic disorders, 9

7th, 513 arthropodborne virus encephalitides, 83

31st, 536 common respiratory infections, 6-9

90th, 124 fevers of undetermined origin, 53-55, 503

118th, 511 meningococcal infections, 241-244

122d, 280, 298 pneumonias, 20, 29, 31

159th, 499 pulmonary diseases, 2, 340, 341, 371

182d, 502, 512, 516 streptococcal infections, 7

225th, 502, 512 See also specific diagnoses.

233d, 123 Incubation period, of304th, 393 common cold, 3

334th, 393 diphtheritic neuritis, 301

362d, 118 Fort Bragg fever, 444

363d, 116, 120 murine t. phus, 221

365th, 341 primary atypical pneumonia, 24

7029th, 393 Q fever, 104-105

Host factors, in precipitation of malarial rabies, 101

paroxysm, 480 scrub typhus, 123

HowzLL, W. L., 123 India, 26, 70, :27, 135, 451, 453, 499, 549,

HoYNE, A. L., 265 560, 571, 574, 580, 582, 585

Human beings, as test subjects. See India-Burma theater, 284, 543

Volunteers. establishment of, 499

Human transmission experiments: malaria in, 498-502

in Fort Bragg fever, 445, 446 scrub typhus in, 127-132

of primary atypical pneumonia, 18, 19, 20 Indian Medical Service, 498

Hydration, in chronic malaria, 487 Indigestion, in relapsing ivax malaria, 487

Hygienic Institute, Dairen, Manchuria, 195 Indochina, 111

HYMAN, A. S.. 491 Indonesia, 493

Hyperhidrosis, in cutaneous diphtheria, 295 Inductees, meningococcal infections in, 241

Hyperthyroidism, 484 Induction stations, 331

Hypoesthesia, residual of scrub typhus, 124 tuberculosis discovered during examinaHypochloremia, associated with typhus tions at, 405

fever, 152 Infantry divisions, Atabrine suppressive

Hypoglycemia, 272 therapy for malaria in, 497

Hypopotassemia, 272 See also Military units.
622 INFECTIOUS DISEASES

Infantry regiments: Insoniia:

malaria in, 471, 496, 497 in dengue, 72, 76

Q fever in, 104 in relapsing vivax niala'c. 4187

scrub typhus in, 121 Institute for the Control ;a Syphilis, 433

See also Military units. Insulin, effect of, on suppressive action of

Infants, common cold in, 3 Atabrine, 470

Infection(s): Interpandemic influenza, 10, 11, 12, 14

airborne, methods for reduction of, 6 See also Influenza.

a 2-9 Invalidism, 32

common upper respiratory, chronic, in primary atypical pneumonia,

meniingoeoccal, 239-273 21

streptococcal, Vincent's, 7 I g 8, 9, 41 Investigationls: of pathology of epidemic typhus, 169-172

Infectious encephalitis: postwar, of antimalarial drugs, 594-598

admissions for, 84 Investigators in Malaria Chemotherapy,

deaths due to, 85 594, 595

See also Encephalitis. Iran, 366

Infectious hepatitis: epidemic typhus in, 145

deaths due to, 243 Iridocyclitis, in malaria, 486

epidemics of, 495 Iron, in treatment of malaria, 512

in recovered prisoners of war, 345 IRoNs, E. N., 119

See also Hepatitis. Isigny, 393

Infectious mononucleosis. See Mononucleo- Italian prisoners of war. See Captured

sis, infectious, prisoners of war.

Inflammation of joints, in meningococcal Italy, 8, 24, 25, 53, 103, 105, 106, 107, 108,

infections, 245, 259 194, 283, 354, 451, 459, 512, 514

sandfly fever during invasion of, 50 Influenza, 1, 9-16, 57 Iwo Jima, 363, 497

antibodies, 11, 13, 14

causative agents of, 10-11

cliica chraceritic of 12JACKSON, E. B., 138 clinical characteristics of, 12 Jail fever. See Epidemic typhus. clinical studies of, 12 Jamaica, 208

course of, 15 JAMES, C. S., 284

deaths due to, 10 JAMES, S. P., 592

diagnosis of, 16 Japan, 81, 87, 111, 128, 155, 447

differential diagnosis of, 76 tuberculosis in native population of, 366

epidemics of, 9-10, 11, 12, 14 Japanese Anti-Tuberculosis Association, 366

immunity to, 11, 13, 14 Japanese B encephalitis, 79, 81

in China-Burma-India theater, 16 antibodies, 87

in European theater, 14-15 anibodies 87

in Mediterranean theater, 15-16 clniales of, 88

in Pacific areas, 16 convalescence following, 89

in Zone of Interior, 12-13 differential diagnosis of, 89

incidence of, 7, 10, 12, 13, 15, 49 diretivesfoni86, 88

introduction, 9-12 laboratory findin 89awags, 

recognition of, 9 outbreak of, on Okinawa, 86-89

serological studies, 12 pathology of, 90

susceptibility to, 11, 13 signs of, 88 vaccination for, 13 supportive measures for, 90

virus of, 2 symptoms of, 88 therapeutic measures for, 90

INGRAHAM, Dr. HOLLIS S., 134n, 315 vaccine for, 90

Inland Sea, 81 Japanese prisoners of war. See Captured

Inner Reich, 166 prisoners of war.
INDEX 623

Japanese river fever. See Scrub typhus. Kuder Preference Record, 390

Japanese troops, scrub typhus in, 128 Kunai grass, 120, 121

JARVIS, 0. D., 581

Jaundice, associated with malaria, 519 Laboratory(ies). See Medical General LabJefferson Barracks, 20, 45, 101 oratory.

See also Military installations. Laboratory aids, in diagnosis ofJOBLING, J. W., 239 epidemic typhus:

JOHNSON, A. S., Jr., 124 complement fixation tests, 183-188

JOHNSON, J. W., Jr., 52 Weil-Felix test, 179-183

Joint fever. See Dengue. Japanese B encephalitis, 89

Joints: lymphocytic choriomeningitis, 100

inflammation of, in meningococcal infec- murine typhus, 213-215

tions, 245, 259 scrub typhus:

involvement of, in rheumatic fever, 230, complement fixation tests, 134-135

235 isolation of strains, 135--136

pain in, in meningococcal infections, 245, Weil-Felix reaction, 133-134

253 Laboratory facilities, fortuberculosis of, 358 detection of tubercle bacilli, 358

JORDAN, A. C., 261 diagnosis of Japanese B encephalitis, 90

Josiah Macy, Jr. Foundation, 237 diagnosis of tuberculosis, 361

Jungle rot. See Cutaneous diphtheria. Laboratory findings, inJungle warfare: Japanese B encephalitis, 89

malaria suppressive therapy, under condi- murine typhus, 208

tions simulating, 497 Q fever, 108

scrub typhus as medical problem of, 112 scrub typhus, 130

Laboratory procedures, in diagnosis of

Kahn test, 40, 490 malaria, 489-491, 509

Kala-azar, 528 blood studies, 489-490

KAPLAN, A., 76 complement fixation test, 490

Karachi, 453 parasite identification, 489

KARELITZ, S., 321n, 322 serological tests, 490-491

KASTLIN, Col. GEORGE J., 386 Lae, 120

Kedani fever. See Scrub typhus. Lancet, 22

KEEFER, C. S., 266 Laoag Army Air Base, 96

Keesler Field, 233 See also Army airfields.

KELLAM, J. W., 278n, 316 Laparotomy, in malaria, 520

KELLEHER, M. J. H.. 581, 587 LAPLACE, Col. Louis B., 394, 395

KELSER, Brig. Gen. RAYMOND A., 81 Laruma River, 126

KERN, R. A., 482, 483n Laryngitis, tuberculous, 383

Kidney: Larynx, tuberculosis of, 369

effect of Atabrine on, 550-551 Las Vegas Army Air Field, 233

tuberculosis, 359, 369 Latin America Area, tuberculosis in, 366

KING, Col. DONALD S., 355 LAUFER, M. W., 299n, 300

KINGSBURY, Maj. LAWRENCE H., 386 LAWRENCE. Maj. EDGAR A., 501

KINSMAN, Lt. Col. J. MURRAY, 250n, 387 LAWSON, Col. HERMAN A., 500

Kline test, 490 League of Nations, Health Organization of,

KLIPPEN, A. J., 278n, 316 429

KNEELAND, Col. YALE, Jr., 21 Ledo, 127, 281, 452

KOCHER, R. A., 324 Ledo Road, 128

Koh's block test, 557 Leghorn, 354

KOLMER, J. A., 266 Le Havre, 345

Kolmer test, 490 LEIFER, W., 419, 420

Korea, 86, 88, 155, 597 Leishmania, 280
624 INFECTIOUS DISEASES

Leishmaniasis, 491 Loflete' fedium, 275, 294

LENNxTTE, E. H., 105 LONG, Col ESMOND R., 331, 349, 384

LzPPER, M. H., 263 Longview State Hospital, 446

Ls.pfoepira, 447, 448 LORANGER, G. L., 209

Leploapira aulumnalis, 447, 448 Louse control, in prevention of epidemic

Leptospiral meningitis, 76 typhus, 201

Lesions, harboring Corynebacterium diph- Louseborne infection. See Epidemic tytheriae, characteristics of, 284-288 phus.

LESSLAR, J. E., 133 Louseborne relapsing fever, confusion of,

Lethargy, in Japanese B encephalitis, 88 with typhus, 217

Letterman General Hospital, 391 Lucky Strike Camp, for recovered prisoners

See also Hospitals, general. of war, 345

Leukemia, acute, 252 See also Military installations.

Leukocytes, diplococci in, 260, 261 Lumbar puncture, as adjuvant therapy, in

Leukocytosis, 17 meningitis, 270

in Fort Bragg fever, 438 Lung abscess, 45-46

in malaria, 489 Lungs:

in meningococcemia, 246 involvement of, in epidemic typhus, 216

in respiratory infections, 9, 13 malignant diseases of, 48

Leukopenia, 200 Luzon, 67, 112, 125, 126

in dengue, 74 Lymph glands, enlargement of, in infectious

in Fort Bragg fever, 438 mononucleosis, 39

in malaria, 489 Lymph nodes:

in sandfly fever, 57 generalized enlargement of, in scrub

Levin tube, 269 typhus, 113, 115, 126, 130

LEVINE, H. D., 123 local swelling of, in cutaneous diphLEwIs, L., 88 theria, 295

LEWTHWAITE, R., 133 tuberculosis of, 358, 367

Leyte, 96 Lymphadenitis, cervical, 6

Leyte campaign, 125 Lymphadenopathy, 76, 483

Liberia, 455 in scrub typhus, 111, 127

Lichen planus, atypical, associated with Lymphangitis, in cutaneous diphtheria, 295

Atabrine suppressive therapy, 477, 501 Lymphatic tissue, inflammation of, 4

Life cycle, of Phlebotomus papatasii, 55 Lymphocytic choriomeningitis, 79, 99-101

LINDGREN, A. J., 76 differential diagnosis of, 100

Lipiodol, 363 directives on, 100, 101

LIPMAN, B. L., 118 incidence of, 100

Liquor arsenicalis, 500 Lymphocytosis, inLiver, 519 dengue, 74

effect of Atabrine on, 550-551 epidemic typhus, 217

involvement of, in malaria, 483 malaria, 489

LIVINGOOD, Maj. CLARENCE S., 281n, 305 Lymphogranuloma venereum, 431-432

LIvscaITZ, J. M., 56 LYON, Dr. JOHN M., 385

Lobar pneumonia, 1, 16, 17, 28 Lysis, in murine typhus, 208, 221

deaths due to, 243

immunity to, 31 M. & B. 693. See Sulfapyridine.

