Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET)

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1 Medical Mycology Advance Access published April 23, 2015 Medical Mycology, 2015, 00, 1 7 doi: /mmy/myv018 Advance Access Publication Date: Original Article Original Article Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET) Todd P. McCarty 1,, John W. Baddley 1, Thomas J. Walsh 2, Barbara D. Alexander 3, Dimitrios P. Kontoyiannis 4,TrishM.Perl 5, Randall Walker 6, Thomas F. Patterson 7, Mindy G. Schuster 8, G. Marshall Lyon 9, John R. Wingard 10,DavidR.Andes 11, Benjamin J. Park 12,MaryE.Brandt 12, Peter G. Pappas 1 and TRANSNET Investigators 1 Department of Medicine, University of Alabama at Birmingham, Birmingham, USA, 2 Departments of Medicine, Pediatrics, and Microbiology and Immunology, New York-Presbyterian Hospital -Weill Cornell Medical Center, New York, USA, 3 Department of Medicine, Duke University School of Medicine, Durham, USA, 4 Department of Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA, 5 Departments of Medicine, Pathology, and Epidemiology, The Johns Hopkins Hospital, Baltimore, USA, 6 Department of Medicine, Mayo Clinic, Rochester, USA, 7 Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, USA, 8 Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, USA, 9 Department of Medicine, Emory University School of Medicine, Atlanta, USA, 10 Department of Medicine, University of Florida, Gainesville, USA, 11 Department of Medicine, University of Wisconsin, Madison, USA and 12 Centers for Disease Control and Prevention, Atlanta, USA *To whom correspondence should be addressed. Todd P. McCarty, Department of Medicine, University of Alabama at Birmingham, Birmingham, USA; Tel: ; tmccarty@uabmc.edu Received 12 December 2014; Revised 10 February 2015; Accepted 16 February 2015 Abstract Transplant recipients are at a high risk for developing invasive fungal infections. The agents of phaeohyphomycosis are environmental molds found worldwide, and they cause a broad spectrum of disease including skin and subcutaneous lesions, pneumonia, central nervous system disease, fungemia, and disseminated disease. Using data from the Transplant Associated Infection Surveillance Network (TRANSNET), we evaluated patients with proven and probable phaeohyphomycosis. Centers collected data on demographics, co-morbid conditions, clinical features, treatment, and three-month mortality. Fifty-six patients with phaeohyphomycosis were identified from 15 centers, comprising 26 stem cell transplant (SCT) and 30 solid organ transplant (SOT) recipients. Median time to diagnosis post-transplant was 358 days (SCT 100 days; SOT 685 days; P = <.001). The most frequent pathogen was Alternaria species (32%). Disseminated disease was found in 55.4%. Cutaneous infection was more common in SOT (53.3% vs C The Author Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please journals.permissions@oup.com 1

2 2 Medical Mycology, 2015, Vol. 00, No %; P =.021), while pulmonary disease was more common in SCT (57.7 vs. 26.7; P =.019). Voriconazole (44.6%) and amphotericin B preparations (37.5%) were the most common antifungal therapies. Overall mortality was 25% and was higher in SCT than in SOT (42% vs 10%; P = <.001). A wide variety of organisms encompass phaeohyphomycosis contributing to varying types of infection in transplant recipients. Site of infection, time to disease, and mortality varies significantly between SCT and SOT recipients. Lipid formulations of amphotericin B and voriconazole were the most common antifungals used to treat this disorder. Key words: phaeohyphomycosis, dematiaceous mold, Alternaria, Exserohilum. Introduction The term phaeohyphomycosis is used to describe an infection caused by a pigmented (dematiaceous) fungus. There are over 100 species of these fungi that