A 43-Year-Old Woman With Acquired Immunodeficiency Syndrome and Fever of Undetermined Origin
A 43-year-old black woman was admitted to our institution in April 2004 because of fever and frontal headache of 2-week duration. She also had complaints of diffuse abdominal discomfort associated with nausea and vomiting. No urinary or respiratory symptoms were noted. The patient had been living in New York City since she migrated to the United States from the Caribbean 20 years ago. One month before her presentation, the patient had traveled to Panama and stayed there for 2 weeks. She did not travel within the United States. She denied any history of insect or tick bites. No exposure to pets was reported. She was a housewife and denied any substance abuse. She had acquired immunodeficiency syndrome (AIDS) since 2000. She had been on antiretroviral therapy (zidovudine, lamivudine, and indinavir) for 1 year. The antiretroviral medications were stopped on admission because of her current condition. On physical examination, the patient's temperature was 38.9°C, pulse rate was 104 beats per minute, respiratory rate was 16 breaths per minute, and blood pressure was 130/70 mm Hg. No skin rash, pharyngitis, sinus tenderness, or lymphadenopathy was noted. Auscultation of the heart and lungs was unremarkable. Abdominal examination showed no hepatosplenomegaly. Genitourinary and neurologic examinations were unremarkable. The extremities were unremarkable. Complete blood count showed the following values: white blood cell count, 2.47 × 103 cells/μL; hemoglobin, 10 g/dL; and platelet count, 69 × 103 cells/μL. White blood cell differential count showed 50% neutrophils, 18% bands, 20% lymphocytes, 6% monocytes, and 6% eosinophils. Serum electrolytes and renal function tests were within reference ranges. Her chemistry profile showed the following values: aspartate aminotransferase, 193 U/L; alanine aminotransferase, 93 U/L; lactate dehydrogenase (LDH), 3383 U/L; and creatine kinase, 5897 U/L. Bilirubin, alkaline phosphatase, amylase, lipase, and lactic acid levels were within reference ranges. Her CD4+ cell count was 150 cells/μL, and her human immunodeficiency virus load was undetectable. Urinalysis was negative. Blood cultures for bacteria were negative. Serology for cytomegalovirus, Mycobacterium tuberculosis, Mycobacterium avium intracellularae, infectious mononucleosis, and viral hepatitis were negative. Cultures of sputum, urine, and cerebrospinal fluid were negative. Radiographic evaluation, including chest x-ray film; ultrasound of the abdomen; computed tomographic scan of the chest, abdomen, and pelvis; and magnetic resonance imaging of the brain with contrast all were unremarkable. The patient remained febrile despite parenteral broad-spectrum antibiotics. During her hospital stay, the patient's condition worsened. A bone marrow biopsy was performed on day 4 of hospitalization while the results of blood cultures for mycobacteria and fungi (ordered on admission) were still pending. Microscopic examination of sections of the bone marrow biopsy stained with hematoxylin-eosin showed ill-formed granulomas scattered among the hematopoietic elements (Figure 1). No giant cells or necrosis were noted. Sparse lymphocytic infiltrate was present. Special stains for acid-fast bacilli were negative. Gomori methenamine-silver (GMS) stain revealed budding yeasts in the granulomas. The yeasts were negative for mucicarmine, a special stain for mucin. The yeasts were extracellular and not clustered within macrophages (Figure 2). Morphologically, the yeasts had a double-contoured refractile wall and a narrow base attaching the bud to the parent cell, and ranged in size from 2 to 4 μm (Figure 3). Based on the result of histopathologic examination of the bone marrow biopsy, intravenous voriconazole was initiated promptly. The patient defervesced within 24 hours and all laboratory values normalized. The patient was discharged on day 10 on oral voriconazole with a plan to resume antiretroviral medications as an outpatient. Two days after the discharge, the blood cultures showed mold growth in the mycelial form, which consisted of hyphae-bearing macroconidia (8–14 μm) and microconidia (2–5 μm). The conidia were trabeculate (Figure 4; arrow points to a trabeculate macroconidium).What is your diagnosis?Disseminated histoplasmosis in patients with acquired immunodeficiency syndrome is a life-threatening condition. Prompt diagnosis and therapy of disseminated histoplasmosis is critically important because of the high mortality rate of untreated cases. Bone marrow biopsy can reveal the diagnosis faster than blood cultures or serologic tests and, therefore, can be crucial for the immediate management. We describe disseminated histoplasmosis in a 43-year-old woman with acquired immunodeficiency syndrome, whose bone marrow biopsy revealed the diagnosis much earlier than cultures or serologic methods. Bone marrow biopsy in this case was crucial for early diagnosis of and life-saving therapy for disseminated histoplasmosis. Our case demonstrates the usefulness of bone marrow biopsy for the diagnosis of febrile illnesses in patients with human immunodeficiency virus infection, particularly when the need for rapid diagnosis and empiric therapy is imperative.Disseminated histoplasmosis is the most severe form of Histoplasma capsulatum infection. It occurs in the elderly, infants, and profoundly immunodeficient patients, including patients with AIDS. In 1985, The Centers for Disease Control and Prevention considered disseminated histoplasmosis as an AIDS-defining condition.1 Disseminated histoplasmosis is defined as evidence of extrapulmonary histoplasma infection demonstrated by either culture or histopathologic examination of material from an extrapulmonary site.2 Because the clinical findings are nonspecific, histoplasmosis should be suspected in patients with AIDS and unexplained febrile illness.1Disseminated histoplasmosis results from hematogenous spread of the organisms to various organs of the body. Infection develops when microconidia are inhaled into the lungs. These spores germinate into yeasts, which parasitize macrophages and are capable of spreading throughout the reticuloendothelial system. The infection usually begins in the lungs, even in cases in which the chest