TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1984) 78, 391-398 391

Epidemiological, clinical and therapeutic features of Bihar kala-azar (including post kala-azar dermal leishmaniasis)

C. P. THAKUR Pam Medical College, Patna, India

Summary This epidemic of kala-azar in Bihar, India, started from a small block and gradually spread to

almost all of North Bihar. Vaishali was the district most affected. with the highest incidence rate of 5.9 per thousand in 1978. The epidemic spread more to the east than to the w&t. In 1977 there were 100,000 cases of kala-azar in Bihar and in Vaishali district the death rate was 28.7%0 of affected cases. It took five years to control the epidemic. 750 parasitologically confirmed cases of kala-azar were studied. The male : female ratio was 5*5:1. 63.4% of cases were aged 10 to 29 years. Clinical features were classical.

Sodium stibogluconate, used as a first line drug, was effective in 92.6% of cases. By increasing the course of antimonial therapy from 10 to 20 days the relapse rate was reduced to 0.5% compared with 15% in the previous epidemic. Kala-azar patients who also had tuberculosis were treated with the antimonial and antituberculosis drugs concurrently and all cases recovered. 86 cases unresponsive to sodium stibogluconate were given pentamidine, which was effective in 93.4%. Side effects with sodium stibogluconate were minimal, but were common and serious with pentamidine. The need for a safer drug effective in cases which do not respond to antimony was very evident. 20 cases of post kala-azar dermal leishmaniasis (PKDL) were reviewed: two had no previous previous history of kala-azar. The relapse rate was higher in PKDL than in kala-azar.

Introduction The previous epidemic of kala-azar in Bihar, India

(Fig. 1) ended in the late 195Os, mainly as a result of the incidental effect of residual DDT spraying undertaken under the National Malaria Eradication Programme (WHO, 1978). The DDT spraying pro- gramme ended in 1962-63, but sporadic cases of kala-azar continued to visit hospitals and cases of post kala-azar dermal leishmaniasis (PKDL) were reported from Bihar (SINGH, 1968). Sporadic cases of kala-azar were also reported from other parts of India (GON et al., 1975; KHAN et al., 1975.; MOOKHERJEE et al., 1975). The rise in vector density after DDT spraying was discontinued, together with an available reservoir of infection in PKDL and kala-azar cases led to the increase in the number of cases of kala-azar in the early 1970s. SEN GUPTA (1962) rightly predicted that when the residual effect of insecticiding for malaria control ended, vector density would rise and a severe epidemic of kala-azar would follow.

According to a survey conducted by the National Institute of Communicable diseases and Government of Bihar, there were 100,000 cases of kala-azar in Bihar in 1977 (ICMR, 1977) and 40,000 cases in 1978 (WHO, 1980). The public health importance of this disease can be gauged from the fact that in 1977, 100,000 out of the 400,000 new cases of leishmaniasis occurring every year in the world, were in Bihar. This report is based on a study of the epidemiological clinical and therapeutic features of 750 cases of kala-azar in Patna Medical College between 1971 and 1981.

Materials and Methods 750 cases of kala-azar, confirmed by demonstration of

amstigotes in the aspirates of bone marrow or spleen, were included in the study.

The patients were referred by their doctor or from other hospitals or came directly for consultation as, in the initial stage of the epidemic, the sites affected were near the hospital; only the River Ganges separates Patna Medical gsf;~; on the southern bank from affected areas m Vaishah

Information about the epidemic was collected from patients, their relatives, civil surgeons (medical officer-in- charge of the district), local practitioners, the kala-azar office of the Government of Bihar and personal visits to the affected areas by the author. History and clinical examina- tions were recorded in detail on a proforma devised for this purpose. Facts concerning the incubation period were also probed in detail. Liver enlargement was measured in cm from the costal margin. Splenic enlargement was measured in cm along the longitudinal axis from the costal margin to the tip in the anterior axillary line. Investigations included total and differential leucocyte counts, estimation of haemoglobin, erythrocyte and platelet count, examination of stools for worm infections, urine for any renal involvement, aldehyde test (MANSON-BAHR, 1972), serum protein concen- tration, electrophoresis of plasma proteins and liver function tests (SGPT and serum bilirubin). Bone marrow aspirates were examined for parasites and haematological features. Splenic puncture was carried out in only five cases when parasites were not found on bone marrow study and there was a strong clinical suspicion of the disease.

