駐一■一The ) ournal Of thc
Am erican Me dical Assoc iation￨ギ■ F=桑書 :::■

it甕 ::盛 ■

圭1■

=::轟

&鯨 五
,.:::壽Published Undsr the Auspicos ol the Board ol Trusteos

Cntcaco,「OL. 143, No. 2｀

PREVEN丁 10N OF RHEUMATIC FEVER︱

Treolment of the Preceding StreptocoCcic lnfection︱ ● ︱CAPT FLOYD ヽ′ DENNY
CAPT. LEWIS W. WANNA^ム AKER
CAPT.WILLIAM R BRINK
Medicol Corps′

Army of the united States︱

CHARLES H. RAMMELKAMP」r,M.D.

Clevelond・︱

ED"ARD A C uSTER′ M.D︲ プ ０フヽ １１ １１１Polo A‖ o, Cclif

Tlrt ::,rc'' cii'.i, 1 of acttte rhetturatic ier-er by the: tr.r.l,,re,,t oi streptococcic i[fections ivitl-r peniii..i:: r.:,s ee11 attenrptecl in this stucly. The results

i',r,-1'-'.'

１ １ ・︱,-,lr::.I:cr,i shi-,\\' that this atternpt was sttccessful, ancl,
i,ecause oi their inrportance, tl.iese resrrlts are preset.rtecl

lrere in a preliminar)r report.
The signihcance of an adeqttate llrea1ls oi preventionＬｒ
じ ︱ ⁚１１ １４コ Ｖ ｌ︐

ma1- be rlalized ri'hen it is cortsidered that rheuuraticち
１１１４１︐ら マ ーーーーー ｌｒ ｉ１ ７ Ｌ

iever develops in au estimatecl 200.000 to 250.000 per,.or.rs ir-r the general population of tl.re Unitecl Statesr-ear1.,-.1 Figures for the Arnecl Serlices sinlilarly
shot" a 1-righ incidence. u,ith all a\rerage oi 7.300 cases{or the se\rel1 year period froni 19-t2 tl-rrougl'r
annuallv-Thegravity of ihe disease itself is enrPhasizecl
l9-lcl.'ltr- the estimate of paul titat at lsn51 -+br,t.[i-i_ p_,er.or.rs
in the coLlntry today har,e rhetturatic htart ciisease."
Not or-r1y is rheumatic fet,er a Lllellace tc l-,ealth. llr:t

it is also a serious econouric problem. -\ c'-,1:.ertative
esiir-nate oi tl.re cost of each case that,,,ccurs in tile.\rmecl Services is $16,000.'-t.l:cIi-ltsots■.IAY 13、 1950

CopyRrcHT. 1950. BY AIIERIC-{\ f,IEDrcnL -{ssocIsTIoN

DIiSCRIPTION OF THE STL_D\
striclr' u'as conclltctecl at Fort Frarlcis E. \\larren.

-\1i patients aciruittecl to the hospital for clisease oftire rejpirator)' tract \\'ere seerl u'ithin a feu' hotlrs b1one of'tire nienrbers of the ilrofessional statt oi thelaboratorr'. Those haling extldate oll the tonsils ortin the pharvngeal u'al1 u'ere iuchtclecl irl the stuclv grottll'.\ totai oi i.O3+ strch patients \\:ere observecl.
A totai oi 798 patients rl'hose Air Force serial utttubers entlecl iu ati even cligit receivecl pellicillin treatrnent, aucl 804 patients u,lhose serial utturllers encleciu'ith au odd digit contprisecl the cotltrol g-roup an^dreceil'ecl uo.peiilr. treatment'a Prior to lIarch 3.
1949 the treatt.uettt consisted of 300,000 ltnits of crvstalline procaine penicillin G (suspended in pear-rr-rt. oii
contair-ring 2 per cent alutuit-ttttrl lllollostearate) given
intramusc1riar!, o. soon after aclnri.:siol.r as possible''firis dose u'ai repeatecl itr sevetrtv-tu'o hottrs. ,'\fterIlarch 3 the following change rvas uracle in tl-re dosage
schecluie : 300,000 tttrits lvere acln.rinisterecl at the tirleof admission ancl agaiu in fortl'-eight hours. ancl 600.000
tunits u,ere given ninetl'-sis ltottrs after the irlitiai close.
Of the 79S"patients who receivecl penicillin. 253 t'ere
treatecl before l{arch 3. liighty-eight per cent oi thetreated 1>atieuts receivecl the lirst penicillin rvithin sixtr.
hours aiter the onset of the svrnptotns oi the streptococcic ilh'ress.

