Heart disease in severe anaemia

465 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vo]. 50. No. 5. September, 1956.

S T U D I E S IN L E I S H M A N I A S I S IN EAST AFRICA. III.

CLINICALFEATURES AND TREATMENT. BY

P. E. C. MANSON-BAHR AND R. B. HEISCH*

(From the King George V I Hospital, Nairobi, and the Division of Insect-Borne Diseases, Medical Research Laboratory, Kenya).

During a recent outbreak of kala-azar in the Kitui District of Kenya, affecting several thousand Africans, the disease was investigated chiefly from an epidemiological point of view (HEISCH, 1954), though some interesting clinical observations were made by CARSWELL (1953). It is now too late to make a really comprehensive clinical analysis, for the outbreak is on the wane, and only a limited number of cases is available for study. The present paper gives in some detail observations made on 40 patients from Tseikuru, the most severely affected location, where cases are still occurring in small numbers. Many of the observations were made in a temporary hospital near Tseikuru, but sometimes patients were transferred to Nairobi and examined there. CLINICAL FEATURES

The onset of the disease was gradual. Most of the 40 patients had been ill for 3 to 4 months before coming for treatment, a few for as long as 8 months ; nearly all were in the 6-20 age-group. HEISCH (1954) and FENDALL (1952) previously noted a similar age distribution, which according to NAPIER (1954, personal communication) is not unlike that found in India. Thirty-one patients were males and nine females. The chief symptom complained of by 36 of the 40 patients, was pain or discomfort below the left costal margin due to enlargement of the spleen. Cough with or without sputum was fairly common being present in 24 cases. Four of 19 patients had generalized bronchitis with numerous rhonchi in both lungs. Fever was not as common as might have been expected, and only 22 complained of febrile symptoms such as headache, backache and shivering. There is some evidence that fever was more marked at the onset of the disease. Of the 40 cases, nine were apyrexial and 21 had slight fever with a temperature of 99 to 100°F ; in ten the temperature was 101 to 102°F. As is usual in kala-azar, the patients felt reasonably well and all were ambulant. The disease round Kitui seems less severe than that seen in the Northern Province of Kenya where affected persons (Somalis) had marked pyrexia, the temperature sometimes reaching 104°F. We wish to thank the Director of Medical Services, Kenya, for permission to publish this paper.

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LEISHlVIANIASlS IN" EAST AFRICA

Epistaxis was fairly common, and 17 of the patients had one or more attacks which were never severe. Haemorrhage from other mucous membranes was never observed. Diarrhoea, though not very common, occurred in 11 cases ; loose stools were passed intermittently but contained no blood. T h e condition was probably due to an intercurrent enteric infection. Tinnitus was noted, and eight patients complained of noises in one or both ears at some stage of the illness ; there was no deafness or giddiness and the symptoms were intermittent. T h e ears contained no wax, and the drums and hearing were normal. Patients were thin and the only signs of nutritional deficiency were dryness of the skin with some scaling of the shins. One patient had some oedema of the shins and lumbar region, with a moderate degree of a albuminuria suggesting renal involvement. Altogether 10 patients had some albumin in the urine, but no pus or red cells. T h e spleen was invariably enlarged, the lower edge being palable two to eight inches below the left costal margin. T h e organ was always hard, freely moveable, and occasionally slightly tender. Leishmania were present in 39 of the 40 spleens. T h e liver was palable in 34 of the cases. T h e enlargement was usually slight and never exceeded four inches below the costal margin. Cirrhosis was found in one of 19 liver biopsies; and one patient developed toxic jaundice. Leishmania were present in 18 of 19 liver smears examined. Enlargement of the lymphatic glands was especially common. T h e posterior cervicals were involved on one or both sides in 13 of the 40 patients, and the axillary glands in 35 ; the inguinals were bilaterally involved in 35, and the femorals on one or both sides in 30. T h e enlargement was never marked, and the glands were usually freely moveable and shotty in texture. T h e axillary enlargement was especially significant, as in Africans these glands are seldom affected by chronic inflammation. KIRK and SATI (1940) quite frequently noted lymphatic enlargement in Sudanese kala-azar, and Leishmania were easily found in smears. In Kenya, parasites were present in the lymphatic glands in 20 of 31 cases. T h e r e was never any cardiac enlargement nor signs of heart failure. One patient had a systolic apical murmur. T h e blood pressure was usually low. T h e systolic pressure was over 120 mm. in two out of 34 cases ; from 111-120 in four ; 101-110 in seven ; 90-100 in fifteen ; and below 90 in six. No definite neurological signs were observed, though the knee and ankle jerks were sometimes absent ; signs of peripheral neuritis were never observed. Varying degrees of anaemia usually developed as early as 2 to 3 months after the onset of the infection. Of the 40 patients, the haemoglobin was 5-6 g. in four ; 6-7 g. in three ; 7-8 g. in 16 ; 8-9 g. in six ; and over 9 g. in eleven. T h e anaemia was normochromic and normocytic. T h e mean corpuscular volume in three cases was 105, 100 and 98 ; and the mean haemoglobin concentration 33, 30 and 34 per cent., respectively. T h e anaemia observed by COLE (1954) in most of his patients was more severe, but they were suffering from an acute toxic form of kala-azar. Leucopenia was not invariably present, and when it occurred took about 3 months to develop. T h e total white cells were below 2000 per c.mm. in seven cases ; 2-3000 in 13 ; 3-¢000 in eight ; ¢-5000 in five ; and over 5000 in seven. T h e white count showed a relative diminution in the n u m b e r of polymorphs early in the disease, but in six cases they were over 50 per cent. of the total. T h e formol-gel test was invariably positive 3 months after the onset of the disease, and was found to be a very useful diagnostic guide. In the 40 cases the test was negative only in four patients

