野口英世著

Journal of Experimental Medicine

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ETIOLOGY OF YELLOW FEVER.
III.

SYMPTOMATOLOG¥AND PATHOLOGICAL FINDINGS IN" ANIMALSEXPERIMENTALLY INFECTED.
BY HIDEYO NOGUCHI, M.D(From the Laboratories o/The Rockefeller Institute for Medical Research.)
PLATES36 TO38.
(Received for publication, March 26, 1919.)
Mention has already been madO of successfully inducing in guinea
pigs symptoms and pathological conditions simulating those observedin yellow fever patients in Guayaquil by inoculating these animals
with the blood or organ emulsions from yellow fever patients. It
has also been stated ~ that in the blood and organ emulsions of theinfected guinea pigs an organism belonging to the genus Leptospirahas been demonstrated and that the organism, after having beenobtained in culture, is capable of inducing the same symptoms andpathological changes in these animals as does the original blood ofyellow fever patients. In this paper the mode and course of thisinfection as observed in guinea pigs, dogs, and monkeys will be
described.

Mode of Experimental Infection.
Infection with this organism may be induced either by injection
into the peritoneal cavity, the blood circulation, or the subcutaneous
tissues, or by application to the scarified, depilated surface of theskin or to the mucous membranes, or by feeding the animal with
infected tissue or culture.

Experimental Infection in Guinea Pigs (Text-Fig. I, a to f).
Incubation Period.--The incubation period varies according to themode of infection and the quantity of virus introduced. When a large
1 Noguchi, H., Etiology of yellow fever. II. Transmission experiments onyellow fever, J. Exp. Med., 1919, xxix, 565.
585

586

ETIOLOGY OF YELLOW ~FEVER. IIIamount is inoculated intraperitoneally or into the circulation thefirst symptoms--inactivity, anorexia, hyperleucocytosis--make theirappearance after 48 hours, followed b y a rise in temperature andslight albuminuria within the next 24 hours. With subcutaneous inoculation the symptoms do not appear until the 4th (72 hours) or
5th (96 hours) day, and with a very small amount of the virus a
few days later. The percutaneous and per as modes of infection require a. period of about 6 and sometimes as many as 12 days of
incubation.
Onset and Course.--The onset is indicated b y loss of appetite, inactivity, injection of the bulbar conjunctivae, and a sudden rise in temperature ranging from 39.8-40.5°C. and rarely 41°C. The animal
offers little resistance to handling, plaintive cries indicating intense
muscular pains. The urine diminishes in quantity from an average
daily output of about 25 cc. to almost half that, and its color changes
from a pale straw tinge to dark brownish yellow. It now contains amoderate amount of albumin, with some epithelial cells and granular
casts. At this stage no bile pigment can be demonstrated in the
blood serum and no jaundice in the scleras or other parts of the
body. The leucocytes are increased during the 1st day, but leucopenia follows within a few days, the differential count showing amarked increase of polymorphonuclear leucocytes. '~ Within the next
24 hours the temperature shows a slight drop, only to return to
39.8-40°C. during the following day.
The fever then subsides
gradually until t h e temperature drops below the normal in 3 or 4days more. In fatal cases it sometimes drops to 34°C. just before
death. Although the temperature begins to fall on the 2nd day all
the other symptoms are aggravated. The urine is reduced still
further in quantity and contains an enormous amount of albumin,
renal epithelia, granular and hyaline casts, and the bile pigment
first appears. At the same time the scleras become deeper yellow
and are intensely suffused. At this stage there is a trace of bile pigment in the serum. On the 3rd day icterus becomes quite distinct
21 am greatly indebted to Dr. Jorge Larrea, Director of the Laboratories of
the Guayaquil Yellow Fever Hospital, for total leucocyte counts on some ofthe experimental animals. My thanks are also due to Dr. F. Rojas of the General Hospital in Guayaquil.

