u. s.

ARMY CHEMICAL CORPS RESEARCH AND DEVELOPMENT COMMAND

u. s. ARMY BIOLOGICAL WARFARE LABORATORIES
FORT DETRICK, FREDERICK, MARYLAND
1 April 1959

YELLOW FEVER:

A LITERATURE REVIEW OF THE CLINICAL PICTURE

1. CLINICAL SYNDROME:

a. Yellow fever in man is an acute infection. The causative agent is

a virus, immunologically related to Dengue, Uganda S, Zika and Ilheus and bas

been classified by Casal in the Group B viruses~/) Yellow fever derives its

name from the jaundiced or yellow color of the akin, mucous membrane and aclerae

which coaaonly develops about the 3rd or 4th day of illne11. (!!/) The textbook

version of yellow fever appear• to be aillple, but often times is very complex.

Clinically, the di1ea1e varies ~from almost 1ymptomle11 infection to a aevere,

fulminating, fatal one. The diaeue bas been clusified according to severity

into 4 varieties: :'(1) very mild, ;.'(2) mild, ~(3) 110derately severe, :'(4) malignant.

~<E._/) A. a aubdivisiou of claH 4, fulainant yellow fever bu bean clucribed

u a hyperacute form. which reaults in death on the 3rd or 4th day. However, in
-ny cues, diagnosis can only be eatabliahed by aerologic teata}'QaJ JJ;/' 1]./,
In a study of yellow fever accidentally contacted in laboratoriea, it was

found that mild caaea •how many of the ch&racteriatic signa and ayaptOIIIS of the

severe cases?]/) The aaclclle-back type of temperature curvu and typical pulae

reaction, Paget'• sign, are al.moat invariably preaent.

b. Prodromal aymptoma are uaually abaent, but if present are very vague

and of short duration.'~Q/' JJ./) The patient •Y a:perience a alight feeling of

general aalaiae accoapanied with a period of mild stimulation or excitation.

The onaet 1a usually very audclan ancl patients frequently r....a,er the aact

~ ~1 ,r,9 .. s-260 l
//
 hour when they were taken ill ;'C.!.U' ~/' E/' 1]./) In general the symptoms

are Faget's sign, haematemesia, jaundice, albuminuria, diarrhoea, hemorrhage,

vomiting, hiccoughs, chilliness, pain in back and weakness; while the signs

are fever, restlessness, delirium, conjunctival injection, leukopenia, enlarge-

ment of liver, tenderness in right hypochrondium and abdominal tenderness

'(!.2./, 19/, 23/, ];!/, ~/).

c. Moderately severe and malignant attacks of yellow fever are

characterized by 3 distinct clinical periods: ;-(1) period of infection or active

congestion, ;·(2) period of remission or stasis, ;'(3) period of intoxicatioJilZ/'

.!!!/, 11:./, 1].I, ~/) During the period of infection which lasts about 3 days,
the virus is present in the circulating blood. The patient feels extreaely ill

to the point of prostration. Be has fever, headache, rigor, frequent voraiting,

fluahed face, awollen lips, conjunctival injection, bright red tongue and a

tendency to bleed. The teaperatm:e rues rapidly to reach its maximuaa,

0
usually from 39 to 40 C, on the first or second day.

- d. The at.age of raiHion is clepetUlent upon the severity of the diMue

and -Y not be pruent at all or -Y verge into frank convalucenee/<!!I> Thi•

period is illdicated by the fall of patient's t-,.rature to or teaarcl normal.

The patient suddenly feels better since his ache and pains are less severe.

