Disseminated Histoplasmosis with ReactiveHaemophagocytosis Presenting as PUO in anImmunocompetent Host

S Saluja , Sunita, S Bhasin, DK Gupta, B Gupta, SP Kataria, M Sharma

Case Report

Disseminated histoplasmosis (DH) with reactive haemophagocytosis has been described in literature mainlyin immunocompromised hosts. Only sporadic case reports exist in immunocompetent hosts. Here, we presenta rare case of DH with reactive haemophagocytosis in an immunocompetent host presenting as PUO. ©


Histoplasmosis, a fungal infection, has been reportedfrom different parts of the world. Sporadic caseshave been reported from India and other SoutheastAsian countries in both immunocompetent andimmunocompromised hosts.1 The clinical manifestationsare variable – acute primary, chronic cavitatory andprogressive disseminated. In an immunocompetent host,it usually leads to chronic disseminated disease. InIndian patients, skin and mucosa are the most commonlyinvolved sites, with or without systemic involvement.2Reactive haemophagocytic syndrome (RHPS) is a non-malignant syndrome characterized by an expansion ofthe monocyte-macrophage population and intensehaemophagocytosis. It can occur de novo, but more oftenit occurs in the setting of another disorder, usually aninfection or a malignancy.3 Here, we report case ofdisseminated histoplasmosis (DH) with reactivehaemophagocytosis in bone marrow presenting as PUOin an immunocompetent host.


A nonalcoholic, nonsmoker 43 year old male, residentof Uttar Pradesh, manufacturer and seller of organicmanure was admitted with complaints of fever for thelast 3 months. Fever was low to moderate grade, notassociated with chills and rigors. There was no historyof cough, jaundice, urinary and bowel complaints.Examination revealed a febrile patient (101°F) withhepatomegaly (3 cm) and splenomegaly (7 cm). Therewas no lymphadenopathy. Respiratory, cardiovascularand nervous system examinations were essentially normal. Patient was investigated on lines of pyrexia ofunknown origin (PUO). Haemogram revealedhaemoglobin 9.2 g%, TLC 6200/cmm, platelets 1,80,000/cmm and ESR 32 mm/1st hour. Routine biochemistryand radiological investigations done for PUO werewithin normal limits. Mantoux test was negative andbacterial cultures did not reveal any growth. ELISA forHIV was negative on two separate occasions withnormal CD4 counts. Giemsa stained bone marrowaspirate smears from sternum revealed a normocellularmarrow, normal M:E ratio, normal trilineagehematopoiesis with increase in plasma cells andhistiocytes. Numerous 2-4 µm oval to round bodies witheccentric to central nuclei and a perinuclear vacuole wereidentified within the histiocytes. These bodies wereidentified extracellularly also. Some of the histiocytesshowed phagocytosed red blood cells and platelets (Fig.1). A provisional diagnosis of histoplasmosis withreactive haemophagocytosis was made and trephinebiopsy was performed. Biopsy revealed similar findingson H & E stain(Fig. 2). Special staining with silvermethanamine and periodic acid Schiff stain confirmedthe diagnosis.

Patient’s consent could not be obtained for any otherinvasive procedure such as liver biopsy. He was put onantifungal therapy (Tab Itraconazole 200 mg BD) andwas continued for 6 months. Bone marrow culturecollected later on was positive for H. capsulatum. Within4 weeks of antifungal therapy, patient became afebrileand hepatosplenomegaly started regressing in size.

Fig. 1 : Bone marrow aspirate smears showing Histoplasma inhistiocytes and evidence of haemophagocytosis (Leishman X1000).

Fig. 2 : Trephine biopsy showing Histoplasma (H &E X 400).

Senior Resident; Senior Medical Officer; Senior MedicalSpecialist; Consultant and Head, Department of Medicineand Hematology, Safdarjung and VMMC, New Delhi.