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efObservations on guinea pigs inoculated with the cultures of the differ-ent strains of Leptospira icteroides. (a) Guinea pig. Strain, Case 5. (b) Guinea pig. Strain,
Case 5. (c) Guinea pig. Strain, Case 5. (d) Guinea pig. Strain, Case 5. (e) Guinea pig.
Strain,' Case 6. (f) Guinea pig. Strain, Case 1.

mDXYO NOGCCH1

587

in the ears, scleras, palms, and soles. There may be ecchymoses inthe scleras. Epistaxis and hematuria are frequent symptoms. The
urine is now a deep grayish brown hue, and only a few cubic centimeters m a y be excreted. The animal still keeps on its feet but isquiet. On the 4th day the jaundice becomes general, and the serum
taken is deep brownish yellow, as is also the urine. Erythrocytes,
renal cells, albumin, and bile pigment are very abundant in the
scanty urine which may still be passed, or there may be total anuria.
Melena or bleeding from the rectum has been observed, and epistaxis
is a frequent phenomenon in a dying animal (Fig. 13). Death occurs
between the 5th and 7th days after onset of the disease and isaccompanied either by clonic convulsions or by gradual asphyxiation,with air-hunger. The blood pressure becomes so low that about
2 days before death very little or almost no blood flows from thelargest ear veins, even when they are completely cut across.
Non-Fatal and Abortive Infections.--Experimental yellow fever inthe guinea pig is not always fatal. A certain proportion of the animals inoculated with a virulent strain of the virus show a temporary
febrile reaction and albuminuria with few casts. Jaundice is slightly
noticeable in the ears (if the animal is white or light in color) andscleras, but it is sometimes apparently absent. The fever and othersymptoms set in as in fatal cases but completely pass away within a
few days. In a week the animal has regained its previous health.
That these reactions are mild or atypical symptoms of the same
infection is evident from the fact that such animals cannot be reinfected, even with a quantity of the virus sufficient to kill control
guinea pigs with the typical symptoms and lesions. Furthermore,these mild infections occur among guinea pigs inoculated with thesame quantity of virus which produces a fatal infection among othersin the same group, and especially do they occur frequently when theamount of the virus injected is rather small or the strain attenuatedin virulence for the guinea pig. As in yellow fever in man, therefore,
so ill the experimental condition in guinea pigs, there apparently
exist varying grades of severity of infection according to the individual resistance to the same virus. Many instances have beenencountered, among many hundreds of guinea pigs purchased in
Guayaquil, ill which the animals showed a complete immunity to the588

ETIOLOGY

OF Y E L L O W

I~EVER.

HI

inoculation of the virus. It is possible that as some of them had beenk e p t in houses or markets for varying periods of time before purchaset h e y were ren~lered immune through a previous mild infection.
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TEX~-FIC. 2, a to d. Observations on dogs inoculated with the cultures ofthe different strains of Leptospira icteroides. (a) Dog (pup). Strain, Case 6.
(b) Dog (pup). Strain, Case 1. (c) Dog (pup). Strain, Case 5. (d) Dog(pup). Strain, Case 3.

Experimental Infection in Dogs (Text-Fig. 2, a to d).
Incubation Period.--This is practically the same as in guinea pigs.
Onset and Course.--The onset and course are also similar to thoseobserved in guinea pigs, some dogs succumbing to the 'infection andI-IIOEYo NO6VCHI

589

others recovering from a mild attack. In a fatal infection the temperature.may reach 40°C., but usually it is not over 39.5°C., and lastsfor 3 or 4 days, when it gradually drops by lysis. Tbe skin then becomes yellowish and the conjunctivae injected, and the animai refuses to eat. It often vomits bilious and sometimes blackish, mucous, frothy contents from the stomach. The amount, of urine
diminishes, with increasing albumin, casts, and bile pigments. Deathoccurs in coma or in clonic convulsions, the temperature falling below
normal.

Experimental Infection in Monkeys (Text-Fig. 3, a to e).
As stated elsewhere, the South American ringtail monkeys were
found refractory to infection with the blood of yellow fever patientsor the culture of the yellow fever leptospira. I With both a temporary
febrile reaction was observed, but the animal invariably recovered.
•Five marmosets, 3 however, proved to be susceptible to the organism,
four.being fatally and one mildly infected.
The incubation period varied from 3 to 4 days, during whichtime the animals appeared well. The disease became noticeable bytheir inactivity, loss of appetite, non-resistance to handling, andslight greenish pigmentation of the urine. Albumin, casts, and bile
pigments began to appear in the urine when the fever reached its
height. Mild jaundice in the scleras, abdominal skin, and oral
mucous membrane became noticeable a day or two after the fever
began to subside. On the day of death the animals lay in a helplessposition, offering only feeble resistance to handling. Death occurred
during a condition of general weakness, coma, and sometimes convulsions. The temperature was usually Subnormal, and the body of
the animal more distinctly and generally yellowish.

