Transplant-Associated Infection Surveillance Network Research Articles

PHAEOHYPHOMYCOTIC OSTEOMYELITIS AFTER BILATERAL LUNG TRANSPLANTATION

SESSION TITLE: Fellows Transplantation Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Phaeohyphomycoses are a heterogenous group of infections caused dematiaceous fungi, which are characterized by melanin pigmentation in the cell wall. While rare, these infections are being increasingly seen in both immunocompromised and immunocompetent individuals.1 Transplant patients are at a higher risk due to prolonged immunosuppression. We present a case of Bipolaris spp. osteomyelitis in a lung transplant recipient. CASE PRESENTATION: A 43 year-old female status post bilateral lung transplant for interstitial lung disease secondary to dermatomyositis on tacrolimus and prednisone, with a history of multiple surgical debridements of a chronic polymicrobial open chest wall wound infected with Vancomycin-resistant Enterococcus (VRE) and Enterobacter spp., presented with poor wound healing of the chest wound. She was taken to the operating room, and areas of devitalized tissue and purulence were debrided to create a single wound. Her empiric antibiotics were adjusted to daptomycin, and liposomal amphoptericin B upon identification of VRE and a mold. Final fungal cultures demonstrated Bipolaris, so voriconazole was substituted for amphotericin. After a fourteen day course of daptomycin, the patient was discharged with voriconazole and wound dressings with Iodasorb. Three weeks later, the patient was readmitted and started on broad spectrum antibiotics and continued on voriconazole after a CT Chest concerning for osteomyelitis was performed. She underwent surgical debridement by thoracic and plastic surgery of the chest wound and sternum. Bone specimens were noted to have invasive fungal elements in the bone consistent with osteomyelitis. Fontana-Masson staining was positive for melanin. Bacterial wound cultures grew VRE, Methicillin-sensitive Staphylococcus aureus, and Beta-Hemolytic Streptococci. She was discharged on oral linezolid and voriconazole for at least 6 weeks. DISCUSSION: Phaeohyphomycosis accounts for approximately for 2.6% of all fungal infections seen and are evenly distributed between stem cell and solid organ transplant patients.2 Bipolaris is an environmental mold associated with allergic fungal sinusitis with a higher prevalence in Southwest United States. Other less common presentations include cutaneous, subcutaneous skin infections, osteomyelitis and keratitis.1 Bipolaris in wound infections is rare, with cases reported only in cardiothoracic surgical patients, typically associated with delayed sternal closures. CONCLUSIONS: Bipolaris infection has not been reported in any other surgery except cardiac in literature. No standardized therapy exists, but in vitro sensitivity study show that itraconazole and voriconazole have excellent activity against Bipolaris.1 This case highlights the importance of considering phaeohyphomycotic infections in lung transplant recipients. Reference #1: Revankar S. G. (2015). Phaeohyphomycosis in Transplant Patients. Journal of fungi (Basel, Switzerland), 2(1), 2. https://doi.org/10.3390/jof2010002. Reference #2: McCarty, T. P., Baddley, J. W., Walsh, T. J., Alexander, B. D., Kontoyiannis, D. P., Perl, T. M., Walker, R., Patterson, T. F., Schuster, M. G., Lyon, G. M., Wingard, J. R., Andes, D. R., Park, B. J., Brandt, M. E., Pappas, P. G., & TRANSNET Investigators (2015). Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET). Medical mycology, 53(5), 440–446. https://doi.org/10.1093/mmy/myv018. DISCLOSURES: No relevant relationships by Sravya Brahmandam, source=Web Response No relevant relationships by Sruti Brahmandam, source=Web Response No relevant relationships by Dibson Gondim, source=Web Response No relevant relationships by ALLAN RAMIREZ, source=Web Response

