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A 27-year-old male presented with history of fever with off and on spikes and altered sensorium for past one month. On examination, pallor was present, spleen was palpable below 3 cm below left costal margin; and liver was palpable 2 cm below right costal margin. No lymphadenopathy noted. His complete blood count revealed hemoglobin of 85 g/L, total WBC count of 3x109/L and platelet count of 3x109/L. Peripheral smear findings were suggestive of pancytopenia, no abnormal cells or parasites seen. He was recently diagnosed to have acquired immunodeficiency syndrome (AIDS) with CD4 count was <50 cells/µL. Clinically, this case was suspected to have sepsis due to pancytopenia and secondary hemophagocytic lymphohistiocytosis in view of increased serum ferritin (386.2 ng/mL), triglyceride (226 mg/dL) and reduced fibrinogen (112 mg/dL).
He was started on empirical antibiotics and blood culture was sterile after two days with persistent fever. Bone marrow examination was attempted for febrile illness work-up in which aspirate was hemodiluted; however there was prominence of histiocytes. Mucicarmine stain and periodic acid Schiff stain did not highlight any fungal organisms. Ziehl-Neelson stain for acid-fast bacilli and molecular test for tuberculosis were negative.
Bone marrow biopsy showed mild prominence of histiocytes, ill-defined granulomas, giant cells, lymphocytes and plasma cells. There were many scattered as well as aggregates of variably sized round to oval encapsulated yeasts with thin and thick walled organisms along with narrow based budding forms seen, morphologically suggestive of Cryptococcus. Gomori methenamine silver stain, periodic acid Schiff stain and Mucicarmine stain had highlighted these fungal organisms. No evidence of necrosis/ hemophagocytosis/ abnormal cell infiltration seen. Cerebrospinal fluid (CSF) for cryptococcal antigen was positive and culture showed Cryptococcus neoformans growth. Subsequently, he was started on anti-fungal (amphotericin B) with significant improvement clinically and discharged home after one week.
1. Cryptococcosis is the second most common fungal infection in acquired immunodeficiency syndrome which increases morbidity and mortality. It typically involves pulmonary and central nervous system. Bone marrow involvement is very rare. Cryptococcus infection in immunodeficiency patients results in cytopenia(s).
2. Disseminated Cryptococcus infection elicits both granulomatous and non-granulomatous response1. Our case showed granulomatous response in bone marrow, in such a case Cryptococcus will not be seen in bone marrow aspiration as there will be fibrosis. The rate of detection is very high when bone marrow aspiration and biopsy were done at a same time2.
1. Pantanowitz L, Omar T, Sonnendecker H, Karstaedt AS. Bone marrow cryptococcal infection in the acquired immunodeficiency syndrome. J Infect. 2000;41:92–4.
2. Bain B.J. Bone marrow trephine biopsy. J Clin Pathol. 2001;54:737–42.
A: Bone marrow biopsy shows intracellular thick-walled capsulated yeast forms of Cryptococcus within histiocytes (red arrows) (H & E stain, 400x); B: Gomori methenamine silver stain (400x) highlights aggregates of yeasts and budding forms (black arrow); C: Periodic acid Schiff stain (400x) shows magenta-coloured intracellular organisms (black arrow) and D: Mucicarmine stain highlights intracellular capsule (black arrows) (400x)