Visceral Leishmaniasis in the Sudan: Clinical and Hematological Features
1990; King Faisal Specialist Hospital and Research Centre; Volume: 10; Issue: 1 Linguagem: Inglês
10.5144/0256-4947.1990.51
ISSN0975-4466
AutoresA.M. El-Hassan, Mirghani A.M. Ahmed, Abdulgaffar Abdul Rahim, A A Satir, A. I. Wasfi, Anwar Ahmed Kordofani, Mustafa D. Mustafa, Salah Wasfi, Hassan Bella, Mohammed O. Karrar,
Tópico(s)Trypanosoma species research and implications
ResumoOriginal ArticlesVisceral Leishmaniasis in the Sudan: Clinical and Hematological Features Ahmed M. El-Hassan, MD Mirghani A. M. Ahmed, MD Abdulgaffar Abdul Rahim, MD Ali Abdul Satir, MD Abdulmoneim Wasfi, MD Anwar A. Y. Kordofani, MD Mustafa D. Mustafa, MD Salah Wasfi, MD Hassan Bella, and MD Mohammed O. KarrarMD Ahmed M. El-Hassan From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Mirghani A. M. Ahmed Address reprint requests and correspondence to Dr. Ahmed: College of Medicine and Medical Sciences, King Faisal University, Dammam 31451, Saudi Arabia. From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Abdulgaffar Abdul Rahim From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Ali Abdul Satir From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Abdulmoneim Wasfi From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Anwar A. Y. Kordofani From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Mustafa D. Mustafa From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Salah Wasfi From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , Hassan Bella From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan , and Mohammed O. Karrar From the Institute of Tropical Medicine, Faculty of Medicine. University of Khartoum, and Ministry of Health, Khartoum, Sudan Published Online:1 Jan 1990https://doi.org/10.5144/0256-4947.1990.51SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractThe clinical and hematological features and response to therapy in 17 Sudanese patients with visceral leishmaniasis are described. The clinical features in our cases were similar to those described from Ethiopia and East Africa. Fever, hepatosplenomegaly, leukopenia, lymphopenia, and thrombocytopenia were common findings. An unusual feature is the relatively high frequency of hepatic dysfunction. One patient died of cerebral hemorrhage and another of gastrointestinal bleeding. Hemorrhagic manifestations were attributed to immune complex vasculitis and thrombocytopenia. The response to sodium stibogluconate was good.IntroductionVisceral leishmaniasis is endemic in several areas of the Sudan. The disease occurs in an area that extends from Kassala on the Sudanese Ethiopian border to Malakal and Nasir in the Upper Nile Province. It also occurs in the Kapoeta region of Equatoria Province in the southern Sudan and Darfur Province in the western part of the country. A form affecting children has recently been identified in Khartoum Province.1The clinical features of visceral leishmaniasis have been described in patients from the provinces of the Blue Nile,2 Equatoria,3 Kordofan, Darfur,4 and the Upper Nile5 (Figure 1). Since most of the reports are at least twenty years old, we thought it worthwhile to study Sudanese visceral leishmaniasis in more depth, concentrating on aspects that were not addressed by previous investigators.Figure 1. Map of the Sudan showing the kala-azar endemic areas.Download FigureMATERIAL AND METHODSSeventeen patients were seen for the first time at the Hospital for Tropical Diseases in Omdur-man. The diagnosis was made by the microscopic demonstration of amastigotes in bone marrow smears and in some patients by lymph node aspiration as well.A complete history was obtained and clinical examination performed. Investigations included: chest x-ray study, electrocardiogram, urinalysis, thick and thin blood films for malaria parasites, stool examination, peripheral blood counts, coagulation studies, and Coombs' test using monospecific anti-IgG, C3 and C4, and broad-spectrum antihuman globulin. In six patients, chromium 51-labeled, heat-damaged autologous red cells were used to assess the rate of clearance and the phagocytic activity of the spleen using a liquid scintillation counter for the former and color scanner for the latter. Red cell