The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

Invasive candidiasis (IC) is a common cause of mortality in solid organ transplant recipients (OTRs), but knowledge of epidemiology in this population is limited. The present analysis describes data from 15 US centers that prospectively identified IC from nearly 17000 OTRs. Analyses were undertaken to determine predictors of infection and mortality. A total of 639 cases of IC were identified. The most common species was Candida albicans (46.3%), followed by Candida glabrata (24.4%) and Candida parapsilosis (8.1%). In 68 cases >1 species was identified. The most common infection site was bloodstream (44%), followed by intra-abdominal (14%). The most frequently affected allograft groups were liver (41.1%) and kidney (35.3%). All-cause mortality at 90days was 26.5% for all species and was highest for Candida tropicalis (44%) and C.parapsilosis (35.2%). Non-white race and female gender were more commonly associated with non-albicans species. A high rate of breakthrough IC was seen in patients receiving antifungal prophylaxis (39%). Factors associated with mortality include organ dysfunction, lung transplant, and treatment with a polyene antifungal. The only modifiable factor identified was choice of antifungal drug class based upon infecting Candida species. These data highlight the common and distinct features of IC in OTRs.

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

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 23.1%; 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.

Epidemiology of Invasive Mold Infections in Lung Transplant Recipients

Invasive mold infections (IMIs) are a major source of morbidity and mortality among lung transplant recipients (LTRs), yet information regarding the epidemiology of IMI in this population is limited. From 2001 to 2006, multicenter prospective surveillance for IMIs among LTR was conducted by the Transplant-Associated Infection Surveillance Network. The epidemiology of IMI among all LTRs in the cohort is reported. Twelve percent (143/1173) of LTRs under surveillance at 15 US centers developed IMI infections. The 12-month cumulative incidence of IMIs was 5.5%; 3-month all-cause mortality was 21.7%. Aspergillus caused the majority (72.7%)of IMIs; non-Aspergillus infections (39, 27.3%) included Scedosporium (5, 3.5%), mucormycosis (3, 2.1%) and "unspecified" or "other" mold infections (31, 21.7%). Late-onset IMI was common: 52% occurred within 1 year posttransplant (median 11 months, range 0-162 months). IMIs are common late-onset complications with substantial mortality in LTRs. LTRs should be monitored for late-onset IMIs and prophylactic agents should be optimized based on likely pathogen.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant‐Associated Infection Surveillance Network (TRANSNET)

Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

Invasive Mold Infection in Kidney Transplant Recipients: Observation of Early-Onset Mucormycosis

From the Division of Infectious Diseases and Tropical Medicine (M.C.), Division of Nephrology (A.V.), Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Methee Chayakulkeeree and Attapong Vongwiwatana receive the Chalermphrakiat grant from the Faculty of Medicine Siriraj Hospital, Mahidol University. Address reprint requests to Attapong Vongwiwatana, MD, Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkoknoi, Bangkok, 10700, Thailand. E-mail: siavw@hotmail. com INVASIVE FUNGAL DISEASE (IFD) is a major complication in solid organ transplant (SOT) recipients, resulting in allograft damage, morbidity, and mortality [1]. The overall incidence of IFD during the first year posttransplantation is about 3% and it varies by type of organ transplantation [2]. Although IFD is rare after 2 years posttransplantation, it can occur many years after transplantation, especially in those receiving high-dose immunosuppressive agents for treatment of graft rejection [3]. Yeasts such as Candida and Cryptococcus and molds such as Aspergillus and Mucorales are the most important pathogens that cause IFD in SOT recipients [4]. According to the Transplant-Associated Infection Surveillance Network report, the most prevalent fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis [2]. Non-Aspergillus mold infection in SOT is relatively rare, but difficult to treat [5]. The mortality of IFD in SOT is reported approximately 40% for aspergillosis, 34% for candidiasis, and 27% for cryptococcosis [2]. IFD was reported at 1.3% among kidney transplant (KT) recipients, which was relatively uncommon compared with other types of organ transplantation [2]. Small bowel and lung transplantation are among the highest risks for fungal infection [2]. Fungal infection in organ transplantation usually occurs after 3 months posttransplantation, when the immunosuppressive agents take greatest effect [3]. However, different fungal pathogens exhibit different onsets of diseases, and geographical factors may affect the epidemiology and manifestations of IFD in such patients. We hypothesize that the prevalence and characteristics of invasive mold infections (IMI) in KT recipients in tropical countries may be different from those in Western countries.

