Abstract
Histoplasma capsulatum is an endemic fungus in eastern Canada. This organism has a wide spectrum of manifestations ranging from isolated pulmonary to disseminated disease. The latter usually occurs in immunocompromised hosts or those with substantial environmental exposure. In rare instances, disseminated histoplasmosis can present as an endovascular infection or chronic progressive disseminated histoplasmosis. If not recognized, these entities are almost uniformly fatal. We report a case of an immunocompetent man with a history of longstanding constitutional symptoms. An infectious cause was initially presumed to be unlikely given the chronic nature of his presentation and an extensive series of negative investigations. A diagnosis was only obtained post-mortem upon the unusual detection of both yeast and hyphal forms in blood culture bottles inoculated with a bone marrow aspirate.
Key words: chronic progressive disseminated histoplasmosis, culture-negative endocarditis, disseminated histoplasmosis, endocarditis, fever of unknown origin, histoplasmosis
Abstract
L’Histoplasma capsulatum est une mycose endémique dans l’est du Canada. Cet organisme présente un vaste spectre de manifestations, de l’atteinte pulmonaire isolée à la maladie disséminée. En général, la forme disséminée s’observe chez des hôtes immunodéprimés ou qui y ont été largement exposés dans l’environnement. Dans de rares cas, l’histoplasmose disséminée peut prendre la forme d’une infection endovasculaire ou d’une histoplasmose disséminée progressive chronique. Non diagnostiquées, ces entités sont pratiquement toujours fatales. Les auteurs déclarent le cas d’un homme ayant une histoire de symptômes constitutionnels de longue date. Au départ, la cause infectieuse était considérée comme peu probable étant donné la présentation chronique et la longue série d’explorations négatives. Le diagnostic n’a été posé qu’après le décès, lors de la détection inhabituelle des formes à levures et à mycélium dans les flacons d’hémoculture inoculés d’un aspirat de moelle osseuse.
Mots-clés : endocardite, endocardite négative à la culture, fièvre d’origine inconnue, histoplasmose, histoplasmose disséminée, histoplasmose disséminée progressive chronique
Case Presentation
A 69-year-old male presented to his local emergency department with a 1-month history of recurrent fevers, night sweats, and anorexia. His past medical history was only significant for a bioprosthetic aortic valve replacement several years prior to presentation. His initial investigations were notable for mild bicytopenia and elevated C-reactive protein (CRP) (Table 1).
Table 1:
Patient laboratory results
| Laboratory test (units) | Result | Reference range | ||
|---|---|---|---|---|
| Initial lab results (day 1) | Subsequence lab results (approx. day 30) | Lab results shortly after admission (approx. day 120) | ||
| Hemoglobin (g/L) | 124 | 112 | 91 | (140–175) |
| Platelet (×109/L) | 107 | 69 | 50 | (150–400) |
| White blood count (×109/L) | 4.0 | 2.5 | 2.9 | (4.0–11.0) |
| Creatinine (μmol/L) | 128 | 148 | 130 | (55–120) |
| ALT (U/L) | 23 | 41 | 105 | (5–40) |
| LDH (U/L) | 315 | 267 | 382 | (110–220) |
| CRP (mg/L) | 38.5 | 90.2 | 67.9 | (0.8–2.2) |
| Ferritin (μg/L) | 676 | — | 6,650 | (50–350) |
ALT = alanine aminotransferase; LDH = lactate dehydrogenase; CRP = C-reactive protein
An extensive set of investigations aimed at determining the etiology of his fever were requested. Blood, urine, throat, and stool cultures were all negative. Empiric treatment with broad spectrum antibiotics was initiated. A computed tomography (CT) scan of the thorax, abdomen, and pelvis revealed splenomegaly (15 cm), and a transthoracic echocardiogram was suspicious for vegetation on the bioprosthetic aortic valve. While this suggested culture-negative endocarditis, a transesophageal echocardiogram failed to detect any vegetations. Antibiotic therapy was subsequently stopped. Despite having received antibiotics, the patient continued to have persistent fevers with the interval development of pancytopenia and a rising CRP (Table 1).
Given the suspicion for an underlying malignant hematological process, a bone marrow biopsy was performed. This revealed epithelioid noncaseating granulomas with giant cells and was deemed suggestive of either sarcoid or lymphoma. Acid-fast and Grocott–Gomori methenamine silver (GMS) stains were negative.
Approximately 3 months after the initial onset of fever, the patient was referred to our tertiary care hospital for a rheumatology assessment and investigations. Despite numerous tests, the diagnosis remained unclear. The patient was referred to hematology for a second bone marrow biopsy. Histopathology revealed epithelioid granulomas and associated T cells but was not diagnostic for sarcoidosis or a lymphoproliferative disorder. A positron emission tomography (PET) scan revealed the spleen and a single mesenteric lymph node to be FDG-avid. The latter was not amenable to biopsy. Given the chronicity of his presentation and the erstwhile negative infectious disease work-up, he was reassessed by rheumatology and thereafter empirically treated for an atypical presentation of sarcoidosis with a trial of corticosteroids. Despite 2 weeks of treatment with prednisone, he remained symptomatic. He was then admitted to our hospital to expedite the work-up.
