Observations during an outbreak of infectious hepatitis in British West Africa

77 TRANSACTIONS OF THE R O Y A L SOCIETY OF TROPICAL MEDICINE A N D HYGIENE.

Vol. 47.

No. 6. November, 1953.

OBSERVATIONS D U R I N G AN O U T B R E A K OF I N F E C T I O U S H E P A T I T I S IN B R I T I S H W E S T AFRICA* BY

R I C H A R D G. HAHN, M.D. AND

J O H N C. B U G H E R , M.D.

In the latter part of August, 1944, an outbreak of jaundice, at first thought to be due to yellow fever, was reported at Unwana, situated in the Afikpo Division, Ogoja Province, of south-eastern Nigeria. This region of the Cross River valley (Fig. 1) is limited by the highlands and mountains of the British and French Cameroons on the east and the sea-coast to the south. The Cross River runs west from Mamfe in the Cameroons to Ikom, Obubra, Afikpo, then south to Calabar and the Bight of Biafra. It furnishes transport by canoe the year round, and by motor-driven river craft during and shortly after the rainy season, May to October inclusive, from Calabar to Afikpo and Obubra. T h e Nigerian railway practically bisects the eastern provinces from Makurdi on the Benue to Port Harcourt on the coast, and so does not directly serve this region. There are numerous year-round roads, except east of the Cross River where the mountainous terrain has retarded construction. The Nigerian Internal Airways connect five airfields (Calabar, Port Harcourt, Onitsha, Enugu, Makurdi) with one another and with the large modern airports at Lagos and Kano. Among the early reports of outbreaks of "jaundice " along the west coast are those of the Yellow Fever Commission in 1915 (RusSELL LEONARD; DALZIELand JOHNSON). Although these were concerned largely with cases of jaundice due to yellow fever, some of the case reports are very suggestive of infectious hepatitis. In 1928 BFJ~UWKESet al. (1931) observed and reported on an outbreak of jaundice (Kukuruku disease) in a localitY about 130 miles northwest of Afikpo. There is no doubt now that it was infectious hepatitis. Mtnvnzi et al. (1942) refer to a small epidemic in 1941 in Kampala, Uganda, East Africa. The disease was reported (1944) among the Armed Forces in North Africa. These reports show that it exists in different parts of the continent among both the indigenous and alien populations.

Although the early report from Afikpo mentioned only Unwana, it was found that several villages near Afikpo were affected and that the outbreak was not so explosive as it was at first believed. A preliminary visit to several of these localities established that an illness associated with jaundice was present; it was widespread and tended to be protracted, although # The studies and observations upon which this paper is based were conducted with the support nnd under the auspices of the International Health Division of The Rockefeller Foundation in cooperation with the Yellow Fever Research Institute, now the Virus Research Institute, Lagos, Nigeria.

78

INFECTIOUS HEPATITIS IN BRITISH WEST AFRICA

there were instances when it had a moderately acute onset terminating fatally within a few weeks. Complaints of abdominal symptoms and " yellow eyes " predominated. The following tables present the data collected at various localities during a lO-day survey. None of the persons interrogated had had any previous experience of an illness similar to this one. The figures were obtained by direct observations, for there was no registration of

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FIG. 1 births and deaths; there were no morbidity records and no census of the population, except for an emuneration of adult taxable males made some 13 years previously. Even with an expert interl6reter, only an approximation as to the duration of illness and the symptomatology could be obtained. Time is not measured in weeks and months, but by seasons--planting, harvesting, rainy, dry. Interrogation to elicit symptoms was kept as simple as possible, and the emphasis was placed on the major complaints.

R I C H A R D G. H A H N

TABLE I.