Endemic Fungal Infections in Solid Organ Transplantation

Endemic Fungal Infections in Solid Organ Transplantation

Aspergillosis in Solid Organ Transplantation

Invasive aspergillosis (IA) occurs in 1–15% of the solid organ transplant (SOT) recipients. Mortality rate in transplant recipients with IA historically has ranged from 65% to 92% (1–4). However, currently reported mortality rate in IA among SOT recipients is 22% (5). An estimated 9.3– 16.9% of all deaths in transplant recipients in the first year have been considered attributable to IA (6). Although the outcomes have improved in the current era, IA remains a significant posttransplant complication in SOT recipients. The review herein discusses the epidemiologic characteristics, risk factors, diagnostic laboratory assays and the approach to antifungal prophylaxis and treatment of IA in SOT recipients.

Antifungal therapy and length of hospitalization in transplant patients with invasive aspergillosis

The impact of antifungal therapy on economic outcomes in patients with invasive aspergillosis (IA) needs further exploration. The purpose of this study was to describe antifungal therapy and factors associated with hospital length of stay (LOS) in transplant patients with IA. Patients were enrolled from March 2001 to October 2005 and IA cases identified through March 2006 from a sub-group of patients in the Transplant Associated Infection Surveillance Network (TRANSNET). Factors associated with hospital LOS were determined by logistic regression analysis. Of 361 patients, the mean age was 49 years, 60.7% were male, and 63% were hematopoietic stem cell transplantation (HSCT) recipients. Primary monotherapy was used in 233 (64.5%) patients, of which voriconazole (93/233, 39.9%) was most commonly used antifungal. Primary combination therapy was used in 128 (35.4%) of 361 patients, with voriconazole plus caspofungin (81/361, 22.4%) the most frequently employed. Mean duration of therapy was 115 days (HSCT 109.7; solid organ transplant [SOT] 125.3). Mean hospital LOS was 35.3 days (HSCT 38.7; SOT 29.7). Regression analysis identified disseminated IA, neutropenia, malnutrition and length of ICU stay as factors associated with increased hospital LOS. Initial voriconazole use was associated with decreased LOS. Further investigation on impact of antifungal therapy on economic outcomes is needed.

Invasive Non-AspergillusMold Infections in Transplant Recipients, United States, 2001–2006

Recent reports describe increasing incidence of non-Aspergillus mold infections in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. To investigate the epidemiology of infections with Mucorales, Fusarium spp., and Scedosporium spp. molds, we analyzed data from the Transplant-Associated Infection Surveillance Network, 23 transplant centers that conducted prospective surveillance for invasive fungal infections during 2001–2006. We identified 169 infections (105 Mucorales, 37 Fusarium spp., and 27 Scedosporium spp.) in 169 patients; 124 (73.4%) were in HCT recipients, and 45 (26.6%) were in SOT recipients. The crude 90-day mortality rate was 56.6%. The 12-month mucormycosis cumulative incidence was 0.29% for HCT and 0.07% for SOT. Mucormycosis incidence among HCT recipients varied widely, from 0.08% to 0.69%, with higher incidence in cohorts receiving transplants during 2003 and 2004. Non-Aspergillus mold infections continue to be associated with high mortality rates. The incidence of mucormycosis in HCT recipients increased substantially during the surveillance period.

In Vitro Echinocandin Susceptibility of Aspergillus Isolates from Patients Enrolled in the Transplant-Associated Infection Surveillance Network

We determined the echinocandin minimum effective concentration (MEC) values for caspofungin, micafungin, and anidulafungin against 288 Aspergillus isolates prospectively collected from transplant patients with proven or probable invasive aspergillosis between 2001 and 2006 as part of the Transplant-Associated Infection Surveillance Network (TRANSNET). We demonstrated that the vast majority of Aspergillus isolates had MEC values at or below the epidemiological cutoff values for caspofungin, micafungin, and anidulafungin, including those from patients who had received caspofungin.