All the fresh cases were treated with sodium stiboglucon- ate (available as a 30% solution of pentavalent antimony, 1 ml containing 100 mg of Sb. (Pentostam, Wellcome Foundation Ltd., London; sodium stibogluconate, Albert David, India; Dibanate, DB Pharmaceutical, India; Stilban- ate, Gluconate Ltd., sodium antimony gluconate, Amoco Pharmaceutical, India; Abanate, Amoco Pharmaceutical India).

At first, adults were given 200 mg of antimony, i.e. 2.0 ml of the drug was given on the first day, 300 mg on the second day and then 6.0 ml daily to a total of 6.0 g, i.e., a lo-day course. After an interval of 10 days, patients were assessed

Address for correspondence: Patna-800001, India.

392 KALA-AZAR IN BIHAR, INDIA

and if required another course of lb injections of 6.0 ml daily was given. Children were given 3.0 ml intramuscularly for 10 days and the dose was repeated after a gap of 10 days. This treatment very soon changed.

Because of the higher incidence of relapses it was thought better to complete 12.0 g of antimony, i.e., 20 injections of 6.0 ml daily for 20 days, because it seemed possible that unresponsiveness to antimony or relapse might be due to the short course of treatment. Test dosage for two to three days proved unnecessary as we found no instance of hypersensi- tivity. As the body-weight of the patients varied greatly it was realized that dosage was better calculated on the basis of body-weight in the range 10 mg Sb per kg for adults and 20 mg Sb per kg for children (WHO, 1982). This regimen was Allowed -

On completion of the 20-day course, the patients were assessed clinically and parasitologically. Initial cure meant abatement of the fever,.improvement in general health and regression in the size of the spleen; parasitological response meant absence of parasites in aspirates after completion of one 20-day course of treatment. Those who responded were advised to attend for follow-up and those who showed no response were transferred to the pentamidine group. Those cases who showed a delayed response, in whom regression in the size of the spleen was slow and aspirates bone marrow showed no diminution in parasite load (WHO, 1982), were given a further lo-day course of sodium sttbogluconate. Patients who did not respond clinically or parasitologically to treatment for 30 days with sodium stibogluconate (18 g Sb) or those referred to us with a history of unresponsiveness to 12 g Sb, were treated with pentamidine, after parasite load had been estimated from bone marrow smears (WHO, 1982). Pentamidine was initially available as pentamidine isethionate (Pentamidine, May & Barker), 200 mg dry powder in ampoule form and was dissolved in 10 ml of normal saline before administration. Later it was available in solution form as Pentamidine dimethanesulphonate (Lomi- dine, Specia). Injections were given slowly intravenously or intramuscularly in the dosage of 4 mg/kg body-weight every second or third day to a total of 15 injections. Glucose drinks were given as advised by MAEGRAITH (1973). After comple- tion of a course of pentamidine the patients were assessed clinically and parasitologically for response. If there was a slow response and parasites persisted, one more course of 15 injections was given after an interval of 10 days.

Patients with concurrent tuberculosis were treated with antimony and INH, streptomycin and rifarnpicin.

Intercurrent infection was sought and treated. Diarrhoea was treated with oral electrolyte mixture or with intravenous fluid if there was severe dehydration and chemotherapeutic agents as indicated by pathological findings.

Patients with Hb below 6.0 g/d1 were closely watched and ferrous sulphate (200 mg three times a day) was given if there was associated hookworm infection. If Hb was below 4.0 g/d1 and the general condition of the patient was poor, a blood transfusion was given. Blood transfusions were given to all cases with haemorrhage. Protein-calorie malnutrition was treated with oral protein supplement. Final cure was defined as initial cure and absence of parasites in bone marrow aspitates two months after the start of treatment, and no relapse for 12 months.

Incidence rate per 1000 was calculated as: total number of kala-azar cases x 1000

total population in one year.

Death rate per 100 was calculated as: deaths from kala-azar x 1000 total number of kala-azar cases

in one year.

20 parasitologically confirmed cases of PKDL were asked about a history of kala-azar and its treatment.

Patients were followed up monthly for 12 months. Haemoglobin was assessed, total and differential WBC counts were made, and total serum proteins were estimated.