survival and surface counting using51 Cr were performed in two patients. All hematological tests were performed according to the methods of Dacie and Lewis.6 The bone marrow examinations, blood counts, and coagulation studies were performed before treatment and two weeks after completion of the sodium stibogluconate therapy.Immune complexes were assayed by the C1Q-enzyme linked immunosorbent assay.7 Rheumatoid factor was tested using the Hoechest Kit (Hoechest Laboratories, West Germany).Patients were treated with intravenous sodium stibogluconate according to the following regimen: Adults: Day 1,2 ml IV; Day 2, 4 ml IV; Day 3 to 15, 6 ml IV. Children: the dose was calculated according to body weight as recommended by the manufacturer (Burroughs Wellcome, England).The development of anorexia, vomiting, rashes or any new symptoms was considered evidence of toxicity. Patient progress was monitored through daily recording of morning and evening temperatures and the size of the spleen and liver.Patients were considered cured when the bone marrow aspiration was negative for parasites, accompanied by improvement in clinical status and laboratory data.RESULTSClinical FeaturesAll 17 patients were males and aged 10 to 48 years (mean, 24 ± 8 years). They were all farmers or laborers who came from endemic areas around Gadaref (15 patients), Darfur (one patient), and Malakal (one patient). Symptoms had lasted from 15 days to 6 months (average, 3 months). The clinical features are summarized in Table 1.Table 1. Frequency of symptoms and signs in 17 patients.Table 1. Frequency of symptoms and signs in 17 patients.Fever, weight loss, and signs of anemia were found in all cases. Ten of the 12 patients with abdominal pain had a dull, dragging, left hypochondrial pain related to the splenic enlargement; the remaining two patients' pain was central, colicky, and associated with melena. One patient was treated in another hospital for severe diarrhea five days before he was seen by us. Six patients were jaundiced and eight had epistaxis. Two had cough that produced blood-stained sputum, clinical signs of consolidation, and multiple pulmonary opacities seen on chest radiographs. With the exception of four patients, the rest felt well, their appetite was good, and they were ambulant.Ten patients had pitting edema of the feet. The average size of the spleen was 6.2 cm (range, 0-10.5) and the liver was 2.6 cm (range, 0-4) below the costal margin. Lymph node enlargement was found in ten patients. The lymph nodes were firm and discrete, and varied from 1 to 3 cm in diameter. The inguinal lymph nodes were enlarged in all the ten patients with lymphadenopathy; two patients also showed cervical and axillary lymph node enlargement. Amastigotes were demonstrated in the inguinal lymph nodes in four of the patients who had aspiration performed.Seven patients also had schistosomiasis man-soni, and an amebic liver abscess developed in one.HematologyThe hemoglobin concentration was low in all patients (mean, 77 ± 12 g/L). The peripheral blood films showed anisopoikilocytosis with a preponderance of macrocytes in nine patients. Slight to moderate polychromasia was common.All patients were leukopenic, with neutropenia in 15 (88%) and lymphopenia in 16 (94%). Ten patients were still lymphopenic two weeks after sodium stibogluconate therapy, but the mean lymphocyte count rose from 0.619 ± 0.392 to 1.414 ± 0.766 × 109 cells per liter. Following sodium stibogluconate therapy, the seven patients with concomitant schistosomiasis developed eosinophilia. Thrombocytopenia was present in all patients. The mean platelet count was 51 ± 41 × 109/L. Counts below 50 × 109/L were found in 11 (65%) patients, and the eight patients with epistaxis also had severe thrombocytopenia.The bleeding time was prolonged in nine patients, while the prothrombin time was only marginally prolonged in four. The partial thromboplastin time was within normal limits.Increased cellularity of the bone marrow with hyperplasia of all elements was found in all cases. Erythropoiesis was megaloblastic in 12 patients (70%) and normoblastic in the remaining five. Variable degrees of erythrophagocytosis and leukophagocytosis by mononuclear phagocytes was a constant feature (Figure 