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Endovascular infections caused by histoplasma capsulatum: a case series and review of the literature.

Histoplasma capsulatum var capsulatum, hereafter referred to as H capsulatum, is a thermally dimorphic fungus that is endemic in certain areas in the Americas, notably the Mississippi and Ohio River valleys in the United States and Rio de Janeiro State in Brazil, and occurs in microfoci elsewhere. (1-4) Most infections result in no or self-limited symptoms. (5) When symptomatic, histoplasmosis most commonly causes a subacute pulmonary illness that is self-limiting. Endovascular histoplasmosis, including H capsulatum infective endocarditis, is a rare manifestation of infection. It is an infrequent cause of native and prosthetic valve endocarditis, (6-12) endarteritis, infected aortic aneurysms, and endovascular graft infections. (13-15) Endovascular histoplasmosis has also been diagnosed by pathologic assessment and analysis of an embolic event. (16,17) Here, we report the clinical presentation as well as diagnostic and histopathologic findings of 5 cases of confirmed H capsulatum endovascular infections at the Cleveland Clinic (Cleveland, Ohio).

MATERIALS AND METHODS

Case definition: A patient was considered to have H capsulatum endocarditis if there was evidence of valvular vegetations with fungal forms consistent with H capsulatum noted on histopathologic specimen and/or positive cultures for H capsulatum from explanted tissue.

Case ascertainment: Case finding was carried out through (1) a review of International Classification of Diseases, 9th revision (ICD-9) codes; (2) positive H capsulatum cultures from any site; (3) positive serology results (titer of 1:32 or greater on yeast or mycelial complement fixation); (4) a review of all patients with pathology specimens positive for Hcapsulatum, taken from any site; and (5) a query of 21 infectious disease physicians in the department.

The study period involved patients seen at our facility between January 1993 and September 2010. A review of the electronic medical record for each patient was carried out and only those with endovascular involvement were included in the study. Data collected for each patient included demographics, comorbidities, description of endovascular involvement, serology, culture data, pathologic findings, treatment, clinical outcomes, and mortality (Table). Of note, one of these patients was previously reported as a part of a case series on fungal endocarditis. (18)

[FIGURE 1 OMITTED]

Case Reports

We selected 2 representative patients, whose histories are discussed below.

Patient 1.--A 67-year-old white woman from Ohio with a past medical history of rheumatic heart disease complicated by mitral stenosis and transient ischemic attacks received a porcine Carpentier-Edwards mitral valve replacement 13 years before presentation.

Approximately 6 months before presentation, she began experiencing night sweats and intermittent fevers. She was seen by a local physician who drew routine blood cultures and performed an echocardiogram, which revealed a thickened mitral valve without vegetations. Blood culture results were negative. She was treated empirically with vancomycin and gentamicin without improvement. Her exposure history was significant only for residence in a heavily wooded area.

The patient then developed pain and a mass in her right groin. She was found to have a femoral artery pseudoaneurysm and was referred to our facility. She underwent resection of a common femoral artery pseudoaneurysm with right common femoral artery to superficial femoral artery bypass. Intraoperative findings revealed a pseudoaneurysm that arose from the right common femoral artery and contained thrombus material surrounded by inflamed tissue. The superficial femoral artery adherent to the posterior wall of the pseudoaneurysm was occluded with a thrombus. Histopathology examination revealed rare fungal organisms consisting of yeast and hyphal elements within the organizing thrombus located in the superficial femoral artery. There was focal mild acute inflammation in the arterial wall but no evidence of vascular invasion. Fungal organisms were not seen in the pseudoaneurysm, which showed only old thrombus contained by chronically inflamed fibroadipose tissue. Shortly after surgery, the patient developed shortness of breath. A 1.3-cm mass attached to the posterior leaflet of the mitral valve was seen on transesophageal echocardiography. She underwent successful replacement of her mitral valve. Examination of the extracted bioprosthetic valve revealed devitalized porcine valve with rare mononuclear cells on the surface of the leaflets (Figure 1, A and B). The fibrin vegetations contained a small amount of mononuclear cells, rare neutrophils, and abundant yeast forms consistent with Histoplasma species. In addition, hyphal forms were noted within the vegetations. Intraoperative fungal cultures of the valve grew H capsulatum, which was confirmed with molecular sequencing. After initial treatment with amphotericin B, she was given oral itraconazole for lifelong suppressive therapy.