Fol1ou'-up studies for tl're cletection r,i riretrrttatic
iever u.ere perforn.red lletrveeu the thircl anci iourtll
rveelis after ihe initial infection. rvithotlt 1<nou'ieclge c,ithe serial nturbers of the patierrts or of their prei'iotl'
rreatment. Those patients sttspectecl oi har-iLrg acr'rte
rheluratic iever n,ere hospitaiized r-lntil a sarisfactor-r'
rliagr-rosis u'as established. Rigicl criteria for cliagnosis
rvere foilorled. -\ niodification of the classincation oi
Jones' u'as lised. This classiticatiot-t tttar' lre seetr itt
the ioliou in.g ta'rLrlatiort:\I^ll on \I.tx ttrl:ST:\rlo\Sヽ ｒ︑ １ １︑ ｉ ａｌ ｌ′ ｌｔ １■１ ■■１ ■１ １１︐

ir-r sotttheasiern \\'-)'onling. fhe Fort is an air for:ce
tecl-rr-rical trair-rir.rg base s'l.rere approxiu.rately B0 per
cent of the nren are trait'Lees ri-ho report aiter tu'e1r'e

Carditisa. Defirite cardiac ettlargemettt
b. -\ppearance of a significallt lllurn.it1r heretolore tirlt

n.eeks oi basic training at a so'.ttht-estertt ltase. The
sttrdr- began Jan. 24. 19-i9 and ratt continttor,tsll' until-fu11- 1, 19-19. except for a teu clar. period in Apri1.
-\lthough the average strer.rgtl-r of the base cltiring the
studv r,vas 8,000 men, ti.re actrral uuurber exposed to

pre sentc. Frictior-r rulr
d. Hea:t block c.r orLrer electrocardiographic huclings inclicatir-e oi carCitis
e. Cardiac iail'.:reiniection n'as much greatef becartse tire uteu renlaiuecl
ir.r school onl1, 6iot11 to thirtr'-tl'o rveeks.

\ [ igrat in e ]', ,l] a r r lr ri:i ;Historl of recL:rrq::ce.

This investigatiorr rras supported through the Courmissiou ott AcuteRespiratory Diseases, Amred Forces Epidenriological Board, Oflice of theSurgeon General, Washington. D. C.
trron the Stieptococcal Di:ease Laloratorl', Fort Francis E, Warren,
Wyo., and the Departmetrt of Prer-erltile lledicine. \\'esteru Reserve
Llniversity School or lledicine, Clevela::d.

Cl-rorea

SubcutaLreous ttoclules.1. Thirtl'-r t\o DarieDts \-ere excluded lrom tile ala11'sis because thelrrere treated sirh arlueous penicillin by the rvard ph1's-ician for variols
reasous. frt Dore of these patieuts did acute rheumatic fever subsequentll
develoD.
5. Joues. T. D.: The Diaglosis of Rheuntatic Ferer. ,T ^-\.\I.:\. 126:

1. Swift, H. F.: Rheuuatic Feve:. ir Cecil. R. L : -\ Textbook of
lledicine. Philadelphia. \\'. B. Sarirders Conpanl-. i9+7, p.168.
f. Depaftment-of Preventire \Iedicile. Surgeon General's Ofice.
3. Pairl, J. R.: The Epidemiolo<l' rri Rhetnlatic Ie-ver and Someoi Its Publi; Health Aspects, Nen-Yorl'-. lletr,rt--oiirar Life Insttrance

481 (Oct. l1t) r 9.1+.

L,,111I-11y, 19,1'.