Autopsy Findings in the Experimental Infection (Fig. 14).
The guinea pigs, dogs, and marmosets dying of the experimental
infection invariably show a pronounced jaundice ranging from alight yellow to a deep bright yellow. Blood clots or stains are often
a Species Midas ~edipusand Midas geogroyi.

590

ETIOLOGYOF YELLOW

FEVER.

III

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TExT-FIe. 3, a to e. Observations on monkeys inoculated with the different
strains of Leptospira icteroides. (a) Monkey 1. Strain, Case 1. Culture ofsecond generation, 2 cc. intraperitoneally. (b) Monkey 2. Strain, Case 3. Culture of first generation, 4 cc. intraperitoneally. (c) Monkey 5. Strain, Case 6.
Guinea pig kidney emulsion, 6 cc. intraperitoneally. (d) Monkey 3. Strain,
Case 1. Culture of second generation, 4 cc. intraperitoneally. (e) Monkey 4.
Strain, Case 5. Guinea pig liver emulsion, 6 cc. intrapefitoneally.

HIDE¥O NOGUCItI

591

present in the nostrils, mouth, anus, or vagina. Subcutaneous
ecchymoses are frequently present in the guinea pig but seldom inthe dog or marmoset. Postmortem rigor and lividity are marked.
In guinea pigs the subcutaneous tissues are intensely jaundiced, andecchymoses are seen in the axillary and inguinal regions. The abdominal muscles are often spotted with minute ecchymoses but sometimes these are absent. In the dog and marmoset the muscles show
very slight or no hemorrhage.
The lungs of the guinea pig almost always show ecchymoses varying in extent from few and minute to numerous and large ones, roughly
round, oval, or irregularly oblong or square, and with or without asharp outline, vivid red, clark, or bluish red in color, sometimes light
red with a darker center. Undoubtedly the color of the spots becomesdarker and more bluish as they become older, since the longer the animal lives the darker are these ecchymoses. Postmortem hypostasis
is marked. There may be some ecchymoses in the pleurm. In
the dog and marmoset the lungs are much less affected, only a few
spots of hemorrhage being found, and the pleurm are usually free.
There m a y be some dilation of the right heart. The pericardium
is often studded with minute hemorrhagic spots. The fluid is clear
and icteric. The muscle is friable ~nd brownish yellow, and there
are few or sometimes many ecchymoses on the surface. The endocardium and papillary muscles seem normal except for occasionalpunctiform ecchymoses. The valves are not altered but are yellowish
in color, the aorta usually being deeply jaundiced. These changes
apply equally to the guinea pig, dog, and marmoset.
The liver is usually slightly enlarged and varies in color from ayellowish brown-red to a bright yellowish brown. In instances inwhich death occurred within the first 3 days the degeneration wasless advanced and the yellowish color not so pronounced. The surface is often mottled or striped with yellowish brown and brownish
red, and the markings are very distinct.
The gall bladder is usually filled with a dark green or greenish
yellow bile, and the wall is often spotted with minute ecchymoses.
The stomach usually contains some undigested food which ismixed with blood from the adjacent ecchymotic area of the mucosa.
The contents are sometimes semifluid containing blackish blood re-

592

ETIOLOGY OF ,YELLOW FEVER.

III

sembling coffee-grounds in appearance. In dogs and marmosets
the greater quantity of mucus renders the appearance of the stomach
contents indistinguishable from those found in human autopsies.
The mucosa is somewhat hyperemic, and numerous ecchymoses arefound, especially near the cardia. The serosa of dogs and marmosets
is free of hemorrhages.
The small intestine and colon, including the rectum, are intensely
injected, and numerous hemorrhages are found in the mucosa. The
serosa is sometimes affected. The contents are blackish in color andmay contain freshly escaped blood (melena). In the dog the character of the intestinal contents is a closer reproduction of what isobserved in man, the serosa in this animal not showing the ecchymoses
which are present in the guinea pig or any appreciable fluid in theperitoneal cavity. The nature of the fmdings in marmosets is about
midway between that of guinea pigs and that of dogs.
In guinea pigs the kidneys are extensively involved. Hyperemia
and puncfiform hemorrhages in the parenchyma are almost constant.
The ecchymoses, however, vary from a few to almost countless
numbers in extreme instances. In dogs and marmosets there may
be only a few minute spots. On section the cortex is broader thannormally and highly hyperemic, with cloudy swelling. The medullary portion is succulent and hyperemic near the border. Bloody
fluid or clot may be found in the pelvis, and sometimes numerous
punctiform ecchymoses.
In the guinea pig hyperemia and hemorrhages were found in the
suprarenal glands, but in dogs and marmosets only a comparatively
slight degree of hyperemia. There were no changes in the pancreasor spleen, except a slight enlargement of the latter in rare instances.
The lymphatic glands show, in guinea pigs, general adenopathy,
with occasional hemorrhages. In dogs and marmosets some glands
only are enlarged and congested.
The bladder frequently contains bile-stained urine full of albumin,casts, and cells.
The testicles are apparently not affected, although in the guinea
pig hemorrhages are frequent in the adipose tissue around them.
The ovaries are usually congested, and the uterus very much so,
and in the pregnant state there were hemorrhages into the amnionicHIDE¥O NOGUCHI