Due to venous stasis, the face is no longer swollen and a •usky pallor replacu
('(23/)
the bright red of the active infection or congestion stage. --

e. The time interval for the period of intoxication is uaually 3 to 4

days but in exceptional cuu bu extended as long u 2 weeks;QZI) During

this period free virua is not uaually preaent in the circulating bloocl. Berry

alMI ~itchen have uaonatrated. the preaence of incr...ing ..,_ts of nautralisia&

antibodies in the blood of patients during this period.:'Q/) Bowever, the tasllllia

2
 and its affects resulting from the vi:us are manifestedi@/) The classical

symptoms of yellow fever become fully developed and the temperature ri1e1 again

but seldom reaches its previous maximum.:·~/) The pulse remain slow, leukopenia

is at its maximum, jaundice becomes moderately evident, vomiting is more

troublesome and vomitus usually contains alter blood described as black vomit.

:'QI, ]]_/, ]1/, J:1./, 25/, Jl/) The gums become swollen, spongey and bleed
spontaneously or on light pressure. The tendency to hemorrhage is marked,

ecchymoses may develop while melena, albuminura, anuria or oligunia are common.

The toxemia of yellow fever affects the liver, heart, the kidney and the blood

vessels as evidenced by marked pathological changes.;·(ll/) In nonlethal cases

recovery from the infection is usually rapid and complete. Deaths usually occur

on the 6th or 7th day, seldom later than 10 days after onset.

2. INCUBATI-ON PERIOD:

a. The incubation period of yellow fever, or the length of time

elapsing between the time of bite of an infectious mosquito or accidental

~culation of the virus and the onaet of 1yrapt0111 is C0111110nly accepted &a 3
tho 10 days/(];]:/, }Jl,/) The most enct information concerning the incubation

period of yellow fever has resulted from infection of hUJl&n volunteers by Reed.

et a{S,!/) Of the 22 case, produced by the bite of 1 to 15 infectecl _.... emt:t

a>squitoes, the mean incubation period was 3 uy1 and 17 hours. The e:a:traes

were 2 hours leu than 3 days and 2 hours more than 6 days. Carter observed an

average incubation period of slightly leas than 4 days in 12 individuals who,

after being in an uninfected enviromaent, were exposed for a •hort time in an

infected one and then returned to the first environaent.'<.!I) During outbreaks

of urban yellow fever, the incubation period ii aeltlom more than 6 days; _/)
··c2s

However, stu41•• of yellow fever caa•• &cf(Uirad froa acc:f.Matal contaaination

of the skin deaonstrated incubation periods ranging from 2 to 10 days

3
 :QI, !:.I, 2!, 2.I, J..I, §.I, 2./, J-.2.I, .!..V, 1:J:.l, 111, lf!./, ,!11, 11./, J.1./, ~/, 1Q/) .
3. },()RTALITY:

a. Mortality rates of yellow fever in specific localities are very

difficult to compute and evaluate. Serological surveys of populations have

shown that for every case diagnosed, there are great numbers of mild cases

never detected. Mortality rates of yellow fever vary according to the clinical

severity of the disease while clinical severity of the disease depends upon the

degree of immunity in a population. In indigenous areas in South America and

Africa the fatality rate in the native population is between 5 and 10 percent

including clinical cases.:(]/' J:1/) However, the mortality rate in Aedes aegypti
transmitted urban epidemics elating from 1646 to 1954, varied from 4 to 100 percent

mortality of total populationa.:'@/) Several populations have been practically

eliminated. In 1804, 103,000 people out of a population of 110,000:'(94 percent)

died of yellow fever in Malaya, SJMLin. During the period of 1793 to 1900, there

were over 100 epideai.ca with 500,000 cases and 100,000 deaths :'(20 percent) in

the United States. When the French were building the Panama Canal in 1879, 22,189

people died resulting in a population mortality of S3 percent. All information

,~ ' .....
concerning yellow fever since 1900 shows 45 epicleadca.:'(~!/) Twenty of tb.ue

epidemics demonatrat• an average mortality rate of 36.3 percent. In epid•ics

of Central America during the period of 1951-1953, there were 207 caau and 57
deaths ;·(27 percent) in Costa Rice.'<!2/) A large number of the population had

been vaccinated with French neurotropic vaccine juat prior to or during the
;'~/) :'(!!/)
epideaic and had. received good hoapitalization. lloaaro and Trejo•

made a special study of 157 caa•• and found that 37 percent of the deatba were

among the unvaccinat ... lo ••aae mortality rate for....._ ucr,t;t tranaittM

4
yellow fever epidemics is valid, since every individual epidemic is dependent' on

the specific population susceptibility and specific environmental conditions in

each locality.