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467

who had been ill for less than 3 months. In 12 cases of chronic brucellosis, the formolgel test was negative. A large number of blood smears from the 40 patients were searched for Leishmania using SHORTT'S technique (SHORTT et al., 1927), five being from patients with heavily infected spleens, but all were negative. Parasites have been seen in the peripheral blood on only one occasion. It is probable, however, that Leishmania are quite frequently present in the blood for LOWRY (personal communication) obtained positive blood cultures in about 60 per cent. of his cases, and we have had positive results on a number of occasions. In Indian kala-azar, SHORTT et al. (1927) saw parasites in the blood of 98.7 per cent. of their patients ; and KNOWLES and DAS GUPTA (1924) in 67 per cent. In the Kapoeta District of the Sudan, ARCHIBALDand MANSOUR (1937) found parasites in the blood of patients with heavily infected spleens but in the Fung District where infections were light, blood films were always negative for Leishmania. HENDERSON(1937), however, found parasites in the blood of 1 per cent. of subjects in the Fung District. WANG (1937) in China, using SHORTT'S technique, found parasites in 39 per cent. of his cases. We are of the opinion that, with the possible exception of Indian kala-azar, examination of blood films for Leishmania is an unreliable and laborious technique, blood culture being far more reliable. Leishmania were present in 14 of 18 marrow smears. (1) (2)

Skin lesions were not uncommon and were of two types :small circumscribed lesions concurrent with the visceral disease, and those included under the term post-kala-azar dermal leishmaniasis.

The solitary circumscribed lesions were always single, and were seen both during first and second attacks of kala-azar ; they were seen in five of the 40 cases, and were almost invariably present on the lower part of the legs, although one was found on the lower part of the back of a child. The lesions were small irregular and sometimes circular hyperpigmented areas from 0.5 to 6 cm. in diameter, often having a central depigmented scar. Leishmania were very numerous in some and extremely scanty in others ; they were usually more numerous in the centre than towards the periphery. The lesions looked remarkably like small healed tropical ulcers. Leishmania were looked for in smears from skin biopsies and in sections of the skin prepared by the Giemsa colophonium method (SHORTT and COOPER, 1948) which demonstrates the parasites vividly with brilliant staining. In some patients smears were taken from apparently normal skin, about six smears being prepared from different parts of the body : results were negative. It is considered possible that the circumscribed lesions are either healed primary chancres following the bites of infected sandflies, or that the presence of Leishmania is a result of trauma. Row (1912) produced a local lesion in the skin of a monkey by inoculating L. donovani intracutaneously. MIRZOIAN(1941) in Asia, and KIRK (1938) in the Sudan, have described facial papules containing Leishmania which apparently preceded the visceral disease. KIRK (1942) described indistinct papules and small ulcers on the head and legs containing Leishmania in 30 per cent. of a group of cases in the Sudan. One lesion on the left shin in an untreated early case, was observed for 3 months during which time the hyperpigmented area decreased in size, and a small area of ulceration in the centre healed. At first the lesion contained numerous Leishmania which were more numerous in the centre than at the edge ; later, after partial healing, parasites became very scanty. Examination of sections, showed Leishmania in large macrophages lying in granulation tissue, with round cells, plasma cells, and newly formed blood vessels. The parasites were usually seen just below the epidermis, sometimes deeper. Although there is no proof that this was a primary

