Leishmaniasis is a major public health problem in Bangladesh, North East India, Nepal, Sudan and North East Brazil. To add to the challenge, there has been emergence of leishmaniasis in new geographic areas and host populations. Visceral infection can remain subclinical or become symptomatic with an acute, subacute or chronic course. Atypical presentations can be equally challenging to the clinician. We present an atypical presentation of kala azar with lymphadenopathy and evidence of auto immune hemolytic anemia. Absence of splenomegaly was the most striking aspect in our patient. Also, lymphadenopathy is commonly seen in Sudan rather than in India.
Keywords: Visceral Leishmaniasis, Kala Azar without splenomegaly, autoimmune hemolytic anemia
Leishmaniasis is a vector borne zoonosis having variable clinical presentations in the form of visceral, cutaneous (of localized or diffuse types) and mucocutaneous types depending upon the Leishmania species and immune responses of the hosts. Leishmaniasis threatens 350 million people in 88 countries across four continents and still remains a major public health problem in several underdeveloped countries. Leishmanial infection does not lead to clinical disease in all cases as asymptomatic and subclinical forms are frequent. These infections may lead to subsequent active clinical disease when the immune status of the patient changes. The classical presentation of kala azar includes fever, asthenia, weight loss, anemia, splenomegaly, hepatomegaly and sometimes adenopathy. Splenomegaly appears early and increases gradually in relation to the duration of the disease. The subclinical forms of the disease in the endemic areas remain undiagnosed and can become a clinical challenge to the treating physician. We present here a case report of an elderly male from the endemic area of kala azar, with an atypical presentation.
An elderly 50 year old male laborer (by profession) from Bihar, India, presented to our hospital with a history of intermittent, medium grade fever for three months associated with swellings in the groin since one month. There were no other significant localizing symptoms. The duration and severity of fever increased since a few days and was associated with the development of macular rash over the extremities. A general physical examination revealed significant pallor, bilateral inguinal lymphadenopathy and macular rash over bilateral extremities. Lymph nodes were discreet, non matted, non tender and firm in consistency. The largest lymph node measured around 5Χ2.5 cms. Systemic examination, including absence of organomegaly on abdominal evaluation, was non contributory. However, bilateral hydrocoele was appreciable.
Hematological parameters revealed pancytopenia on admission with hemoglobin 3.2 gm%, total leukocyte count of 1900, absolute neutrophil count of 120, platelet count of 37000 and peripheral smear showing a leucoerythroblastic picture. Lactate Dehydrogenase (LDH) on admission was 8750. Kidney function test was suggestive of prerenal failure with blood urea nitrogen of 57.6 mg% and serum creatinine of 1.9 mg%. Liver function test on admission was as follows: Total bilurubin of 0.87 mg%, aspartate aminotransferase (AST) – 470 U/L, alanine aminotransferase (ALT) -74 U/L, Alkaline phosphatase- 677 U/L, total proteins-7.83 gm% and S. albumin- 1.61 gm%. Hypergammaglobulinemia with albumin globulin ratio of 0.3 was seen. Peripheral smear for microfilariae was negative and absolute eosinophil count was 48. Human immunodeficiency virus (HIV), Hepatitis B (HBsAg), hepatitis C (HCV) and dengue serologies were negative. Chest X ray and skeletal profile on admission was normal. Blood cultures were sent on admission, which subsequently grew Escherichia More Details. coli with ESBL production. Ultrasound of whole abdomen was a normal study and that of scrotum revealed normal size and echotexture of testes and epidydimis with bilateral hydrocoeles. Fine needle aspiration cytology from the lymph nodes [Figure 1] was done along with bone marrow aspirate examination, both of which revealed Leishmania Donovani (LD) bodies. RK-39 was positive; bone marrow also showed megaloblastic changes. Vitamin B-12 level was low (less than 150, N: 174-878) and serum ferritin level was high (greater than 1500, N: 28-397). Direct Coomb’s test and ANA were positive and indirect Coomb’s test was negative [Table 1].