x-ray film is normal. The primary pulmonary lesions could be subclinical and go unnoticed. Involvement of virtually every organ system has been reported. The mortality rate is 80% without antifungal treatment.12Histoplasmosis is endemic in the regions of the Mississippi and Ohio River valleys as well as certain areas of Central and South America and the Caribbean. It occurs sporadically on the East and West coasts. Risk factors include travel to or living in an endemic area, working in construction or remodeling, or hobbies that bring patients into contact with microfoci contaminated with H capsulatum, such as caves and farms.Histoplasma capsulatum is thermally dimorphic. At 25°C, it grows as a mold and attains the mycelial form. It consists of hyphae-bearing, large trabeculate macroconidia (8–14 μm), and smaller microconidia (2–5 μm), which are the infectious form of the organism.1 In tissue sections, H capsulatum organisms are yeastlike, uniform, 2 to 4 μm in diameter, and uninucleate. The yeast typically has double-contoured refractile walls and the bud is attached to the parent cell with a narrow base. They are often clustered within the cytoplasm of macrophages, but in patients with AIDS or other profound cell-mediated immunodeficiencies, the yeasts may produce extracellular aggregates or "yeast lakes."2The differential diagnosis of histoplasmosis on histopathologic examination includes mycobacterial infections, Blastomyces dermatitidis and Leishmania donovani. Histoplasmosis mimics mycobacteria, because both organisms can cause granulomas in the affected organs. These granulomas may show caseous necrosis in both conditions or may be noncaseating.1 Special stains for acid-fast bacilli and fungi, for instance GMS, are helpful in finding the offending organism. The yeasts of B dermatitidis typically have double-contoured refractile walls resembling those of H capsulatum yeasts, but the base attaching the bud to the parent cell is broad.1 The intracellular budding yeasts of H capsulatum are similar to Leishmania, but do not contain kinetoplast.1 Definitive diagnosis can be made by culturing the organisms. In disseminated histoplasmosis, the highest yield is obtained by culturing blood or bone marrow.1 The major disadvantage of cultures is the fact that they are limited by slow growth (2–4 weeks). Serologic tests to detect antibodies against H capsulatum are also limited by a long interval between infection and antibody production (4–12 weeks).34 These serologic tests are further complicated by less sensitivity resulting from the inability of the immunocompromised patients to mount an effective immune response. In addition, false-positive results can occur from a previous infection as well as from other fungal infections, including blastomycosis, coccidioidomycosis, and paracoccidioidomycosis.1It is important to diagnose disseminated histoplasmosis expeditiously in patients with AIDS because of the high mortality rate of untreated cases. Bone marrow biopsy most likely provides rapid presumptive diagnosis before the culture or serologic tests. Bone marrow biopsy also helps in revealing the diagnosis if the cultures or serologic tests turn out to be negative.56 In a series study of 36 adult patients with AIDS with disseminated histoplasmosis, histopathologic examination of bone marrow specimens resulted in relatively rapid identification of nearly one third of the infected patients who underwent bone marrow examination, and also identified infections in some patients whose blood cultures were negative.7Histoplasma polysaccharide antigen can be detected in blood and other body fluids and it is positive in most patients with disseminated histoplasmosis.12 Urine serology for histoplasma antigen in our patient was moderately positive (level = 8), whereas the serum level of histoplasma antibodies was in the undetectable range. Another interesting finding in this case was the markedly high value of the serum LDH (3383 U/L). Butt et al8 reported that disseminated histoplasmosis in patients with AIDS is usually associated with high LDH (greater than 600 U/L) and this can be used as an adjunct clinical marker to differentiate between histoplasmosis and other opportunistic infections, such as Pneumocystis carinii, in which the LDH values are less than those observed in disseminated histolapsmosis. Similarly, in their series study, Corcoran et al9 found that markedly elevated LDH may serve as a clinical clue in the diagnosis of disseminated histoplasmosis. However, this finding does not help to differentiate between different types of mycoses, because LDH can be elevated in any disseminated fungal infection. The high creatine kinase in this patient (5897 U/L) was most likely caused by AIDS-associated myopathy as well as zidovudine-induced myopathy.10It is important to mention that histopathologic examination of the bone marrow biopsy in disseminated fungal infections may not give definitive diagnosis. In addition, it is sometimes difficult to distinguish between fungal species based on their morphology seen on tissue sections. Furthermore, fungal special stains have lower sensitivity than cultures or antigen detection.1 Therefore, the combination of bone marrow biopsy with cultures and serologic tests offers greater sensitivity. However, bone marrow biopsy can give relatively faster results for the purpose of immediate initialization of the antifungal management, without the need to wait for the results of the cultures. Cultures and serologic tests can later confirm the histopathologic diagnosis and identify the fungal species. Identification of fungal species can be important for treatment adjustment and patient counseling, such as habits or lifestyle modification. In the current case, H capsulatum was presumptively diagnosed on bone marrow biopsy, but the definitive diagnosis was made later by blood culture and detection of histoplasma antigen on urine serology.Bone marrow biopsy was crucial for the life-saving therapy for disseminated histoplasmosis in this patient. Our case underscores the usefulness of bone marrow biopsy for the rapid diagnosis of febrile illnesses in patients with human immunodeficiency virus infection, particularly when the need for early therapy is imperative.
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