593

fluid. The endometrium is congested, sometimes with a clot in thecavity.
No gross changes are observed in the nervous system. The membranes are hyperemic and the fluid is icteric.

Histological Examination (Figs. 1 to 12).
Lungs (Figs. 3 and 6).--The areas of hemorrhage are most abundant and extensive in the guinea pig. The alveoli in the hemorrhagic areas are completely filled with blood corpuscles, and in theadjacent zone a marked degree of edema is evident. There are also
small accumulations of polymorphonuclear leucocytes and endothelial cells. In marmosets and dogs these changes are far lessextensive. The leptospiras were demonstrated in the tissues by the
Levaditi method.
Liver (Figs. 1 and 4).--The degree of degeneration of the liver cells
is variable in different animals. In well marked instances the majorityof the cells are swollen and necrotic. Vacuoles are found in somecells. The nuclei are swollen and degenerated. In some areas theliver cells are dissociated, swollen, and appear to have lost their
sharp hexagonal outlines. The liver cells near the blood vessels
seem to be less affected than those around the portal canal.
Hemorrhagic foci of varying dimension are distributed irregularly.
The endothelial cells of the bile ducts are increased in size, andthere are some lymphoid cells around the portal canal zone. Mitotic figures are found. The organisms were found in the tissues
stained by Noguchi's method (Figs. 7 and 10).
Kidneys (Figs. 2 and 5).--The epithelium of the convoluted tubules
shows granular, swollen, and sometimes vacuolated cytoplasm. The
cells may be detached from the membrane and fill up the lumen,which is distended with granular and hyaline casts. The glomeruli
are considerably injected, and numerous hemorrhages are foundthroughout the cortex and medulla (Figs. 8, 9, 11 and 12).
Stomach.--There are superficial congestion of the mucosa and somehemorrhagic loci. In certain areas there is an accumulation oflymphoid and plasma cells.
Large and Small Intestines.--The intestines show injection andoccasional hemorrhages.

594

ETIOLOGYOF YELLOW

FEVER.

Ill

Iteart.--Certain fibers are swollen and contain vesicular nuclei.
Spleen.--There are hemorrhages, and the pulp is rich in blood.
Lymph Nodes.--These show phagocytosis and central degenerationof the follicles.

Adrenal.--In guinea pigs there are parenchymatous degeneration,congestion, and hemorrhages in some instances. These changes areless frequent in dogs and marmosets.
Pancreas.--Little change.
Nervous System.--Little change.
SUMMARY.

Studies are reported on the type of disease induced in guinea pigs,
dogs, and monkeys by inoculating them (1) with the blood or organ
emulsions of guinea pigs or other susceptible animals experimentally
infected with Leptospira icteroides, and (2) with a pure culture of
the organism. Particular attention has been given in these experiments to the clinical features of the experimental infection in thevarious animals and to the pathological changes resulting from theinfection.
The symptoms and pathological lesions induced in guinea pigs aremuch more pronounced than those observed in dogs or marmosets.
The period of incubation is nearly the same in all three species, 72
to 96 hours with intraperitoneal or subcutaneous inoculation, and a
day or more longer when the infection is induced percutaneously or
per os. The febrile reaction in the guinea pig and marmoset is about
the same; in the dog there is less fever. The amount of albumin,casts, and bile pigments in the urine is more abundant in the guinea
pig and marmoset than in the dog, and these animals also appear on
the whole to become more intensely icteric. The black or bilious
vomit, however, though occurring frequently in dogs during life, isobserved in the guinea pig and marmoset at autopsy. The hemorrhagic diathesis is most pronounced in guinea pigs, less so in marmosets, and least in dogs. In dogs, for example, subcutaneous hemorrhages almost never occur, and the lungs usually show only a few
minute ecchymoses. The pleurae, pericardium, and other serous surfaces of the thorax and abdomen remain free from ecchymoses,