An infectious disease consultation was requested. Collateral history revealed that the patient resided near the island of Montréal, close to a forested nature reserve and approximately 10 km from the river. He also lived in close proximity to, and had occasional contact with, animals including sheep, horses, chickens, and wild birds. His travel history was unremarkable. Four days into his admission, he suddenly deteriorated and necessitated transfer to the intensive care unit for cardiogenic and distributive shock; there, he received intravenous meropenem and vancomycin, vasopressors, and stress-dose steroids. Laboratory investigations revealed pancytopenia and a markedly elevated ferritin level (Table 1). A bone marrow biopsy was performed, and samples were inoculated directly into an aerobic blood culture bottle and a mycobacterial/fungal blood culture bottle. Voriconazole was added as empiric antifungal treatment. Within 24 hours of his transfer to the intensive care unit (ICU), he developed multi-organ system failure and subsequent succumbed with cardiorespiratory collapse. The patient’s family consented to an autopsy.
Diagnosis
Three days post-mortem, the aerobic blood culture bottle inoculated with the bone marrow aspirate revealed numerous yeast and hyphal forms on Gram stains (Figure 1). Both forms were also observed in the inoculated mycobacterial/fungal culture bottle. The organism was subsequently identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI–TOF) mass spectrometry as Histoplasma capsulatum. The result of an MVista urinary Histoplasma antigen test (MiraVista Diagnostics, Indianapolis, IN; miravistalabs.com) requested on admission was subsequently reported as positive but above the limit of quantification. The bone marrow biopsy findings were consistent with hemophagocytic syndrome, and GMS staining revealed intracellular yeast forms. The autopsy revealed disseminated fungal microabscesses in the spleen, bone marrow, kidney, thyroid, and lung as well as fungal endocarditis. The bioprosthetic aortic valve leaflets were thickened with tan–yellow, friable vegetations extending into the aortic lumen. Histopathology of these vegetations revealed abundant yeast and hyphal elements.
Figure 1:
Gram stain of aerobic blood culture
Discussion
Histoplasmosis is an endemic fungal infection in eastern Canada (1). Disseminated histoplasmosis is a potentially life-threatening condition usually seen in immunocompromised hosts, patients with hematological malignancies, and those who have had a high burden of environmental exposure. However, our patient had both chronic progressive disseminated histoplasmosis and Histoplasma infective endocarditis. Both entities are rarely encountered manifestations of disseminated Histoplasma infection and are predominantly described in apparently immunocompetent hosts (2,3). Their presentation is often non-specific with constitutional symptoms. Moreover, the diagnosis of these potentially fatal complications of disseminated histoplasmosis is often delayed because of the chronicity of the disease and failure to detect the organism on blood culture.
Several unusual microbiologic features were notable. Although Histoplasma can rarely be isolated using modern standard blood culture methods, it is remarkable that this isolate was detectable within 4 days of inoculation. Also, the presence of both yeast and hyphal forms in a freshly inoculated sample incubated at 35°C was unexpected and has only been reported on one previous occasion (4). However, the remarkable finding of both yeast and hyphal forms in a host has been described in the histopathology literature, and notably in cases of endovascular histoplasmosis (5). It is unclear whether a high fungal burden, the valvular vegetation microenvironment, or unique host or pathogen factors contribute to this feature.
Early consideration of potential progressive disseminated histoplasmosis in seemingly immunocompetent hosts is crucial for the diagnosis and initiation of treatment of this potentially curable disease. Histoplasma should also be considered as a potential causative organism in patients with culture-negative endocarditis, including those with prosthetic valves. If suspected, testing urine or serum for Histoplasma antigen should be performed, as this test is readily available and highly sensitive and specific (6).
Acknowledgements
The authors would like to acknowledge the contributions of the following colleagues, whose painstaking efforts allowed us to achieve a definitive diagnosis, including Mina Patel and the Jewish General Hospital’s (JGH) microbiology laboratory staff; the Laboratoire de Santé Publique du Québec, including Philippe Dufresne, Marie-France Sirois, Thérenne Desmeules, Mélanie Côté, and Lyne Désautels; Chantal Cassis (Hematology, JGH); Richard Fraser (Pathology, MUHC); and Blair Schwartz (Intensive Care, JGH).
Funding Statement
Publication of this article was funded by the Association of Medical Microbiology and Infectious Disease (AMMI) Canada.
Competing Interests:
The authors have nothing to disclose.
Ethics Approval:
N/A
Informed Consent:
The patient’s family consented to an autopsy.
Registry and the Registration No. of the Study/Trial:
N/A
Animal Studies:
N/A
Funding:
Publication of this article was funded by the Association of Medical Microbiology and Infectious Disease (AMMI) Canada.
Peer Review:
This article has been peer reviewed.
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