incidence of, 21 MACARTHUR, Gen. DOUGLAS, 466

prevalence of, 29 Macedonia, 449

treatment of, 30, 32 Machine Records Unit, Allied Force HeadSee also Bacterial pneumonia; Pneumonia. quarters, 508

Lobectomy, 45 MAHON, Col. HUGH W., 385

in tuberculosis, 384, 385 MAHONEY, J. F., 414, 423

L6FFLER, FRIEDERICH, 318 MAIER, Dr. J., 136, 195
INDEX 625

Malaise, in- Malaria--Coutinued

Brill's disease, 202 in the Pacific, 495-498

epidemic typhus, 143 in South Pacific Area, 495-498

meningococcal bacteremia, 245 incidence of, 453, 503-506

poliomyelitis, 94 during Spanish-American War, 450

Q fever, 106 during U.S. Civil War, 450

rheumatic fever, 231 during World War I, 450

sandfly fever, 56 involvement of nervous system in, 485-486

scrub typhus, 111 lack of knowledge of, 493

Malaria, 7, 16, 57, 66, 68, 82, 257, 449-463, morbidity, 514

465-477, 479-492, 493-524 mortality, 514

admissions for, 450, 460 noneffectiveness due to, 37, 451, 495, 504

anemia in, 487, 490, 501, 508 onset of, 481

attack rates for, 454, 455, 456, 457, 458 quinine-Atabrine-Plasmochin treatment

blood picture in, 489-490 recommended for, 510

breakthrough of, during suppressive treat- readmissions for, 460

ment, 469, 475, 535, 536 reclassification of patients with, 508

case histories, 517-523 relapses in, 455-459, 488-489

cerebral, 130, 484-485 combined quinine-Plasmochin treat ment

chronic, 487-488, 496 on rate of, 579-592

classification of patients with, 508 statistics of, 449-463

clinical aspects of, 479-492 studies of liver function in, 490-491

clinical attacks of, 468, 471, 480, 498 summary, 492

clinical types of, 504 suppression of, 465-477

complications of, 484-487 action of sulfamerazine in, 470, 529 compicaion of,484487by Atabrine therapy, 466-468

deaths due to, 243, 450, 460-462, 514 fe experine in, 471 -46

diagnosis of: field experience in, 471,546

aids in, 482 suppressive treatment of:

blood studies in, 489-490 effect of Atabrine withdrawal in, 468-

laboratory evidence in, 489-491 469

laboratory procedures in, 509 factors in early failures of, 466-468 in Southwest Pacific Area, 498

parasite identification in, 489 Sym tom of, s 479, 566

serological tests in, 490-491 symptoms of, 479, 566

differential diagnosis in, 76, 491-492 prodromal, 481

directives on, 465, 499, 500, 508, 510, 511, transfer diagnosis of, 507

540, 546 treatment of, 452, 493-524

drugs used in, toxic reactions of, 501, 536, antimony compounds in, 528

550-558, 561, 574-576, 585-588 arsenicals in, 526

etiological agents of, 455 Atabrine in, 465, 466-477, 510-511

factor of, in activating tuberculosis, 360 bismuth compounds in, 528

factors predisposing to, 480 chloroquine diphosphate in, 566

historical note, 449-451 cinchona alkaloids in, 531-538

hospitalization for, 506-509 directives on, 499, 500, 509-510, 511

duration of, 459, 460, 508-509 drug of choice in, 531

in evacuation hospitals, 506-507, 509 effectiveness of drugs used in, 500-502,

in general hospitals, 507-508, 509 532, 536, 541, 542, 543, 548, 560, 563,

in medical battalions, 506 573, 574

in station hospitals, 508, 509 in South Pacific Area, 495-498

immunity to, 489 introduction, 493-495

in civilian populations, 502 iron, 512

in India-Burma theater, 498-502 oxophenarsine hydrochloride in, 526

in infantry divisions, 451-452, 458 penicillin in, 525-526

in Mediterranean theater, 502-524 plan of, 500
626 INFECTIOUS DISEASES

Malaria-Continued Measles-Continued

treatment of-Continued introduction, 32-34

Plasmochin in, 501, 511, 579-592 susceptibility to, 32, 34

quinine in, 510, 531-535 "Medical and Surgical History of the War

results of, 514-517 of the Rebellion," 329

Sontochin, 559-562 Medical battalions:

Sontoquine in, 512 in chain of evacuation, 506

sulfonamides in, 512, 528-529 management of malaria in, 506

to reduce relapse rate, 513-514 Medical causes, for evacuation:

types of, 454-455 asthma, 44

Malaria Committee, Allied Force Headquar- malaria, 517

ters, 494 Medical circular letters, pertaining to diphMalaria transmission, areas of, 471 theria, 279

Malaya, 111, 493 See also Directives, pertaining to diphMALLORY, Lt. Col. TRAcv B., 25 theria.

Malnutrition: Medical Consultants Division, Office of the

factor of, in tuberculosis, 345, 392 Surgeon General, 553

in recovered prisoners of war, 345 Tropical Disease Treatment Branch of,

Management, of- 283

asthma, 43 Medical Department Professional Service

chronic bronchitis, 42-43 Schools, 138, 437, 444

primary atypical pneumonia, 21 Division of Virus and Rickettsial Diseases

spontaneous pneumothorax, 47 of, 179, 180

venereal diseases, 425 Medical General Laboratory:

Manchuria, 81, 86, 195 1st, 138

MANIFOLD, J. A., 581, 585 15th, 8, 25, 104, 105

Manila, 93, 125, 210 19th, 96

Manitoba, 82, 85 Medical Laboratory:

Mapharsen, 419, 421, 426 2d, 104

in malaria, 526 3d, 119

MARANGONI, B. A., 255 4th, 302

Marches, effect of, on suppressive action of 6th, 359

Atabrine, 470 7th, 302

Marianas Islands, 68, 284 Medical Research and Development Board,

Markham Valley, 112, 120 U.S. Army, 380, 384

Mateur, 49 Medical shock, complicating malaria, 486

MATSON, R. C., 331 Medical Statistics Division, Office of the

MATTHEWS, Lt. Col. EDWARD DES., 15, 24, 25 Surgeon General, 2, 395

MAXCY, K. F., 204 Mediterranean Sea, 52, 53

Mazzine test, 490 Mediterranean theater, 9, 99, 125, 279,

McDANIELS, H. E., 306, 321 453, 455, 458, 459, 479

MCDONALD, W., 59 bacterial pneumonia in, 32

McGAVACK, T. H., 255 consultant in medicine in, 8

McGuiNNEsS, A. C., 36n, 37 common respiratory infections in, 7

McLESTER, Col. JAMES B., 480, 515 diphtheria in, 276

MEADE, Lt. Col. RICHARD H., 382 evacuation policy in, 507

Measles, 1, 32-35, 217 fever of undetermined origin in, 53-55

complications of, 32, 34 influenza in, 15-16

epidemiology, 33-34 malaria in, 453, 502-524

immunity to, 32 Atabrine for suppression of, 494-495

in continental United States, 34-35 evacuation for, 516

in oversea theaters, 35 hospitalization for, 506-509

incidence of, 33 incidence of, 503-506
INDEX 627

Mediterranean theater-Continued M Lningococcal antitoxin, in treatment of

malaria in-Continued mr'eningitis, 265-266

treatment of, 502, 509-512 Meningococcal bacteremia, 244-249

measles in, 35 cutaneous n anifestations of, 245

mumps in, 38 onset, 245

primary atypical pneumonia in, 23-25 rash in, 245-246

Q fever in, 103 symptoms of, 244-245

rheumatic fever in, 229 transition from, to meningitis, 248-249

sandfly fever in, 49, 51, 53-55 variations in, 246-248

streptococcal infections in, 7 See also Fulminant meningococcal bactuberculosis in, 353-357 teremia.

admission rates for, 353-354 Meningococcal infections, 239-273

care of patients with, 359 carriers of, 244

disposition of patients with, 355-356 case history, 256

epidemiology of, 356-357 complications of, 258-259

evacuation of patients with, 357 conjunctivitis in, 260

hospitalization for, 354-355, 359 death due to, 242, 243, 252

special problems related to, 359-360 cause of, 252

therapy, 355-356 diagnosis of:

Melbourne, 360 clinical, 261

MELENEY, Dr. HENRY E., 493 laboratory, 260-261

MELNICK, J. L., 447 directives on, 242, 261, 266, 269

Membranes, serous, tuberculosis of, 367 discussion of, 273

Meninges: epidemic of, 241

reactions in, in epidemic and scrub typbus, historical note, 239-240

170 incidence of, 241-244

tuberculosis of, 358 mortality for, 243

Meningismus: pathogenesis, 244

in cerebral malaria, 485 pneumonia in, 259

in falciparum malaria, 481, 484 treatment of, 26i-270. 271-272

Meningitis, 491 antibiotics in, 266-269

case histories, 247, 248 sulfonamides in, 239, 240, 242, 271, 272

cerebrospinal fluid in, 266 Waterhouse-Friderichsen syndrome in,

complications of, 258-259 249, 251, 252, 253n

deaths due to, 7 Meningococcal meningitib. See Meningitis.

differential diagnosis of, 76 Meningococcemia, 217, 244-249

duration of life with, 257, 258Meigccma,272429 ease histories, 246, 247, 249, 250, 251

epidemics of, 239 forms of, 246-247

in European theater, 241 rash in, 245-246

meningococcal, 239, 256-258 symptoms of, 244-245

antiscrum in, 239 temperature in, 246

complications of, 258-259 treatment of, 262

confused with typhus, 217 variations in, 246-247

mortality in, 262 Meningococci, types of, 260, 261

myocarditis in, 258 Mnnooctpso,20 6

pathological 

pholgca fings in, 257 Mental confusion, in Japanese B encepha- findings in, 270-271lis,8

resemblance of cerebral malaria to, 485 litis, 88

sequelae of, 258 Merano, 283, 315

treatment of, 272-273 Meta-aminobenzoic acid, 196

adjuvant therapy in, 269-270 Metabolic studies, in epidemic typhus, 152-153

antitoxin, 265-266 Methods, for reduction of airborne infecserum in, 265 tion, 6

sulfonamides in, 262, 273 Mexico, 143

tuberculous, 100, 367 MEYER, Dr. KARL F., 80
628 INFE'TiOUS DIISEASES

Micro-organisms, of common upper respi- Military units:

ratory infection, 2, 4, 7, 17, 26, 33 Airborne Infantry, xMth, 443

Microhus monlebelli, 111 Field Artillery, 77th, 165

Middle East, 94, 99, 297, 454, 460, 488 Infantry Division:

sandfly fever in, 56 25th, 279, 307, 313, 317, 452, 458, 497

Middle East theater, 102 27th, 279, 280, 297, 304, 313

rheumatic fever in, 229 32d, 121,452

tuberculosis in, 366 36th, 50

Middle Pacific Area, tuberculosis in, 364 37th, 458

diagnosis of, 364 41st, 122

evacuation for, 364 43d, 279, 313, 317, 452, 458

incidence of, 364 Infantry Regiment:

MIDDLETON, Col. WILLIAM S., 293, 321 35th (25th Division), 307

Miliary tuberculosis, 358, 367 147th, 496, 497

Military campaigns, effect of malaria in, 449- 164th (Americal Division), 280

450 186th, 122

Military discharges. See Disability separa- 339th, 104

tions. 362d, 104

Military government, in Germany: Parachute Infantry Regiment, 503d, 120

Public Health Branch of, 398 Milk:

tuberculosis control program of, 397-399 directives on purchase of, 368

Military Government Research Center, 87 unpasteurized, factor of, in nonpulmonary

