Journal of The Association of Physicians of India ■ Vol. 64 ■ July 201678

Progressive Disseminated Histoplasmosis with Coomb’s Positive Hemolytic Anemia in an Immunocompetent HostRadhey Shyam Chejara1, CL Nawal2, MK Agrawal3, Pradeep Mittal3, Abhishek Agrawal4, Sujata Agarwal1

Introduction

Histoplasma capsulatum, a thermal dimorphic fungus, is the etiologic

agent of histoplasmosis . I t i s the most prevalent endemic mycosis in North America. Human infection is acquired by inhalation of mycelial forms. Clinically it manifests as three main types- acute pulmonary, chronic pulmonary/cavitatory and progressive d i s s e m i n a t e d h i s t o p l a s m o s i s . 1 I t can present as fever of unknown origin (FUO) in immuno-deficient as well as immuno-competent and non-neutropenic subjects. Although uncommon in Indian subcontinent, high index of suspicion is necessary for early diagnosis and treatment.

Case Report

A 3 0 - y e a r - o l d m a l e p a t i e n t was admitted in our hospital with complaints of high-grade fever with chi l l s and r igors associated with profuse sweating since two months. He developed cough since last 20 days, that was non-productive in nature and had no diurnal variation. He complained of fatigue and exertional dyspnoea for last 8 days.

On general examination, the positive findings were fever (103°F) and pallor. Systemic examination revealed a tender palpable liver (4 cms below costal margin) and a non-tender palpable spleen (4 cms below costal margin). Rest of the systemic examination was normal.

Laboratory investigations revealed pancytopenia. Hemoglobin was 4.5 gm/dl, total leucocytes count was

Au t o i m m u n e h e p a t i t i s w a s considered a differential diagnosis and liver biopsy done which showed mild increase in lymphocytes with Kupffer and stellate cells packed with intracellular capsulated yeast which was positive for PAS and methylamine s i l v e r s u g g e s t i n g H i s t o p l a s m a capsulatum infection (Figure 1). A repeat bone marrow biopsy was done to confirm infiltration in the bone marrow as a cause of pancytopenia that showed intracellular and extracellular yeast positive for PAS and methylamine silver (Figure 2). So a diagnosis of disseminated histoplasmosis with autoimmune hemolytic anemia was finalized. Subsequently the culture report confirmed the diagnosis.

Patient was started in infection amphoter ic in for 2 weeks during hospitalization and Itraconazole 200 mg twice daily was prescribed for 15 days on outpatient basis. He became afebrile within a week, total leucocyte count and platelet counts were 3.78 × 103 /µl and 1.6 lacs/µl respectively after two weeks. He is under close medical observation and follow-up on outpatient basis thereafter.

Discussion

Histoplasmosis is not an endemic mycosis in India. Majority of progressive disseminated histoplasmosis cases are diagnosed on immune-compromised hosts who cannot mount effective cell mediated immunity. There are few case reports in immuno-competent subjects from various parts of our country.2,4 Present case is probably first of its kind, diagnosed in an immuno-competent subject in our institution.

Bone marrow abnormalities in the form of cytopenias are reported due to diffuse marrow infiltration. Isolated thrombocytopenia is rare but reported.2 In our case all three cell lineages were

1.66 × 103/µl (differential leucocyte count showed N-60%, L- 37%, E-02%, B- 01%), platelet count was 56 ×103/µl]. Peripheral blood film examination was normochromic normocytic RBCs with thrombocytopenia and no atypical cells. Malarial antigen by card test and peripheral smears (thick and thin) were negative. Widal test and dengue profile (IgM, IgG and NS 1) were negative. Antibodies for HIV-1 and 2 were not detected.

Urine examination revealed presence of mild proteinuria. Liver function test showed mildly elevated liver enzyme levels -AST—87 U/l , ALT—72 U/l , ALP—235 U/l and LDH—4650 U/l. Serum electrolytes and renal function tests were normal.