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lesion, the site is suggestive, for anthropophilic sandflies round Kitui have been caught only biting below the knee. Post-kala-azar dermal ]eishmaniasis was uncommon and only observed nine times during the present epidemic ; none of the 40 patients showed it. The eruption consisted of papules and depigmented petechiae which started on the face and neck and later spread to the legs and arms ; it was never marked on the trunk. Leishmania were only seen once in skin smears, and never in sections. In five patients the rash did not appear until I-9 months after treatment. This seems different from cases seen in the Sudan (KIRK and SATI, 1940), and from near Lake Rudolph (COLE, 1944), where the eruption usually appeared during or immediately after treatment, and lasted for a comparatively short time. In Indian kala-azar the rash is said not to appear for 1-2 years after treatment, and persists for a long time (NAPIER and DAS GUPTA, 1930). The nature of post-kala-azar dermal leishmaniasis is unknown. In two subjects seen during the Second War, the rash appeared after treatment, disappeared when the visceral disease relapsed, and then re-appeared after treatment of the relapse. In two cases the eruption temporarily disappeared after cortisone. Patients with post-kala-azar dermal leishmaniasis never showed signs of visceral involvement. An unusual case was an untreated patient with visceral disease, having a skin eruption almost identical with that described for post-kala-azar dermal leishmaniasis. The eruption was faint and widespread affecting the face, forehead, arms, legs and back. The rash on the face and forehead was mainly papular, and that elsewhere chiefly macular. The back showed some lichenification. Leishmania were widely distributed throughout the skin being present in smears from the forehead, the dorsum of the forearm, the back, and from over the right internal malleolus, where there was what looked like a healed tropical ulcer. There was some depigmentation round the mouth. The spleen was enlarged and contained Leishmania. The blood culture was negative. Generalized eruptions in untreated cases of visceral leishmaniasis have been noted before in India and China (CHRISTOPHERS, 1904 ; CASH and HIJ, 1927), with Leishmania in the skin. The distribution of parasites in the skin of such patients is rather similar to that found in dogs in certain parts of the world, and it seems possible that these persons are as important reservoirs as their canine counterparts. Although cancrum oris was not uncommon in untreated cases, true muco-cutaneous lesions, as described by KIRK (1942) in the Sudan, were never seen. However, PIERS (1947) has described typical espundia in a Mkamba from the Kitui District. East African kala-azar, like the Sudan variety, shows a marked tendency to relapse even after intensive treatment. In the present series, 12 had experienced more than one attack ; one had two ; and two, three attacks. The later attacks, which usually occurred 1-2 years after treatment, were presumably relapses, though some may have been re-infections. NAPIER and KRISHNAN (1931) analysed a large number of relapses in India, and concluded that in only two of them was there a possibility of re-infection. COLE (1944) is of the opinion that if a patient is still well 6 months after treatment he will never relapse ; our findings conflict with this view. Although the 40 patients showed mild symptoms, this may have been because they were examined towards the end of the epidemic. The disease in East Africa can be very severe, and a number of acute toxic cases, with bleeding from mucous membranes, have been admitted to the King George VIth Hospital, Nairobi, from time to time. Some of

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P. E. C. MANSON-BAHR AND R. B. HEISCH