Military importance, of- tuberculosis, 367, 368

dengue, 59, 70, 76 Milkborne streptococcal infection, 8, 17, 28

lymphocytic choriomeningitis, 101 MILLER, Lt. L. M., 86

sandfly fever, 49 Milne Bay, 112

seasoning of troops, 5, 7, 23 Mindanao, 210

Military installations: Mindoro, 112, 125, 126

Camp Adair, 36 Ministry of Health, England, 15

Camp Bullis, 441 Ministry of Public Health, Egyptian GovernCamp Claiborne, 19 ment, 145-146, 157

Camp Dix, 33 Mite ulcer, of scrub typhus, 130

Camp Forrest, 394 Mobile X-ray Team No. 3, 341

Camp Lee, 28 Mobilization Regulations No. 1-9, 238, 340

Camp Lucky Strike, 345 Mode of transmission, ofCamp McCoy, 37 acute respiratory diseases, 1

Camp Patrick Henry, 106, 107 dengue, 59

Camp Pike, 33 epidemic typhus, 143

Fort Belvoir, 44 murine typhus, 204

Fort Benning, 597 Q fever, 108-109

Fort Bragg, 6, 12, 19, 105, 108, 267, 384, Moist heat, in treatment of poliomyelitis, 98

417, 421, 437 Monilia. 280

Fort Eustis, 44 Mononucleosis, infectious, 38-41, 100, 489

Fort Knox, 226, 545, 597

Fort McClellan, 97 antibodies in, 40

Fort Sam Houston, 96, 97 cephalin flocculation reaction in, 39

Fort Sill, 34 classical form, 39

Fort Francis E. Warren, 226 communicability of, 39

Military Mission of U.S.S.R., in Great differential diagnosis of, 76

Britain, 349 epidemics of, 40

Military service, tuberculosis detected before in continental United States, 40-41

induction into, 331-333 in oversea theaters, 41

Military significance, of Q fever, 109 introduction, 38-40
INDEX 629

Mononucleosis, infect ious-Conti nued Murine typhus-Continued

serological reactions in, 40 foci of, 205

sex in, 38 incidence of, 205, 207, 208

MOORE, Dr. JosEPH E., 416, 424, 426 incubation period of, 221

Moore General Hospital, 387-388 laboratory findings in, 208

census of tuberculous patients in, 387 mode of transmission of, 204

designation of, as specialty center for serological findings in, 211, 213, 214

tuberculosis, 382, 387 summary, 221-223

transfer of, to Veterans' Administration, clinical picture, 221-222

388 diagnosis, 222

See also Hospitals, general. immunity, 222

MoosER, H., 204 natural course, 222

MORAGUES. V., 195 prophylaxis, 223

Morale, 390 therapy, 223

factor of, in scrub typhus, 137 vector of, 205

Morocco, 210, 453, 502 MURRAY, E. S., 136, 197

Morphine, 76 MURRAY, R., 280

use of, in meningitis, 270 Muscle pain, in relapsing vivax malaria, 487

Morphology, of diphtheritic lesions. 284-288 Musclest, aching of, in meningococcal bacMortality. See Death(s). teremia, 245

MOSHER, W. E., Jr., 87 Muscular aches, in Q fever, 106

Mosquito control, for prevention of dengue, Muscular weakness, in murine typhus, 221

60. 61, 63, 64. 66, 67, 69. 71 Musculoskeletal system:

Mouse-brain formalin (inactivated) vaccine, defects of, disability discharge for, 339

in Japanese B encephalitis, 90 symptoms referable to, complicating maMouse neutralization test, in typhus fever, laria, 487

190 Mustard gas, as cause of chronic bronchitis,

MTOUSA (Mediterranean Theater of Opera- 43

tions, U.S. Army). See Mediterranean Mycobacterium tuberculosis, 32

theater. MYERS, Lt. Col. DANIEL W., 15, 24, 25

MUCKENFUSS, Col. RALPH S., 21, 81 Myitkyina, 128, 136, 281

Mucous membranes, effect of Atabrine on, Myocardial damage, associated with scrub

552-553 typhus, 124

MuiR, E. G., 297, 312 Myocarditis, 259

Mumps, 35-38

complications of, 35-37 complicating cutaneous diphtheria, 295

epidemics of, 37 following scrub typhus, 125

in continental United States, 37-38 in diphtheria, 321

in oversea theaters, 38 death due to, 302

introduction, 35 in meningitis, 258

meningoencephalitis, 100 Myocardium, involvement of, in epidemic

noneffectiveness due to, 36 typhus, 216

occurrence of, 37

quarantine for, 38 Nadzab, 120, 122, 123

Munda, 451 Naples, 8, 103, 104, 107, 220, 354, 502, 506

Murine typhus, 204-215, 252, 257 epidemic typhus in, 154

case histories, 212

causative agent of, 204, 205 Nasopharyngeal diphtheria. See Diphtheria.

clinical description of, 204 Nasopharyngitis, 2

clinical experience with, 205-213 Nasopharynx, autoinfection of, from skin,

clinical findings in, 208 298

diagnosis of, laboratory aids in, 213-215 National Guard, federalization of, 241, 330

epidemiology of, 204-205 National Institute for Medical Research, 138
630 INFECTIOUS DISEASES

National Institute(s) of Health, U.S. Public Neurocirculatory asthenia, 125

Health Service, 108, 135, 179, 190, 444, complicating malaria, 487

594 following rheumatic fever, 234

National Research Council, 30, 47, 228, 409, Neurological disease, disability discharge

412, 538 due to, 339

Committee on Medical Research of, 525 Neurological involvement, degree of, in

Committee on Medicine of, 420 epidemic typhus, 146

D)ivision of Medical Sciences of, 94, 136, Neurosyphilis, 427-428

171, 493 treatment of, 428

Subcommittee on Tropical Diseases of, 493 Neurotropic virus, diseases due to, 79-102

Subcommittee on Tuberculosis of, 374, 384 Neutralization test. See Test(s).

Subcommittee on Venereal D)iseases of, Neutropenia, in epidemic typhus. 217

409, 419, 420, 423, 424, 425, 426 "New and Nonofficial Remedies," 266

National Tuberculosis Association, 389, 406 New Britain, 112. 120

Nausea, in- New Caledonia. 359. 360, 451-452

cutaneous diphtheria, 303 outbreak 63

dengue, 72 New Geoi

malaria, 483 New Guieiw,, i i•1, 112, 120, 122, 123,

meningococcal infections, 245, 253 282, 451, 452, 469-470, 498

pancreatitis, 36 outbreak of dengue in, 65-68

sandfly fever, 56 New Hebrides, 279, 284, 298, 304

suppressive malaria therapy, 466, 495, 536, outbreak of dengue in. 62-63

556 New World, 143

Naval Medical Research Unit No. 2, 86, 90 New York Port of Embarkation, 378

Nazi Party, 349 New York State Department of Health, 315

Negro troops: New Zealand, 95. 279, 317, 318, 359. 452, 497

blackwater fever in, 486 NICOLLE. 143

mumps in, 38 Nitrogen balance, in typhus fever, 153

toxic reactions to Plasmochin, 501 Nitrogen retention, in epidemic typhus, 146

Negros, 126 Noneffectiveness, due toNEILL, 204 common upper respiratory infections, 5-6

Neisseria intracellularis, 258, 259 cutaneous diphtheria, 307-30S

Neoarsphenamine, 500 dengue. 65

in malaria, 526 dermatophytosis, 37

in syphilis, 418 malaria. 451

Nephritis, 1 measles, 34

hemorrhagic, 75 mumps, 36-37

Nervous system, involvement of, in malaria, rubella, 42

485-486 sandfly fever, 49

Nervousness, in relapsing t'irax malaria, 487 spontaneous pneumothorax, 47

Net herlands, diphtheria in civilian popuila- Nonhemolytic streptococcus, 19

tions in, 316 Nonimmune military personnel, 67

Netherlands East Indies, 282 factor of, in dengue epidemics, 59

Netherlands New Guinea, 112, 121, 125 suppression of malaria in, 535

Neurasthenia, during convalescence from Nonparalytic poliomyelitis, 93. 96. 97. 100

dengue, 75 See also Poliomyelitis.

Neuritides, associated with malaria, 486 Nonpulmonary tuberculosis, incidence of,

Neuritis: 369

complicating cutaneous diphtheria, 288, Nonspecific urethritis. 418

295 Nordhausen concentration camp. 349

diphtheritic, 299-302 Normandy, 393

incubation period of, 301 NORRus, R. F., 280, 482, 483n
INDEX 631

North Africa, 49, 53, 94, 97, 102, 104, 143, Optic nerve:

284, 451, 559 atrophy of, in meningitis, 259

North African campaign, 275 blanching of, in malaria, 485

North African Theater of Operations, U.S. Oran, 50

Army. See Mediterranean theater. Orchidotomy, 37

Northern Hemisphere, 10 Orchitis, 37, 38, 76

Norway, diphtheria in civilian populations surgical decompression for, 36

in, 316 Organisms, of common upper respiratory

Nottinghamshire, 38 infections, 3, 4, 7, 39

Nova Scotia, 240 Orient, 343

Nurses, tuberculosis in, 342-343 Orientation, of tuberculous patients, 388-390

Nursing care, in epidemic typhus, 192 Orlando Army Air Base, 233

Nutrition, factor of, in tuberculosis, 359-360 Oro Bay, 116, 124

NUTTALL, G. H. R., 318 Ortho-aminobenzoic acid, 196

Osipov, Col. B. A., 349

Occupational therapy, in care of tuberculous Osteoperiostitis, in meningitis, 259

patients, 390 Otitis, 15

Occurrence. of- Otitis media:

mumps, 37 complicating measles, 32, 34

primary atypical pneumonia, 19 complicating typhus, 147, 222

Q fever, 103-106 in respiratory infections, 9

OCHS, L., .Jr., 262, 263, 269 OTTO I, 449

Ocular conditions, complicating malaria, 486 Outbreaks. See Epidemic(s).

Office of Scientific Research and Develop- OWEN, Lt. Col. GEORGE C., 386

ment, 494, 525, 594 Owen Stanley Range, 113

Office of the Air Surgeon, 227, 379 Owi, 125

Office of the Chief Surgeon, European outbreak of scrub typhus on, 121-123

theater, 422, 425 Oxford University, 550

Preventive Medicine Division of, 410 Oxophenarsine hydrochloride, 419

Office of the Provost Marshal General. 394 in treatment of malaria, 526

Office of the Surgeon, South Pacific Area, 496 Oxychloroquine, 577-578

Office of the Surgeon General, 93. 346, 349, absorption, 577

350, 357, 365, 378, 379, 380, 387, 389, antimalarial activity of, 577

391, 414, 419, 583 clinical testing of, 577-578

Consultant in Tuberculosis in, 398, 406 dosage of, 577

subordinate elements of: general properties of, 577

Medical Consultants Division, 283, 553 in falciparum malaria, 577

Medical Statistics Division, 2. 395 in vivax malaria, 577

Preventive Medicine Service, 80, 410, plasma levels of, 577

424 toxicity of, 577

Professional Service Division, 2, 9. 12, Oxytetracycline, effectiveness of, in30; 410 bacteremia, 269

Officers' Training Center, Army Ground meningitis, 269, 273

Forces, 341 Q fever, 109

Okinawa, 76 scrub ývphus, 139

outbreak of Japanese B encephalitis on,

86-89 PABA. See Para-aminobenzoic acid.

Old World typhus. See Epidemic typhus. Pachymeningitis, 252, 257

Oliguria: Pacific, 275

in epidemic typhus, 146 Pacific areas, 8

in meningococcemia, 263, 269 influenza in, 16

OPIE, Maj. EUGENE L., 368 See also South Pacific Area; Southwest

OPPEL, T. W., 282n, 298, 304 Pacific Area.
632 INFECTIOUS DISEASES

Pacific Ocean Area: Paraldehyde, 102, 192

dengue in, 69 in meningitis, 270

tuberculosis in, 358 Paralytic poliomyelitis, 93, 97

in recovered prisoners of war, 391 See also Poliomivelitis.