HIDEYO NOGUCHI

595

which, however, with hyperemia, are v e r y m a r k e d along the gastrointestinal tract.
T h e s y m p t o m s and lesions observed in animals experimentally
infected with Leptospira icteroides closely parallel those of h u m a nyellow fever.
T h e pathological changes occurring in h u m a n cases of yellow
fever are similar to those induced b y inoculation in guinea pigs a n d
m a r m o s e t s and in respect to their intensity s t a n d i n t e r m e d i a t e between those arising in the two animals mentioned.
EXPLANATION OF PLATES.
PLATE 36.
Sections of tissues from yellow fever cases, fixed in Zenker's fluid and stainedwith eosin and methylene blue. × 150.
FIa. 1. Section of the liver of a marmoset inoculated with the organism isolated from Patient E. Ch., Case 5, showing hemorrhage and necrosis, vacuolization, and dissociation of the liver cells.
FIG. 2. Section of the kidney from the same marmoset, showing necrosis, detachment, and some vacuolization of the renal epithelia. Some of the lumina
are seen to contain granular casts. The glomeruli seem to be highly congested;hemorrhage in some portions of the tissue.
FIG. 3. Section of the lung from the same marmoset, showing hemorrhage inthe tissue.
FIG. 4. Section of the liver from a guinea pig inoculated with the organism
isolated from Patient M. G., Case 3. The liver cells are seen to have been largely
disintegrated and replaced by red corpuscles and debris.
FIG. 5. Section from the kidney of same guinea pig, showing advanced degeneration of renal epithelia, with granular and hyaline casts in the lumen.
FIG. 6. Section of the lung from a guinea pig inoculated with the strain isolated from Patient A. Ce., Case 7. There is a considerable degree of hemorrhage
and edema. Some leucocytic infiltration seems to be evident.
PLATE 37.

Sections from the liver and kidney of marmosets and guinea pigs inoculatedwith the strains of Leptospira icteroides derived from Cases 1, 3, and 5. Figs.
10 to 12 are stained by the method of Levaditi, Figs. 7 to 9 by the writer's modification of that method. X 1,000.
FIG. 7. Liver of marmoset, showing the organism between the hepatic cells;strain from Case 5.

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ETIOLOGY OF YELLOW FEVER.

III

FIG. 8. The same strain. There are two minute, delicate organisms in thelumen of a kidney tubule.
FIG. 9. The same.
FIG. 10. The organism in the guinea pig liver, in which it appears somewhat
coarse.
FIGS. 11 and 12. The organism in the kidney; coarse and quite numerous.
PLATE 38.

FIG. 13. Epistaxis in a guinea pig inoculated with a culture of Leptospiraicteroides isolated from Patient A. Ce., Case 6. The picture was taken at the
moment of death.
Fro. 14. Autopsy of a guinea pig killed on the 6th day after inoculation witha culture of Leptospira icteroides isolated from Patient A. Ce., Case 6. The animal showed typical symptoms and was killed at the time of collapse. The picture shows the general jaundice of the skin and subcutaneous tissues and theyellowish liver. Hemorrhages are evident in the lungs, and can be seen to havetaken place in the stomach, as shown by its dark color. The kidney is congested,and sometimes a few ecchymotic spots can be seen. The spleen appears to benormal. The intestines and also the muscles along the thorax, abdomen, andpostperitoneal region are comparatively free from hemorrhage, presenting astriking contrast to the highly congested condition of these muscles in guinea
pigs inoculated with the organism of infectious jaundice. The strikingly yellow
color of the liver is far more intense than is usually observed in experimental infectious jaundice in the guinea pig.

THE JOURNAL OF EXPERIMENTAL MEDICINE VOL. X X I X .

PLATE 36.

FIG. 1.

FIG. 4.

FIG. 2.

FIG. 5.

FIG. 3.

FIG. 6.

(Noguchi: Etiology of yellow fever. III.)THE JOURNAL OF E X P E R I M E N T A L M E D I C I N E VOL. X X l X .

PLATE 37.

FIG. 7.

FIG. 10.

FIG. 8.

FIG. 11.

FIG. 9.

FIG. 12.
(Noguchi: Etiology of yellow fever. III.)THE JOURNAL OF EXPERIMENTAL MEDICINE VOL. X X l X .

PLATE 38.

FIG. 13.

FIG. 14.
(Noguchi: Etiology of yellow fever. III.)