A final diagnosis of kala azar with autoimmune hemolytic anemia with secondary E. coli sepsis was made. Bilateral inguinal lymphadenopathy and absence of splenomegaly were outstanding findings in our patient. Patient was started on amphotericin B, antibiotics according to culture sensitivity and other supportive therapy including blood and platelet transfusions during his stay in hospital. He became afebrile soon, lymph nodes regressed and hematological parameters improved gradually with normalization of hemoglobin, total leucocyte counts and platelet counts. Kidney function tests and liver function tests also improved.
Leishmaniasis is a vector borne zoonosis with rodents and canids as common reservoir hosts and humans as incidental hosts. The two Leishmania species usually held responsible for visceral leishmanaiasis are L. donovani and L. infantum. Visceral leishmaniasis ranges over the intertropical zones of America and Africa, and extends into temperate regions of South America, Southern Europe and Asia. There are an estimated 12 million cases worldwide with one and a half to two million cases occurring each year.  90% of the visceral leishmaniasis cases in the world are in Bangladesh, India, Nepal, Sudan and Brazil. Population movements such as rural to suburban migration in Northeastern Brazil  are factors for visceral leishmaniasis extension by exposing thousands of non immune individuals to the risk of infection.
Visceral leishmaniasis has variable clinical presentations in the form of visceral, cutaneous (of localized or diffuse types) and mucocutaneous types depending upon the species and immune response of the hosts. Visceral leishmanaiasis is a disease of the mononuclear phagocytic system, commonly affecting the spleen, liver, lymph nodes and bone marrow. But other organs (intestines, lung) and tissues (skin) may also become involved, as they contain the elements of mononuclear phagocytic system. In immunosuppressed individuals and in advanced cases, all body organs are involved.
The presence of amastigotes within macrophages remains the hallmark of Leishmania infection. It is a chronic disease, evolving slowly over many months or even a few years. Spontaneous evolution is fatal in 90% of cases, mainly caused by intercurrent infections or hemorrhages. The incubation period is difficult to evaluate precisely. It is generally two to six months, but can range from 10 days to many years. Long incubation periods, up to 10 years have been occasionally reported,  related to clinical outcome of asymptomatic infection following immune system alteration. The onset of the disease may be sudden or gradual. In sudden onset there is rapid rise in temperature, gradual insidious onset includes irregular fever, slowly increasing, sometimes, with a transitory fall to sub febrile levels which can delay diagnosis.
The classical presentation of kala azar includes fever, asthenia, weight loss, anemia, splenomegaly, hepatomegaly and sometimes adenopathy. Splenomegaly appears early and is almost invariably present. Spleen size increases gradually in relation to the duration of the disease. Discrete superficial lymph nodes can appear during evolution. The nodes are small, firm painless and mobile. Peripheral adenopathy is more common in Sudan, and Indian kala azar is usually not accompanied by peripheral lymphadenopathy. Leishmanial infection does not lead to clinical disease in all cases; asymptomatic and subclinical forms are frequent. This has been demonstrated in various epidemiological surveys. , Badro et al.  characterize the subclinical form of visceral leishmaniasis as non specific mild clinical manifestations lasting for more than three weeks including fever, cough, diarrhea, malaise, mild hepatomegaly and eventually splenomegaly presenting as fluctuating course that evolves over a prolonged period of time.
The authors found that the subclinical form of illness which progressed on to disease were 15.1% of the patients who tested positive for leishmanial antibodies and those with subclinical form that resolved after a prolonged period of time constituted 44.2% of the patients who tested positive for Leishmanial antibodies. These infections may lead to subsequent active clinical disease when the immune status of the patient changes. They can therefore present as diagnostic dilemma for the clinician because of different clinical characterizations.