PADDOCK, Maj. FRANKLIN K., 511 Parasite factor, in precipitation of malarial

Paestum, 453, 502 paroxysin, 480

Pagliana, 24 Parasite identification, in malaria, 4,9, 509

Pain, 76 Parasite species, of malaria, effect of supin back: pressive therapy on, 469-470

in nmalaria, 481 Parasitemnia, 529

in mnurine typhus, 221 control of:

in poliomnyelitis, 94, 97 with chloroquine diphosphate, 565

in chest, in Q fever, 107 with quinine, 510, 532-533

in joints, in ineningococcal infections, 245, effect of penicillin on, 526

253 effect of sulfonamides on, 529

in shoulder, in rabies, 101 of falciparutm malaria, 529

retro-orbital, 56 of vivax malaria, 529

Palate, discoloration of, factor of Atabrine action of arsenicals upon, 526

in, 553 Parasitological studies, of diphtheria. 280

Palermo, 165 Paresis, residual, of cerebral malaria, 485

Palestine, 275, 284, 318 Paris, 138, 302

Palpitation, in relapsing vivax malaria, 4.S7 Parotid glands, 35

Pamaquine naphthoate, 498 Parotitis, complicating typhus, 147, 220, 222

clinical experience with, 585-588 Paroxysm, malarial, 490, 491

historical review, 579-582 action of arsenicals upon, 526

studies of: action of bismuth compounds upon, 528

at a specialty center, 582-585 factors in precipitation of, 480

materials for, 583 Pasadena College, 97

methods of, 583 PASRICHA, C. L., 292

)rewar, 580-581 Pasteur Institute, 105, 210

results, 583-585 Pathogenesis, of meningococcal infections,

summary, 582, 592 244

wartime, 581-582 Pathogenicity, of Corynebacteriunm heinolytitherapeutic use of, 588-589 cure, 320

toxicity of, 585-589 Pathological findings, of meningitis, 270-271

See also Plasmochin naphthoate. Pathology:

Panama, 42, 76, 101, 103, 106, 108, 451, 491, of epidemic typhus, 169-172

535, 582, 587 of scrub typhus, 132-133

Pancreatitis, complicating mumps, 36 Patients:

Pandemic influenza, 10, 11, 16, 17 disposition of, 123-125, 233, 236-237, 341-

See also Influenza. 342. 355-356

PANJA, GA., 292 duration of hospitalization for, 459, 509

Pappataci fever, 506 early ambulation of, 233

See also Sandfly fever, evacuation of, to Zone of Interior, 98,

Papua, 112, 116, 120, 122, 125 132, 360, 361, 262, 363, 364, 378-381

Para-aminobenzoic acid, 136 orientation of, 388-390

in murine typhus, 223 quarantine of, for mumps, 38

regimen of treatment of, 199 reclassification of, 508

study of, on growth of typhus rickettsiae, reconditioning of, 235

195-200 rehabilitation of, 388-390

use of, in epidemic typhus, 155 Patrol activity, factor of, in diphtheritic

Parachute infantry regiment, scrub typhus lesions, 286

in, 120 PAUL, Dr. JOHN It., .52. 56, 57, 443, 447

See also Military units. PAULLIN, 204
INDEX 633

PECK, J. L., 86 Photophobia, 76

Pedicidus humanus var. corporis, 143 in sandfly fever, 56

PELOUZE, Dr. P. S., 412 Physical activity, effect of, on suppressive

Penicillin, 30, 32, 414-418 action of Atabrine, 470

fractions of, 426 Physical examination, for military service:

m common upper respiratory infections, 9 at induction, 45

in cutaneous diphtheria, 299, 305-306 detection of tuberculosis by, 331

in diphtheria, 321-325 Physical findings, in Q fever, 107

in epidemic typhus, 194, 195 Physical signs, of dengue, 74-75

in malaria, 525-526 PIATr, A. D., 350

in meningococcal infections, 266-269 PINCOFFS, Col. MAURICE C., 469, 498

in scrub typhus, 136 PINKERTON, 1I., 125, 194, 195

in syphilis, 423-427 Pisa, 393

Penicillium chrysogenum Q-176, 426 Plasma:

Penicillium notalurn, 426 concentrations of Atabrine in, 510, 539,

Peninsular Base Section, 507 540

Pentaquine, 592, 594 concentrations of quinine in, 532

Pericarditis: infusions of, in treatment of malaria, 512

death due to, 225 Plasma levels, ofin meningitis, 259 chloroquine diphosphate, 563, 568, 573

Peripheral edema, 272 cinchonidine, 537

Peripheral neuritis: cinchonine, 537

complicating scrub typhL.., 119 oxchloroquine, 577

in malaria, 485

quinacrine hydrochloride, 539, 540, 541, Peripheral vascular failure, in typhus fever, 542, 543, 544, 545, 549, 557

220

Peritonsillar cellulitis, 4, 7 quinine, 532, 537

PERKINS, R. F., 299n, 300 Sontochin, 559, 561

Perspiration, profuse, in malaria, 48259 Plasmochin naphthoate, 498, 511, 559, 579-

Peru, 571, 572, 574 592

Pescadores Islands, 111 combined with quinaerine hydrochloride,

PESQUERA, Lt. Col. GILBERTO S., 398 582

PETERS, M., 262n, 263 combined with quinine, 580, 581, 582, 383,

Pfeiffer's bacillus, 10 585 clinical use of, 590

Pharyngeal diphtheria, 275, 297, 299 discuss of, 595

Pharyngitis, 8 discussion of, 589-591

exudative, 4 gametocytes of P. falciparum eradicated

nonstreptococcal exudative, 7 by, 579

Pharynx, 2 historical r-.view, 579-582

Phases, of Waterhouse-Fridtrichsep: syn- prewar studies on, 580-581

drome, 255 recommendations for therapeutic use, ,588

Phenobarbital, 76 summary, 592

PHILIP, Lt. Col. CORNELIUS B., 52, 56, 57, tovicity of, 501, 585-589

208n, 443 wartime studies on, 581-582

Philippine Islands, 93, 95, 96, 99, 101, 112, Plasmodium cynomolgi, 596

282, 391, 451,553, 574 Plasmodium falciparum, 454, 455,W460, 481,

chancroid in, 431 526, 529

dengue in, 65-68 effect of Atabrine c-i, 469, 470, 496

murine typhus in, 208 gametocytes of, 476

scrub typhus in, 125-126 in cerebral malaria, 499

Phlebotomrus, 53 Plasmodium malariae, 454, 455, 461, 526

Phlebotomus fever. See Sandfly fever. Plasmodiurm vivax, 454, 455, 460, 468, 470,

Phlebotomus papatasii, 49, 50, 52, 53 479, 482, 488, 526, 529

life cycle of, 55 effect of Atabrine on, 496
634 INFECTIOUS DISEASES

Plasm odium viv'x-Continued Pneumot horax:

gametocytes of, 476 in tuberculosis, 342, 355-356, 379

strains of: spontaneous, 46-47, 373

McCoy, 526 tension, 46, 47

New Guinea, 488 Poland, 143

relapsing tendency of, 470, 488 Policy, on problem of diphtheria, 283

Pleura, tuberculosis of, 369 Poliomyelitis, 79, 91-99

Pleural effusion: age, as factor in susceptibility to, 92

complicating scrub typhus, 119 deaths due to, 243

primary, 354, 356 diagnosis of, 94, 97-98

Pleurisy, tuberculous, 342, 356 epidemics of, 93, 96-97

Pleurisy with effusion, tuberculous, 370-372 epidemiology, 95

coding of, 370 immunity to, 93, 95

directive on, 370 in continental United States, 96-97

prognosis in, 371, 372 in oversea theaters, 94-96

symptoms of, 371 incidence of, 91, 96

PLOTZ, Col. HARRY, 138, 179n, 183, 184, morale problem of, 97

188, 190, 194, 195, 203, 208, 210, 214 onset of, 94

Pneumococci, 3, 8, 10, 13 symptons, 97

in common upper respiratory infection, 7 treatment, 98-99

typing of, 29, 31 Polyneuritis, in German prisoners of war, 283

Pneumonia, 1, 8 Polysaccharides, in immunization against

admissions for, 26, 27 lobar pneumonia, 30

antibiotics in treatment of, 27 POND, 11. S., 128

as differential diagnosis with malaria, 491 Pontine .Marshes, 453. 502

bacterial, 220, 222 Port Lyautey, 453, 502

classification of, 16 Port Moresby, 112, 116, 118, 119

clinical concept of, 17 PORTEOUS. W. M., 94

complicating measles, 32, 33 Postvaccinal encephalitis:

factor of, in activating malaria, 480 admissions for, 84

hemolytic streptococcal, 31 deaths due to, 85

influenzal, 13, 15, 17 See also Encephalitis.

mortality fox, 26 Postwar studies, on scrub typhus, 138-139

noneffectiveness due to, 37 See also Clinical research.

primary, 28, 29 President ROOSEVELT, 144

primary atypical, 16-19, 57, 259 Prevalence:

admissions for, 20-21, 23, 27 of nonpulmonary tuberculosis, 367

characteristics of, 17, 19 of poliomyelitis, 91-92

clinical recognition of, 20 Prevention, of malaria, penicillin ini, 526

incidence of, 20 Preventive measures:

incubation period of, 24 for sandfly fever, 57

mortality in, 26 for scrub typhus, 122

studies on etiology of, 18-19 Preventive Medicine Division, Office of the

reporting of, 28, 29 t i ;,.f Surgeon, European theater, 410

secondary, 28 -revenii 4 Medicine 1)ivision, Office of the

staphylococcal, 11 Surc..on General, 80

viral, 76 t: . e Medicine Service, Office of the

Pneumonitis, 108 Surgeon G.neral, 410, 424

in bronchiectasis, 45 Venereal D)isease Control Division of, 429

in infectious moxinucleosis, 40 PRIcE, A. H., 266

in influenza, 13 Primary atypical pneumonia, 16-26, 57, 103,

in scrub typhus, 130 259

Pneumoperitoneuni, in tuberculosis, 383, 385 admissions for, 20-21, 23, 27
INDEX 635

Primary atypical pneumonia-Continued Psittacosis, as type of virus pneulnonia, 17

age in, 17 Psittacosis virus, 22

agglutinins in. 19~, 22, 24, 25 Psychoneurosis, disability discharge due to.