C. P. THAKUR 393

Blood sugar was estimated in the pentamidine group at each visit. Bone marrow aspirates were examined in the second monthly follow up. Any illness during this period, which could be due to drug toxicity or relapse of the disease was noted.

Physiography Results

Bihar stretches from Nepal in the north to Orissa in the south, and West Bengal in the east to United Province in the west (Fig. la). It is divided by the River Ganges into the north and south Gangetic plains. The northern portion is almost entirely a level tract, whereas the south of the south Gangetic plain is wooded and hilly. The elevation varies between 300 and 1300 m.

The climate is very hot in summer (38°C to 46°C) and very cold in winter (4” to 8°C). The rainy season is June to September and when the humidity is high maximum temperature drops to below 30” to 35°C in the shade. The annual rainfall is between 100 and 127 cm. The soil is alluvial. Most of the population are either farmers or farm labourers and most farmers have cowsheds, or bathans, where they keep cattle. These cowsheds have been found heavily infested

Fig. 1. Map showing physiography of Bihar and distribution of kala-azar cases by district per 100,000 population of Bihar in 1978.

Key to numbers-names of the districts: (1) Patna, (2) Nalanda, (3) Gaya, (4) Nawadah, (5) Aurangabad, (6) Bhojpur, (7) Rohtas, (8) Saran, (9) Siwan, (10) Gopalganj, (11) East Champaran, (12) West Champaran, (13) Muzaffarpur, (14) Sitamarhi, (15) Vaishali, (16) Darbhanga, (17) Madhubani, (18) Sarnastipur, (19) Bhagalpur, (20) Monghyr, (21) Begusarai, (22) Purnea, (23) Katihar, (24) Saharsa, (25) Dumka, (26) Ranchi, (27) l’alamau, (28) Hazaribagh, (29) Giridih, (30) Singhbhum, (31) Dhanbad.

PLAN OF A REPRESENTATIVE HOMESTEAD

COOKING wm

ONE ROOM HOUSE

HOUSE HOLD CONSISTS THREE ROOMED HOUSE

5 ADULTS A = CATTLE 8 CHILDREN

4 cows 2 BUFFALOES 2 GOATS OR CHICKENS

Fig. 2. Showing representative homestead.

Incidence by district Vaishali was the most heavily affected district. The

incidence of the disease was 3*8%0 in 1977 but it increased to 5.9%0 in 1978. This 1977 official figure was an underestimate. With adequate preventive measures taken and curative facilities provided by the Government, the incidence rate declined to 2.5%0 in 1979, 0*8%0 in 1980 and 0.41%0 in 1981 (Table I).

Not all the villages in the district were affected. A survey of mildly affected villages revealed an inci- dence of 3.3%0 but the incidence in a heavily infected tola (part of a village) was 58.5%0.

Monghyr district was affected during the middle phase of the epidemic, showing a maximum incidence of 0.6 per 1000 in 1979 and Purnea was affected during the last phase of the epidemic, showing a maximum incidence of 1.5%0. The involvement of these and other districts showed that the incidence of the disease was highest in the initial phase of the epidemic.

Incidence by household This varied according to the intensity of the disease

in a particular village. In one village of Vaishali district the disease occurred in 30 of a total of 300 houses surveyed. In another village south of the Ganges (Patna district) one in every four houses was affected. The number of persons infected per house also varied. In one village 30 infected persons belonged to 30 different houses, whereas in another eight of 18 persons in one house were infected. In one family of five, only the wife was unaffected. Where the houses were crowded with cowsheds between, the incidence was higher (Table II).

Table II-Infection rates by household

Area

Total no. No. of of houses affected surveyed houses %

with sandflies. The cattle are looked after by the male members of families of rich farmers and higher castes and by farm labourers. Children often play in the bathans during the day but do not sleep there at night. Females of poor families also tend the cattle.

1. Ismailpur (village) Vaishali District

2. Sabalpur (village) Patna District

300 30 10

125 31 24.9

394 KALA-AZAR IN BIHAR, INDIA

Effect of living conditions The disease occurred mainly in the rural areas

although sporadic cases were seen in towns. The patients lived in houses built of bricks, mud or hay, depending on their economic status (Fig. 2). The pukka houses were either cement plastered inside or mud plastered. Mud plastered houses and rooms had cracks and crevices which form day-time resting places for sandflies (MINTER, 1972). In most houses females and children slept inside and males on the verandah. Two to 25 persons lived in one house.

