Limb Embolism in a 52-Year-Old Woman

(See page 1289 for the Photo Quiz.)

Diagnosis: Arterial thrombus caused by Histoplasma capsulatum deriving from native valve endocarditis caused by the same organism.

Microscopic examination of the surgically extracted thrombus revealed numerous narrow budding, round to oval yeast and hyaline, septate hyphae branching at 90 degrees with occasional pseudohyphael forms (Figure 1). Based on this analysis, the patient was placed on liposomal amphotericin B, voriconazole, and micafungin to provide coverage for dimorphic fungi as well as Candida and Aspergillus species. Transesophageal echocardiography demonstrated a 6 × 9-mm vegetation on the ventricular surface of the noncoronary cusp of the aortic valve. Computed tomography of the chest was negative for any parenchymal infiltrates, and fungal cultures of blood and the resected thrombus remained negative. Serum galactomannan, serum and urinary Blastomyces antigen, and human immunodeficiency virus antibody tests were all negative. While the urinary Histoplasma antigen was negative, the serum (1,3)-β-D-glucan (163 pg/mL) and Histoplasma antigen (Miravista Diagnostic, Indianapolis, Indiana) (1.22 ng/mL) tests were positive. Broad-range (18S ribosomal RNA and internal transcribed spacer) polymerase chain reaction (PCR) of the paraffin-embedded thrombus confirmed infection caused by H. capsulatum.

Figure 1.

A, Most of the thrombus contains fungal elements. The yeast and hyphae are both intermixed and in discrete areas. B, Budding yeast (white arrow) and hyaline, septated hyphae (black arrow) are present. Hyphae branch at right angles (dashed arrow).

The patient underwent replacement of her aortic valve with a bovine pericardium biological valve 9 days after admission, given that follow-up cardiac imaging failed to demonstrate interval regression of the valve vegetation. A 10-mm ×8-mm × 1-mm vegetation that had been excised from the underside of the noncoronary cusp of the native aortic valve demonstrated budding yeast and hyphal elements similar to those observed in the embolus (Figure 2). Despite the mixed morphologies, tissue cultures grew only H. capsulatum after 14 days. The patient was discharged home on liposomal amphotericin B and was subsequently transitioned to oral posaconazole due to inability to tolerate itraconazole. She currently remains healthy and has not manifested further embolic or systemic symptoms of illness.

Figure 2.

A, Excised aortic valve with a fungal vegetation. B, Grocott methenamine silver–stained aortic vegetation, ×100 objective. Multiple forms present including yeast (white arrow), septate hyphae (black arrowhead), pseudohyphae (black arrow), and large round forms (white arrowhead).

Histoplasmosis remains a rare infection. In endemic regions, the estimated incidence of infection is 6.1 per 100 000 person-years [1–3]. Endocarditis caused by H. capsulatum is a rare complication of disseminated histoplasmosis, with approximately 50 cases reported in the literature [4, 5]. Histoplasma species are the third most common cause of fungal endocarditis, followed by Candida and Aspergillus species [6]. Cases involving both native and prosthetic valves have been described, as have cases involving hosts with apparently intact immunity. Histoplasma endocarditis predominantly manifests with involvement of the left-sided valvular structures and is frequently associated with systemic embolization [4, 7]. Histoplasmosis is acquired by inhalation of mycelial fragments and microconidia. However, patients with Histoplasma endocarditis do not necessarily have pulmonary findings or abnormal chest imaging at presentation [1, 4].

Blood cultures from patients with Histoplasma endocarditis are often negative, although cultures of tissue or thrombus specimens are usually positive [4]. Antigen detection and PCR assays are useful to supplement and facilitate diagnosis in conjunction with clinical, radiological, and histopathological assessment. However, PCR testing is often only available in reference laboratories, leading to prolonged result turnaround and a delay in diagnosis [8, 9]. At 37°C in vitro and in tissue, Histoplasma is typically 2- to 4-µm oval, narrow-based budding yeasts, whereas it exits as mold form at ambient temperature in the environment [9]. In contrast, with endovascular infection, mycelial forms can predominate and be mixed with variably sized yeast forms measuring up to 30 µm in diameter [10]. The mechanism for this unusual morphologic appearance for Histoplasma in vascular tissue is unknown. It is important for surgical pathologists and clinical microbiologists to be aware of this rare manifestation of histoplasmosis so that delays in diagnosis and treatment are avoided.

Amphotericin B is a cornerstone treatment for Histoplasma endocarditis and was directly associated with reduced mortality in a recent multicenter case series [5]. Although Histoplasma endocarditis has rarely been treated with medical management only [4, 5], the strategy that combined valve replacement surgery with lipid formulation amphotericin B, followed by step-down treatment with itraconazole, is recommended by most authorities [5].

This case underscores the importance to frontline infectious disease clinicians and pathologists to suspect Histoplasma endocarditis in the proper epidemiologic and clinical setting and to be aware that it can display atypical histopathological manifestation. Further antigen detection and nucleic acid test are warranted for accurate diagnosis. Moreover, once Histoplasma endocarditis is suspected clinically, prompt empiric antifungal therapy with amphotericin B and surgical management in selected patients are crucial while awaiting laboratory confirmation.