have been associated with human disease. Most human disease is noninvasive (e.g., onychomycosis, superficial cutaneous infection, chronic allergic fungal sinusitis) and is associated with varying morbidity but little mortality. Rarely, phaeohyphomycosis can lead to invasive complications including skin and subcutaneous disease, pneumonia, central nervous system (CNS) disease, fungemia, and multi-organ disseminated disease. This group of organisms has gained notoriety since 2012 when a particular species of this group, Exserohilum rostratum, was found to be the etiologic agent of the large outbreak of fungal meningitis associated with contaminated methylprednisolone injections [1,2]. The published experience of phaeohyphomycosis dedicated to studying the infection in transplant recipients is limited. Most of the available literature is composed of case reports, small case series, and single center reviews. It is an uncommon infection usually limited to immunocompromised patients, which significantly limits the ability to study its epidemiology and implications in detail. Herein, we describe cases of phaeohyphomycosis that were identified prospectively as part of a large US observational study of transplant patients to better understand epidemiology, treatment, and outcomes. Materials and methods Patient cohort The Transplant Associated Infection Surveillance Network (TRANSNET) is a Centers for Disease Control and Prevention (CDC) and industry co-sponsored prospective surveillance network comprised of 23 US transplant centers that has been described previously [3,4]. Enrollment of stem cell transplant (SCT) and solid organ transplant (SOT) recipients in the cohort occurred between March 2001 and September 2005 and the surveillance period for cases was March 2001 through March A total of 16,200 SCT and 16,808 SOT were enrolled and followed prospectively for the development of invasive fungal infection, as defined by European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) 2008 criteria [5]. Clinical data and definitions A case of phaeohyphomycosis was defined as a culture positive for a dematiaceous mould or histopathological evidence of a dematiaceous fungus plus clinical findings consistent with infection. Isolates were identified at the participating institution using morphological methods, and the identity of available isolates was confirmed at the CDC Mycotic Diseases Branch Reference Laboratory. Abstracted patient data included demographics, co-morbid conditions, clinical features, fungal species, treatment, and mortality. Data on antifungal therapy were limited to antifungal drug and usage for prophylaxis, empiric use, or treatment. Neutropenia was defined as an absolute neutrophil count (ANC) <500/mm 3 within 30 days of diagnosis of infection. Cytomegalovirus (CMV) infection was defined as CMV detected in blood (antigen, polymerase chain reaction) or histopathologic evidence of CMV, in association with signs and symptoms consistent with infection. The following definitions of co-morbid conditions were applied at the time of diagnosis of phaeohyphomycosis: renal insufficiency as a creatinine 3.0 mg/dl or a creatinine clearance <30 ml/min; hepatic insufficiency as ascites, other clinical stigmata of liver disease, or abnormal laboratory values (prothrombin time, INR, liver enzyme tests); malnutrition as a serum albumin <2g/dl or 95% ideal body weight if albumin between 2.1 and 2.5g/dl. Disseminated phaeohyphomycosis was defined as involvement of more than one noncontiguous site of infection. Crude mortality was determined at 90 days post-diagnosis of phaeohyphomycosis.