151
Ｅ Ｅ鷺 □

PRE/E」 TJOAr OF

152

=11√
̲4rrσ
R″ 贋 ′V・

MINOR MANIFESTAT10NS

Arthralgia
Skin rasha. Erythema marginatum
b. Erythema multiforme

Probable acr.ire rheun.iatic fever cleveiopeci in 2
patients in ri:e treated gror-rp ancl in 6 patients in the

Epistaxis
Pulmonary changes
Nonspecifi c electrocardiographic changes
Elevated erythrocyte sedimentation rate (20 or above considered abnormal)^{nemia

For a diagnosis oi definite acute rheumatic iever apatient had io have two major manifestations or one
major and trl-o minor manifeltations. For a diagnosis
of probable acute rhaumatic fever a patient had to haveone major and one minor, one major or t\l'o minor
nlanifestations. Instances of abdominal pain. epistaxis.
Tenrs l.-Cases of Rheuntatic Ferer Found at the Follout'Uf
Eramination it the Trected and, Untreated, Groufs
NuDber of Patients

Treateduntreated

2

17‐

2

6

4

231

f--i: o: -.:gr:licance shows that probability is 0.0006.
T.i: ,:: iignificance shows that probability is 0,00m.
T:atx 2.-Persisteuce of Grottp A Beta Hettolltic StreltococcLin the Treated attd Untreated GrotL!srreatEd

L ntreateal

7S=

ゞ1 ,

(Perceotrg: rPiraentage)
Persots sith group A beta heDrolytic
strcptococci on adrnission...
Persons with group A beta hemoll'tic
strfL,tococci on tollow-up examjnation

J. A NI A

ゝIay 13, 1950

cltance onl1'6 tin.res in 10.000 Oi the 2 patients in thetreated group u,ho becanre i11 r'ith rheurratic fever,
1 u,as treated rvithir.r eight iroLrrs after the onset ofthe syrnptoms of streptc)coccic disease ar.icl the seconcl
approxirl-ratelr' selentr'-tn'o hours aiter the onset.

Fever
Abdominal pain:= ・ : it i■ 二 ::■ 、tic fevけFE/ER̲」 DEArArl' ET ̲4L

1,1

lttrtreatecl grorip. Oi the 2 patients in t1're treatecl group,i receivecL i,eniciilin iortl'-eight hours after the onset

oi- slnrp!c,nts of streptococcic clisease and the seconcl
oue h'.ln11red and eight hours after the onset. \\,'hether

the tinre oi treatment oi the initial infection is relatecl
to ri:e cler-e1opr-r.rent of poststreptococcic nonsuppuratil'e
conrplications cannot be determinecl at this time.
Tl:re eltect oi penicillin treatl.nent on the presence oi
betahen-ro1r-tic streptococci in cultures oi the throat isshou-n in table 2. In the treated eroup the nuutber ofpersrns havir.rg streptococci u'as reclncecl irortr 78.3 percent on aclnrission to 18. 1 per celtt at the time oi theiollou--r.rp examination. The untreatecl group shon'ecl
a recltrction lrom 81.7 per cellt to only 52.7 per cefi.
The cleveloprnent of antistreptoly'sin O in the treatecl
and nntreated groups \yas also dillerent. In the treatedgroup on11'51 per cent of the patients shou'ed a risein titer of tu,o or more tubes. rvhile 73 per cent oi theuntreated patients shou.ed a similar rise. Tests of signihcance snpport the r.a1idit1' of these clitterences.
'fhe prevention of rheumatic iever, the inhibition of
antibod,v and the partial eraclicatior.r of streptococci ilr
the group of patients treatecl l'ith peniciliin assun.rernore significance rvhen the composition oi the treatecl
g_roup ancl that oi tl-re control group are collpared.
That the tr,vo groups u'ere contpaiable is clernonstratecl
in table 3, in which various features are presentecl.
)Ioreover, a large proportion of the illnesses in botl-r
grotlps rvere streptococcic in origin, since group A beta
hemolytic streptococci u-ere isolatecl frorn 80 per centoi all cultures made at adn-rission ancl since 73 per centoi the untreated patients shou'ecl ar-r antistreptolvsin
response o{ tu.o or rnore tubes.
CO}I }IE NT

pr-rimonary changes and anemia 11'ere encotlntered br-rt
di.1 not contribute to the classification of these patients.
\,: patient rvith chorea or subcutaneous nodules was:ncountered. Only persons in lvhom acttte rheumatic.tler developed betu.een ten to thirty-five clays after the:rsii ,,f the observecl streptococcic infection are included't. :l.ir

rc,,

ri

Throat cultures and blood specimens lvere obtained
fronr the patielrts on admission ancl again at the tinre of
the lr:11,-'.r'-,.ip e-rainination. Strains oi beta hemolr'tic::rcpiucocci is,iaied irom cultures 1\'ere grollped al1d
ilpecl according to the n-rethod of Lancefield.u Antistreptolr'sin O titration was performecl on acute ancl
cc,nvalescent serllms according to a modification of thenrethocl of Hodge and Slvift.'
RESULTSOf the 798 patients that lvere treatecl u'ith penicillin.
clefinite acute rheumatic fer-er developed in onlr' 2. In
contrast, the disease developed in 17 oi rhe unrreared