British recogi ji of, 22 3:39

cold agglutinin wits for, 22, 24 Psychosis, 257

communicability of, 20, 24 Atabrine as factor in, 556-557

convalescence, 21 disability discharge due to, :339

course, 17, 19, 21 in suppressive malaria therapy, 477

deaths due to, 21, 243 residual of cerebral malaria, 485

differential diagnosis, 362 Public Health Branch, Military Government

etiology of, 18 for Germany (United States), Preventive

in continental United States, 19-21 M iedicine Branch of, 398

in ovcrsea theaters, 21-26 Public Law 16, 78th Cong., 390

incidence of, 20 Public Law 346, 78th Cong., 390

incubation period, 24 Puerto Rico, 366, 451

introduction, 16-19 Pulmonary edema, in bactereinia, 271, 272

management of, 21 Pulmonary emphysema, 48

occurrence of, 19 Pulmonary fibrosis, 47-48

onset, 17 Pulmonary infarction. complicating scrub

pleural effusions in, 21 typhus, 119

recognition of, 18, 22 Pulnonary tuberculosis, 358

reporting of, 20, 23 See also Tuberculosis.

residual of, 26 Pulse, elevated, in cutaneous diphtheria, 295

serological reactions in, 18-19 Purpura hemorrhagica, 252

summary, 25-26 Purulent complications, of common cold,

See also Pneumonia. 3-4

Primary pleural effusion, 354 Pyrimethamnine, 597, 598

PR1NZ!NG, F., 449

Prisoner-of-War General Hospital No. 2, Q fever, 25, 103-109

Camp Forrest, 394, 395 antibodies, 104, 105, 106

Prisoners of war. See Captured prisoners clinical features of, 106-108

of war. convalescence, 107-108

Prodromal symptoms: course of, 107-108

of malaria, 481 cross-immunity in, 108

of meningococcal bacteremia. 244-245 differential diagnosis, 104

Professional Service Division, Office of the dust associated with, 105, 108, 109

Sinrgeon General, 2, 9, 12, 30, 410 epidemics of, 105-106

Prognostic sign, of scrub typhus, 131 in Apennines, 103-105

Promin, 382 in Greece, 105-106

Promizole, 382 in Zone of Interior, 106

Prophylaxis, against epidemic typhus, 201 epidemiology, 108-109

Prostration, associated with epidemic ty- incidence of, 104

phus, 146 incubation period in, 104-105

Proteins, serum content of: laboratory findings, 108

in epidemic typhus, 217 laboratory or breaks of, 105

in typhus fever, 153 military significance of, 109

Proteus, strains of: mode of onset, 106

Kingsbury (K), 133 mode of transmission, 108-109

OX-K, 112, 113, 115, 119, 125, 126, occurrence, 103-106

127, 139, 179 physical findings, 107

OX-2, 179 recognition of, 103

OX-19, 127, 1:13, 179 rickettsia of, 104, 105, 108

"Pseudobronchiectasis," 45 roentgenological findings, 107
6W6 INFEWTI( kUS DISEASES

Q fever-Continued Quinine-Continued

symptoms, 106-107 malaria suppression by, effect of combat

treatment, 108 conditions on, 466

Quarantine, for mumps, 38 oral administration of, 511

Quartan malaria, 489 plasma concentrations of, 532

Queensland, 60, 103, 111, 112 level of, 532

QUILLINAN, 300 source of, 493

Quinacrine hydrochloride, 115, 452, 465, toxicity of, 501, 534

538-558

aplastic anemia ascribable to. 551-552 Rabat, 453, 502

as cortical stimulant, 558 Rabies, 79, 100, 101-102

clinical trial of, 538-558 deaths due to, 101

dosage schedule, 538, 540, 545-549 incubation period, 101

hepatic dysfunction related to, 550-551 symptoms, 101-102

in acute attacks, 540-542 Race, factor of, in tuberculosis, 367, 375

in falciparum malaria, 534, 539, 540, 542- RAMMELKAMP, C. H., 266

545 RAMP's. See Recovered Allied military

in relapsing malaria, 534 personnel.

in suppression, 545-549 Randolph Field, 235

in v•ax malaria, 539-540 See also Army airfields.

relative efficiency of, 569 Rash, inphysiological disposition of, in human Brill's disease, 202

body, 539 dengue, 72

plasma concentrations of, 540 epidemic typhus, 216, 217

levels of, 540, 541 Fort Bragg fever, 438

reactions, acute, to short-term administra- meningococcal bacteremia, 245-246, 249

tion of, 555-559 murine typhus, 221, 222

central nervous system, 556-558 RASMUSSEN, AARON F., Jr., 99n, 100

gastrointestinal tract, 556 Reaction(s):

skin, 556 cephalin flocculation, in mononucleosis, 39

skin discoloration associated with, 552 Pandy, in Japanese B encephalitis, 89

studies on, 538-558 serological, in primary atypical pneuclinical use, 540-549 monia, 18-19

general properties, 539-540 toxic, tosummary, 558 Atabrine, 495, 550-558

toxicity, 550-558 chloroquine diphosphate, 574-576

superiority of, to quinine, 532, 533, 534 oxychloroquine, 577

toxic manifestations of, 534, 550-558 pamaquine, 585-589

See also Atabrine. quinine, 501, 534

Quinine, 115, 511-512, 525, 529, 583 Sontochin, 561

clinical trial of, 531-535 Weil-Felix, 40

combined with Plasmochin, 580, 581, 582, in epidemic typhus, 157, 179-183

583, 585 in Fort Bragg fever, 441

dosage of, 532 in Q fever, 103, 104

in falciparum malaria, 532, 534 in infectious mononucleosis, 40

in relapsing malaria, 534 in scrub typhus, 119, 125, 133-134

in vivax malaria, 532 in typhus, 157, 181, 182

relative efficiency of, 569 Proteus OX-K in, 125, 126, 127, 128,

in treatment of malaria, 466. 531-535 133-134, 179-183

inferiority of, to Atabrine, 470 Proteus OX-19 in, 133, 179, 180, 181,

intramuscular injections of, 5.35 183, 208, 213

intravenous injections of, 500, 501. 512, Proteus OX-2 in, 179, 180, 183

534 REAGAN, R. L., 138
INDEX 637

Reconditioning: Respiratory tract, diseases, 1-48

after rheumatic fever, 235 acute, 2-42

for scrub typhus convalescents, 124 bacterial pneumonia, 26-32

for tuberculous patients, 388-390 common upper respiratory infection, 2-9

Recovered Allied military personnel, tubercu- infectious mononucleosis, 38-41

losis in, 346-349 influenza, 9-16

Recovered American prisoners of war, measles, 32-35

tuberculosis in, 344-346 mumps, 35-38

Recovered prisoners of war, tuberculosis in, primary atypical pneumonia, 16-26

390-392 rubella, 41-42

Recruits: chronic, 42-48

incidence of common respiratory diseases chronic bronchitis, 42-44

related to proportion of, 5 bronchiectasis, 44-45

incidence of measles in, 33 lung abscess, 45-46

Red Cross, 344, 389 malignant disease of lungs, 48

canteens of, 368 pulmonary emphysema, 48

Redistribution Station, Army Ground pulmonary fibrosis, 47-48

Forces, 346 spontaneous pneumothorax, 46-47

Reflexes, in Japanese B encephalitis, 88 disability discharge due to, 339

Regiments. See Military units. general considerations, 1-2

Registrants, for military service: in malaria, 48.3-484

rejection of, for venereal disease, 433 See also specific diagnosis.

screening of, 333 Restlessness:

Rehabilitation: in dengue, 72, 76

after primary atypical pneumonia, 22 in meningitis, 270

of tuberculous patients, in Zone of Interior Retinopathy, in scrub typhus, 130

hospitals, 388-390 REYNOLDS, F. H. K., 59

REILLY, Col. WILLIAM A., 165 Rheumatic disease, 1

Rejection, for military service, due to Rheumatic fever, 225-238, 247

tuberculosis, 331 acute, 231

Relapsing malaria: arthralgia in, 235

causative agent of, 469 carditis in, 231

morbidity of, 514-517 clinical investigation of, 238

treatment to reduce rate of, 513-514 clinical picture of, 229-231

See also Malaria. complications of, 234-235

Renal complications, of sulfonamide therapy, control programs for, 237-238

in meningitis, 262-263 death due to, 231, 232

Report(s): directives on, 227, 232, 233, 236. See

essential technical medical data, 51, 500 also Directives.

statistical health, 28, 50, 51, 96 disposition of patients with, 233, 236-237

summary health, 28 epidemics of, 227

Reporting- epidemiology of, 228-229

of pneumonia, 20, 23, 28, 29 in oversea theaters, 229

of tuberculosis, 406 in young adults, recovery from, 234

Research: incidence of, 226, 228

information on, clinical and historical, 230 in rheumatic fever, 238 military importance of, 225

on dengue, 76-78 natural history of, 229

Reservoir host: outbreaks of scarlet fever following, 226

of epidemic typhus, 143 reconditioning during convalescence from,

of scrub typhus, 111 235

Residual, of scrub typhus, 124 statistics, 228-229

Respiratory aids, in poliomyelitis, 98 sulfonamide prophylaxis for, 227, 228
638 INFECTIOUS DISEASES

Rheumatic fever-Continued ROSENBERG, Dr. D. H., 266

summary, 238 Royal Air Force, tuberculosis in, 402-403

treatment of, Royal Navy, tuberculosis in, 400-402

directive on, 232 ROYSTER, H. P., 306

early, 232-233 Rubella, 41-42

late, 233-235 cominmunicabilit y of, 41

results of, 233-235 diagnosis, 41

Rheumatic fever convalescent centers, hos- differential diagnosis of, 76

pitals designated as, 233 incidence of, 42

Rheumatism, death due to, 225 noneffectiveness due to, 42

Rhine, 343 Rural typhus. See Scrub typhus.

Rhineland, 166 Russell Islands, 451, 452

Rhinitis, fibrinous, 297 Russi, S., 250

RicH, A. R., 47, 250 Russia, 10

Rickettsia burneti, strains of: Ryukyu Islands, 81, 86

"Balkan grippe," 105, 106, 108

Henzerling, 104, 105, 108 Saar, 343

Paige, 104, 105 SABIN, Lt. Col. ALBERT B., 52, 56, 57, 76, 77,

Seale, 105 83, 86, 90, 92, 96, 446

Rickettsia mooseri, 189, 204, 205, 212 Sacral edema, 272

Rickettsia prowazeki, 143, 195, 202 Saddleback fever, in dengue, 72

strains of: SADLSK, J. F., Jr., 159, 165

Breinl, 156 SAENZ, A., 59

identification of, 190-192 SAFFRON, M. H., 279

isolation of, 190-192 Saidor, 121

Rickettsia tsutsugamushi, 111, 112, 123, 135, ST. JOHN, J. H., 59

136, 137, 138 St. Louis encephalitis, 79, 81, 88

Rickettsiae, of- Saipan, 288

epidemic typhus, 143 outbreak of dengue in, 68-70

murine typhus, 205 Salerno, 50, 453, 502

Q fever, 104, 105, 108 Salicylates, in treatment of rheumatic fever,

scrub typhus, 111 232, 233, 235

Rickettsial agglutination, in epidemic Salmonellal infection, 491

typhus, 188-189 Samar, 125

Rickettsial infections, antibiotics in treat- Samoa, 496

ment of, 139 SAMPSON, J. J., 283n, 299-300, 302

RIGHTS, F. L., 138 San Francisco Port of Embarkation, 380

RITTMAN, G. E., 417 Sandflies, 49, 50, 51, 53

ROBBINS, Maj. FREDERICK C., 103, 104, 105 Sandfly fever, 7, 16, 49-58, 491

Rockefeller Institute of Medical Research, clinical course, 56-57

81, 239 diagnosis of, 56-57

Rockhampton, 61 laboratory confirmation of, 57

Rocky Mountain spotted fever, 190, 252 differential diagnosis, 57

Roentgenographic examination: epidemics of, 50, 56

at induction, 2, 45, 331 epidemiology of, 53-55

tuberculosis detected by, 334 etiology, 52-53

Roentgenological findings, in Q fever, 107 hospitalization for, 57

ROLLESTON, J. D., 318 immunity to, 55-56

ROMANSKY, M. J., 417 incidence of, 51, Z3-55

Rome, 105, 502 onset of, 56

ROOSEVELT, THEODORE, 450 reporting of, 50

ROPER, Maj. WILLIAM H., 384, 391 summary, 57-58

ROSENBERG, A. A., 490 susceptibility to, 56
INDEX 639

Sandfly fever-Continued Scrub typhus-Continued

symptoms, 56-57 diagnosis:

treatment of, 57 complement fixation tests in, 134-135

vector of, 52, 53 laboratory aids in, 133-136

virus of, 52-53 Proteus OX-K in, 113, 115

Sanding of tent floors, as preventive measure strain isolation and identification in,