3 McCarty et al. 3 Statistical analysis Descriptive statistics were calculated for demographic and clinical characteristics and for antifungal therapies. For analysis of the relationship of site of infection and transplant type, univariate analyses were performed using the two-group chi-square test, or Fisher exact test. Statistical tests were two-sided and performed using a 5% significance level (α = 0.05). All analyses were performed using SAS, version 9.4(SAS Institute, Cary, NC). Results Among 2,191 invasive fungal infections (IFIs) described in the TRANSNET cohort [3 4], 56 (2.6%) cases were categorized as phaeohyphomycosis. A summary of patient characteristics can be found in Table 1. Mean age of patients was 50.4 years, and 58% were male. There were a similar number of SCT (n = 26, 46.4%) and SOT (n = 30, 53.6%) recipients. Phaeohyphomycosis comprised 2.5% of all IFIs in SOT patients and 2.6% of all IFIs in SCT patients in the cohort. The median time to diagnosis for all patients was 358 days post-transplantation but significantly longer for SOT than SCT recipients (685 vs 100 days; P <.001). A wide range was evident in both groups, 1 3,058 days for SCT recipients and days for SOT recipients. Most cases occurred greater that one year after transplantation. Among the 26 SCT recipients, 24 (92.3%) occurred in patients who received allogeneic transplants. Among SOT recipients, 16 cases (53.3%) occurred in lung transplant recipients. Southern states comprised the majority of cases with 44 at a rate of 3.2 cases per 1,000 transplant recipients enrolled. Centers from the Midwest contributed eight cases (1.0 case per 1,000 transplant recipients), the Northeast three cases (1.5 per 1,000), and the West 1 case (0.7 per 1,000). Co-morbidities were common among transplant recipients with phaeohyphomycosis. Renal insufficiency, diabetes mellitus, and/or neutropenia were present in greater than 25% of patients. Graft versus host disease (GVHD) occurred in 65.4% of SCT patients. Respiratory tract symptoms comprised the vast majority of symptoms recorded (Table 1). Almost 25% of patients experienced cough, fewer had sinonasal congestion, sputum production, and/or dyspnea. Fever was the most common symptom with nearly a third of patients having a fever in the seven days preceding diagnosis. A computed tomography scan of the chest was the most common abnormal radiographic study, assisting in the diagnosis of 24 (42.9%) patients. Nodular and lobar findings were the most common abnormalities with 10 (41.7%) Table 1. Characteristics of 56 transplant patients with phaeohyphomycosis. Characteristic N = 56(%) Mean Age (+/ SD) 50.4 (12.6) Male Gender 32 (58.2) Median Time to Infection, days (range) 358 (1 3058) Race White 45 (86.5) Black 5 (9.6) Other 2 (3.9) Ethnicity Hispanic 6 (10.7) Non-Hispanic 50 (89.3) Transplant Type Stem Cell 26 (46.4) Autologous 2 (7.7) Allogeneic 24 (42.8) Matched related 17 (65.4) Matched unrelated 7 (26.9) Solid Organ 30 (53.6) Lung 16 (53.3) Kidney- 6 (20) Heart 3 (10) Pancreas 2 (6.7) Liver 2 (6.7) Kidney/Pancreas 1 (3.3) Comorbidities Graft vs. Host Disease 17/26 (65.4) Renal Insufficiency 18 (32.1) Diabetes Mellitus 17 (30.4) Neutropenia 15 (26.8) CMV Infection 13 (23.2) Malnutrition 8 (14.3) Hepatic Dysfunction 4 (7.1) Clinical Signs and Symptoms Fever 18 (32.1) Cough 13 (23.2) Sinonasal congestion 9 (16.1) Sputum production 8 (14.3) Dyspnea 8 (14.3) Hemoptysis 3 (5.4) Seizures 3 (5.4) Mental status change 2 (3.6) Headache 1 (1.8) Radiologic Study CT Chest 24 (42.9) Chest x-ray 4 (7.1) CT Head 7 (12.5) Magnetic Resonance Imaging Head 3 (5.4) Abbreviations: CMV = Cytomegalovirus, CT = Computed tomography, SD = standard deviation. and 15 (62.5%) patients exhibiting these findings, respectively. One patient had a crescent sign and none had a halo sign. These findings were supplemented by culture and histopathology to classify cases as proven and