these patients had nephritic complications with gross oedema, heavy albuminuria, and high fever, the nephritis resembling the Type 2 variety. A severely ill child was seen by one of us (R. B. H.) at Saricho on the Uaso River in the Northern Province of Kenya in 1942 ; and COLE (1944) noted severe symptoms in African soldiers who became infected near Lake Rudolph during the second World War. A striking feature of toxic cases in the Northern Province o f Kenya was marked wasting of the intercostal muscles, and a heaving cardiac apex beat was often visible from a distance. FENDALL(1952) also noted intercostal wasting in some of the early cases seen by him round Kitui. Mild ambulant cases with little or no fever, and varying degrees of splenomegaly, have been found near Machakos as well as in the Kitui District. It is considered possible that such mild infections may be dangerous and act as reservoirs perpetuating the infection for long periods. However, there is no actual proof of this, and we do not know at what stage in the patient's illness he is infective for sandflies, and whether they become infected from the skin, the blood, or both. Recently in the Kitui District during a month of low incidence, 10 mild eases of kala-azar, four of which had relapsed, were found amongst 448 persons examined in the field ; four had circumscribed lesions on the legs containing Leishmania. Clinically, East African kala-azar resembles the Sudan variety, though there are perhaps some slight differences. Both types differ from the Indian form of the disease. Some of these differences are now tabulated : Indian kala-azar

Sudanese kala-azar

East African kala-azar

Skin lesions w i t h visceral disease

D o n o t occur

Fairly c o m m o n o n h e a d and legs

S o m e t i m e s seen o n legs

F r e q u e n c y of Leishmania in b l o o d

O f t e n seen

Rarely seen

Rarely seen

R e s p o n s e to t r e a t m e n t w i t h trivalent antimony.

Good

Little or none.

Little or n o n e .

I n c i d e n c e of relapses.

Not common.

Common.

Common.

Post-kala-azar

L a t e n t p e r i o d 1-2 years, d u r a t i o n long, f o u n d i n 5-

Little or n o latent period, d u r a t i o n short, f o u n d in 30% cases

Latent

leishmaniasis.

dermal

10% cases.

p e r i o d 5-9 months, duration found in a very small proportion of cases.

Post-kala-azar dermal leishmaniasis is usually common in areas like Bengal where kala-azar has been present for a long time, and rare in places like Assam where the disease is of more recent introduction. The low incidence round Kitui suggests that the disease had been introduced quite recently. With regard to diagnosis. Acute toxic kala-azar must be differentiated from other acute fevers such as typhoid, typhus, essential thrombocytopenia, and pulmonary and miliary tuberculosis. The toxic form of the disease can easily be overlooked, particularly when there is an epidemic amongst large bodies of men visiting a kala-azar area for the first time. Chronic brucellosis with a moderate enlargement of the spleen can easily be mistaken for the less acute forms of kala-azar, but as previously noted, the formol-gel test is of great

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L E I S H M A N I A S I S I N E A S T AFRICA

value in distinguishing the two conditions. During a recent survey at Tseikuru, 12 patients with brucellosis came for treatment, and all had negative formol-gel reactions. Other causes of splenic enlargement such as mansonian schistosomiasis, cirrhosis of the liver, and chronic malaria must also be excluded. TREATMENT.

East African kala-azar, like the Sudanese variety is extremely resistant to treatment, and trivalent antimony compounds, such as tartar emetic, are of little value. The remarks which follow are partly general in nature and do not only refer to the 40 cases in the present series. The chief drugs used during the Kitui epidemic were urea stibamine, pentostam and pentamidine isethionate. However, during the war, two patients in the Northern Province of Kenya, were treated with stilbamidine (HEIsCH, 1947). The initial response was dramatic the temperature falling in a few days ; one patient was cured but the other relapsed. COLE (1944) also treated 14 patients with the same drug and cured seven, the others relapsing and needing several courses of the drug before they were cured. Twelve intravenous injections were given over a period of 14 to 30 days, each patient receiving a total of 1 to 1.3 gramme. Stilbamidine fell into disrepute because of occasional toxic symptoms, but perhaps it should be given a further trial. Of the other drugs, urea stibamine seems the most effective. There was often a marked response to even one course of treatment, and in one child the spleen became impalpable and the formol-gel test negative, after courses of pentamidine and pentostam combined and pentostam alone had proved ineffective. We now give six daily intravenous injections of 0.17 gramme making a total of 1.0 gramme for an adult. This has reduced the time of treatment. Pentamidine isethionate (4:4' diamidine diphenoxypentane) has been used alone. An adult is given 10 daily intramuscular injections, which total 2.0 grammes. Although superior to trivalent antimony compounds, Leishmania were sometimes present in the spleen after a full course. The drug by itself gives a lower cure rate than either pentostam or urea stibamine ; this is also the experience of FENDALL (1952). Pentostam (nitrogen glucoside of sodium p-amino phenyl stibinate) has been used extensively in the treatment of East African kala-azar since 1952. Four ml. (0.4 gm.) were given daily by intramuscular injection to adults and 2 ml. to children ; 10 daily injections were given. Results were sometimes excellent, and 13 subjects treated with one course were all well 3-12 months later, with impalable spleens and negative formol-gel reactions. On another occasion a small series was almost completely resistant to pentostam therapy. For the last 2 years patients have been treated with pentostam and pentamidine combined ; a course of pentamidine being followed by one of pentostam. Of 28 patients treated in this way and examined 1-2 years later, 13 were apparently cured, but 15 still had considerable splenic enlargement. Twelve of the 15 were tested and one had a positive formolgel test with Leishmania in the spleen. However, spleen smears were only examined from six of the 12 patients. It is difficult to draw conclusions from such incomplete results but the combined treatment seems superior to either drug given alone. That the combined treatment is not really satisfactory, is shown by the fact, that 17 to 50 per cent. of patients seen at Tseikuru during 1954 and 1955, had previously received it. The disease round Kitui seems more resistant than Sudanese kala-azar which is usually quite easily cured by pentostam alone (KIRK, personal communication).