AND JOHN

C. B U G H E R

79

Distribution of persons with jaundice by age, sex and locality. Age-group and Sex 1

1-9

10-19

20-29

30 and over Total

Locality M

F

M

Amas (ch)ari Kpognikpo Anofia gnwana

1 -

1 1

F

M

F

M

F

M

F 2 3 4 10 1 2 4 10

5 8 17 27 3 20 14 34 128

1

-

3

1

1 1

1 -

1 4

10 4

2 3

-

1

4

8

2 -

7 3 9

2

2

3

4 5

5 4

-

3 5 13 17 2 18 10 24

9

35

17

24

6

92

36

5.0 72

28

Achara Ebor Awutu Edda* Oso Edda Ndibe**

-

2

6 7 11

Totals

1

4

32

Per cent. of total

0.8

3.1 25.0

7.0 27.3

1

1

4

2

13.2 19.0

Grand total

Date illness firs known: '44 August July-August July-August May August June July-August April

* Includes villages of Amoso, Asi Ede, Ufu. ** Ndibe is on the east bank of the river; other localities are on the west bank. All of these 128 p e r s o n s h a d definite a n d easily recognizable icterus of the c o n j u n c t i v a a n d sclera. S i x t y - s e v e n of t h e m were i n t e r r o g a t e d r e g a r d i n g t h e i r early s y m p t o m s , a n d the results are p r e s e n t e d i n t h e following table. TABLE II.

Early symptoms in 67 persons with icterus of the eonjunctiva and sclera. Initial symptoms

Age-group

" Belly Dark palaver " urine

Later symptoms

No

symptoms : "Yellow " Belly Dark "Yellow[ Anorexia and "yellow eyes" eyes" palaver " urine eyes" gen. weakness only

1-9 10-19 20-29 30 and over

2 6 15 11

1 4 4

1 4 7 6

2 4 10 7

1 2 1

Totals

34

9

18

23

4

1

4 8

6 19

15

T h e following table p r e s e n t s the d u r a t i o n of illness of the 61 p a t i e n t s with the s y m p t o m s recorded i n T a b l e I I . TABLE III. Age-group

Duration of illness of 61 patients with icterus of the conjunctiva and sclera. 1-2 wks.

3-4 wks.

1-3 mos.

3 mos. and over

1-9 10-19 20-29 30 and over

2 6 14 7

1

D

4 9 7

1 2 4

3 11 26 21

Totals

29

21

7

61

Total

¸

I N F E C T I O U S H E P A T I T I S I N B R I T I S H WEST AFRICA

80

T h e r e was only one person who mentioned or complained of headache as an initial symptom, although quite a few mentioned it in connection with " belly palaver." T h e latter expression connotes the stomach or abdomen " talking " or remonstrating: as some expressed it, " the belly feels ill " ; " I feel to vomit " ; " the belly moves " ; " the belly feels like big thing " ; all expressions consistent with distention, griping, feeling of a mass or lump in the stomach. Some complained of a frequent urge to defaecate with little or no result even with straining. Very few noticed a change in the colour of the stool; none volunteered such information, but on questioning some stated that their stools were very light in colour early in the illness and later became darker. It was obvious that very few had observed their stools at any time. Anorexia frequently accompanied the abdominal discomfort and was a common complaint throughout the illness. Vomiting was not a c o m m o n symptom, although many felt nauseated. Several who vomited had taken medicine or brews prescribed by the local medicine man, which may have had some emetic properties. T h e majority of the patients continued to do some work but noticed easy fatique. At almost every clinic there were those among the spectators who had had " yellow eyes "several days to 2 or 3 weeks, with either no symptoms or very few. None of the patients gave any definite information of fever, and only a few said they had felt " hot and cold " early in the illness. Although more males appeared at the clinics than females, it does not follow that males were attacked more frequently than females. It was stated quite often that the women refused to appear, or had only a mild illness and had gone to market or to the field for the day's work. In general, the later symptoms followed the initial ones in 1 to 2 weeks or else distinct improvement was noted and recovery ensued. T h e most persistent symptom was abdominal discomfort accompanied by anorexia with a change in bowel habits, usually constipation, and an increasing weakness leading in some instances to complete prostration. Although there were no reports to indicate that communities on the east bank of the river were affected, the survey at Ndibe (Table I) had disclosed a considerable n u m b e r of cases. Rapid surveys were made of other localities on the east bank by inspecting the eyes of school children at the schools and of adults encountered in the market places. T h e results are presented in Table IV, together with additional information obtained from the dispenser at the local medical station. TABLE IV.