4 4 Medical Mycology, 2015, Vol. 00, No. 00 Table 2. Site of infection by transplant type. Site Stem cell transplant Solid organ transplant Total P value n = 26 (%) n = 30 (%) n = 56 (%) Pulmonary 15 (57.7) 8 (26.7) 23 (41.1) Disseminated 12 (46.2) 19 (63.3) 31 (55.4) Cutaneous/SC 6 (23.1) 16 (53.3) 22 (39.3) Sinus 6 (23.1) 3 (10) 9 (16.1) Bloodstream 3 (11.5) 0 3 (5.36) CNS 1 (3.85) 0 1 (1.79) Abbreviations: CNS = central nervous system, SC = subcutaneous. probable. Skin (23 specimens) and respiratory tract, including sinuses (20 specimens), were the most frequent sites to provide positive cultures. Histopathology added to the diagnostic information in 15 patients with 13 (86.7%) of those being skin specimens. The most common sites of infection were pulmonary, cutaneous, and invasive sinus infection (Table 2). Disseminated disease was present in 55% of patients. Several differences were noted in frequency of site involvement among transplant types: pulmonary disease was significantly more common in SCT (57.7% vs. 26.7%; p = 0.019), while cutaneous disease was more common in SOT (53.3% vs. 23.1%; p = 0.021) patients. Bloodstream and central nervous system infections were uncommon and were only seen in SCT patients. Overall mortality 90-days posttransplant was significantly greater in SCT patients than in SOT patients (42% vs. 10%; p = 0.005). Of the 14 deaths, ten had pulmonary infection and five had disseminated disease. The only patient with CNS infection died, while one of the three (33%) with positive blood cultures died. Of 22 patients with cutaneous infection, only two died. Fourteen different dematiaceous genera were identified; many were not identified to the species level (Table 3). Alternaria was the most frequent genus (32%), followed by Exophiala (10.7%). Three cases of Exserohilum infection were identified. Of the 23 pulmonary cases, Alternaria (six, 26.1%) and Scopulariopsis (five, 21.7%) were the most common genera. Approximately 30% of isolates were identified to the species level. Of the 22 cutaneous cases, Alternaria (nine, 40.9%) and Exophiala (six, 27.3%) were the most common. Three positive blood cultures identified Cladophialophora and Phialemonium, while the third isolate was unable to be identified to the genus level. The only CNS isolate was Chaetomium. Alternaria was associated with disseminated disease in ten (56%) of 18 cases. All six isolates of Exophiala as well as four (80%) Cladophialophora, and three (75%) Phialemonium isolates were classified as disseminated disease. Six (33.3%) Table 3. Organisms causing phaeohyphomycosis. Organism Genus Number (%) Number of deaths (%) n = 56 Alternaria 18 (32.1) 6 (33.3) Exophiala 6 (10.7) 0 Cladophialophora 5 (8.9) 1 (20) Scopulariopsis 5 (8.9) 2 (40) Curvularia 4 (7.1) 1 (25) Phialemonium 4 (7.1) 1 (25) Exserohilum 3 (5.4) 1 (33.3) Sterile Black Mold 3 (5.4) 0 Microascus 2 (3.6) 0 Bipolaris 1 (1.8) 1 (100) Chaetomium 1 (1.8) 1 (100) Cladosporium 1 (1.8) 0 Ochroconis 1 (1.8) 0 Phaeoacremonium 1 (1.8) 0 Rhinocladiella 1 (1.8) 0 Alternaria cases and two (40%) Scopulariopsis cases died, while one (25%) Curvularia case and one (25%) Phialemonium case died. Treatment details are summarized in Table 4. Voriconazole was used most frequently for treatment of phaeohyphomycosis and was administered to 44% of patients (Table 4). Combination therapy was infrequent with 15 (27%) patients receiving two or more antifungal agents simultaneously. The most frequent combination, used in four patients, was triple therapy with lipid formulation of amphotericin B (LFAmB), voriconazole, and an echinocandin. Discussion We describe the epidemiology and clinical spectrum of phaeohyphomycosis across a large number of transplant centers throughout the United States over a 5-year interval. Although phaeohyphomycosis is a rare fungal infection, trends toward an increasing incidence have been noted together with a growing population of at-risk patients [6].