The clata presentecl concerning the incidence of rher-rmatic iever in the treated ancl control groups establish
the iact that penicillin therapy of acute sireptococcic
infectior.rs n'i11 almost completely pre\.ent the subseqrlent occt-lrrence oi rhenmatic fever. These results
emphasize again the close relationship betu.een streptococcic disease arrtl rheunraric ieler.
Atter-npts to prevent the occurrence or the recrtrrellce
c-rf rheumatic fever during the last clecacle have centerecl
arouncl the streptococcic clisease t1'rat prececles urost
cases of acute rheumatic iever, Coburn,s liuttner andRerersbacll ! ancl Hodges 10 shou'ecl that sr-rlionamide

clrugs, girren prophr.lacticallr-. not on11' reduced tl-re inciclence of streptococcic disease but also reclncecl theoccrlrrence of rheuntatic feler. This rvor-rld seent to bea practical ineans oi prevention in tlvo sitr-rations : ( o) in

closed groups in u-hich the incidence of streptococcic
clisease is estrenrelv high and (b) in select grorrps, suchas patients u'ith inactive rheumatic fever or rheumatic
hearr disease. in rvhich the clar-rger of recurrence is great.

6.S、 ift,II F:ヽ ヽ1lsOn..ヽ T.and■ anccicid.R C: T,ping Group
A:Hem。 lytic strcptOcOcci by卜 I Prcciniliュ RcactiOns in Capillary Pipcttes.

_ _8. Coburr, ,1. -I.:. The Preventiou of Respirarurl. Tract Bacterial
Iuiections b1, Sulfadiazine.
Pr-ophylaxis rn thj Uniied St"t.i Ni"i,l.^\.1I.-{. 126:88 (Sept. 9) 19.14.
9. Kuttner,.{. G., 1n{ Re}-ersbach. G.: The Prevention of Streptococ-‐
ヽarying Hcm01ytic and ConstantCombining
Capacity
Of Strcpt。
' Hodge,
B. E"and
Swift,H.
F.: In3uence cil Tcsting fOr .ヽ nti
lysins:Str C,tOl,sins. J Expcr
ヽIed. 58:277(Sept.)1933

22t 77 (Jan.) 1943.
G.:,,The_Use oi Suliadiazine As a Prophylactic Against_ 10. Hodge1.R.
Respiratorl' Disease, Ne$ Enelan,1 -T fled ?31: 817 (Dec. 21) 1914.

patients (table 1), a dirierence n'hich could be dne to‐

I Exper.Mied. 78:127(Aug.)1943

cal L:pper Respiratory Infections and Rheumatic Recurrences in Rheirmatic
Clildren _by the Prophylactic Use of Sulianilamide, J. Clin. Investigatior

PRE/EⅣ TfOAr OF RffEこ ‐]r̲4T′ σ FE″ER― DEAi「 N/ ET

VoLUME 143
NultBER 2

This method of prevention has not proved to be practical

for the general population, holvever, because of the

toxicity oI the sulfonan-ride drugs, the high precentage
oi sulfonan-ride-resistant strains of streptococci thatdevelop and the diFtrculty tl-rat is entailed in mass
prophvlaxis.s
Treatr.nent after tl.re cleveloptuent of the streptococcic

infection has beer.r another approach to the probler-n.
Sulfonamide drugs hale proved to l:e ineffective lvllen
rlsed in this uranner.ll Experience rvith per-ricil1in has

been conflictirrg. \\'einstein, Bachrach and Perrin t2
treated 225 patients rvith streptococcic disease lvith
penicillin ; in 7 of these patients rhetlmatic {ever subse-