Whether different clinical presentations including atypical ones are due to different stages of clinical evolution of a chronic disease or variations in the pathogenicity of the organism or the immune status of the host is open for debate. A cohort study was planned in Brazil from January 1998 to December 2000 on 784 children aged between 0-5 years to study clinical-laboratory profile of sub clinical form of visceral leishmaniasis.  This cohort study also demonstrated that the combination of fever, hepatomegaly, hypergammaglobulinemia and increased blood sedimentation rate can predict the subclinical form of visceral leishmaniasis provided it is not associated with splenomegaly or leucopenia. Whereas the study by Badaro et al.  demonstrated that the subclinical form of the disease was more common (almost 60% of patients testing positive for antibodies to Leishmania), this study from Brazil had only 17.4% of the patients as subclinical cases. The occurrence of splenomegaly and leucopenia distinguished the acute form from subclinical form.
Badro et al.  did not find lymphadenopathy as one of a common clinical sign in the subclinical form of disease. Though lymphadenopathy along with splenomegaly has been characterized in kala azar; lymphadenopathy without splenomegaly is not very well known in the disease. This opens a question for debate that can “active” kala azar present without splenomegaly. Anemia is the major and most frequent hematological sign. Generally of normocytic and normochromic type, it progressively and regularly increases until becoming intense (can become as low as 4 gm/dl). Causes of anemia in kala azar are multifactorial.  In the pathogenesis of anemia, sequestration and destruction of red blood cells (RBC) in the enlarged spleen, immune mechanisms, increased plasma volume due to splenomegaly, dyserythropoetic changes of marrow, concomitant infections, malnutrition leading to Vitamin B-12, folic acid or iron deficiencies, action of proinflammatory cytokines that inhibit erythropoetin and alterations in the RBC membrane permeability have been implicated. Decreased RBC life span has been suggested in active disease due to underlying autoimmune hemolytic mechanism.
In this context a number of studies have demonstrated positive direct antiglobulin test (DAT) in kala azar patients in Kenya  and Nairobi.  A study by R.B. Vilela et al.  demonstrated that the prevalence of positive DAT on day 1 was significantly greater than the prevalence of positive DAT performed on day 30 and day 90. Interestingly it has also been observed that the decrease of circulatory immune complexes titers paralleled the regression of clinical symptoms. Our patient also had evidence of auto immune hemolytic mechanism contributing to anemia which improved on treatment. Leucopenia with neutropenia is also frequently reported, which is responsible for frequent infections. Thrombocytopenia can be present and when associated with hepatic coagulation factors alterations results in hemorrhages which can be dramatic.
Visceral leishmaniasis misdiagnosed as connective tissue disorders is well reported in literature. ,, Hematological abnormalities found in systemic lupus erythematosus namely anemia, leucopenia or lymphocytopenia and thrombocytopenia due to presence of auto antibodies can also be found in kala azar. Leishmania. donovani infection induces a nonspecific, as well as specific antibody production, much of which is probably due to parasite-released substances which act as B cell mitogens. As a consequence of B cell hyperactivity, Leishmania. donovani may cause hypergammaglobulinaemia and production of auto antibodies such as ANA, as in our patient. This might cause confusion in diagnosis. Known connective tissue disease patients might have clinical features confused between disease activity and kala azar. For this reason careful clinical approach is required to come to a definitive conclusion.
Our report reinforces the recommendation that in endemic areas the possibility of visceral leishmaniasis be considered in patients presenting with vasculitides or connective tissue disorders, especially if they respond poorly to steroid therapy. The present case report highlights a number of atypical presentations of kala azar.
Firstly, patient remained undiagnosed for a considerable period of time being in the subclinical time frame. Once the disease evolved into active disease due to a superadded infection, it had many atypical things attached to it. There were lymph nodes without splenomegaly, which is not very well heard of. Lymph nodes in Indian variety of kala azar are rare, but lymph nodes without splenomegaly have not been reported so far as an active disease. ANA and Coomb’s test positivity may also add to the confusion in diagnosis making. Delayed diagnosis due to atypical manifestations can lead to fatal outcome in patients. Instead of relying solely on the classical clinical features of visceral leishmaniasis, simple laboratory findings like pancytopenia, altered albumin/globulin ratio and a positive aldehyde and rK 39 dipstick tests can help make an early diagnosis even in atypical cases, thereby reducing the mortality of visceral leishmaniasis.
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