2). No iron was seen on stained smears of bone marrow.Figure 2. Bone marrow smear showing (A) erythrophagocytosis and (B) neutrophil phagocytosis by reticulum cells, which contain several amastigotes. (Wright stain; original magnification × 1500.)Download FigureThe half-time clearance of 51Cr-labeled, heat-damaged red cells was markedly shortened in five of six patients and was prolonged in one. However, the spleen was not palpable in the latter and color scanning showed scattered activity that was most likely over the abdominal lymph nodes. Splenic scanning performed 24 hours later showed markedly increased activity, indicating sequestration and destruction of erythrocytes.SerologyRheumatoid factor was positive in all cases. High concentrations of immune complexes were found in five of the six cases tested (Table 2); two also had schistosomiasis.Table 2. Immune complexes in cases of visceral leishmaniasis.Table 2. Immune complexes in cases of visceral leishmaniasis.Direct Coombs' test using monospecific anti-IgG was positive in 14 cases, and using both anti-IgG and anti-C3 was positive in three cases. Broad-spectrum anti-human globulin serum, however, yielded a negative result to the direct Coombs' test in all cases.Response to TreatmentAll patients responded well to treatment. Sixteen eventually were discharged and were afebrile four weeks after treatment. Follow-up for longer periods was not possible. During the period of observation, the patients gained weight and felt and looked better. The spleen and liver size started to decrease, with the most dramatic reduction in large spleens. The hematological profile improved (Table 3). After the sodium stibogluconate therapy, two patients developed fever. An amebic abscess of the liver was found in one and this responded well to treatment. The other patient had a urinary tract infection that was controlled with appropriate antibiotic therapy.Table 3. Hematological changes in kala-azar before and after treatment.Table 3. Hematological changes in kala-azar before and after treatment.One patient had had delirium for three days before the start of sodium stibogluconate therapy. Following this, he went into a coma and died. Autopsy revealed a hemorrhage in the right temporal lobe that had ruptured into the ventricular septum and subarachnoid space. This patient had the lowest platelet count in the group. He had no hypertension or vascular anomaly. A second patient died of massive intestinal hemorrhage.DISCUSSIONBecause the cases are from a hospital population, no definite conclusions can be drawn regarding the age and sex distribution. The disease had no predilection for infants and affected more males than females,5 but the difference in the sex distribution in our patients is attributed to the reluctance of females to seek medical care. In the outbreak which occurred in Khartoum Province, the disease was confined to children.1 The response of visceral leishmania to treatment varies in different parts of the world.Sodium stibogluconate was very effective in our patients, all of whom tolerated it well and have shown no relapse. A similar beneficial effect was observed in Indian patients who generally responded well during 10 to 20 days of treatment with antimony.8 In East Africa the disease is more resistant to treatment, and despite the standard 30-day course of 10 mg of sodium stibogluconate per kilogram of body weight, some patients are not cured; moreover, relapse sometimes occurs after successful treatment.9 A recent study revealed a relapse rate of 7.6% among 38 Kenyan patients who had been cured after receiving an average of 35 injections (mean dose, 405 mg/kg of antimony).9Fever was a consistent finding in our patients. They had a good appetite, were usually ambulant, and felt remarkably well despite their pyrexia and emaciation. Those who suffered complications such as amebic hepatitis or urinary tract infections looked ill, lost their appetite, and were usually confined to bed. Diarrhea, which was severe in one patient, has been observed before in Sudanese kala-azar.10Splenic enlargement was usual in our patients. In one patient, who had had fever for only 15 days, the spleen was not palpable. The liver was enlarged in 15 patients, but it did