Patient 2.--A 31-year-old white man from Indiana with Marfan syndrome had valve-sparing aortic root and ascending aortic replacement with a woven Dacron graft, performed at our institution 11 years before presentation. The patient had recurrent fevers 4 months before presentation and was evaluated at an outside hospital and thought to have cholecystitis. He underwent a laparoscopic cholecystectomy and was given oral ciprofloxacin and metronidazole empirically. However, he remained persistently febrile. Exposure history was significant only for outdoor activities (camping, fishing, hiking) in rural areas of Indiana. He had routine blood cultures drawn, which yielded negative results, and underwent a transthoracic echocardiogram, which was unremarkable. He was referred to our facility for further evaluation.

Serology for H capsulatum, obtained for the evaluation of fever of unknown origin, revealed mycelial and yeast complement fixation titers of 1:512 with a positive M and H band on immunodiffusion. A transesophageal echocardiogram revealed a small mobile echodensity within the aortic graft. Cardiac magnetic resonance imaging revealed a 1.5-cm linear density within the ascending aortic graft, suggestive of vegetation versus thrombus. The patient underwent graft extraction and replacement with distal homograft implant. Pathologic findings showed a synthetic vascular graft with fibrotic neointima and luminal thrombus containing fungal yeast and hyphal forms (Figure 1, C through E). Intraoperative cultures grew H capsulatum, which was confirmed with DNA sequencing. The patient was treated with a course of amphotericin B and subsequently given oral itraconazole for lifelong suppressive therapy.

RESULTS

We identified 5 patients with H capsulatum endovascular infections during the study period. All cases were confirmed with pathologic analysis of specimens. In all patients, disease manifested as a prolonged febrile illness. The median time from symptom onset to diagnosis was 6 months (range, 3 to 12 months) with the median time from initial medical evaluation to diagnosis being 3.5 months (range, 1 to 8 months). The median age was 62 years; 4 of 5 patients were older than 55 years. All patients were white. Three patients were male. Four of 5 patients responded to combined medical and surgical treatment. One patient died shortly after diagnosis. All patients had involvement of prosthetic endovascular material. The median time from implant of material to infection was 4 years (range, 1 to 13 years).

The vegetations consisted of fibrin with large aggregates of yeasts and only mild chronic inflammatory cell infiltrates, predominantly macrophages. Of note, there was absence of acute inflammatory reaction to the infectious process in the bioprosthetic valves or synthetic vascular graft. Tissue necrosis was absent. A combination of yeast (Figure 2, A through D) and mycelial forms (Figure 1, E) was observed in 4 of 5 samples submitted for pathologic examination. Typical, small oval yeasts morphologically consistent with Histoplasma (Figure 2, A and C) were admixed with variably sized large round forms (Figure 2, B and D). The hyphal elements were segmented with short straight or branched forms (Figure 2, E). The fungal morphology, particularly the presence of large yeasts and hyphae, did not correlate with antifungal therapy before surgery.

Serologic results were positive for all patients; the median peak mycelial complement fixation titer was 1:1024. The median peak yeast complement fixation titer was 1:512. Immunodiffusion test result was positive for all 5 patients. Four of 5 patients had positive M and H bands, 1 patient had positive H band alone. Urinary antigen (Miravista Diagnostics, Indianapolis, Indiana) was positive for 3 of 4 patients. Embolic events were diagnosed in 3 of 5 patients, with brain emboli occurring in 2 patients and vascular emboli occurring in 2 patients, including 1 patient with coronary and renal artery embolization confirmed at autopsy (patient 4). All patients had specimen culture results confirmed with DNA gene probe for H capsulatum. Universal fungal polymerase chain reaction analysis performed on excised valve tissue from 2 patients confirmed the presence of H capsulatum DNA (University of Washington Medical Center, Seattle, Washington).

Initial antifungal treatment for all patients was amphotericin B. This course was followed by oral itraconazole for 3 of 4 survivors. The fourth survivor could not tolerate itraconazole and was treated with 4g of amphotericin B and close follow-up. The patient did not have a recurrence during his remaining years of life.

COMMENT

Histoplasma capsulatum most commonly causes disease of the respiratory tract. Other common manifestations of histoplasmosis include disseminated disease and mediastinal disease such as mediastinal fibrosis and granulomatous mediastinitis. Endovascular and cardiac infections are rare but well established. Histoplasma capsulatum should be considered in the differential diagnosis of bacterial culture-negative endovascular infections, particularly for those patients who currently reside or have resided in endemic areas, or who have high-risk hobbies (eg, spelunking) or occupations (eg, excavation).

