Histoplasma Infection in a Case of Multiple Myeloma Presenting as a Diagnostic Conundrum

Histoplasma is a common dimorphic fungus in the environment. Infection by this fungus in an immunocompetent host might present with flu-like symptoms or might be innocuous. However, in immunocompromised host, it can cause any of the clinical subtypes: pulmonary, disseminated, or systemic disease.1 Here we present a case of a patient of multiple myeloma who developed disseminated histoplasmosis post allogenic bone marrow transplant.

A 45-year-old gentleman, a known case of pulmonary tuberculosis, who presented with back pain. The patient had taken complete course of ATT. Bone marrow examination showed 80% plasma cells. Electrophoresis showed the presence of the M band, which was proven to be IgG kappa subtype by immunofixation studies. Serum-free light chain ratio was deranged. The patient received induction chemotherapy with bortezomib, lenalidomide, and dexamethasone; however, it did not achieve complete remission, hence he was advised for autologous stem cell transplant. He underwent stem cell transplant, and was on lenalidomide therapy for 8 months. However, his condition relapsed in 10 months and he was started on pomalidomide 4 mg with dexamethasone for 6 cycles, followed by single agent pomalidomide 2 mg and was on follow-up.

Presently, 3.5 years post-transplant, the patient came with persisting thrombocytopenia. Bone marrow showed hypercellular marrow and trephine biopsy showed single granuloma consisting of a few histiocytes with a single giant cell. PAS and GMS staining was negative. Over 2 months, the patient developed pancytopenia with generalized skin rash (Fig 1). Skin showed papular lesions and penile ulcer. Oral mucosa showed a few ulcers. Bone marrow aspiration and biopsy were repeated for the worsening cytopenia. The bone marrow aspirate showed normal cellularity with 8% plasma cells, serum electrophoresis showed ‘M’ band of 0.1 g% and serum light chain ratio was 1:1.83 (range 0.27–1.63). The plasma cells were morphologically normal. Scattered histiocytes were seen showing cytoplasm distended by organisms. These organisms were multiple, round to oval in shape, showing thick unstained “clear zone” around them. No budding or filamentous forms were noted (Fig 2A and B). Bone marrow biopsy showed similar findings of histiocytes distended by small round organisms. PAS and Grocott Methenamine stain (GMS) highlighted the organisms (Fig 2C and D). Morphological diagnosis of histoplasmosis was made. Bone marrow culture failed to detect these organisms. PET-CT done as part of workup showed multiple lytic lesions with abdominal lymphadenopathy. Left adrenal gland was mildly bulky with minimal pleural effusion. The patient did not have any gastrointestinal symptoms. The patient was on pomalidomide for 23 months, which was stopped when he presented with pancytopenia at this presentation. The patient was started on liposomal amphotericin B, he took the treatment for 10 days, and then discontinued due to personal reasons and opted out of treatment at present center. The patient died around 1 month thereafter.

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Fig. 1: Clinical picture of the generalized papular rash on the body (image courtesy: Dr Goutam.)

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Fig. 2: (A) Peripheral smear showing intracellular Histoplasma in the monocytes, presence of clear zone can be seen around the yeast forms (Leishman stain, 400x). (B) Bone marrow showing the presence of multiple Histoplasma in the macrophages, inset shows magnified image. (Leishman stain, 400x). (C) Trephine biopsy section shows presence of organisms, inset picture show pink staining by PAS stain (400x). (D) The organisms take up black stain in GMS done on trephine biopsy (400x).

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In the present case, the patient developed progressive disseminated infection which generally occurs in immunocompromised individuals such as those with AIDS, organ transplant or use of biological agents such as TNF-α inhibitors.23 The present case developed disease well after stem cell transplant, was on maintenance therapy with pomalidomide, which is an immunomodulatory agent that acts by decreasing TNF-α, IL-12, and macrophage inflammatory protein 1α (MIP1α).4 Ineffective cell-mediated immunity is also a factor in disseminated infection,23 which might also have been a cause in the present case as the patient was earlier treated for tuberculosis, which is a disease manifesting in deficient cell-mediated immunity. Progressive disseminated histoplasmosis generally involves the liver, spleen, bone marrow, gastrointestinal tract, adrenals, and lymph nodes.23 The patient presented with thrombocytopenia progressing to pancytopenia, which can be attributed to the hemophagocytosis that occurs in the infection. Bone marrow cellularity and megakaryocyte count were normal in this case. In the present case, the bone marrow, skin, and oral mucosa were involved, PET scan showed lymphadenopathy. Very rarely genital tract involvement is described,5 large penile ulcer was noted in present case.

Histoplasmosis is many a time under diagnosed or wrongly interpreted as tuberculosis, which is very common in the Indian subcontinent due to granulomatous reaction to the fungus. A strong clinical suspicion with proactive search for the organisms with adjunct ancillary tests can help to arrive at the diagnosis. Amphotericin forms the mainstay of treatment, various regimens have been recommended to treat ongoing infections and prevent relapses.5

Histoplasmosis is a challenging diagnosis, the present case highlights the unusual but possible clinical scenario of disseminated Histoplasma infection in a patient receiving immunomodulatory agent presenting with a triad of pancytopenia, skin lesions, and gastrointestinal involvement.