not exceed 4 cm in those who had schistosomiasis. Hepatic and renal dysfunctions were common in these cases, which is contrary to the findings of Kager et al in East Africa.9 Both renal and hepatic functions improved after sodium stibogluconate therapy. The hepatic and renal manifestations and pathology in kala-azar patients will be reported (Mustafa et al and El-Hassan et al, in preparation).All patients had anemia of varying degrees, with a multifactorial etiology. Nutritional factors have an important bearing, as patients are from a low socioeconomic group. Iron deficiency is evidenced by depletion of the bone marrow stores. The megaloblastic erythropoiesis is probably due to folate deficiency caused by poor diet as well as increased demand from greater marrow activity. A third factor in the pathogenesis of the anemia is hemolysis. There was decreased red cell survival in these patients, rapid clearance of labeled red cells from the circulation, and increased sequestration in the spleen as seen in the colored scanning. Erythrophagocytosis was seen in the bone marrow. The positive Coombs' test indicates an immune mechanism for the hemolysis. This was also suggested by others.11,12 Musumeci et al13 reported similar findings in Mediterranean kala-azar. The erythrocytes were positive for direct antiglobulin tests using antisera to IgG and complement C3. Erythrophagocytosis with increased deposits of hemosiderin in the liver and spleen was demonstrated in our patients. The red cells may have absorbed immune complexes on their surfaces and then been phagocytosed by cells of the reticuloendothelial system.The leukopenia and thrombocytopenia are due to increased peripheral destruction rather than failure of production. This is shown by the increased bone marrow activity and the phagocytosis of white cells in the bone marrow. A contributory factor may be the megaloblastic hemopoietic abnormalities in some of the patients. We believe that thrombocytopenia, immune complex vasculitis, and disseminated intravascular coagulation are the major causes of the hemorrhagic manifestations.14 The patient with the lowest platelet count died of a cerebral hemorrhage. Such hemorrhagic manifestations have been observed by others.8,15 Decreased platelet count as well as shortened platelet survival occurred in five infants with acute kala-azar,16 but this was not associated with hemorrhagic manifestations. Kager et al12 have confirmed the occurrence of red cells, white cells, and platelet autoantibodies in blood specimens from their patients. 13The hematological parameters in our patients showed some changes even as early as two weeks after treatment. The hemoglobin concentration increased slowly even though there was no significant difference from pretreatment level. There was a consistent marked increase in platelets and white cells after therapy.No primary skin lesions were observed in our patients. Such lesions were described by Kirk17 from the Sudan and were seen in five of 40 patients in Kenya.18 Post-kala-azar dermal leishmaniasis occurred in one of our patients immediately after therapy. This agrees with the observations of Kirk and Sati2 in Sudanese kala-azar in which the eruption usually appeared during or on completion of treatment or within a comparatively short period afterward. In Indian patients, the dermatitis is reported to appear one to two years after treatment and persist for a long time.19The eosinophilia that occurred following sodium stibogluconate therapy in kala-azar patients who also had schistosomiasis is difficult to explain. Eosinophils might have been destroyed, along with other formed elements of the blood, in the untreated kala-azar patients and then reappeared in the blood after therapy. Another possibility is that, during active Leishmania infection, there is reversible depression of T-cell function,20 and therefore the eosinophil response to bilharzia infection, which depends on T lymphocytes, is temporarily lost.21ARTICLE REFERENCES:1. Hamza YO, Abdella RE, Ahmed MAM, et al. "Northward spread of visceral leishmaniasis in the Sudan" . Trans R Soc Trop Med Hyg. 1976; 70: 266. Google Scholar2. Kirk R, Sati MH. "Studies in leishmaniasis in the Anglo-Egyptian Sudan. II. The skin and lymph