4.
- - -- -
LENGI'H AND DEGREE OF INCAPACITATION OF HUMAN CASES NOT TERMINATING IN
.....
DEATH

a. Most deaths resulting from the yellow fever virus occur on the 6th

or 7th day and seldom later than 10 days after onset.'°~!) Complications are

infrequent while recovery from the infection is usually rapid and complete in

nonlethal cases. It is the concensua of the ablest clinicians that there are

no late sequelae of yellow fever. No clinical relapse of yellow fever has ever

been demonstrated u the resulting i.Dlllunity is very enduring_'.(l 7/) Since

neutralising antibodies appear so early in disease and remain over a long period

of time in auch appreciable quantities, the concept of nonaterile i.nmrunity has

been developed. Autopsies have proven the cauae of death to be other than yellow

fever in a great number of caa .. in which an apparent relapse had been observed
r't28/)
after the 10th day of illneH; \ :

b. Although clinical yellow fever is relatively free from compli-

cations, supperative parotitis, uaually unilateral, ia the moat striking coaipli-

cation.''C.!!l) It is probably asaociated with the dry mouth and fauces that

clev·elop in some patients, -peci&lly if the fluicl intake baa been low. !neuaouia,

while not frequent, can be a serious complication. Abscesses of the kidney,

possibly resulting from catheriaation, have also been observed. Aaethemia,

sometimes very marked, . .Y last a week or longer after the temperature returns

to normal. Extreme weakness and fatigue are characteristic of a convalescent

of yellow fever.r(J/' ]./) Myocardial failure after apparent full recovery baa

been a definite huard.1'Q/' .!Q/) Several dutha occurred frca ayocar4ial failure

5
in African patients who left the hoapital in the early convalescence period.

c. Recovery from nonfatal yellow fever infection is usually short

and without complication,. The duration of the diaease is 5 to 7 days. How-

ever, long convaleacent period, have been recorded in cases infected accidentally

in laboratoriea .: (11' .!QI) Berry and Kitchen obaerved convalescent periods

ranging from 15 to 60 days and one case required 80 days before the patient was

able to go back to work. All of these patients were apparently recovered, but

complained of extreme fatigue in performing their usual daily tasks.

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• I

REFERENCES
1. Reed, W., Carroll, J., Agramonte, A., and Lazear, J. W.: "Yellow Fever: A
Compilation of Various Publications." U.S. 61st Congr., 3rd sess. Senate
Doc. no. 822, Washington, 1911. Cited from "Viral and Rickettaial Diaeases11 ,
Rivers, T. M. and Horsfall, Frank L., J.B. Lippincott Company, Philadelphia,
3rd Edition, 343-360, 1959.

2. Carter, H. R.: "Yellow Fever, an Epidemiological and Historical Study of

its Place of Origin." Williams and Wilkins, Baltimore, 1931.

3. Berry, G. P. and Kitchen, s. F.: "Yellow Fever Accidentally Contracted in

Laboratory: Study of 7 Cases". Am. Jour. Trop. Med., 11:365-434, 1931.

4. Low, G. c. and Fairly, N. H.: "Observations on Laboratory and Hospital

Infections with Yellow Fever in England." Brit. Med. Jour., 1:125-128,
1931.

5. Jungmann, P.: Zur Klinik des Gelbfiebers. Ein Beitrag zur Pathologie der
Leber." Klin. Wchnschr., 8:14-17, 1929.

6. Hindle, E.: "Experimental Study of Yellow Fever." Tr. Roy. Soc. Trop. Med.
and Hyg., 22:405-434, 1929.

7. Hindle, E.: "TranamiHion of Yellow Fever." Lancet, 2:835-842, 1930.

8. Snijdera, E. P.: "Beitrag zur Klinik under Pathologiachen Anatomie des

Gelbfiebua." Arch. f. Schiffa-u-Tropen-Byg., 33:87-9.3, 1929.