Number of persons seen with icterus of the conjunctiva and sclera---east bank of the Cross River. Known to dispenser

Additional found by survey

Akuna Kuna Ediba Obubra Ugep Itigidi

10 28 1 30 5

5 15 9 no survey

15 43 1 39 5

Total

74

29

103

Locality

Total

Date first case known, 1944 May-June June ? January ?

A few typical histories of patients at Unwana and vicinity follow : A. Patients critically ill (1) Male, about 50 years of age: onset, 3 months ago with abdominal discomfort, urine becoming

RICHARD G. HAHN AND JOHN C. BUGHER

81

darker and anorexia. Anorexia continued accompanied by an increasing weakness, practically confining him to bed for the past 3 weeks. Pulse rate, 106; temperature, 99.8°F. Conspicuous icterus of the conjunctiva, sclera, base of tongue and soft palate. Generalized emaciation of the face, thorax and arms. Moderate oedema of the lower third of the legs. T h e abdomen was greatly distended and rounded with evidence of a large amount of fluid. T h e liver could not be felt but was diminished in size to percussion; the area of splenic dullness increased but the spleen was not felt. (2) Male, about 18 years of age. Onset 3 months ago when he noticed that his urine was becoming darker and about t h e same time his eyes became yellow. A feeling of abdominal fullness developed, accompanied by an increasing anorexia and generalized weakness. Physical status similar to that of the previous patient, except that the liver was enlarged and easily detected by ballottement several fingers below the costal margin, but the edge was not felt. Th er e was evidence of fluid at both lung bases. (3) Male, 40 years, whose illness began about 6 weeks ago with abdominal discomfort--belly felt full as though there were a lump in it--followed by " y e l l o ~ eyes." He has had an increasing anorexia with generalized weakness particularly during the past few weeks. He feels that he is becoming more ill and weaker. Pulse rate, 96 ; temperature, 99.2 ° F. Evidence of recent loss of weight. Conspicuous icterus of the conjunctiva and sclera, less marked at the base of the tongue and soft palate. Liver palpable about two fingers' breadth below the costal margin in the nipple line; firm edge, not tender. No evidence of ascites. Spleen palpable about one finger's breadth below the costal margin in the auxiliary line; notch not felt. T h e lungs in these three patients were clear, the level of the diaphragm posteriorly was elevated, more on the right, with practically no change on deep inspiration--particularly in Cases 1 and 2. B.