C h e s t x - r a y h a d m i l d h i l a r prominence. HRCT thorax showed multiple enlarged lymph nodes in the pre and paratracheal region with confluent patches of ground glass haziness in bilateral lower lung fields suggest ive of in ters t i t ia l pat tern of pneumonit is . Ultrasonography revealed hepatosplenomegaly.

Sputum for AFB, gram stain and KOH mount was negat ive . Blood and urine culture yielded no growth. Autoimmune workup showed positive CRP, negative ANA and positive direct coombs test suggesting autoimmune hemolytic anemia. Reticulocyte count was 6.8%. BM aspiration and biopsy showed erythroid hyperplasia with decreased megakaryocytes.

AbstractProgressive Disseminated Histoplasmosis (PDH) is mainly described in immuno-compromised individuals and rare in immuno-competent subjects. Here we report a case of progressive disseminated histoplasmosis with Comb’s positive hemolytic anemia, which is infrequently reported from a country like India where histoplasmosis is not an endemic mycosis.

1Asst. Prof., 2Prof. and Head, 3Prof., 4Asso. Prof., Dept. of Medicine, SMS Medical College, Jaipur, RajasthanReceived: 20.05.2015; Revised: 20.07.2015; Accepted: 17.08.2015

Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016 79

affected and there was pancytopenia. Despite bone marrow involvement, the bone marrow examination didn’t report conclusive pathology and we had to think of alternative diagnosis. Further we performed liver biopsy, keeping auto-immune hepatit is in our mind and asked pathologist to co mme n t u p o n so m e i n f i l t r a t i ve disorder with fungal stains. Here he identified the intracellular PAS positive and methylamine silver stained intracellular and extracellular pathogen as Histoplasma species.

Comb’s positive hemolytic anemia i s r a r e l y r e p o r t e d e l s e w h e r e a s

in our case with histoplasmosis . 5 Acquired hemolytic anemia may be due to immune mediated as well as non immune mediated mechanisms.

For the management of moderately severe to severe h i s top lasmos i s , l i p o s o m a l a m p h o t e r i c i n B i s recommended for 1–2 weeks followed by oral Itraconazole 200 mg twice daily for at least 12 months. The deoxycholate formulat ion of amphoter ic in B is recommended as an alternative to the lipid formulation in patients who cannot afford or are at a low risk for nephrotoxicity.3 In our patient we started conventional amphotericin B

for two weeks and then Itraconazole 200 mg twice daily. The patient is improving well and he is under close follow-up in medical OPD.

I n c o n c l u s i o n , p r o g r e s s i v e disseminated histoplasmosis with hemolytic anemia is rarely reported in immuno-competent subjects from the Indian subcontinent. We as clinicians should keep this uncommon cause of fever of unknown origin (FUO), as differential diagnosis for early detection and management of this treatable illness.

References1. Chadi A. Hage. Histoplasmosis. Harrisson’s principles of

internal medicine 18th edition1640-1643.

2. Subbalaxmi MVS, Umabala P, Paul R, et al. A rare presentation of progressive disseminated histoplasmosis in an immunocompetent patient from a non-endemic region. Medical Mycology Case Reports 2013; 2:103-107.

3. L. Wheat J, Freifeld AG, Kleiman MB et al. Clinical practice guidelines for the management of patients with histoplasmosis: update by the infectious. Diseases Society of America. Clini Infect Dis 2007; 45:807–825.

4. Chakrabarti A, Slavin MA. Endemic fungal infections in the Asia pacific region. Medical Mycology 2011; 49:337–344.

5. Chang YT. Disseminated histoplasmosis presenting as haemolytic anaemia. Postgrad Med J 2010; 86:443-444.

Fig. 1: Methinamine silver stain showing intracellular histoplasma species in liver biopsy specimen

Fig. 2: Intracellular histoplasma species 100× magnification (H and E) noted in bone marrow