glands in kala-azar" . Trans R Soc Trop Med Hyg. 1940; 33: 501–6. Google Scholar3. Kirk R. "Primary cutaneous sore in a case of kala-azar" . Trans R Soc Trop Med Hyg. 1938; 32: 271–2. Google Scholar4. Archibald RG. "Kala-azar in the Sudan with special reference to its treatment by tartar emetic" . Am J Trop Med Hyg. 1923; 3: 207–324. Google Scholar5. Van Peenin PFD, Reid TP. "Leishmaniasis in the Sudan Republic. VI: Clinical and laboratory aspects of kala-azar in hospitalized patients from Upper Nile Province" . Am J Trop Med Hyg. 1962; 11: 723–30. Google Scholar6. Dacie JV, Lewis SM. Practical haematology. Edinburgh: Churchill Livingstone, 1975. Google Scholar7. Lunde MN. "A C1Q enzyme-linked immunosorbent assay (ELISA) using polyethylene glycol for immune complexes" . Am J Trop Med Hyg. 1982; 32: 392–6. Google Scholar8. Geneva World Health Organization. Report on the informal meeting on the chemotherapy of visceral leishmaniasis, TDR/CHEM LEISH/VL 82. 3, 1982. Google Scholar9. Kager PA, Rees PH, Manguyu FM, et al. "Clinical, haematological and parasitological response to treatment of visceral leishmaniasis in Kenya: a study of 64 patients" . Trop Geogr Med. 1980; 36: 21–35. Google Scholar10. Sati MH. "Leishmania enteritis as a cause of intractable diarrhoea and death" . Sudan Med J. 1962; 1: 216–8. Google Scholar11. Woodruff AW, Topley E, Knight R, Downie CGB. "The anemia of kala-azar" . Br J Haematol. 1972; 22: 319–29. Google Scholar12. Kager PA, Van Der Plas-Van Dalen C, Rees PH, et al. "Red cells, white cells and platelet autoantibodies in visceral leishmaniasis" . Trop Geogr Med. 1984; 36: 143–50. Google Scholar13. Musumeci S, D'Agata A, Fischer A. "Antiglobulin consumption test in kala-azar" . Trans R Soc Trop Med Hyg. 1974; 68: 261–7. Google Scholar14. Blount ER, Hartman R, Nernoff J. "Kala-azar as a cause of disseminated intravascular coagulation" . Clin Pediatr. 1988; 19: 139–40. Google Scholar15. Maru M. "Clinical and laboratory features and treatment of visceral leishmaniasis in hospitalized patients in north western Ethiopia" . Am J Trop Med Hyg. 1979; 28: 15–8. Google Scholar16. Li Volti S, Fischer A, Musumeci S. "Haematological and serological aspects of Mediterranean kala-azar in infancy and childhood" . Acta Trop (Basel). 1980; 37: 351–65. Google Scholar17. Kirk R. "Studies in leishmaniasis in the Anglo-Egyptian Sudan. I. Epidemiology and general considerations" . Trans R Soc Trop Med Hyg. 1939; 32: 533–44. Google Scholar18. Manson-Bahr PEC, Heisch RB. "Studies in leishmaniasis in East Africa. III. Clinical features and treatment" . Trans R Soc Trop Med Hyg. 1956; 50: 465–71. Google Scholar19. Napier LE, Das Gupta CR. "Quoted by Manson-Bahr PEC, Heisch RB. Studies in Leishmaniasis in East Africa. HI. Clinical features and treatment" . Trans R Soc Trop Med Hyg. 1956; 50: 465–71. Google Scholar20. Carvalho EM, Teixiera RS, Johnson WD. "Cell mediated immunity in American visceral leishmaniasis: reversible immune suppression during acute infection" . Infect Immun. 1981; 33: 498–506. Google Scholar21. Phillips SM, Diconza JJ, Gold JA, Reid WA. "Schistosomiasis in the congenitally athymic (nude) mouse: thymic dependency of eosinophilia, granuloma formation and host morbidity" . J Immunol. 1977; 118: 594–9. Google Scholar Previous article Next article FiguresReferencesRelatedDetailsCited byAl-Sohaibani M (2019) Bone Marrow Histopathological Changes in Visceral Leishmaniasis, Annals of Saudi Medicine , 16:3, (304-307), Online publication date: 1-May-1996.Benjamin B, Annobil S and Bassuni W (1994) Clinical and Laboratory Features of Childhood Visceral Leishmaniasis in Southwestern Saudi Arabia, Annals of Saudi Medicine , 14:2, (107-110), Online publication date: 1-Mar-1994. Volume 10, Issue 1January 1990 Metrics History Accepted10 July 1989Published online1 January 1990 ACKNOWLEDGMENTWe are indebted to Drs. F. Neva and Milford Lunde of the National Institutes of Health, Bethesda, Maryland, U.S.A., for assaying the immune complexes in their laboratory.We also thank Abdel Moneim El-Tayeb and A. Archibald for the photographs and Syed Mohammad Zahid for typing the manuscript.InformationCopyright © 1990, Annals of Saudi MedicinePDF download
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