Patients recovering or recovered

(1) Male, 18 years, whose illness began about 3 weeks ago with " chilly sensations," a " feeling to vomit " soon followed by abdominal discomfort and anorexia. About a week before he became ill he went to Calabar by canoe and began to feel ill while there. He had not seen anyone with yellow eyes at Calabar, nor did he know of anyone there with an illness similar to this. For a while his stools had a pale colour, and later friends told him his eyes were yellow and had been for several days. During the past week his stools have become darker, his appetite has improved and strength is returning. Temperature and pulse rate normal. Moderate icterus of the conjunctiva and sclera. Thorax and lungs normal to percussion and auscultation. Liver edge palpable at the costal margin; firm, smooth and not tender. (2) Female, 20 years. Became ill 3 weeks ago with " belly fullness " and a few days later was told that she had yellow eyes. She was not confined to her home, but noticed that she tired easily at work and had a poor appetite for 2 weeks. During the past week she has been eating more and feeling stronger. She had been to market early this morning and working actively. Her sclera are still icteric. (3) Male, 30 years. Became ill 3 months ago with " yellow eyes " and then noticed that his urine was very dark. He does not remember any other symptoms except a feeling of tiredness or weakness and anorexia which came on about the same time and persisted. He has not felt acutely ill at any time, but has not noticed any sustained improvement until the past month when his appetite and strength have improved slowly and steadily. T h e feeling of discomfort and fullness in the " belly " associated with eating has practically disappeared, and he has been told that his eyes are no longer yellow. Temperature and pulse normal. Faint icteric tinge of the conjunctiva, none of the mucous membranes of the mouth. Thorax and lungs normal; liver edge palpable at the costal margin on deep inspiration only; smooth, firm and not tender. Spleen not felt. Of the 67 patients with icterus who were interrogated (Table II), the pulse rate and temperature of 42 were recorded and the abdomen of 40 was examined. T h e highest temperature was 101°F., recorded once, with the pulse 84; five bad temperatures of 100 ° to 100.5°F.; the remainder ranged from 98.2 ° to 99.4°F. T h e r e were no instances of bradycardia, and only two had a relatively slow pulse, 62 to 68; in three the rate was 85 to 95, and in the remainder from 75 to 85. T h e liver was not considered enlarged in 18 (45 per cent.), the edge was palpable at the costal margin in 8 (20 per cent.) on deep inspiration, and in the remaining 14 (35 per cent.) it was palpable just below the costal margin on normal respiration and in a few instances at two to four fingers' breadth below. T h e edge was smooth, firm, not irregular and in only a few instances did the patient complain of soreness or discomfort. T h e spleen was not felt and the area of splenic dullness not considered increased in 15 (37.5 per cent.), the edge was not made out definitely although the splenic area was considered to be enlarged to percussion in 12 (30 per cent.), and in 13 (32.5 per cent.) it was palpable below the costal margin between the midaxillary and nipple lines--in several instances at two to three fingers' breadth when the splenic notch could be felt. All of these patients except six were ambulatory.

82

INFECTIOUS HEPATITIS I N BRITISH WE~T AFRICA

Seven urine specimens were collected from persons with jaundice. All were dark amber in colour and showed varying degrees of intensity of yellowish foam on shaking. Two showed the presence of albumin on testing, with heat and acetic acid.

Yellow Fever Studies One hundred sera from persons at Unwana and Ndibe were tested for yellow fever antibodies, and the results of the protection tests are given in Table V. Of six sera secured from persons less than 10 years of age, none was positive; of five from persons 10 to 14 years of age, two (40 per cent.) were positive, and this proportion remains approximately the same in the older-age groups, suggesting that there was an extensive epidemic of yellow fever in this area about 1930 to 1935 which infected nearly half the population. T h e r e are no records of yellow fever in this part of Nigeria, but there were several proved cases at Mamfe on the upper Cross River in 1931 and it is probable that an epidemic spread downriver at that time. Aedes aegypti is abundant in the villages along the river and inland, breeding in the numerous water pots throughout the villages both inside and outside the habitations. T h e data in Table V show that there is no correlation between the cases with jaundice and positive protection tests; this is consistent with the clinical impression that the disease has no relation to yellow fever.

Kahn Tests* Ninety-two of these sera were subjected to Kahn tests; 34 gave clearly positive reactions and an additional 18 were doubtful. T h e results are presented in Table VI. Syphilis and yaws are probably chiefly responsible for the high proportion of positive reactions, although conditions such as malaria and leprosy which may give positive Kahn tests have a relatively high incidence among these people. TABLE V.

Yellow fever protection tests. Males

Age-group

Unwana sera. Both sexes

Females

Pos.

Neg.

Total

0-4 5-9 10-14 15-19 20-29 30-39 40 -49 60 and over

0 0 2 2 11 11

0 2 4 7 20 21 4

0 0 0 3 3 7

1 1

0 2 2 5 9 10 3 0

1

1

2

0 0 2 5 14 18 2

1

0

0

0

Totals

28

31

59

14

27

41

Per cent. positive ----42.

Vos.

Neg.

Total

1

1

3

3

1

1

5 10 6

8 13 13

Pos.

Neg.

Total

1

1

1

5 3 10 19 16 4 0

5 5 15 33 34 6 1

42

58

100

RICHARD G. H A H N AND J O H N C. BUGHER

TABLEVI.