5 McCarty et al. 5 Table 4. Antifungal therapy. Antifungal agent N = 56 (%) Any azole 34 (60.7) Voriconazole 25(44.6) Itraconazole 9 (16.1) Posaconazole 1 (1.8) Any amphotericin B preparation 21 (37.5) LFAmB 20 (35.7) Inhaled amphotericin B 2 (3.6) Any echinocandin 9 (16.0) Caspofungin 7 (12.5) Micafungin 2 (3.6) Flucytosine 1 (1.8) Combination Therapy 15 (26.8) LFAmB, Voriconazole, Echinocandin 4 (26.7) LFAmB, Voriconazole 3 (20.0) Voriconazole, Echinocandin 3 (20.0) LFAmB, Echinocandin 2 (13.3) LFAmB, Itraconazole 2 (13.3) Voriconazole, Flucytosine 1 (6.7) Note: Data collection regarding anti-fungal therapy was limited to antifungal drug and start date, no stop dates were recorded. Abbreviations: LFAmB = lipid formulation of amphotericin B. A review from Schieffelin and colleagues of cases in solid organ transplant recipients at the Oschner Clinic Foundation identified 27 cases among 3,441 patients over a 22-year period for an overall incidence of 0.7% [7]. Disseminated disease was a rare complication with 89% of cases having infection restricted to the skin. A review of 101 patients with CNS phaeohyphomycosis described brain abscess as the most frequent presentation [8]. In this series, approximately half of patients had no known immunodeficiency, and the infections were associated with a very high mortality (73%). Among the patients with a compromised immune system, only 18 were transplant recipients. Another review of 72 cases of disseminated disease observed immune dysfunction in 76% of these patients, which included 13 (18%) transplant recipients [9]. It is difficult to accurately determine the incidence of phaeohyphomycosis in the SOT and SCT populations. Because of the rarity of the disease, previous studies are limited to case reports and retrospective studies. In our cohort, with a similar number of SOT and SCT patients being followed prospectively, the number of cases suggests that the overall incidence in these groups is very similar. There were too few data collected on uninfected patients in the cohort to adequately assess individual risk factors for developing phaeohyphomycosis. The fourteen genera identified in our series represent the large number of organisms responsible for the disease and is consistent with other series and reviews that involve a relatively large number of cases. In our series, Alternaria was the most common genus while Exophiala was the only other genus to account for more than 10% of cases. Ben- Ami and colleagues described ten genera from 39 cases in SCT recipients with Alternaria and Curvularia comprising almost half of all isolates [6]. Schieffelin and colleagues also identified ten genera from their 27 cases in SOT recipients with Exophiala constituting roughly half of the identified isolates [7]. The review of CNS phaeohyphomycosis consisted of 24 different species, with Cladophialophora bantiana contributing almost 50% of all cases [8]. Ben- Ami identified 27 species, most commonly Bipolaris and Wangiella (Exophiala), among his review of disseminated phaeohyphomycosis [9]. Alternaria is most often associated with subcutaneous disease, and is supported by a review of 210 cases of Alternaria infection reported up to 2007 and which consists only of oculomycosis, rhinosinusitis, onychomycosis, and cutaneous infection [10]. This differs significantly from our data which identify Alternaria as the etiologic agent of pulmonary and disseminated disease. Given the rarity of the disease and the difficulty of effective treatment, understanding the time to development of disease is an important consideration in earlier diagnosis and in limiting mortality and morbidity. Our study noted a significant difference in the onset of disease when comparing SCT and SOT recipients. SCT recipients generally had a median onset of disease within 4 months while the median onset of disease for SOT recipients was over 18 months. The relatively early onset of disease in SCT recipients differs from previously published data from Ben Ami and colleagues who reported a median onset of disease at 388 days from transplantation, with a range of 4 1,863 days [6]. It is difficult to determine whether this difference is meaningful given the small number of patients in both groups. One potential explanation for the difference in time to diagnosis is the prospective nature of our study, which allowed for active surveillance to potentially decrease the time to diagnosis. Pulmonary, skin, and sinus disease were the most common sites of infection. The distribution of site of infection differed by transplant type. SCT recipients had a higher rate of pulmonary infection, while SOT recipients had a higher rate of cutaneous disease. Disseminated disease was commonly observed in both groups. Reported cases in the literature have shown a propensity for disease limited to the skin in solid organ transplants. Schieffelin and colleagues demonstrated an overwhelming majority of their solid organ transplant patients developed disease limited to the skin, comprising 24 (88%) of 27 cases in a 21-year period [7]. Ogawa and colleagues prospectively followed 17