The cowshed was usually situated just adjacent to the house but in some villages in Vaishala district it was further away, usually in banana fields and cows, buffaloes and goats, were kept there. Muslims kept fowls and ducks there also. In a village south of the Ganges in Patna district, members of one family were infected. The houses and nearby garbage were infected with sandflies.

Death rate The death rate for the whole of Bihar was 12.3%0

patients in 1977 (Table III) and for Vaishali district 28.7%0. With increasing treatment facilities the death rate for all Bihar dropped to 1.4 in 1978 and 0.09 in 1979 and for Vaishali district to O-21 in 1978 and zero in 1979. In most districts the death rate was higher in the initial stage than subsequently. The death rate in Saharsa district was high, 35.08%0 in 1977, 1.47 in 1978,2*75 in 1979? 5.19 in 1980 and 3.9 in 1981. The interior of this district is not easily accessible and medical facilities arrived late.

Seasonal distribution The maximum number of cases was seen from

April to June with a gradual decline subsequently (Fig. 3) The peak was during the summer.

Control of the epidemic As part of the government control measures, cases

were actively detected by house-to-house visits by rural doctors and patients sent for treatment. This increased public awareness, already aroused by press

5 1961

El 1960

MONTHS J-M A-J J-S O-D

Fig. 3. Seasonal distribution of cases in years 1980-81.

C. P. THAKUR 395

old. Males were more affected than females (M:F ratio of 5S:l).

m RS IN LACS al 30- z I.- GlZO- ZllO- El NO OF CASES 2

F’OO- ;: 2

2 90. z E 80-

11 78-79 70 79-W 79 80-82 80 W-82 81

Fig. 4. Showing the relationship between number of cases and money spent on DDT spraying programme.

cn % 50-

2 40-

z 30- 2 a 20 14 16 W lo- 9 a 2

O- o-9 IO-19 20-29 30-39 40-49)50

Age in years Fig. 5. Showing age distribution of patients.

publicity. Government doctors posted to epidemic areas were trained intensively in detecting and treat- ing kala-azar. DDT spraying was done twice a year.

In Vaishali district, which had the most cases, it took five years to control the epidemic (Table I). Occasional new cases and some relapses were seen in 1982. It could not be concluded that the disease had been eradicated. In three districts of the southern plateau (Hazaribagh, Giridih and Dumka) with few cases reported, the disease did not occur in 1981 and 1982. It was difficult to assess the relative roles of DDT spraying and treatment of cases in control. Analysis of expenditure on the preventive programme showed a gradual decline in expenditure on the spraying programme as treatment facilities and drugs became available. Drugs were provided free by the State Government. In spite of the reduction in the budgetary allocation for the spraying programme, the epidemic declined steadily (Fig. 4).

Age and sex distribution Although patients belonged to all age groups, two

thirds were between 10 and 29 years old (Fig. 5) but in one village, 18 of 30 patients were under 10 years

Incubation period The shortest incubation period observed was 40

hours. One patient went to Vaishali district to hunt and stayed for 16 hours; he developed fever after 24 hours. Another short incubation period was in a male who went to Muzaffarpur for three days before returning to Manglore where the developed fever on the 10th day. It was difficult to estimate the incuba- tion period of patients in an epidemic area. In this series the maximum interval between infection of two members of a family was nine months.

Symptoms Fever was the predominant symptom for which

patients sought medical advice: this could be remit- tent, intermittent with a double rise, continuous, or a period of pyrexia followed by a period of apyrexia. The last type of fever caused remission of fever to be ascribed to drugs given by local practitioners. Some cases of fever with toxic symptoms resembled enteric fever and the diagnosis was further confused because of leucopenia. Cases with rigor and fever were clinically indistinguishable from malaria. Some had typical rigor, fever and sweating stages of malaria.