Results of Kahn tests.

Males Age-group

Pus.

Unwana sera. Both sexes

Females

Doubtful Neg.

Pos. D oubfful Neg.

Pos.

0

1 1 5 8 10 7

0 0 0 2 6 9

83

0-4 5-9 10-14 15-19 20-29 30-39 40-49 50

0 1 4 3 8 6 2 0

Totals

24

13

20

10

5

20

Per cent.

42

23

35

29

14

57

1

0 2 1 1

Doubtful Neg.

Totals

0 2 0 3 8 5 0 0

0 1 0 3 13 18 4 1

1 4 5 14 31 30 6 1

34

18

40

92

37

20

43

Bilirubin Studies* Eighty of the sera were examined, and in 33 (41.3 per cent.) the icterus index was greater than 10. Quantitative estimations of bilirubin were made in 19 sera with a high icterus index. T h e highest value was 16 mg. per 100 ml. of serum in a specimen which gave an icterus index of 93. Some difficulty was encountered with the colour reaction because the sera were not fresh and some had a slight haemolysis. All of the sera with a high icterus index showed an increased concentration of bilirubin, but many of those that were less deeply coloured showed a normal or only slightly elevated concentration of bilirubin. T h e dark colour of the serum was attributed in part to the consumption of palm oil which can give it a deep yellow colour and may colour the sclera, simulating jaundice. No doubt some of the persons selected because of their " yellow eyes " were not true cases of jaundice. On the other hand, several sera of the 20 selected as " normal " had a slightly elevated icterus index. It is evident that the intensity of the disease is h~ghly variable, with many mild cases (inapparent infections) passing unrecognized. T h e van den Bergh tests of the blood sera gave direct and indirect readings showing the presence of free and bound bilirubin, indicating that rather extensive liver damage had occurred.

Spirochaetal Agglutinations* Although the history and examination of the patients did not suggest Weil's disease, the sera were examined for the presence of agglutinins against Leptospira icterohaemorrhagiae. T h e following results were obtained : Positive agglutination Negative agglutination

Dilutions 1 : 50

Total 1 : 100

10 2 93 By comparison with known sera as controls, the agglutinations in serum dilutions of N o . of sera:

81

84

INFECTIOUS HEPATITIS IN BRITISH WEST AFRICA

1 : 50 were definitely non-specific and those in dilutions of 1 : 100 were of doubtful significance, confirming the clinical impression that the outbreak was not due to spirochaetes. Blood Studies At the time of bleeding for other tests, thin blood films were also made and examined later. Fifty-four were considered satisfactory for examination and were stained (Giemsa). It was of interest that 25 (46 per cent.) showed a pronounced achromia. Judged qualitatively, leucopenia was present in three films and leucocytosis in 16. Malaria parasites were found in four films and filaria in five. Twenty-two (40.7 per cent.) of the films were judged to be within the normal limits of stained films in all respects. The outstanding observations were the relative lymphocytosis and the eosinophilia. Of the total white cell count the lymphocytes constituted over 30 per cent. in 43 (80 per cent.) of the films, and the eosinophils over 4 per cent. in 30 (56 per cent.) of the films. The former probably is related to the illness (jaundice), and the latter to the high incidence of intestinal parasites in the population as reported by the medical officer. General Observations During the interrogation and examination of patients in Unwana and other localities on the west side of the river, it was noticed that the general population was conspicuously undernourished. This was particularly true at Unwana. Not only were the people underweight but also there was evidence of a quantitative deficiency. Nearly all had dry, atrophic and scaly skin with hyperkeratosis. Moist desquamation of the mucosa of the lips was frequent, and there was a high incidence of conjunctival changes, especially pterygium. Arcus senilis could be seen even in children. The diet of these people during most of the year is composed largely of yams which are harvested and stored twice a year. Very little meat is available at any time, and palm oil is used extensively in cooking. Fruit and vegetables are utilized very little even when in season. The farming, particularly for yams, is on a communal basis and a certain amount from each farm is set aside and stored for use by the community. A poor harvest affects the entire community. In sharp contrast were the communities on the east side of the river. Their general nutritional state did not show the evidence of deficiency quantitatively or qualitatively. They have a more abundant and mixed diet due in part to greater fertility of the soil and in part to different food habits. Throughout the towns of Ediba and Ugep casual examination of persons in the market places disclosed many with definite jaundice of the eyes. The dispenser knew that the disease had been present for many months, yet few people had reported for treatment and none was severely ill. At Unwana the chiefs and elders stated that many more people than usual had died during the last 3 to 4 months, and many of these had the disease w i t h " yellow eyes." There was no general agreement that the disease affected one sex more than the other, or that any particular age-group was attacked. These gross observations led to the impression that the general nutritional state might be an important factor in the severity of the disease, although of less consequence with respect to the case frequency.

