An Infant With Fever, Hepatosplenomegaly, and Pancytopenia

A previously healthy 8-month-old white female was admitted with a history of fever for 3 weeks. She had daily temperatures as high as 39.4°C associated with decreased activity. A mild nonproductive cough without rhinorrhea was noted by the mother during the first week of illness. There was no history of vomiting, diarrhea, rash, hand swelling, or redness of the eyes. Her appetite remained normal throughout the illness. The infant was initially diagnosed with a viral illness by her physician, but because of persistent fever, she was subsequently admitted to a community hospital 1 week after the onset of her illness. Her evaluation there included chest radiography, complete blood counts, urine culture, and blood culture. She was discharged home after 2 days when all of the test results were negative. Two weeks later, she was brought to the emergency department at Children's Hospital of Michigan because of persistent fever, and was again admitted. The patient had no significant past medical history. Her growth and development were appropriate for her age. Her immunizations were complete for her age. She lived with her parents in Detroit and had never traveled outside Michigan. There were no pets at home, and she did not attend day care. Upon admission the infant was alert, interactive, and in no distress. She had a temperature of 40°C, pulse of 150 beats/min, respiratory rate of 32 breaths/min, blood pressure of 90/69 mm Hg, and oxygen saturation of 100% in room air. Abdominal examination revealed an enlarged spleen and liver that were palpable 7 cm and 4 cm below the costal margin, respectively. The remainder of the physical examination was normal. The patient's white blood cell count was 6300/mm3 with 15% neutrophils, 76% lymphocytes, 8% monocytes, and 1% eosinophils. The hemoglobin was 11 g/dL, and the platelet count was 150,000/mm3; the peripheral blood smear showed no cellular atypia. A repeat CBC on the next day showed white blood cell count of 4000/mm3 with 23% neutrophils, 63% lymphocytes, and 14% monocytes. The hemoglobin decreased to 9.8 g/dL, and the platelet count decreased to 88,000/mm3. Aspartate aminotransferase and alanine aminotransferase were 162 and 163 units/L, respectively. Alkaline phosphotase was 152 units/L, serum albumin was 2.9 g/dL, lactate dehydrogenase was 357 units/L, serum uric acid level was 2.9 mg/dL, and ferritin level was 180 ng/mL. Epstein-Barr virus, cytomegalovirus, toxoplasma, and parvovirus serologies were negative. In addition, rapid plasma reagent and human immunodeficiency virus antibody by enzyme-linked immunosorbent assay were negative. A tuberculin skin test had 0 mm of induration. Chest radiograph was normal, but abdominal ultrasonography confirmed the presence of massive hepatosplenomegaly without any identifiable intraabdominal mass. In light of her fevers, hepatosplenomegaly, and pancytopenia, the hematology-oncology service was consulted. A bone marrow aspiration was performed; the bone marrow smear examination and additional laboratory tests confirmed the diagnosis. Denouement The bone marrow smear examination revealed a macrophage containing 2 intracellular yeast-like structures with clear surrounding zones, suggestive of histoplasmosis (Fig. 1). The diagnosis was later confirmed by a positive M band on histoplasmosis serology, a positive Histoplasma antigen in the urine, and a positive fungal blood culture for Histoplasma capsulatum.FIGURE 1.: Wright-Giemsa stain of the bone marrow smear showing a macrophage containing 2 intracellular yeast-like structures with clear surrounding zones.Based on the suspicious bone marrow examination, the patient was treated with intravenous amphotericin B lipid complex at a dose of 5 mg/kg once daily. She showed a dramatic response with defervescence within 24 hours, recovery of pancytopenia within 4 days, and resolution of hepatosplenomegaly within 10 days. The urine antigen for histoplasmosis became negative after 2 weeks of treatment. Additional investigations to rule out an underlying immune deficiency were performed. Absolute CD4 lymphocyte count was 2450/mm3 (49%), absolute CD8 lymphocyte count was 650/mm3 (13%), and absolute natural killer cell count was 50/mm3 (1%), all essentially normal for age. In addition, serum immunoglobulin values, neutrophil respiratory burst assay, and mitogen-induced lymphocyte stimulation assay were normal. The patient was treated with 6 weeks of intravenous amphotericin B lipid complex, and then therapy was changed to oral itraconazole. Because of the severity of illness, we treated for a total duration of 6 months with periodic monitoring of the Histoplasma urine antigen and liver transaminases. In the