As in other causes of endovascular infection involving prosthetic material, surgical excision should be pursued. In our series, all survivors underwent surgical resection. In contrast, in only 10 of 43 case reports reviewed by Bhatti et al (19) was surgical intervention mentioned. In the subset of 8 patients with implantable prosthetic material, survival was noted in 3 patients, all of whom underwent surgical extraction. (18,19)

In addition to decreasing the burden of infection and repairing mechanical lesions, surgery provides a sample for definitive diagnosis through fungal tissue stains, fungal culture, and nucleic acid amplification of tissue. These tissue samples obtained during surgery most frequently provided the evidence supporting the diagnosis in prior reports as well as in our series. (19)

As previously reported in endovascular H capsulatum infections, we noted that mycelial forms were often present on pathology slides of involved tissue. Histoplasma capsulatum is found in a mycelial form in soil at environmental temperatures and converts to a yeast form during mammalian infection. (20) Temperature is thought to be the primary determinant of phase in H capsulatum through pathways involving the transcriptional regulators Ryp1, Ryp2, and Ryp3. (21-23) In fact, transition from mycelial to yeast form is a major virulence determinant for H capsulatum. Studies have shown that H capsulatum can be grown as mycelial forms in vivo at 37[degrees]C, after certain chemical treatments. (24) Mycelial forms in human tissue were first noted in a necrotic lung specimen in 1940 by Arthur Humphrey. (25) The presence of mycelial forms may be related to an altered microenvironment producing unusual conditions of nutrition or oxygenation. (17,26) Mycelial forms associated with endovascular infections were originally noted in 1955. (27,28) It is not clear why mycelial forms are so common in endovascular infections, during which necrosis and lack of nutrients are less likely to play a role. Clinically, the presence of mycelial forms in vivo has the potential to cause diagnostic confusion and delay. Because hyphal forms are rarely encountered in tissue, a correlation between complement fixation titers and immunodiffusion result patterns has not been established in the literature. Noninvasive diagnostics such as fungal serology, fungal blood cultures, and urinary antigen testing were useful methods among our patients for suggesting endovascular histoplasmosis preoperatively. However, the high percentage of positive test results for our patients may be associated with the timing of these tests, that is, relatively late in the course of disease.

[FIGURE 2 OMITTED]

In summary, endovascular histoplasmosis is a rare but serious disorder and should be considered among patients with the appropriate exposure history who present with bacterial culture-negative endovascular infections and for patients with prosthetic cardiac valves or vascular grafts who present with fever of unknown origin. Serologic testing may provide a clue to diagnosis and shorten the delay in this uncommon diagnosis. Serology, urinary antigen, and fungal blood cultures should be obtained if endovascular Hcapsulatum infection is suspected, and these tests in combination may suggest a microbial diagnosis before surgical intervention. The pathologic features of Histoplasma endovascular infections are notable for bland-looking fibrinous vegetations with scant inflammatory cells and absent to minimal tissue inflammatory reaction. In contrast to other sites of infection, the presence of hyphae and variably sized large spherical forms of yeasts, in addition to the usual small oval yeasts, is commonly observed in endovascular Histoplasma infection.

References

(1.) Edwards PQ, Palmer CE. Nationwide histoplasmin sensitivity and histoplasmal infection. Public Health Rep. 1963; 78(3):241-260.

(2.) Chamany S, Mirza SA, Fleming JW, et al. A large histoplasmosis outbreak among high school students in Indiana, 2001. Pediatr Infect Dis J. 2004; 23(10): 909-914.

(3.) Huhn GD, Austin C, Carr M, et al. Two outbreaks of occupationally acquired histoplasmosis: more than workers at risk. Environ Health Perspect. 2005; 113(5):585-589.

(4.) Brodsky AL, Gregg MB, Loewenstein MS, Kaufman L, Mallison GF. Outbreak of histoplasmosis associated with the 1970 Earth Day activities. Am J Med. 1973; 54(3):333-342.

(5.) Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007; 20(1):115-132.

(6.) Wang Z, Duarte AG, Schnadig VJ. Fatal reactive hemophagocytosis related to disseminated histoplasmosis with endocarditis: an unusual case diagnosed at autopsy. South Med J. 2007; 100(2):208-211.