quently developed. Tliis observation supports Finland's 13 conclusion, from a revierv of the literature,that penicillin is not effective lvheu ttsed in this manner
for the prevention of rheumatic fever. On the contrary, N'Iassell, Dorv and Jones 1{ en'rployed penicillin totreat ten clinical ar.rd fir'e subclinical hemolytic strepto-

coccic infections ir-i patients hospitalized Ior r1.rer-rn-ratic
fever or rheun-ratic iieart disease, the patients failed tc
exhibit subsequent recurrences. Jersild 15 has shon'r.r
tl'rat poststreptococcic complications. incltiding nephritis,
T l.et'r. 3.-C otnparability oJ Treated and L' tttrcoted, GrotLps

153

in this strldv because it was a rapid, easily standardized
method. Ii rvas thought that ir-rch a criterion rvould
include the majority of streptococcic infections of therespiratorv tract, since various studies have sllou,n that
exudatile lesions of the tl-rroat appear in 60 to 90 per
cent of streptococcic ir-r{ections,'7 particularly in a population experiencing epicler.nic rates of streptococcic i1lnesses. The isolation of group A streptococci fron-r 80
per cent of the patients and the den.ronstration of anincrease in the ar.rtistreptollsir.r O titer in 73 per cento{ the control group indicate that the majority of thepatients actr-ralh' had sireptococcic disease. A {ewtindoubtedll. had nonstreptococcic exuclative tonsillitis.
If the incidence of rheumatic iever is to be reduced
rr-taterially by early treatment n'ith penicillin, it becon-res
necessary that streptococcic infections be diagnosed
accurately and early. In sorne cases the clinical lindings
alone lvill pern.rit an almost certain diagnosis oi streptococcic iniection. Characteristicallv, such illnesses
present a sr-rdden onset of sore tl-rroat rvith pain on su,allorrir-rg. feler an,-1 lt1 :er c,-r'r.tiir-liit,na1 reactio:rs. CitLrse
redness and eden'ra of the soft paiate, tonsils and orophar)rnx, discrete or conflnent exudate and large or tender
cervical lymph nodes. Supportive data ma1, be obtained

from the laboratorr'. )Iany' patients
r,vi11 have an e1e^vated total leukocl:te cor-tni. Cultrrres of the pharl,r-rx
r,vill almost a1n'avj shon- a predorninant gror'vtli of beta
henrolytic strepiococci. Depending on the availability
and use oi the prececling criteria. a large percentage of
streptococcic respiratorv iniections can be reliably and

?9S

51)l

TTCated

Untreated(PerceDtage)(PerreDt a ge)

6r.0
3.5

69.0
38.0
4.4

i2.'l

70;l

in-rmediately.

5".1

46.3

r{.i

OD.J

streptococci at adulission....

iS.3

E1.?

less at adnission...,.......

;0.3
Sl.7

69.1
82.8

SU ]I ]I.\R \Evidence is presented to irCica:e th:.: r:,e,1:natic fever
can be prevented by the trealr-..i:: , : ::r.i:,:cl-,ccic disease r,vith penicillin. A total ,1; f!-t p:r:ii:r:: i.,.ith streptococcic infections r'vere treaie -j r,. ::h ;.:rit:.-::r ; in only
2 did acute rheumatic iever.'-:1.,.r,::r-it::1 . :r.'.ti,,,o. Of

Patientsloa

ИL.

Patirnts/uarrcl'1?-19 .. .....,....

..
20 and over,....
Previous history of rheumatic teler.....

fonsils present.

Cervical nories enlarged or tendEr.....,..
Leucocyte count 1J,000 or over at adDission

Persons with group -\ beta hellrolttic

Artistreptolysin O titer ot la; unjts or
Iollow-up obtained.........

39.0

are reduced after penicillin treatmeut of the initial i11ness, but he n'rakes no staternent about the occurrence of
rl-reumatic fever.

The theory has been advanced that rheumatic fever
is associated r,vith a peculiar response to an unknor,r'nantigen-antibody reaction. Kilbourne and Loge'ushor,ved that early and intensive pencillin therapy asaitr.t

streptococcic disease suppressecl the production of art:istreptolvsin O. It has been shou'n here tl.rat adequate
irea.tnrent rvith penicillin not onll' suppr.sses the antistreptolysin response but also prevents rheurratic fever.
'i\-hether the antibody suppression is only a reflectionof tire inhibition oi some n-rore basic process in tl-ie
mechanisrl of rl.reumatic iever or is in itself t1.re responsib1e factor is entirell- speculative at this time.