Table IV-Symptoms of patients with kala-azar

Symptoms

1. Febrile

No. of patients %

737 98.1

Intermittent fever with double rise

Continuous fever Intermittent fever With chills With rigors Without chills or rigor

150 20.9 15 2.0

561 74.8 547 72.9

28 3.7 161 21.4

2. Loss of weight 648 86.4 3. Anorexia 107 14.2 4. Cough 42 5.6 5. Swelling of feet 42 5.6 6. Haemoptysis 4 0.5 7. Loose motions 38 5.06

Table V-Physical signs present in patients

Signs

1. Splenomegaly

2. Hepatomegaly 3. Pallor 4. Sparse and brittle

hair 5. Dry and rough skin 6. Pedal oedema 7. Hyperpigmentation of

skin 8. Haemorrhage 9. Jaundice

10. Cancrum oris 11. Ascites

No. of patients

750

738 662

353 280 218

t :

: 4

%

100

Z88.2

46.9 37.3 29.1

8.1 7.1 1.1 0.5 0.5

396 KALA-AZAR IN BIHAR, INDIA

Sometimes patients were unmindful of the fever and more bothered by other symptoms, e.g.., swelling due to splenomegaly (three cases), anorexia and weight loss (five cases), haemorrhagic manifestations (epista- x&-one case, haemoptysis-two cases, purpuric spots-one case), diarrhoea (two cases) and cough (two cases), responding only to antimonial.

Sig?lS The spleen was enlarged in all cases (Table V) and

always more than was the liver in the ratio of 1.4: 1. In some cases, even in the early stage splenic enlarge- ment was more than expected for that duration but this may have been because patients were unmindful of the mild fever and could not be exact about the duration of the illness. In contrast, some chronic cases did not have spleen as large as expected for the duration. Earthen grey pigmentation of the skin was seen all over the body in the early stage of the disease and true hyperpigmentation in late chronic cases.

Table VI-Total leucocyte count in patients with kala-azar

Leucocyte count No. of patients %

1-3 x IO911 3-5 x IO911 4:: 5-7 x lo911 200 26.6 >7 x 109/1 22 2.9

Investigations Aldehyde test of the serum was positive in 612

cases. This test was also non-specific and was negative even in some chronic cases.- Total plasma protein levels varied between 53 and 95 a/l. A reduction in the albumin and rise in the globulin fractions were almost constant features. As the disease advanced, levels of alpha-l, alpha-2 and beta-globulin fell and gamma- globulin rose.

Table VII-Haemoglobin concentration in patients with kala-azar

Haemoglobin No. of W-W patients %

t4 10.9 4-8 5:: 75.7 8-12 10.2 >12 52 3.2

Leucopenia was a constant feature and the degree was related to the duration of illness; complete agranulocytosis, as reported by some workers, was not observed in any of the cases; the lowest count observed was 1300 X 109/1. Granulocytopenia, eosi- nopenia, relative lymphocytosis and monocytosis which varied between 5 and 19% (Table VI) were constant features.

Anaemia tended to increase with the duration of illness but not in all chronic causes. Some of the anaemic cases were also infected with hookworm. Bone marrow studies in this series revealed hypoplasia of the marrow with depletion of erythrocyte precur- sors. Folic acid was not used in any of the cases and anaemia improved as the parent disease improved (Table VII).

The tuberculin skin test was negative in 58 of 63 patients and became positive after treatment in 47.

Result of treatment Sodium stibogluconate and pentamidine showed

cure rates of 91.4 and 93.4% resoectivelv (Table VIII). Side effects were negligible with- sodium stibogluconate but common and serious with penta- midine (Table IX).

Four cases of cancrum oris were encountered in the early phase of the epidemic when drugs were scarce. With specific treatment, general management with blood transfusion and oral protein supplements and crystalline penicillin, cancrum oris improved.

Eight cases of kala-azar also had pulmonary tuber- culosis but in the practitioners’ opinion, the incidence of tuberculosis during this kala-azar epidemic was much less than in the last. It was a coincidence that the kala-azar of all the eight patients was sensitive to pentavalent antimonial. Treatment for tuberculosis and kala-azar was started concurrently and all the patients improved. Malaria (nine cases), hookworm (134) and filariasis (16) associated with kala-azar were also treated concurrently.

Most of the patients treated with antimonials responded with a downward trend in temperature from the second or third day, becoming afebrile by the seventh to tenth day. Those in the pentamidine group who responded showed a fall in temperature by the fifth day and were afebrile by the 10th day.