against scrub typhus, 122 135-136

Sanitation, factor of, in poliomyelitis, 93, 95 Weft-Felix reaction in, 125

Sansapor, 121, 122, 123, 124, 125 differential diagnosis of, 491

Santa Ana Army Air Base, 233 disposition of patients with, 123-125

Sardinia, 53, 453, 502 epidemics of, 120, 121

SARTWELL, Dr. PHILIP E., 5 epidemiological study of, 119

Saskatchewan, 82 eschar of, 111, 113, 115, 117, 122, 123,

SAYEN, J. J., 128n, 129, 130 125, 126, 128, 130

SAYERs, Lt. Col. M. H. P., 135 factor of morale in, 137

Scabies: fever in, 111, 113, 127

as a venereal disease, 432-433 geographic distribution of, 111, 112

incidence of, 432-433 immunity to, 137, 138-139

Scarlet fever, 1, 226 in Chinese troops, 127-128

differential diagnosis of, 76 in India-Burma theater, 127-132

epidemics of, 226 in Japanese troops, 128

incidence of, 226, 228 in Philippines, 125-126

Schick test: in South Pacific Area, 126-127

in diphtheria, 278 in Southwest Pacific Area, 112-126

reactions to: incidence of, 112, 113, 121-125

interpretation of, 297 incubation period, 123

relation of cutaneous lesions in, 296-297 investigations of, 116-121

Schistosomiasis, 198, 491, 528 mode of onset, 111

SCHMIDT, Dr. L. H., 594, 596 mortality in, 119, 120,"122, 128, 129

SCHNEIDER, Lt. Col. LEO V., 398 orientation in, 112-116

SCHOENBACH, Lt. Col. EMANUEL B., 283, 300 outbreaks of, 120, 121-122

School of Tropical Medicine, 499 pathology of, 132-133

Schouten Islands, 112 postwar studies on, 138-139

SCHVILEMANN, 579

SCHWENKTER, Dr. FRANCIS F., 226 preventive measures against, 122

Sclera, effect of Atabrine on, 552 prognosis in, 129, 131

Scott Field, 20, 226 rash in, 111, 113, 128

See also Army airfields. rickettsia of, 111

SCOVILLE, A. F., Jr., 210 serotherapy in, 136

Scrub typhus, 68, 111-142 severity of, 128, 129

antibiotics in, 136 signs of, 111, 113, 126, 130

antibodies in, 134 summary, 139-142

autopsy findings in, 115, 116 clinical picture, 140

chemotherapy in, 136-137 diagnosis, 140-142

clinical characteristics of, 111 natural course. 142

clinical experience with, 112-132 nrophcours, 142

first phase, 112-116 prophylaxis, 142

second phase, 116-121 therapy, 142

third phase, 121-125 symptoms of, 111, 113

clinical picture of, 112, 113, 118, 128 treatment, 131, 136-138, 139

complications of, 118-119, 131 vectors of, 111

convalescence in, 123-125, 131 Weil-Felix reaction in, 119, 127, 133-134

deaths due to, 114, 128 SEAGRAVE, Lt. Col. GORDON S., 499
640 INFECTIMU8 D)ISEASES

Season (s): Shillong, 312

for measles, 32 Shingbwiyang, 127

for pneumonias, 17, 20 Ship fever. See Epidemic typhus.

malarial, 500, 502 Shock, evidence of, in fulminating meninSeasoning of troops, 23 gococcal bacteremia, 253

military importance of, as related to Shoulder pain, in rabies, 101

common respiratory diseases, 5, 7 Sicilian campaign, 52, 453, 504, 507

Secretary of War, 144 Sicily, S, 50, 51, 52, 53, 165, 451, 453, 502

Section for Research on Minimal Tubercu- Siege of Mantua, 449

losis, Medical Research and Develop- SIEmsEN, W. J., 324

ment Board, U.S. Army, 379-380, 384 Sign(s):

Sedation, as adjuvant therapy: Babinski, 88

in meningitis, 270 of dengue, 74

in tuberculosis, 363 of Japanese B encephalitis, 88

Sedimentation rate, in malaria, 490 SILER, J. F., 59, 409, 410

Seitz filter, 319, 445 SIMMONs, Brig. Gen. JAMES S., 59n, 81, 144,

Selective service registrants, examination of, 424

344 Single phase fever, in dengue, 72

Senior Consultant in Dermatology, European SINTON, J. A., 580

theater, 432 Sinusitis. 7. 15

Senior Consultant in Medicine, South chronic, 1

Pacific Area, 496 Sister Kenny method, in poliomyelitis, 98

Senior Consultant in Tuberculosis, European Sixth U.S. Army, 121. 466

theater. 340, 341, 342, 345 Skeletal muscles, involvement of, in epidemic

Separation centers, tuberculosis detected in typhus, 216

troops in, 340 Skin:

Separation from service. See Disability abscesses of, complicating typhus, 220

separations. discoloration of, in suppressive malaria

Serological tests. for- therapy, 466, 476

epidemic typhus, 217 effect of Atabrine on, 552-553, 556

murine typhus, 222 involvement of, in epidemic typhus, 216

primary atypical pneumonia, 25 Skin lesions, associated with malaria, 517

Serotherapy, 30 See also Cutaneous diphtheria.

in bacterial pneumonia, 32 SMADEL, JOSEPH E., 99, 100, 138, 195, 447

in epidemic typhus, 192-194 Smallpox, confused with typhus, 217

in meningitis, 264 Smears, from cutaneous lesions, Corynebacin scrub typhus, 136 terium diphtheriae in, 293-294

Serum, antimeningococcal, in meningitis, 265 SMITH, P. K., 223

Serum therapy, in lobar pneumonia, 30, 32 SMORODINTSEV, investigator of epidemic inService Command(s): fluenza, 10

First, 396 SN 6, 911. See Sontochin.

Third, 31, 38, 44 SN 7, 618. See Chloroquine diphosphate.

Fourth, 19, 37, 40, 260, 262, 265, 414 SN 8, 137. See Oxychloroquine.

Sixth, 29 SN 13, 276. See Pentaquine.

Seventh, 227, 229 SNYDER, Dr. JOHN C., 136, 180n, 188, 192,

Eighth, 40, 381 193, 195, 197

Ninth, 227, 283 Sodium benzoate, 196

Servicemen's Readjustment Act of 1944, 390 Solomon Islands, 126, 279, 359

SETTLE, E. B., 125 Solomon Islands campaign, 280, 492

Seventh U.S. Army, 155, 453, 504, 506, 507 Sontochin, 559-562

incidence of sandfly fever in, 51 absorption, 559

Sex, factor of, in infectious mononucleosis, 38 clinical testing of:

Seymour Johnson Field, 46 for suppression, 560-561

SHANNON, J. A., 539n, 586 in acute attacks of vivax malaria, 560
INDEX 641

Sontochin--Continued SPITZ, D)r. SOPHIE H., 132, 133, 169, 171, 322

general properties of, 559 Spleen, 519

in fakiparum malaria, 559. 560, 561 enlargement of, in chronic malaria, 487

in vivax malaria, 559, 560 involvement of, in epidemic typhus, 216

plasma levels of, 559, 561 palpable:

toxicity of, 561 in diagnosis of malaria, 506

Sontoquine, in treatment of malaria, 512 in infectious mnononucleosis, 39

Sore throat: rupture of, 486, 496

in infectious mononucleosis, 39 technique of palpating, 482

peritonsillar cellulitis as complication of, 4 Splenectomy, 41

streptococcal, 8 Splenic infarction, complicating scrub tySouth America, 82, 366 phus, 119

South Pacific Area, 9, 279, 284, 453, 454, Splenic pain, in relapsing vivax malaria, 487

460, 468, 479, 488, 496, 498 Splenomegaly, 508

diphtheria in, 279-280 in Fort Bragg fever, 438

malaria in, 495-498 in malaria, 482

scrub typhus in, 126-127 Spontaneous pneumothorax, 372-375

Senior Consultant in Medicine in, 496 admissions and readmissions for, 373

tuberculosis in, 357-360 problem of, 374

diagnosis of, 358-359 See also Pncumothorax.

evacuation for, 360 Spring-summer encephalitis, Russian, 79, 82,

incidence of, 357-358 84

mortality in, 360 Sputum:

types of, 358 meningococci in, 259

Southwest Pacific Area, 95, 112-126, 130, pneumococci in, 8, 9

227, 288, 453, 454, 458, 460, 466, 475, Sputum control, in tuberculous patients,

476, 479, 481, 482, 488 378-379

diphtheria in, 282 Staphylococcus, 27

malaria in. 452, 498 Slaphylococcus aureus, 293

poliomyelitis in, 96 STAR (Specialized Training and Reassignscrub typhus in: ment) unit, poliomyelitis in, 97

directive on, 124 Station hospitals: first cases of, 112-115 Sainhsias firctecaes of, 112-125 in chain of evacuation, 508

invides ons of, 121-121 malaria patients in, 485

period of hospitalization for, 508-509

measures for control of, 121-125 treatment of, 508

outbreaks of, 120-121 role of, intuberculosis in, 360-362 diagnosis of tuberculosis, 333

diagnosis of, 361 disposition of tuberculous patients, 381

evacuation for, 362 See also Hospitals, station.

incidence of, 360-361 Seetal Hoals, station.

special medical problems in, 361-362 Statistical Health Report (WD Form 86ab),

Spanish-American War, 330, 450 28, 29, 49, 50, 51, 96, 227, 241,357, 503

Specialized centers: Statistics:

establishment of, 387 dengue, 65

for treatment of tuberculosis, 381-388 malaria, 449-463, 514-517

Speech disturbances, in Japanese B encepha- attack rates, 454, 456, 457, 458

litis, 88 deaths, 460-461

SPILLMAN, R., 331 duration of hospitalization, 459

Spinal fluid: relapse rates, 455-459

in cerebral malaria, 485 types, 454-455

pleocytosis in, 38, b7, 89 rheumatic fever, 228-229

protein levels of, in diphtheritic neuritis, STEIN, Capt. S. C., 398

300 Sternal puncture, in malaria, 489

639243-3------44
(i42 INFECTIOUS DISEASES

STERNBER(;, T. H., 415, 419, 420 Siifamaerazine--Coutinued

Stibopheit, 432 inferiority of, to Atabrine, 529

Stiff neck, in pt, ioinyelitis, 97 suppr(essive activity of, 529

Stilwell Road, 127 toxicity of, 529

STONE, Col. WILLIAM S., 194 Sulfainethazine, effect of, on falciparum maSTRATMA..'-THjoM•S, W. K., 484 laria, 529

Streptococcal infection(s). 4 Sulfanilniide, 196, 262, 263

directives on, 7-8, 227. See also D)irec- Sul.apyrazine, experimental field tests with,

tives. 530

epidermicity of, 228 Sulfapyridine, 262, 263

epidemics of, 227 in gonorrhea, 411

in Mediterranean theater, 7 in pneumococcal infections, 17

in Zone of Interior, 6 Sulfathiazole, 262, 263

incidence of, 228 in gonorrhea, 411, 412

penicillin therapy for, 9 Sulfonamide-resistant gonorrhea, treatment

sulfadiazine in treatinent of, 9 of:

sulfonamide prophylaxis for, 227, 228 directives on, 415,416. See also Directives.