P. E. C. MANSON-BAHRAND R. B. HEISCH

471

SUMMARY.

(1) A description is given of the clinical feature of 40 cases of kala-azar from the Kitui district of Kenya. (2) T h e chief symptom was pain and discomfort beneath the left costal margin. Cough, epistaxis, diarrhoea, tinnitus, headache, backache and shivering were also noted. (3) Enlargement of the spleen, liver and lymph glands was present in most of the cases. Fever was slight, and never exceeded 102°F. T h e r e was usually a moderate normochromic, normocyfic anaemia, and only half showed a leucopenia. T h e formol-gel test was invariably positive 3 months after the onset of the disease. (4) Leishmania were present most commonly in the spleen and liver, and sometimes in the lymphatic glands and marrow. Parasites were not seen in the blood of any of the 40 patients. (5) Small solitary circumscribed skin lesions containing Leishmania were sometimes observed on the legs. None of the 40 patients showed post-kala-azar dermal leishmaniasis, but the condition has been seen on several occasions, and one untreated subject of kalaazar had a generalized eruption with parasites widely distributed in the skin. (6) Pentamidine, pentostam, and urea stibamine were used in treatment. Urea stibamine was the most effective, though a combined course of pentostam and pentamidine cured many patients. T h e disease round Kitui was very resistant to treatment. REFERENCES ARCHIBALD, R. G. & MANSOUR, H. (1937). Trans. R. Soc. trop. Med. Hyd., 30, 395. CARSWELL, J. (1953). E. Aft. reed. J., 30, 278.

CASH, J. R. & Hv, C. H. (1927). J. Miner. reed. Ass., 89, 1576. CHRISTOPHERS, S. R. (1904). Sci. Mere. reed. san. Dep. India Ns., No. 11. COLE, A. C. E. (1944). Trans. R. Soc. trop. Med. Hyg., 37, 409. FENDALL, N. R. E. (1952). J. trop. Med. Hyg., 55, 193. HEISCH, R. B. (1947). E. Afr. med. J., 24, 11. - (1954). Trans. R. Soc. trop. Med. Hyg., 48, 449. HENDERSON, g. H. (1937). 1bid., 31, 179. KIRK, R. (1938). Ibid., 32, 271. - (1942). Ibid., 35, 257. - & SATI, M. M. (1940). Ibid., 34, 213. KNOWLES, R. & DAS GUPTA, B. M. (1924). Indian reed. Gaz., 59, 438. MIRZOIAN, N. A. (1941). Med. Parasit., Moscow., 10, 101. (Abstr. Trop. Dis. Bull., 40, 295). NAPIER, L. E. & GUPTA, C. R. DAS (1930). Indian reed. Gaz., 65, 249. & KRISHNAN, K. U. (1931). Ibid., 66, 603. PIERS, F. (1947). Trans. R. Soc. trop. Med. Hyg., 40, 713. Row, R. (1912). J. trop. Med. Hyg., 15, 327, and (1913), 16, 1. SHORTT, H. E., DAS, S. & LAL, C. (1927). Indian J. reed. Res., 15, 529. - & COOPER, W. (1948). Trans. R. Soc. trop. Med. Hyg., 41, 427. WANG, C. W. (1937). Chin. med. J., 52, 433.