United States, Histoplasma capsulatum is endemic in the Mississippi and Ohio River valleys.1 It exists in soil that contains large amounts of bird or bat guano, and thus caves are a known risk factor for exposure to H. capsulatum.2 The clinical manifestations of histoplasmosis range from asymptomatic infection or mild disease in most of cases to severe pulmonary disease or progressive disseminated disease in rare cases. Although symptoms of histoplasmosis are often similar in adults and children, certain manifestations seen in adults, such as chronic pulmonary infection, mediastinal fibrosis, and subacute meningitis, are uncommon in children. Patients who are immunosuppressed and unable to mount an effective cell-mediated immune response against the organism are more likely to develop disseminated disease. This includes patients with acquired immunodeficiency syndrome, transplant recipients, those with hematologic malignancies, and those receiving corticosteroid therapy.3 Presumably because of their immature cell-mediated immunity, infants are a special group that can also develop severe life-threatening Histoplasma infection.4 Prolonged fever, failure-to-thrive, and massive hepatosplenomegaly are the common manifestations of progressive disseminated histoplasmosis in otherwise healthy infants.5 Meningitis often accompanies this form of disease in infants aged less than 2 years.6 Because our patient maintained normal neurologic status throughout the course of her illness and because treatment does not require modification when disseminated disease in infants is accompanied by meningitis, we chose not to perform a lumbar puncture in our case. Laboratory findings in infants with progressive disseminated histoplasmosis include pancytopenia and disseminated intravascular coagulopathy.7 The diagnosis may be confirmed by serologic testing, enzyme immunoassay for Histoplasma antigen in the urine, tissue examination, and fungal culture. The histoplasmin skin test is only useful as an epidemiologic tool. Positive serologic tests accompany acute infections in most instances. The presence of an H band or M and H bands together by immunodiffusion precipitin testing is strongly suggestive of acute or recent infection.8 The Histoplasma antigen assay in urine is not only useful for diagnosis in immunocompetent and immunocompromised individuals, but can also be used to monitor the effectiveness of therapy.9,10 Histologic findings of granulomas and/or yeast forms in infected tissue or bone marrow are strongly suggestive of disseminated disease.8 Although fungal culture of tissue, blood, or bone marrow remains the gold standard for diagnostic confirmation, this requires a lengthy incubation period. The differential diagnosis for an infant presenting with fever, hepatosplenomegaly, and pancytopenia includes a number of infectious diseases such as Epstein-Barr virus, cytomegalovirus, and other disseminated fungal infections such as coccidioidomycosis and blastomycosis. For patients with a relevant travel or exposure history, one should consider malaria, babesiosis, brucellosis, visceral leishmaniasis, bartonellosis, toxoplasmosis, and disseminated tuberculosis. Hemophagocytic syndrome, which may be triggered by variety of infectious pathogens, is another consideration. Noninfectious etiologies including lymphoma, leukemia, histiocytosis, neuroblastoma, metastatic tumors, collagen vascular diseases, and storage diseases, such as Niemann-Pick disease and Gaucher disease, are also potential causes of hepatosplenomegaly and pancytopenia in a young infant. Progressive disseminated histoplasmosis is fatal if untreated. For children with this severe form of disease, treatment with amphotericin B deoxycholate (1 mg/kg daily for 4–6 weeks) is recommended; an alternative regimen is amphotericin B deoxycholate (1 mg/kg daily for 2–4 weeks) followed by itraconazole (5–10 mg/kg daily in 2 divided doses) to complete 3 months of therapy.11 When itraconazole is used, blood concentrations should be monitored. Human immunodeficiency virus testing and assessment of cellular immunity to rule out primary immunodeficiency is recommended in any child with disseminated histoplasmosis. Longer therapy may be necessary for patients with severe disease, immunosuppression, or an underlying immune deficiency syndrome. Histoplasma antigenuria in patients with severe disseminated infection should be monitored to ensure that the concentration decreases appropriately.10 Antifungal therapy can be safely stopped if the patient is clinically well and the recommended duration of treatment has been completed. To monitor for relapse, Histoplasma antigen levels in the urine should be measured for at least 6 months after completion of therapy.11