"Streptococcal sore throat," directive o0) fever therapy in, 412, 413

application of term of, 8 penicillin in, 414-418

Streptococcus, 10 Sulfonainide therapy, complications of, 262-

hemolytic, 2, 33, 275 263

group A, 226, 259 Sulfonamides, 1, 4, 6 13, 31,498

infections due to, 4, 7 ant imalarial activity of, 528-529

Streptococcus iridans, 17-8, in bacterial pneumonia, 31, 32

St reptomycini, 382 in lobar pneumonia, 30

effect of, on scrub typhus, 136 in lar 470, 51

STROL, A, 30 ii malaria, 470, 512

STROHL, A., 301 in meningococcal infections, 239, 242

STRONG, R. P., 143 in primary atypical pneumonia, 21

STuART-,iARRIs, C. H., 188 in rheumatic fever, 227, 228

Stupor, in rabies, 101 it streptococcal infection, 227, 228

Suaba, 451 indications for use of, 9

Subcommittees, of National Research Coun- See also specific drugs by name. cii:

on tropical diseases, 493 Sumatra, I11

on tuberculosis, :374, 384 Smmary health reports, 28

on venereal diseases, 409, 413, 419, 420, Supplies, X-ray film, shortage of, 391

423, 424, 425, 426, 430 Supportive measures:

Sulfadiazine, 30, 32, 34, 35, 259, 260, 262, in epidemic typhus, 192

263, 266 in scrub typhus, 136

effect of, on---- Suppressants, 467, 510

cervical lymphadenitis, 6 Suppression of malaria. 465-477

falciparum malaria, 529 blood levels of Atabrine for, 473-476

parasitemia, 512 effect on parasite species in, 469-470

in bacteremia, 271 effects of Atabrine withdrawal on, 46: 169

in gonorrhea, 412 factors in eariy failures in, 466-468

in lobar pneumonia, 30 long-term clinical experience in, 471-472

in meningococcal infections, 246, 247, 249, penicillin in, 525-526

262 quinine in, 531-535

in streptococcal infections, 6, 9 Sontochin in, 559-562

policy for administration of, 242 sulfonamides in, 470, 528-529

Sulfamerazine: totaquine in, 536

effect of, on falciparum malaria, 529 undesirable effects of Atabrine in, 476-477

experimental field test with, 530 See also Atabrine; Atabrine suppressive

in suppressiov of malaria, 470 therapy.
INDEX 643

Suppressive efficacy, of chloroquine dilphos- Syphilis-Continued

phate, 572-576 treatment of:

Suppressive therapy, for malaria, 452 intensive arsenotherapy in, 420-423

See also Atabrine; Atabriue suppressive penicillin in, 423-427

therapy, records on, 428-430

Suppuration of glands, complicating dengue, See also D)irectives, pertainilg to venereal

75 diseases.

Surgeon General, The, 13, 19, 20, 94, 226, Syphilis register, 420, 425

227, 236, 237, 329, 391, 410, 412, 115, treatment recorded on, 429

417, 425, 427, 429, 442, 465, 597 Syria, 318

See also Office of the Surgeon General.

Surgical Group, 1st Auxiliary, 341 Tachycardia:

Surgical treat ment: in cutaneous diphtheria, 295

'or bronchiectasis, 45 scrub typhus, 124

for orchitis, 37 Tagap, 452, 453

Survival period: TAKEMORI, N., 195

in fulminating bacteremia, 252, 253 Tank respirators, 95, 98

degree of adrenal hemorrhage in relation Taranto, 106

to, 253, 255 TA'rLOCK, Capt. HUGH, 445, 446, 447

in meningitis, 257, 258 TAUSSIG, S., 52

Susceptibility, to- Technical bulletins. See Directives, pertaininfluenza, 11, 13 ing to specific subject. measles, 32, 34 Technical memorandums. See Directives,

sandfly fever, 56 pertaining to specific subject.

Technique:

SUTHERLAND, G. F., 300 of palpating spleen, 482

Suva, 63 of thick-drop blood film, 509

SWANTZ, H. E., 586 Tellurite medium, 295

Sweats: Temperate climates, pattern of common

in malaria, 482, 487 upper respiratory infection in, 8

in Q fever, 106 Temperate Zone, 359

Swine influenza, II Temperature, body, elevated. See Fever.

SYLVESTER, J. C., 266 Temperature, factor of, in activating malaria,

"Symposium on Human Malaria," 480 480

Temperature curve, in- Symptomatology, vague, in malaria, 518 Fort Bragg fever, 438

Symptoms, of- Japanese B encephalitis, 89

dengue, 72, 74-75 malaria, 481, 519

epidemic typhus, 146 Q fever, 107

Fort Bragg fever, 437 scrub typhus, 115

malaria, 481-484 TENBROECK, Dr. CARL, 80

meningococcal bacteremia, 244-245 Tendon reflexes, in Japanese B encephalitis,

Q fever, 106-107 88

rabies, 101-102 Tension, in relapsing vivax malaria, 487

sandfly fever, 56 Tent floors, sanding of, as preventive meastuberculosis, 354 ure, against scrub typhus, 122

Syndrome(s): Terrain, factor of, in scrub typhus, 121, 122

Guillain-Barr6, 300 Terramycin, effectiveness of, inWaterhouse-Friderichsen, 249, 250, 251, bacteremia, 269

254-256, 260 meningitis, 269, 273

Syphilis, 418-430 Q fever, 109

noneffectiveness due to, 37 scrub typhus, 139

serological tests for, effect of malaria on, Tertian malaria, malignant, in India-Burma

490 theater, 498
644 INFECTIOUS DISEASUB

Test (s): Throat cultures:

cold agglutinin, 22, 24, 40 Corynebacterium diphtheriae in, 8

complement fixation, 25 Hemolytic influenzae in, 7

in Brill's disease, 203 hemolytic streptococci in, 7, 13

in encephalitis, 83, 86, 89 pneumonococci in, 7, 8, 13

in endemic typhus, 208, 213 Thrombophlebitis, complicating scrub

in epidemic typhus, 157, 183-188 typhus, 119, 131

in lymphocytic choriomeningitis, 100, TIERNEY, N. A., 137, 152

101 TIGEwRr, Lt. Col. WILLIAM D., 87

in malaria, 490 Tinnitus, 484, 534

in scrub typhus, 134-135 in epidemic typhus, 216

Eagle, 490 TOMPKINS, V. N., 261

exercise tolerance, in scrub typhus, 123 Tonsillitis, 1, 8

for cure of gonorrhea, 411 sulfadiazine in treatment of, 9

Frei, 431 Tonsils, 2

HIinton, 490 TOPPING, Dr. NORMAN If., 190, 443

Kahn, 40, 490 Totaquine, 498

Kline, 490 advantage in use of, 536

Koh's block, 557 comparison of:

Kolmer, 490 with quinacrine, 536

Kuder vocational interest, 390 with quinine, 536, 538

Mazzini, 490 in vivax malaria, 536

neutralization: study of qualities of:

in encephalitis, 83, 86, 89 at Bushnell General Hospital, 536

in epidemic typhus, 189-190 at Kennedy General Hospital, 536

rickettsial agglutination, in endemic in New Caledonia, 536

typhus, 213, 215 toxicity of, 536

Schick, in diphtheria, 278, 296-297 Toxicity, ofserological, 25 Atabrine, 466, 495, 498, 550-558

in encephalitis, 84, 88 oxychloroquine, 577

in epidemic typhus, 217 pamaquine, 585-589

in infectious mononucleosis, 40 quinine, 501, 534

in lymphocytic choriomeningitis, 100, totaquine, 536

101 Trachea, tuberculosis of, 369

in malaria, 490 TRAIL, Air Commodore R. R., 402

in murine typhus, 222 Transmission, mode of, ofin primary atypical pneumonia, 25 acute respiratory diseases, I

Weil-Felix, 104, 119, 125 dengue, 59

See also Weil-Felix reaction. epidemic typhus, 143

Widal, 40 murine typhus, 204

Tetanus, 100 Q fever, 108-109

"The Hump," 113 Transmission experiments:

Theaters of operations, U.S. Army. See in common cold, 3

specific theater. in infectious mononucleosis, 39

Therapy: "Transport cold." See Common cold.

for meningitis, 262-263

scrub typhus, 119 TRASK, Dr. JAMES D., 226

Thick-drop blood film, in diagnosis of Trauma, factor of, in cutaneous lesions, 307,

malaria, 509 310, 312

Thirst, in epidemic typhus, 216 Treasury Islands, 451

THOMAS, H. M., Jr., 251, 262, 264, 265 Treatment, ofTHOMAS, L., 86 chancroid, 431

THOMPSON, K., 581, 587 common upper respiratory infections, 9
INDEX

Treatment, of-Continued Troops-Continued

cutaneous diphtheria, 304-307 Nt-gro:

dengue, 76 infectious mononucleosis in, 40

diphtheria, 278, 304-307 mumps in, 38

epidemic typhus, 192-201 tuberculosis in, severity of, 354

antibiotics in, 194-195 Trophozoites, of Plasmodium falciparutm, 529

chemotherapy, 195-200 Tropical diseases, factor, in activating tuberserotherapy in, 192-194 culosis, 360

supportive therapy, 192 Tropical typhus. See Scrub typhus.

fulminant ineningococcal bacteremia, 263- Tropical ulcer, and diphtheria, 279-319

265 See also Cutaneous diphtheria.

gonorrhea, 410, 411 Tropics:

Japanese B encephalitis, 90 diphtheria in:

malaria, 493-524 among natives, 310-312

Atabrine in, 510-511, 538-558 among soldiers, 312

cinchona alkaloids in, 531-538 incidence of allergic disorders in, 9

in South Pacific Area, 495-498 Truax Army Air Field, 20

iron in, 512 Tsutsugamushi disease. See Scrub typhus.

penicillin in, 525-526 Tubercle bacilli, 344, 354

Pla.smochin in, 511. 579-592 isolation of, 363

quinine in, 511-512, 531-535 Tubercular diseases, in Civil War, 330

results of, 514-517 Tuberculosis, 1, 329-407, 491

Sontoquine in, 512 admission rates, 330, 335, 336, 353-354

sulfonamide drugs in, 512, 528-529 aspects of, 367-377

to reduce relapse rate, 513-514 extrapulmonary tuberculosis, 367-370

nmingococcal infections, 261-270, 271 pleurisy with effusion, 356, 370-372

drug of choice in, 263 spontaneous pneumothorax, 372-375

neurosyphilis, 428 control of, 405-407

poliomyelitis, 98-99 death due to, 243, 354, 360, 375-377

Q fever, 108 diagnosis of, 358-359, 361, 362, 364

rheumatic fever, 232-235 differential diagnosis, 354

sandfly fever, 57 discharge rates for, 334-339

scrub typhus, 130, 131, 136-138 discovery of--

postwar studies on, 139 before induction, 331-333

streptococcal infections, 6 in service, 333-334

syphilis, 420-427 epidemiology of, 356-357

tuberculosis, 363, 378-390 evacuation for, 360, 362, 363, 364, 378-381

in prisoners of war, 390-396 historical perspective, 329-331

Tremors, hand, residual of scrub typhus, 124 hospitalization for, 354-355, 359, 378-390

Trenchfoot, 103 in Army Air Forces personnel, 343-344

factor of, in activating malaria, 480 in British military forces, 399-403

Tribromolthanol, 102 Royal Air Force, 402-403

Trigeminal nerve, 258 Royal Navy, 400-402

in Canadian military forces, 403-405

Trimus of the jaw, complicating dengue, 75 in Cad prisnrs ofcwa, 3903

in captured prisoners of war, 3.90-396

Trinidad, 86, 102 in Chinese troops, 364

Trombiculae, 126 in concentration camps, 349-353

Trombiculid mite, vector of scrub typhus, in nurses, 342-343

111 in oversea areas, 339-367

Troops: in recovered Allied military personnel,

military importance of seasoning of, as 346-349

related to common respiratory diseases, in recovered American prisoners of war,

5, 7 344-346
N46 INFECTIOUS DISEASES

Tuberculosis-Continued TuRNER, T. B., 415

in recovered prisoners of war, 390-392 Type(s):

ij U.S. Army, 329-339 of pneumococcus, 30

in Zone of Interior, 340, 378-390 of tuberculosis, 358

incidence. 334-339. 340, 343-353, 357, Typhoid fever, 491

360-361, 362, 364 confused with typhus. 217

in Alaskan Department, 365 Typhusexanthematiqut (French). See Epiin China-Burma-India theater, 364-365 demnic typhus.