Exudate on the tonsils or oropl.rarl'nx was used as
the sole means of selectior.r of patients to be included

16. Kilbourne, E. D., and Loge, J. P.: The Comparative Eiiects oi
Continuous and Inrermittent Penicillin Therapy on the Fornratron oi
Antistreptolysin in H.mrlttic Streptococcal Pharyngitis, J. Clin. Illesrisation 27: 413 (.Iui1 ) 19+S.

-_ : :::.:t.

II

Patents, Commissions, Rebates and Secret Remedies.--\: e:hic'.. i: -v::.'i"n i ill r: : rs.eiuq r<nr:r., ratiou ironr p:ltents
C:l :r::.i .ai. -: S::-::tal ::1.::::--..:.:. ;'-.r-:-.-:-- -t:rl::t:']i:it::s.
nor profit from a copyright on methods or procedures. The
receipt of remuneration from patents or copyrigl'rts tempts theorvners thereof to retard or inhibit research or to restrict thebenefits derivable therefrom to patients, the public or the medical

profession. The acceptance of rebates on prescriptions orappliances, or o{ commissions irom attelrdants rrho aid in thecare of patients, is unethical. -{n ethical phl'sician does notengage ir-r barter or trade in the appliances. der-ices or remedies
prescribed for patients, but limits the sources of hrs professional

income to professior.ral services rendered the patient. He should
receive his remuneration lor proiessionai services rendered onlyin the amour-rt of his fee specifically announced to his patient
at tl're time the service is rendered or in the form oi a subsequent
statement, and he should not accept additional compensation

secretly or openiy, directiy or indirectly, Irom any other source.
The prescription or dispensing by a physician of secret medicines or other secret remedial agents. of ,.', 1:r:r-.-. , -. notknor,l, the composition, or the matrufact'l:e ::r-::otion of theiruse is unethical.-Section 6, Cha:':.: I,-': ire PnrxctpLrs or
trIrorcel Ernrcs of tl.re -\mti:cz,:.. \ledical Associaticn.

キュ一
■■一
●一●

Penicillin Therapy in Scarlet Ferer and Conp)icating

Arcb. Int. IIed. 7S: 369 (Oct.) 1!-:贅 謬

15. Jersild, T.:

Otitis, Lancet 1:671 ()Iay 1) 1948.

17. Rantz, L. A. ; Boisvert, P. -T.. -, r i- _: i1 . \\'.: Hemolytic
Streptccoccic and Nonstreptococcic D: :.:::::: :::e Rtspiratory Tract,■
ま一・(Dec.4) 19.18.

804 untreated patients, the ,-iise:... ,-.tl, e. -'-r,-f in 17.
Penicillin therapy liken'ise :iipL,res:es ri.' r,:rtistreptolysin O response and eraciica.tes :he :::.'-:,-,crrcci inllany cases.

麟 馨姜 苺霞軽

11. Commission on Acute Respirarcrl Di:e:.:esr A Study of a FoodBorne Epidemic of Tonsillitis and Pl:arj::gi:is Dre to Beta-Hemolltic
Streptococcus, Type 5, Bull. Johns Ilopki:: H::r. 77:113 (Sept.) l9'15.
12. Weinstein, L.; Bachrach, L., an,i Pe::::.. T. S.: Studies of thelnfltrence of Penicillin on the Immulle Reacti::r: ir Streptococcal PharSngitis, J. Clin. Investigation 28:817 (Juil) ll:-,:.
1i. Finland, NI.: Use of Penicillin in Iniecti:rs Or:er Than Bacterial
Icdocarciiris, Advances Int. NIed. 2: i50, i9.;1-1. Ilasseli, B. F.; Dow, J. W., and Jones. T. D.: Oralll' ^\dninistered
Penicillin in Patients \rith Rheumatic Ferer, J.-\.)L-\. 13S: i0i0

rapidly diagnosed, particularl_r- i'"irirg an epidemic
period. Treatment r'vith peniciliir car tl:'.rs be instituted