It took one to three months for the haemoglobin to return to the previous level. A rise in haemoglobin was rapid in early cases and slow in late cases. Weight was regained in one to five months. Earlv cases gained weight- rapidly. Some, who also had some oedema, showed a fall in weight initially. Gamma-globulin returned to normal in one to three months. Total and differential count returned to normal two to four

Table VIII-Results of treatment of patients with kala-azar

No. of Initial Final Drug patients (%) cure (%) cure (%)

Sodium Stibogluconate 658 (100%) 603 (91.6) 602 (91.4) Pentamidine 92 (100%) 86 (93.4) 86 (93.4)

Final cure-patients who were cured with no relapse for one year ** Responded with the same drug.

*** One responded with the same drug and two did not respond.

Unresponsive W)

52 (7.9) l(1.1)

Relapse (%I

Death W)

Nil 5 (5.4%)

C. P. THAKUR 397

Table IX-Side effects of sodium stibogluconate atid pentamidine

Sodium Side effect stibogluconate Pentamidine

1. G.I.T. disturbance 2.9 (%) 14.1 (%) 2. Immediate hypoglycaemia 0 8.2 (%) 3. Collapse 4. Permanent Diabetes i 5. Death 0

maximum temperature below lOO”F, minimum above 40”F, with diurnal variation less than 20”F, abundant vegetation and subsoil water, and a rural environment (NAPIER. 1926: SHIVARAMA KRISHNAN & RAMA- NATHAN, 1967). These factors indicated that the epidemic should have started from Assam or Bengal. Simmering foci of kala-azar and a rise in vector density may have led to this epidemic, or it may have been one of many cycles of kala-azar recurring every 10 to 15 years, -as -suggested by NAPIER (lg46). -

Climatic factors nossiblv favoured the snread of the epidemic towards the east and the drier &mate and more extreme temperatures in U.P. may have pre- vented spread to the west.

Combined measures are needed to orevent future weeks after completion of treatment; delay occurred in chronic cases.

Deaths Five patients died in this series; all were being

treated with pentamidine which caused the deaths. Three deaths were due to hypersensitivity to pentami- dine, which was given intramuscularly in one patient and intravenously in two. The patients developed severe sweating and went into shock and despite treatment died within 6 to 24 hours. One patient developed severe anorexia and weakness after nine injections of pentamidine. Treatment was discon- tinued but in spite of attempts at resuscitation the patient died on the 14th day. The exact cause of death could not be ascertained. One patient developed hepatic failure after the third injection but might have had viral hepatis as some of his family later developed hepatitis.

PKDL 20 cases of PKDL were studied. None belonged to

the author’s series of VL. The minimum incubation period was two years and the maximum seven years. There was no history of obvious kala-azar in two cases, indicating a sub-clinical course of the disease. They had all been treated previously with alternate daily injections of antimony. They did not remember the exact dose of the drug. Lesions in 14 cases were mainly hypopigmented patches with a few papules in eight, in four cases, were mainly papules with some hypopigmented patches in two and nodules in two, and in two cases mainly nodules with papules and hypopigmented patches. The mixed lesions made the diagnosis easier. The face was involved in all cases, the- trunk in 82% and limbs in 46%; four cases had marked eosinoohilia. All cases irnnroved initiallv but 64% relapsed.* Papules disappeared first, then nodules and finally the hypopigmented patches. All cases were cured by repeated courses of treatment. The effect of longer courses (30 days) of antimonial therapy is being assessed.

Discussion Why did this epidemic start in Bihar and what

would have happened if adequate measures had been taken when the first cluster of cases was seen in 19702 As it was, it took five years to control but adequate measures taken in 1970 could have prevented it.

Previous epidemics started from Bengal and spread to Bihar and Assam and these three states were heavily affected in the last epidemic. Certain factors favour the development of epidemics: altitude below 2000 ft above sea level, annual rainfall more than 50 in with a mean humidity over 70%, alluvial soil,

epidemics. These include detection and rapid treat- ment of cases, vector control, good reporting and reporting procedures for VL and public health education by all possible means (see MARINKELLE, 1980).

The measures look ideal but will be expensive to implement. As only demonstration of the parasites in the aspirates could confirm diagnosis a safe, cheap and easy diagnostic method is needed.