9. Kucsynaki, M. H. and Bohenadel, B.: "Aetiology of Yellow Fever, with Special

llaference to lrobl• of InNct-borne DS..UN." Tr. Roy. Soc. Trop. 'Mad.
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10. Burke, A~ W. and Davia, N.' c.': "Note, on Laboratory Infections with Yellow
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11. Annual Report, Rockefeller Foundation, 1928.
12. Obituary, Brit. Med. Jour., 2:615-618, 1927.

13. Theiler, M.: "Studies on Action of Yellow Fever Virus in Mice." Ann. Trop.
Mad., 24:249-272, 1930.

14. Obituary, Brit. Mad. Jour., 1:1005, 1928.

15. Boorman, J.P. T. and Porterfield, J. s.: "A S111.ll Outbreak of Yellow Fever
on the Gold Coast." Trana. Roy. Soc. Trop. MIMI. and Hyg., 51'(4):439-449,1957.

16. llollllro, A. and Trejos, A.: "Clinical and Laboratory FincU.nga of Yellow r...-
in Costa 'lica." l.ev. Biol. Trop. ((Coata lica), 2/2:113-168, 1954.

7
17. Kerr, J. Austin: "The Clinical Aspects and Diagnosis of Yellow Fever."
Yellow Fever, edited by George K. Strode, 2nd Edition, McGraw-Hill Book
Company, Inc., New York, pp. 389-425, 1951.

18. Bauer, J. H.: "Yellow Fever." Public Health Reports, 55'(9):362-371, 1940.

19. Wattley, G, H.: "Clinical Aspects of Four Fatal Cases of Yellow Fever in
Trinidad in 1954." Caribbean Med. Jour., 11'(1-2) :15-23, 1955.

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Sudan." Ann. Trop. Med., 35:67-112, 1941.

21. BWL Technical Study 7, Part B, Table II. Short Title: XYA-8121, July
1958, pp. 225-229.

22. Klotz, 0. and Belt, T. H.: "Identity of Yellow Fever Lesions in Africa
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23. Theiler, Max: "Yellow Fever." Virus and Rickettsial Diseases of Man.
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3rd Edition, pp. 343-360, 1959.

24. Casals, J'ordi and R-eeves, William C.: "Arthropod-Borne Animal Viruaea."
T. M. Rivers and Frank L. Horsfall, J.B. Lippincott Company, Philadelphia,
3rd Edition, pp. 269-285, 1959.

25. Theiler, Max: "Yellow Fever." T. M. Rivera, J. B. Lippincott Company,

Philadelphia, 2nd Edition, pp. 531-551, 1952.

26. Elton, Norman W., Romero, Arturo, and Trejos, ilfronao: "Clinical Pathology
of Yellow Fever." Am. J'our. Clin. Path., 25:135-146, 1955.

27. Dowu, Wilbur G., Thomas, H. G., and Anderson, Charles R..: "Activities
of the Triniclu ltegional Virus Laboratory in 1953 ani.1954 with Special
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MIid. and Byg., 4:837-843, 1955.

28. Soper, Fred L.: "Yellow Fever." Clinical Trop. Mu., ?aul B. Roeber,
Inc., Mad. Book Dept. of Harper and 'Brothers, . _ York, Nev York, pp.
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29. Theiler, Max: ''Yellow Fever, The Virua," Yellow Fever, edited by George
IC.. Strode, 2nd Edition, McGr.,..Bill Book O Jany, Inc., New York, pp.
50-54, 1951.

30. Sulkin, s. Edvard and Pike, Robert M.: "Viral Infections Contracted in
the Laboratory." Nev Eng. Jour. Med., 241:20S-213, 1945.