(7.) Wilmshurst PT, Venn GE, Eykyn SJ. Histoplasma endocarditis on a stenosed aortic valve presenting as dysphagia and weight loss. Br Heart J. 1993; 70(6):565-567.

(8.) Scapellato PG, Desse J, Negroni R. Acute disseminated histoplasmosis and endocarditis. Rev Inst Med Trop Sao Paulo. 1998; 40(1):19-22.

(9.) Bradsher RW, Wickre CG, Savage AM, Harston WE, Alford RH. Histoplasma capsulatum endocarditis cured by amphotericin B combined with surgery. Chest. 1980; 78(5):791-795.

(10.) Gaynes RP, Gardner P, Causey W. Prosthetic valve endocarditis caused by Histoplasma capsulatum. Arch Intern Med. 1981; 141(11):1533-1537.

(11.) Kanawaty DS, Stalker MJ, Munt PW. Nonsurgical treatment of Histoplasma endocarditis involving a bioprosthetic valve. Chest. 1991; 99(1):253-256.

(12.) Isotalo PA, Chan KL, Rubens F, Beanlands DS, Auclair F, Veinot JP. Prosthetic valve fungal endocarditis due to histoplasmosis. Can J Cardiol. 2001; 17(3):297-303.

(13.) Miller BM, Waterhouse G, Alford RH, Dean RH, Hawkins SS, Smith BM. Histoplasma infection of abdominal aortic aneurysms. Ann Surg. 1983; 197(1): 57-62.

(14.) Harris RL, Lawrie GM, Wheeler TM, et al. Successful management of Histoplasma capsulatum infection of an abdominal aortic aneurysm. J Vasc Surg. 1986; 3(4):649-651.

(15.) Matthay RA, Levin DC, Wicks AB, Ellis JH Jr. Disseminated histoplasmosis involving an aortofemoral prosthetic graft. JAMA. 1976; 235(14):1478-1479.

(16.) Berman SS, Kazlow GA, Fields BT Jr, Weinberg S. Disseminated histoplasmosis with embolic endovascular complications: a case report. J Vasc Surg. 1990; 12(5):577-580.

(17.) Hutton JP, Durham JB, Miller DP, Everett ED. Hyphal forms of Histoplasma capsulatum: a common manifestation of intravascular infections. Arch Pathol Lab Med. 1985; 109(4):330-332.

(18.) Melgar GR, Nasser RM, Gordon SM, Lytle BW, Keys TF, Longworth DL. Fungal prosthetic valve endocarditis in 16 patients: an 11-year experience in a tertiary care hospital. Medicine (Baltimore). 1997; 76(2):94-103.

(19.) Bhatti S, Vilenski L, Tight R, Smego RA Jr. Histoplasma endocarditis: clinical and mycologic features and outcomes. J Infect. 2005; 51(1):2-9.

(20.) Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore). 1981; 60(4):231-266.

(21.) Nguyen VQ, Sil A. Temperature-induced switch to the pathogenic yeast form of Histoplasma capsulatum requires Ryp1, a conserved transcriptional regulator. Proc Natl Acad Sci USA. 2008; 105(12):4880-4885.

(22.) Holbrook ED, Rappleye CA. Histoplasma capsulatum pathogenesis: making a lifestyle switch. Curr Opin Microbiol. 2008; 11(4):318-324.

(23.) Webster RH, Sil A. Conserved factors Ryp2 and Ryp3 control cell morphology and infectious spore formation in the fungal pathogen Histoplasma capsulatum. Proc Natl Acad Sci U S A. 2008; 105(38):14573-14578.

(24.) Medoff G, Sacco M, Maresca B, et al.Irreversible block of the mycelial-to-yeast phase transition of Histoplasma capsulatum. Science. 1986; 231(4737):476-479.

(25.) Humphrey AA. Reticuloendothelial cytomycosis (histoplasmosis of Darling). Arch Int Med. 1940; 65:902-918.

(26.) Maresca B, Medoff G, Schlessinger D, Kobayashi GS. Regulation of dimorphism in the pathogenic fungus Histoplasma capsulatum. Nature. 1977; 266(5601):447-448.

(27.) Binford CH. Histoplasmosis: tissue reactions and morphologic variations of the fungus. Am J Clin Pathol. 1955; 25(1):25-36.