Received : 4.10.2004; Revised : 21.7.2005; Accepted : 13.9.2005


Disseminated histoplasmosis (DH) is a systemicillness which usually presents in a non-specific mannerwith persistent fever and constitutional symptoms.4Differential diagnosis of histoplasmosis includesleishmaniasis, toxoplasmosis and other fungalinfections like cryptococcosis, candidiasis and coccidioidomycosis.4,5 It is a disease of worldwideoccurrence, endemic in great river valleys of Americanand African continents. In India, it is as yet a raredisease. Few case reports are available from Bengal,Maharashtra and other parts of the country.5

Infection is usually acquired by inhalation of soilenriched with bird and bat droppings. Clinicalmanifestations are of three types- acute primary, chroniccavitatory and progressive disseminated. In animmunocompetent host, it usually leads to chronicdisseminated disease. Signs and symptoms of DH arefever (most common), headache, weight loss, cough (inless than 50% of cases), hepatomegaly, splenomegaly,lymphadenopathy and jaundice.2

The diagnosis of DH depends on demonstrating theorganism in an extrapulmonary location in a patientwith progressive illness either by culture of body fluidsor infected tissue, or by microscopic examination ofmaterials obtained from involved sites (liver, spleen,lymph node and bone marrow). The disadvantage ofculture is the several week period required for growthand identification of H. capsulatum. A distinct advantageof the microscopy is the speed with which diagnosiscan be made and appropriate treatment instituted.6Confusion of H. capsulatum with another yeast is unlikelyby histopathology as the 2-4 µm intracellular forms arediagnostic of histoplasmosis. Other investigations thatcan be utilized to diagnose histoplasmosis includeserological tests to detect antigen in urine and serum byradioimmunoassay (RIA) that has a sensitivity of 92%.Detection of antibody titres in serum (more than 1:32)also helps make the diagnosis with a sensitivity of 71%.

Haemophagocytic syndrome, a clinicopathologicalentity characterised by inappropriate monocyteactivation, has been described in association with avariety of bacterial, parasitic and fungal infections(tuberculosis, typhoid, brucellosis, malaria,leishmaniasis, histoplasmosis etc.) and malignancy (T-cell lymphoma, acute leukemia). The syndrome ischaracterised by fever (> 7 days, peak > 38.5°C),splenomegaly (> 3 cm below costal margins), cytopenias (affecting > 2 of three lineages) and morphologicalevidence of haemophagocytosis in bone marrow orlymph nodes or spleen. Some of the above findings maynot apply to a secondary haemophagocytic state andthere may be reactive haemophagocytosis only, withoutmeeting all the criteria of the full blown syndrome.1 Thefew case reports of DH with haemophagocytosis havebeen described in literature mostly inimmunocompromised patients.

In our case, patient presented with history ofprolonged fever which was diagnosed as a case of DHwith reactive haemophagocytosis by the bone marrowsmears, bone marrow biopsy and cultures from bonemarrow. This patient was successfully treated withantifungal therapy. Perhaps, this patient acquiredinfection during handling of the organic manure (aprofessional hazard).

In countries like India, where the prevalence oftuberculosis is high, clinical diagnosis of DH is oftennot suspected. Though majority of patients of DH areimmunocompromised, the diagnosis should also besuspected in an immunocompetent host with PUO ashighlighted in our case. Timely diagnosis andmanagement of this serious but potentially reversiblecondition is essential as 100% mortality is seen inuntreated patients.


1.Kumar N, Jain S, Singh ZN. Disseminated histoplasmosiswith reactive haemophagocytosis: Aspiration cytologyfindings in two cases. Diagn Cytopathol 2000;23:422-24.

2.Mukherjee AK, Mukherjee D, Mukhopadhyay M.Histoplasmosis in India: A clinico-pathological review withreport of a case in a child. J Pathol Microbiol 1986;29:263-70.

3.Rao RD, Morice WG, Phyliky RL. Hemophagocytosis in apatient with chronic lymphocytic leukemia andhistoplasmosis. Mayo Clin Proc 2002;77:287-90.

4.Davies SF, McKenna RW, Sarosi GA. Trephin biopsy of thebone marrow in disseminated histoplasmosis. Am J Med1979;67:617-22.

5.Sane SY, Patel MG, Patel BM, Kokal K. Disseminatedhistoplasmosis (a case report). J Postgrad Med 1983;29:270-3.

6.Cooperberg AA, Schwartz J. The diagnosis of disseminatedhistoplasmosis from marrow aspiration. Ann Intern Med1964;61:289-95.