6 6 Medical Mycology, 2015, Vol. 00, No. 00 renal transplant recipients with phaeohyphomycosis, all of whom had subcutaneous disease [11]. A retrospective review of 18 cases in Brazil included seven cases occurring in SOT recipients, of which six had subcutaneous disease [12]. Our study presents a larger number of transplant patients with a wider variety of sites of infection, particularly pneumonia and disseminated disease, compared to these previous case series. There are no comparative studies of antifungal therapy in phaeohyphomycosis; however, reports of successful treatment with a variety of agents have been published. An in vitro susceptibility study of voriconazole, itraconazole, and amphotericin B demonstrated fairly consistent susceptibility to all three agents against the agents of phaeohyphomycosis and ascomycetous fungi with the noted exception of Scopulariopsis [13]. An evaluation of 66 clinical isolates of Exophiala dermatitidis demonstrated good in vitro activity of posaconazole, itraconazole, voriconazole, and amphotericin B; a separate study of 42 strains of Cladophialophora from CNS disease demonstrated that posaconazole and itraconazole had better activity compared to voriconazole and the experimental triazole isavuconazole [14,15]. Current treatment recommendations in SOT patients from the American Society of Transplantation Infectious Diseases Community of Practice regarding phaeohyphomycosis identify itraconazole, voriconazole, and posaconazole as first-line therapy while also recommending that antifungal susceptibility data be obtained [16]. The European fungal Infection Study Group of the European Society of Clinical Microbiology and Infectious Diseases released treatment guidelines for phaeohyphomycosis in 2014 [17]. Their recommendations vary depending on site of disease and whether the host is immunocompromised, however generally find amphotericin B, posaconazole, and voriconazole to be first-line agents. Interestingly they do recommend against amphotericin B in the setting of cerebral abscess due to concern for excess failure rates. Our study noted voriconazole and amphotericin B were the most commonly used antifungal agents. Echinocandins and flucytosine were used very infrequently. Antifungal usage in our study is consistent with the published experience prior to and during the study period, with voriconazole and itraconazole being the favored triazoles for mold infections at that time. Both agents have been used successfully in published reports from similar patients [11,18,19]. Moreover, voriconazole is the predominant antifungal agent used in the recent Exserohilum outbreak [20]. Posaconazole was not approved for oral use until 2006, and thus its use was limited during this observational study. Since the study period, reports of success with posaconazole in transplant patients have also been published [21,22]. There are several limitations to this study. First, the number of cases is likely underestimated due to the restriction to include only proven or probable cases by EORTC/MSG criteria [5]. Additionally, the primary goal of the study was to collect data on incidence, burden of disease, and impact on mortality. Given these limitations, an exhaustive analysis of risk factors, details pertaining to antifungal therapy, and other interventions such as surgery, and outcome relating to the fungal infection is problematic. Finally, it is possible that eligible cases were overlooked, but our review of data integrity demonstrated few issues with case finding among the 23 sites [3,4]. In summary, this large observational study of phaeohyphomycosis in transplant patients identified several important distinctions between SOT and SCT patients. The prospective, multicenter nature of the study with a focus on transplant recipients likely makes our observations more representative of the actual case type and frequency experienced in the United States. The increasing incidence of mold infections, particularly in transplant recipients, will continue to be a challenge. Surveillance studies that involve large patient databases will likely provide more meaningful information relating to risk factors for both the development of disease and the development of significant morbidity and mortality associated with disseminated disease. Funding Funding was provided by the Centers for Disease Control and Prevention (Grant 5U01CI ) and grants from Merck & Co., Inc.; Astellas US, Inc.; Pfizer, Inc.; Enzon Pharmaceuticals, Inc.; and Vicuron Pharmaceuticals. Acknowledgments This work was presented in part at the 50th Annual Meeting of the Infectious Diseases Society of America, October 18, 2012; San Diego, CA. The findings and conclusions of this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper. References 1. Pettit AC, Kropski JA, Castilho JL et al. The index case for the fungal meningitis outbreak in the United States. NEnglJMed 2012; 367(22):

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