in European theater, 339-341 Typhus fever, 112

in Far East, 366-367 epidemics of. 143

in Latin American Area, 366 severe, resemblance of cerebral malaria to,

in Mediterranean theater, 353-357 485

in Middle East, 366 See also Epidemic typhus; Murine typhus;

in Middle Pacific, 364 Scrub typhus.

in South Pacific Area, 357-360 Typhus vaccines, potency test for, 190

in Southwest Pacific Area, 360-362

in Western Pacific Base Command, 362- Ulcer(s):

363 disability discharge due to, 339

miliary, 350, 358, 367 tropical, 279-319

mortality from, 329, 375-377 Undifferentiated respiratory disease, 5, 12, 39

nonpuhnonary, 367-368 virus of, 3, 4, 5

nonpulmonary tuberculous complications See also Common cold.

of, 383 United Nations Relief and Rehabilitation

occurrence of, in oversea areas, 339-367 Administration, 398

patients with: United States. See Zone of Interior.

disposition of, 341-342, 355-356 United States Armed Forces Institute, 390

evacuation of, 360, 362, 363, 364, 378- United States of America Typhus Commis381 sion, 116, 122, 134, 137, 151, 154, 157, 179

orientation of, 388-390 creation of, 144

rehabilitation of, 388-390 field laboratories of, 135, 136

problems of, 359-360, 361-362, 363 study facilities of, 145

pulmonary, 329, 358 University:

racial resistance to, 375 Harvard, 39

severity of, in Negro soldiers, 354 Indiana, 97

significance of Army experience, for con- of California, 80, 82

trol of, 405-407 of Chicago, 596, 597

treatment of, 355-356, 359, 361, 363, 364, of Colorado, 380, 384, 385

378-399 of Maryland, 596

directive on, 342. See also D)irectives. of Notre Dame, 596

specialty centers for, 381-388 of Pennsylvania, 433

under military government in Germany, Yale, 443, 444

397-399 Upper respiratory infection. See Common

types of, 358 upper respiratory infection.

Tuberculosis centers, hospitals designated as: Urban typhus. See Murine typhus.

in Mediterranean theater, 354 Urethritis, nonspecific, 418

in Zone of Interior, 381-388 Urinary frequency, in relapsing rit,ax

Tuberculosis Control Division, U.S. Public malaria, 487

Health Service, 405, 406 Urinary retention, in epidemic typhus, 146

Tuberculous meningitis, 100, 367 Urogenital tract:

Tuberculous patients. See Patients. involvement of, in dengue, 76

Tulagi-Florida Islands, 451 tuberculosis of, 367

Tunis, 49, 453, 502 Urticaria, in malaria, 484, 517

Tunisia, 24, 49, 53, 354, 453, 495, 502 U.S. Army Medical Museum. 40
INDEX 647

U.S. Army Medical Research and Develop- Veterans' hospitals, admission to, for

ment Board, Section for Research on tuberculosis, 332

Minimal Tuberculosis of, 379-380, 384 Veterinary Corps, 368

U.S. Army Signal Corps, 22 ViEuss5Eux, M., 239

U.S. Army Veterinary Corps, 368 Vincent's angina, 8, 9

U.S. Marine Corps, 1st Marine Division, 451 Vincent's infections:

U.S. Navy, 13, 144, 228 admission rates for, 5

U.S. Penitentiary, Atlanta, 597 complicating infectious mononucleosis, 41

U.S. Public Health Service, 64, 144, 443, penicillin therapy for, 9

444, 594 sulfadiazine in treatment of, 9

National Institute(s) of Health of, 108, 135 Vincent's organisms:

Tuberculosis Control Division of, 405, 406 appearance of throat lesions produced by, 4

U.S.S.R., 81, 82, 86, 143, 349 in common upper respiratory infection, 2

Virus(es), ofVaccination: common cold, 3

for epidemic typhus, 201 encephalitis, 82

for influenza, 11, 13 mumps, 35, 36

Vaccine(s): influenza, 2

Cox, 156, 157 A, 10, 12, 13, 14

Craigie, 168, 183 B, 11, 12, 13, 14

epidemic typhus, 156-172 undifferentiated respiratory disease, 3, 4, 5

influenza, 11, 13 Virus and Rickettsial Diseases Laboratory,

mouse-brain formalin, 90 133

VAN RAVENSWAAY, A. C., 20, 45 Virus encephalitides, arthropodborne, 79-91

VAN RooYEN, C. E., 188 Vision, blurring of:

Vasculitis, generalized, acute, in scrub in cerebral malaria, 485

typhus, 125 in treatmentVector(s), of- with dihydroquininc, 537

dengue, 59, 61 with totaquine, 536

epidemic typhus, 201 Visual acuity, effect of Atabrine on, 501

murine typhus, 205 Visual disturbances, factor of chloroquine

sandfly fever, 52, 53 diphosphate in, 575

scrub typhus, 111 Vivax infections:

V-E Day, 433, 435 chloroquine diphosphate in, 560-561

Vella Lavella, 451 relapse rate in, therapeutic regimen for

Venereal diseases: reduction of, 513--14

control program for, 434-435 Vivax malaria:

diagnosis of, 409-435 acute attacks of, 540-542

directives on. See Directives, pertaining quinacrine hydrochloride in, 540-542

to venereal diseases. 543

historical note, 409-410 quinine in, 532

induction of registrants with, 433-434 qunin in, 532

mino of 430433Sontochin t e in, 559-562

minor types of, 430-433 chloroquine diphosphate in, 562, 563-571

treatment of, 409-435 572- 576

See also specific diseases. deaths due to, 461

Venezuela, 102 due to blood infections, 526

Venezuelean encephalitis, 79, 82, 86 factor of antimony compounds in precipiVentilation, factor of, on incidence of tating clinical attacks of, 528

respiratory diseases, 7 naturally acquired, 528

Vertigo, in treatment with totaquine, 536 oxychloroquine in, 577

Veterans' Administration, 332, 339, 375, 383, Plasmochin naphthoate in, 579-592

385, 386, 387, 388, 389, 390, 392 prodromal symptoms of, 481

transfer of tuberculous patients to, 388 relapses of, 487, 496, 532
648 INFECTIOUS DISEASES

Vitvax inalaria-Continued War fever. See Epidemic typhus.

splenomegaly in, 482 War Production Board, 531

sulfonamides in, 529 WARN(;, Dr. JAMES J., 47, 374, 380, 384

See also Malaria. WARN.•k, Maj. FRANK B., 104

Vocational interest test, Kuder, for tuber- WARREN, R. (). Y., 52

culous patients, 390 WARSHA'ER, S. E., 124

Vocational Rehabilitation Act, 390) Wasting, in chronic malaria, 487

VOE.LCKER, A. F., 252 Water transportation, care of tuberculous

V-J Day, 70, 334 pal ients during, 378

Volturno River, 502 \Vaterhouse-Friderichsen syndrome, 24).

Volunteers: 254-256, 260

for experiments in- in fulminant meningococcal bacteremia,

dengue, 76 251, 252

malaria, 470 WAUD, Maj. SIDNEY P., 499

sandfly fever, 52, 56, 57 WD MD Form 86ab, 28, 357

for study of murine typhu" vaccine, 2 10 See aiso Report(s).

in clinical trials of antimalarial drugs. 574, WD MED Form 78, Syphilis Register, 4!;.

575, 577, 596, 597 425, 429

in trials of Atabrine, 494 See also Syphilis register.

Vomiting, in- Weakness,

dengue, 72 in attacks of malaria, 481, 487

malaria, 483 in meningojoccal bacteremia, 245,'253

meningococcemia, 245, 253, 262 in Q fever, 106

pancreatitis, 36 muscular, in murine typhus, 221

poliomyelitis, 97 WEBSTER, Col. BRUCE P., 124

sandfly fever, 56 WEBSTER, Dr. L. T., 81

suppressive malaria therapy, 466, 494, 534, WEED, Dr. LEwis H., 493

556 Wehrmacht, 51, 52, 395

treatment with totaquine, 536 WEICHSELRAUM, A., 239

Von Economo's disease, 80 Weight loss, in Q fever, 107

WEIGL, 156

Waikiki Beach, 63 Weil-Felix reaction, 40

Wakde Task Force, 121 in epidemic typhus, 157, 179-18&3

WALSHE. F. M. R., 299 in Fort Bragg fever, 441

Walter Reed Army Medical Center, 447 in Q fever, 103, 104

War Between the States. See Civil War, in scrub typhus, 119, 125, 127, 133-134

American. in typhus, 157, 181, 182

War Department Circular No. 109, 26 Apr. See also Reaction(s).

1943, 383 Weimar, 353

War Department General Orders No. 6, 13 WEINBERG, L. D., 255

Feb. 1923, 429 Wellcome Research Laboratories, New York,

War Department Prisoner of War Circular 597

No. 11, 8 FO). 1944, 393 WERTMAN, K., 181,182, 183, 210

War Department technical bulletins, per- WEST, J. B., 586

taining to-- West Africa, 529, 532

diphtheria, 283 Western equine enceph:dc iyelitis, 79, 80,

meningococcal infections, 266 82, 88

uneurotropic virus diseases, 79, 86, 88, 100, Western Pacific Base Command:

101 tuberculosis in, 362-363

rheumatic fever, 227, 232, 236 diagnosis of, 362-363

tuberculosis, 370, 388, 389 evacuation for, 363

venereal diseases, 415, 416, 425, 427, 428, incidence of, 362

429, 430 special problems, 363

,See also Directives. treatment of, 363
INDEX 649

WHITTAKER, S. R. F., 56 ZARAFONETIS, C. J. D., 134, 136, 157, 180,

WILLIAMS, Lt. Col. S. W., 113 184, 186, 197, 211, 212

WOLBACK, 152 ZIMMERMAN, Lt. Comdr. H. M., 90

WOOD, Col. FRANCIS C., 128, 499 ZiNssER, H., 143, 202

WOODWARD, Maj. THEODORE E., 125, 151, Zone of Interior, 340, 479, 516, 517

152, 154, 194, 208, 210 antimalarial drug studies in general hosWorld War 1, 5, 34, 36, 41, 80, 225, 243, pitals in, 536

275, 330, 334, 368, 375, 450 bacterial pneumonia in, 28-31

death rate from lobar pneumonia during, common upper respiratory infection in,

29 5-6

deaths from diisease in, 156 evacuation of paralytic patients to, 98 measles in the Army during, 32, 33 infectious mononucleosis in, 40-41

meningococcal infections during, 239 influenza in, 12-14

mumps in, 35 measles in, 34-35

tuberculosis in Army during, 332 meals in, 37-35

Wright's stain, in diagnosis of malaria, 509 mumps primary in, atypical 37-38 pneumonia in, 19-21

WYMAN, Capt. STANLEY M., 104 Q fever in, 103, 106

Xenopsylla cheopiB, 205 study of cutaneous diphtheria in hospitah

X-ray examination. See Roentgenographic of, 282-283

examination, tuberculosis in:

X-ray facilities, for diagnosis of tuberculosis, admission rates, 336

361 hospitalization for, 378-390

in captured prisoners of war, 393-396

Yale University School of Medicine, 443, 444 incidence rates for, 340

Yellow fever, 65, 82 specialty centers for treatment of, 378-

YEOMANS, A., 151, 152, 193, 194, 197 388

Yugoslavia, 180, 192 treatment of, 378-390

U,S. GOVERNMENT PRINTING OFFICE:1963