Sodium stibogluconate was used as a first line drug but the course of treatment was increased from 10 to 20 days. This treatment regimen was approved at an informal workshop on the chemotherapy of visceral leishmaniasis (WHO, 1982). Test dosing with 1.0 or 2.0 ml, increasing to a dose of 5 ml and alternate-day therapy was abandoned. This antimonial was effective in 92.6% of cases in the present series and side effects were minimal, as found by DASTIDAR (1943, CHAUDHARY (1946) and KIRK & SATI (1947); these results differ from those obtained by MAEGRAITH et al. (1947) who noted severe rigors and febrile reactions in five of eieht oatients. and HUANG (19401 who attributed 17 cases 0; agranulocytosis to pehtava: lent antimonials.

The longer course of treatment may have resulted in the fall in the relanse rate from 15% in the nrevious epidemic (SEN GUP?A, 1953) to 0.5% in thenresent one. The antimonial was also successful in kala-azar associated with tuberculosis. thus disnelline the belief that antimonials fatally aggravated p&no&y tuber- culosis, despite anti-TB drugs (SEN GUPTA, 1960).

7.9% of cases in the present series unresponsive to antimony but most had taken the drug in irregular and inadequate doses. Only three cases with no history of previous antimonial injection failed to respond. In the 1960s when there were only sporadic cases of kala-azar, all patients responded to antimony. As the number of cases increased and the drug was used indiscriminately by local practitioners, so the number of unresponsive cases increased and test dosing may have also contributed to unresponsive- ness. Therapy on alternate days was also unscientific, and most practitioners used a low dose, 3 to 5 ml. Use of the drug under controlled conditions was expected to reduce-the incidence of antimony unresponsive- ness. AIKAT et al. (1979a, b, c), treating patients in rural areas, had fewer antimo~y’unrespo&ive patients in their series. All those unresponsive to antimony responded to pentamidine initially.

Pentamidine, although effective in 93.4% of cases had frequent and severe toxic effects including diabetes which responded only to insulin, and not to

398 KALA-AZAR IN BIHAR, INDIA

hypoglycaemic drugs, and the insulin requirement was high in most cases. Pentamidine was also found to be quite effective by KIRK & MACDONALD (1940), KIRK & SATI (1943), ADAMS (1941), NAPIER & SEN GUFTA (1943) and HAZARIKA (1949) but toxic effects were also observed.

The death rate was very high in the earlier stage of epidemic. This might have been due to shortage of drugs. Later on the death rate became quite low. In this series death was caused by drugs, not by the disease. In Iran, the death rate was about 30% in hospital in-patients as reported by NASAB & SHERAJI (1980) who attributed this to malnutrition and the poor general condition of the patients. In controlled conditions, both the death rate and unresponsiveness could be minimized.

PKDL presented some contrasts to the parent disease: it had a very long incubation period, the relapse rate was very high despite the good therapeu- tic response, and the general health of the patient was not affected in spite of parasites persisting in the body. However, in-depth immunological studies of the parent disease and PKDL are required to elucidate various unexplained features of the disease.

References Adams. A. R. D. (1941). Studies in chemotherauv XXVI. A

cask of Indian kala-azar treated with 4:4’~diamidino diphenoxy pentane. Annals of Tropical Medicine and Parasitology, 35, 53-54.

Aikat, B. K., Sahaya, S., Bhattacharya, P. K., Desai,, N., Prasad, L. S. N., Misra, S. & Jain, S. (1979a). Clinical profile of cases of kala-azar in Bihar. Indian Journal of Medical Research, 70, 563-570.

Aikat, B. K., Mohanty, D., Pathania, A. G. S., Chari, N. C. V., Kumar, S., Sahaya, S. & Prasad, L. S. N. (1970b). Haematological investigations in Indian kala-azar. Indian Journal of Medical Research, 70, 571-582.

Aikat, B. K., Pathania, A. G. S., Sehgal, S., Bhattacharya, P. K., Dutta, U., Pasricha, N., Singh, S., Parma, R. S., Sahaya, S. & Prasad, L. S. N. (1979~). Immunological responses in Indian kala-azar. Indian Journal of Medical Research, 70, 583-590.

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Accepted for publication 28th November, 1983.