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Christopher Ledtke, MD; Susan J. Rehm, MD; Thomas G. Fraser, MD; Nabin K. Shrestha, MD; Carmela D. Tan, MD; E. Rene Rodriguez, MD; J. Walton Tomford, MD; Anil Jain, MD; Bruce Lytle, MD; Douglas Johnston, MD; Joseph Sabik, MD;

Accepted for publication September 8, 2011.

From the Departments of Infectious Diseases (Drs Ledtke, Rehm, Fraser, Shrestha, Tomford, Gordon, and van Duin); Clinical Pathology (Dr Shrestha); Anatomic Pathology (Drs Tan and Rodriguez); Internal Medicine (Dr Jain); Thoracic and Cardiovascular Surgery (Drs Lytle, Johnston, and Sabik); the Quality and Patient Safety Institute (Dr Fraser); and the Division of Information Technology (Dr Jain), Cleveland Clinic, Cleveland, Ohio.

Dr van Duin is on the speaker's bureau for Astellas and serves on an advisory board for Pfizer. The other authors have no relevant financial interest in the products or companies described in this article.

Reprints: Christopher Ledtke, MD, Department of Infectious Diseases, Mail Code G21, Cleveland Clinic, 9500 Euclid Ave, Cleveland, Ohio 44195 (e-mail: ledtkec@ccf.org).
Characteristics of Patients With H capsulatum Endovascular Infections

Patient Age/ Duration of
No. y/Sex Comorbidities Symptoms Before
 Diagnosis, mo

1 67/F Rheumatic heart 6
 disease, anemia,
 TIA

2 31/M Marfan syndrome 4

3 56/M HTN, HLP, CRI 6

4 62/F Sarcoidosis, CAD, HLP 3

5 65/M CAD, CHF, Afib, CRI 12

Patient Time From Histoplasma
No. Type of Prosthetic Implant Blood Culture
 Material to Infection, Results
 y

1 Porcine valve in 13 Positive
 mitral position

2 Woven Dacron graft in 11 Negative
 ascending aorta

3 Bovine pericardial 2 Negative
 valve in aortic position,
 woven Dacron graft
 in ascending aorta

4 Bovine pericardial valve in 4 Positive
 aortic position

5 Bovine pericardial valve in 1 Positive
 aortic position

Patient Peak Mycelial Peak Yeast Peak Urinary
No. CF Titer CF Titer Antigen, ng/mL

1 1:1024 1:512 3.1

2 1:512 1:512 1.58

3 1:512 1:64 6.5

4 1:2048 1:512 2.46

5 1:2048 1:2048 Not assessed

Patient
No. Pathologic Findings Antifungal Treatment

1 Yeasts and hyphal Amphotericin B lipid
 forms on valve and complex, 8 g, now
 superficial femoral treated with
 artery thrombus lifelong
 itraconazole
 200 mg QD

2 Yeasts and hyphal Amphotericin B 1.9
 forms on aortic g, ongoing
 graft maintenance
 therapy with
 itraconazole
 400 mg BID
3 Yeasts and hyphal Amphotericin B 2 g,
 forms on aortic now treated with
 valve and graft lifelong
 itraconazole
 100 mg QD

4 Yeasts and hyphal Died while taking
 forms on aortic amphotericin B
 valve, septic lipid complex,
 emboli to RCA, 5 mg/kg/d
 LIMA graft to
 LAD, kidney, and
 brain

5 Yeast forms on Amphotericin B 2.4
 aortic valve g, did not
 tolerate
 itraconazole

Patient
No. Outcome

1 Alive at 5 months

2 Alive at 7 months

3 Alive at 10 years

4 Died before surgery

5 Recovered, died 8
 years later of
 unrelated causes

Abbreviations: Afib, atrial fibrillation; BID, twice daily;
CAD, coronary artery disease; CF, complement fixation; CHF,
congestive heart failure; CRI, chronic renal insufficiency;
HLP, hyperlipidemia; HTN, hypertension; LAD, left anterior
descending artery; LIMA, left internal mammary artery; QD,
every day; RCA, right coronary artery; TIA, transient ischemic
attack.
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Title Annotation:Original Article
Author:Ledtke, Christopher; Rehm, Susan J.; Fraser, Thomas G.; Shrestha, Nabin K.; Tan, Carmela D.; Rodrigu
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2012
Words:3269
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