DISCUSSION Regarding the origin and spread of this epidemic, a medical officerstated that 67 cases

RICHARD G. HAHN AND JOHN C. BUGHER

85

had been reported from Ikom, most of them early in the year. Ikom is located on the Cross River up-river from Afikpo and about half-way to Mamfe. Throughout the year there is traffic by road and path from Mature in the Cameroons to Ikom, thence by river clown stream to Afikpo and Calabar; also by path and road to Ugep, which is on the main and only road draining traffic into Ediba on the riverside. The information at hand suggests that the disease followed the main routes of traffic and trade, appearing at Ugep and Ikom before it was known at Unwana and surrounding localities. People in this area live under very primitive conditions of sanitation and housing. At some time of the day or night practically all members of a household or compound are in close proximity to one another. The living conditions and habits provide ample opportunity for the dissemination of disease throughout a household and to other households by the respiratory route, and by the oral-intestinal route through contamination of food and water. There is no control of intermediate hosts or vectors except that exercised by the natural environment. The chief occupation of the people is farming. The absence of beasts of burden or mechanical aids necessitates that all labour is done by hand, a factor which promotes both direct and indirect contact among members of a household and of a community. Water is obtained from shallow wells, small streams or stream beds and one source serves many households, especially during the dry season. These sources are subject to obvious pollution by adults and children. VOECT (1942) demonstrated that the disease, epidemic hepatitis, could be induced in human beings by feeding them with duodenal juice of persons ill with the disease; also, one of his volunteers developed the usual clinical picture in a mild form, and two developed a subclinical or inapparent infection as demonstrated by liver tolerance tests. Undoubtedly such cases as the latter two occur in outbreaks of the disease under natural conditions. The reports of CAMERON (1943), MACCALLUM and BRADLEY (1944), and HAVENS et al. (1944, 1945, 1946) have demonstrated that the infectious agent or virus is present in the blood serum and faeces of patients in the early stages (preicteric and icteric) of their illness, and that the ingestion or parenteral administration of the serum and extracts of the faeces will induce the disease in human volunteers. Evidence indicating person-to-person spread of the disease in military groups is cited by GAULD (1946), who also suggests water-borne transmission in one instance, a medium notably implicated in the epidemic at a summer camp reported by NEEFE and STOKES(1945). The latter was explosive in character, as were the small outbreaks attributed to a contaminated milk supply by MURPHY et al. (1946) and to food by READ and his associates (1946). In this epidemic the clinical picture, character and course of the illness readily excluded yellow fever, spirochaetal jaundice and other diseases associated with jaundice. Confusion might arise at times in the differential diagnosis of infectious hepatitis and infectious mononucleosis, particularly when only a few persons are involved. In large outbreaks there are striking differences. Among a relatively large number of patients with infectious mononucleosis WECHSLER, ROSENBLUMand SILLS (1946) reported an incidence of 6 per cent. with jaundice and 73 per cent. with pharyngeal involvement; BENNETT et al. (1950) found 11 per cent. with jaundice and only 5 per cent. with gastro-intestinal symptoms, findings considerably different than those reported here. A number of the prevalent diseases in this area are treated by intramuscular injections. It is the practice to assemble groups of persons for mass treatments. Under these conditions

