Histoplasma capsulatum Endocarditis

Infective endocarditis is an uncommon manifestation of infection with Histoplasma capsulatum. The diagnosis is frequently missed, and outcomes historically have been poor. We present 14 cases of Histoplasma endocarditis seen in the last decade at medical centers throughout the United States. All patients were men, and 10 of the 14 had an infected prosthetic aortic valve. One patient had an infected left atrial myxoma. Symptoms were present a median of 7 weeks before the diagnosis was established. Blood cultures yielded H. capsulatum in only 6 (43%) patients. Histoplasma antigen was present in urine and/or serum in all but 3 of the patients and provided the first clue to the diagnosis of histoplasmosis for several patients. Antibody testing was positive for H. capsulatum in 6 of 8 patients in whom the test was performed. Eleven patients underwent surgery for valve replacement or myxoma removal. Large, friable vegetations were noted at surgery in most patients, confirming the preoperative transesophageal echocardiography findings. Histopathologic examination of valve tissue and the myxoma revealed granulomatous inflammation and large numbers of organisms in most specimens. Four of the excised valves and the atrial myxoma showed a mixture of both yeast and hyphal forms on histopathology. A lipid formulation of amphotericin B, administered for a median of 29 days, was the initial therapy in 11 of the 14 patients. This was followed by oral itraconazole therapy, in all but 2 patients. The length of itraconazole suppressive therapy ranged from 11 months to lifelong administration. Three patients (21%) died within 3 months of the date of diagnosis. All 3 deaths were in patients who had received either no or minimal (1 day and 1 week) amphotericin B. (Medicine 2014;93: 186–193) Abbreviations: CF = complement fixation, EDTA = ethylenediaminetetraacetic acid, EIA = enzyme linked immunoassay, Hb = hemoglobin, ID = immunodiffusion, IDSA = Infectious Diseases Society of America, PCR = polymerase chain reaction, TEE = transesophageal echocardiogram, TTE = transthoracic echocardiogram, WBC = white blood cells. INTRODUCTION Infection with Histoplasma capsulatum is a rare cause of endocarditis. A review of cases of fungal endocarditis reported from 1965 to 1995 identified H. capsulatum as the etiologic agent in 15 of 270 (6%) cases, and a subsequent review encompassing the years 1995 to 2000 noted that only 2 of 152 (1%) cases were due to H. capsulatum. Focusing specifically on fungal prosthetic valve endocarditis, histoplasmosis assumes a greater role; Boland et al reported that 3 of the 21 cases (14%) seen at the Mayo Clinic from 1970 to 2008 were caused by H. capsulatum. A total of only 43 cases of Histoplasma endocarditis, most reported as single cases, have been noted in the 60 years from 1943 to 2003. The diagnosis of Histoplasma endocarditis is challenging because the automated blood culture systems that are commonly used do not favor the growth of this organism. Many cases have been identified only at autopsy. The diagnostic approach to culture-negative endocarditis has improved over the last decade, and optimal management of fungal endocarditis in regard to antifungal treatment and surgical intervention has evolved. To our knowledge, there has been no contemporary multicenter case series focusing on endocarditis caused by H. capsulatum. In the current study, we sought to describe the clinical manifestations, the use of newer diagnostic tools for the diagnosis of Histoplasma endocarditis, the approach to treatment, and the outcomes of patients who had Histoplasma endocarditis. METHODS A convenience sample of cases of Histoplasma endocarditis seen from January 2003 to December 2012 was From the University of Michigan Health System, Division of Infectious Diseases (JR, CAK), Ann Arbor, Michigan; Veterans Affairs Ann Arbor Healthcare System (CAK), Ann Arbor, Michigan; University of Wisconsin, Division of Infectious Diseases (JAS), Madison, Wisconsin; University of Kansas School of Medicine (MA), Wichita, Kansas; Sawtooth Infectious Diseases (SB), Boise, Idaho; Idaho Falls Infectious Diseases (MIB), Idaho Falls, Idaho; Stanford University, Division of Infectious Diseases and Geographic Medicine (SD), Palo Alto, California; Vanderbilt University, Division of Infectious Diseases (PWW), Nashville, Tennessee; University of Oklahoma College of Medicine, Division of Infectious Diseases (DAD), Oklahoma City, Oklahoma; Community Infectious Disease (SAN), Indianapolis, Indiana; Mayo Clinic, Division of Infectious Diseases (HRV), Phoenix, Arizona; North Dakota State University, Master of Public Health Program (PJC), Fargo, North Dakota; Mayo Clinic, Division of Infectious Diseases (PV), Rochester, Minnesota; Scott and White Clinic (JC), Texas A&M University College of Medicine, Temple, Texas; Infectious Diseases Specialists (SMS), Dallas, Texas; and MiraVista Diagnostics (LJW), Indianapolis, Indiana. Correspondence: James Riddell IV, MD, University of Michigan Health System, Infectious Diseases Division, 1500 E. Medical Center Drive, 3120 Taubman Center, SPC 5378, Ann Arbor, MI 48109-5378 (e-mail: [email protected]). Financial support and conflicts of interest: L.J.W. is President and Director of MiraVista Diagnostics. The other authors have no funding or conflicts of interest to disclose. Copyright © 2014 by Lippincott Williams & Wilkins. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000034 186 | www.md-journal.com Medicine • Volume 93, Number 5, July 2014 identified from multiple sites across the United States through laboratory records at MiraVista Diagnostics, Indianapolis, IN. To be included in the study, patients needed to meet the case definition as follows: 1) endocarditis with a vegetation or a cardiac mass documented by echocardiography or at surgery; 2) no other pathogen isolated; 3) at least 1 of the following: a positive Histoplasma antigen test later verified by histopathology or culture, histopathologic evidence of budding yeasts with or without hyphal forms in heart valve tissue, a culture yielding H. capsulatum from blood or another sterile site, polymerase chain reaction (PCR) positive for H. capsulatum from heart valve tissue. A standardized data collection form was used to collect clinical data on patients who met the case definition. Participating clinicians provided protected health information according to the regulations of their local oversight authority and/or approval through their local Institutional Review Board. Simple statistical analysis using means, medians, and standard deviations was utilized. SELECTED CASE REPORTS Case 1 (Table 1, Patient 12) A 71-year-old man who had undergone aortic valve replacement with a porcine allograft in 2004 for aortic stenosis and who had recently been treated for prostate cancer, presented with a 6-month history of malaise and mild dyspnea and the recent onset of confusion, lower extremity weakness, and syncope. He lived in Acapulco, Mexico, during the winter and resided in Michigan during the summer. He was admitted to hospital in October 2010 with fever and mental status changes. Examination revealed a temperature of 101.8 °F, pulse 114/min, and blood pressure 111/66mm Hg. A harsh 3/6 systolic ejection murmur was audible throughout the precordium and radiated to the carotids. There were no peripheral stigmata of endocarditis. There was mild leftgreater-than-right weakness of the lower extremities. He was alert and oriented to self and place but not to time. He was unable to provide the details of much of his medical history and had deficits in short term memory. White blood cell (WBC) count was 8800/μL, hemoglobin (Hb) 13.6g/dL, platelet count 111,000/μL, creatinine 1.1mg/dL. An MRI of the brain showed no changes and a lumbar puncture revealed no abnormalities. A transthoracic echocardiogram (TTE) revealed a severely thickened bioprosthetic aortic valve and severe aortic stenosis. A transesophageal echocardiogram (TEE) identified a large amount of soft-tissue density material encompassing the bioprosthetic valve leaflets with mobile components consistent with vegetations. Splenic infarcts consistent with emboli were identified on abdominal ultrasound. Multiple sets of blood cultures processed by the BacTAlert system and the lysis-centrifugation (Isolator tube) system were obtained prior to the initiation of antibiotic therapy, and all yielded no growth. A Histoplasma antigen enzyme immunoassay (EIA) test was positive in urine (4.26ng/mL) and serum (13.58ng/mL). The complement fixation (CF) assay for antibodies against H. capsulatum was negative, but the immunodiffusion (ID) assay showed antibodies to both H and M antigens of H. capsulatum. Therapy with liposomal amphotericin B, 5mg/kg per day, was initiated, and 10 days later the patient underwent replacement of his aortic valve and ascending aorta with a homograft as an inclusion root. Histopathology of the resected aortic valve revealed both yeast and hyphal forms (Figure 1). PCR assay performed at the Centers for Disease Control and Prevention (CDC) was positive for H. capsulatum, and culture yielded growth of H. capsulatum. After 6 weeks of treatment with liposomal amphotericin B, therapy was changed to oral itraconazole for a total treatment course of 12 months. The serum and urine antigen assays became negative after 6 months of treatment. Three years later, in August 2013, he felt well and had no evidence of recurrent infection. Comment: This patient had a prolonged illness with many negative blood cultures. The presence of H. capsulatum antigen and antibodies in concert with the TEE showing vegetations on the bioprosthetic valve led to the diagnosis of Histoplasma endocarditis. A noteworthy feature of this case was the predominance of hyphae, rather than small oval yeasts, noted on the excised prosthetic valve, which led to the request for the PCR assay to verify the identity of the organism before the culture yielded H. capsulatum. Case 2 (Table 1, Patient 11) A 58-year-old man who had hepatitis C-related cirrhosis complicated by ascites was admitted to hospital in March 2006 with a 3-month history of weakness, lower extremity edema, nausea, vomiting, loose stools, urinary incontinence, a 15-pound weight loss, and a 1-month history of fevers. On admission, he was febrile to 101.8 °F, blood pressure was 63/43mm Hg, and pulse was 90/min. He appeared cachectic; jaundice, ascites, and lower extremity edema were noted. No heart murmur was heard. The WBC was 3600/μL, Hb 11.0g/dL, platelets 66,000/μL, creatinine 2.7mg/dL, and bilirubin 2.9mg/dL. A TEE demonstrated mild mitral valve regurgitation and a mildly dilated left atrium that contained a 7.8cm multilobulated, frondlike, mobile mass that prolapsed across the mitral valve (Figure 2). An Isolator blood culture obtained at admission yielded H. capsulatum 2 weeks later. Repeated Isolator blood cultures taken 7 days after admission also yielded H. capsulatum. The initial Histoplasma urinary antigen was 4.90ng/mL, and the serum Histoplasma antigen was negative. Antibody studies (CF and ID) were negative. Resection of the atrial mass was performed because of near-complete obliteration of the left ventricular cavity with prolapse of the mass across the mitral valve and hypotension FIGURE 1. Histopathology of resected prosthetic aortic valve from Case 1 (Patient 12 in Table 1). Grocott methenamine silver stain demonstrating both yeast forms and hyphal elements. ã 2014 Lippincott Williams & Wilkins www.md-journal.com | 187 Medicine • Volume 93, Number 5, July 2014 Histoplasma capsulatum Endocarditis