86

INFECTIOUS HEPATITIS I N BRITISH WEST AFRICA

it is well to bear in mind experiences such as that reported by DROLET (1945), and the possibility that with inadequate sterilization of needles and syringes the icterogenic virus may be transferred from an infected to an uninfected person, complicating the picture with homologous serum jaundice. Considering that many persons have a very mild or an inapparent illness without frank jaundice, it is possible that some present themselves for treatment of one of the prevalent diseases such as yaws and thereby serve as a source for transmission of the virus. It is our impression that this possibility had little if any part in the present outbreak. The inquiries in several of the affected communities showed that very few of the people had had parenteral treatment for any illness. In some instances there were suggestions that the outbreak was of a rather explosive nature, for a relatively large proportion of those who had frank jaundice had developed it within a few weeks of each other. Similarly, those who had been ill for 2 months or more stated that about the time they had become ill, many other persons were affected in varying degrees of severity and chronicity. During this survey it was not possible to obtain specific information as to the method of transmission of the disease. It was quite clear that ample opportunities existed for dissemination by any of the usual modes--person-to-person, the intestinal-oral route, or via some intermediate arthropod vector. S U M M A R Y

An outbreak of infectious hepatitis was observed among Africans in localities on both sides of the Cross River in the vicinity of Afikpo, Nigeria. Althoughthe disease had a high incidence in all these localities, as judged by the number with frank jaundice, the illness was universally mild among those living on the east side of the river and fatalities were unknown, while among those on the west side there were many persons affected severely and even fatally. Among the latter there was conspicuous evidence of gross malnutrition, both quantitative and qualitative, which was not present among the former; and it is suggested that this might have had some bearing on the severity of the disease. REFERENCES BEEUWKES,H., WOLCOTT,A. M. ~ KUMM,H. W. (1931). Trans. R. Soc. trop. ivied. Hyg., 24, 429. BENNirrr, H. D., FRANKEL,J. J., BEDINGER,P. & BAKER,L. A. (1950). Arch. intern, iVied., 86, 391. Bull. U.S. Army med. Dept., (1944). No. 76, 23 (Editorial). CAMERON,J. D. S. (1943). Quart. ft. ivied., 12, 139. DALZIEL,J. H. & JOIrNSON, W. B. (1915). Yell. Fev. Bur. Bull. Supplement. 2, 561. DROL~r, H. (1945). Brit. ,ned. 07., 1, 623. GAULD, R. L. (1946). Amer. ft. Hyg., 43, 248. H^vmqs, W. P., JR. (1945). Proc. Soc. exp. Biol., 58, 203. (1946). ft. exp. ivied., 83, 251. --, WARD,R., DRILL, V. A. & PAUL,J. R. (1944). Proc. Soc. exp. Biol., 57, 206. MAcCALLUM,F. O. & BRADLEY,W. H. (1944). Lancet, 2, 228. MURPHY, W. J., PETRIE, L. M. & WORK, S. D. JR. (1946). Amer. 07. publ. Hlth., 36, 169. MUWAZI, E. M. K., TROWELL,H. C. & HENNeSSEY,R. S. F. (1942). E. Jlfr. reed. 07, 19, 40. NEEFE, J. R. & STOKES J., JR. (1945). 07. Amer. reed. Ass., 128, 1063. REED, M. R., BANCROFT,H., DOULL, J. A. & PARKER,R. F. (1946). Amer. 07. publ. Hlth., 36, 367. RUSSELLLEONARD,T. M. (1915). Yell. Fev. Bur. Bull., Supplement. 1, 304. VOEGT, H. (1942). Bull. Hyg., 17, 331. WeCHSLm% H. F., ROSENBLUM,A. H. & SILLS, C. T. (1946). Ann. intern. Med., 25, 113 and 236. * Kahn tests, bilirubin studies and spirochaetal agglutinations were made by the Medical Research Institute, Yaba.