Comparison of In Vitro Susceptibility Characteristics of Candida Species from Cases of Invasive Candidiasis in Solid Organ and Stem Cell Transplant Recipients: Transplant-Associated Infections Surveillance Network (TRANSNET), 2001 to 2006

Invasive fungal infections (IFI) are a major cause of morbidity and mortality among both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Candida is the most common cause of IFI in SOT recipients and the second most common cause of IFI in HSCT recipients. We determined susceptibilities to fluconazole, voriconazole, itraconazole, posaconazole, amphotericin B, and caspofungin for 383 invasive Candida sp. isolates from SOT and HSCT recipients enrolled in the Transplant-Associated Infection Surveillance Network and correlated these results to clinical data. Fluconazole resistance in C. albicans, C. tropicalis, and C. parapsilosis isolates was low (1%), but the high percentage of C. glabrata and C. krusei isolates within this group of patients increased the overall percentage of fluconazole resistance to 16%. Voriconazole resistance was 3% overall but was 8% among C. glabrata isolates. On multivariable analysis, among HSCT recipients fluconazole nonsusceptibility was independently associated with C. glabrata, non-Hodgkin's lymphoma, cytomegalovirus (CMV) antigenemia, diabetes active at the time of the IFI, and any prior amphotericin B use; among SOT recipients, fluconazole nonsusceptibility was independently associated with any fluconazole use in the 3 months prior to the IFI, C. glabrata, ganciclovir use in the 3 months prior to the IFI, diabetes acquired since the transplant, and gender.

Factors Associated with Mortality in Transplant Patients with Invasive Aspergillosis

Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA. Transplant patients from 23 US centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network. IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression. Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT patients (239 [57.5%] of 415) than in SOT patients (78 [34.4%] of 227; P<.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA, and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition, and central nervous system disease were poor prognostic indicators, whereas prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death. There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.

Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant‐Associated Infection Surveillance Network (TRANSNET)

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET)

Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET)

Patterns of Susceptibility of Aspergillus Isolates Recovered from Patients Enrolled in the Transplant-Associated Infection Surveillance Network

We analyzed antifungal susceptibilities of 274 clinical Aspergillus isolates from transplant recipients with proven or probable invasive aspergillosis collected as part of the Transplant-Associated Infection Surveillance Network (TRANSNET) and examined the relationship between MIC and mortality at 6 or 12 weeks. Antifungal susceptibility testing was performed by the Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth dilution method for amphotericin B (AMB), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), and ravuconazole (RAV). The isolate collection included 181 Aspergillus fumigatus, 28 Aspergillus niger, 27 Aspergillus flavus, 22 Aspergillus terreus, seven Aspergillus versicolor, five Aspergillus calidoustus, and two Aspergillus nidulans isolates and two isolates identified as Aspergillus spp. Triazole susceptibilities were < or = 4 microg/ml for most isolates (POS, 97.6%; ITR, 96.3%; VOR, 95.9%; RAV, 93.5%). The triazoles were not active against the five A. calidoustus isolates, for which MICs were > or = 4 microg/ml. AMB inhibited 93.3% of isolates at an MIC of < or = 1 microg/ml. The exception was A. terreus, for which 15 (68%) of 22 isolates had MICs of >1 microg/ml. One of 181 isolates of A. fumigatus showed resistance (MIC > or = 4 microg/ml) to two of three azoles tested. Although there appeared to be a correlation of higher VOR MICs with increased mortality at 6 weeks, the relationship was not statistically significant (R2 = 0.61; P = 0.065). Significant relationships of in vitro MIC to all-cause mortality at 6 and 12 weeks for VOR or AMB were not found.

Molecular Identification of Aspergillus Species Collected for the Transplant-Associated Infection Surveillance Network

A large aggregate collection of clinical isolates of aspergilli (n = 218) from transplant patients with proven or probable invasive aspergillosis was available from the Transplant-Associated Infection Surveillance Network, a 6-year prospective surveillance study. To determine the Aspergillus species distribution in this collection, isolates were subjected to comparative sequence analyses by use of the internal transcribed spacer and beta-tubulin regions. Aspergillus fumigatus was the predominant species recovered, followed by A. flavus and A. niger. Several newly described species were identified, including A. lentulus and A. calidoustus; both species had high in vitro MICs to multiple antifungal drugs. Aspergillus tubingensis, a member of the A. niger species complex, is described from clinical specimens; all A. tubingensis isolates had low in vitro MICs to antifungal drugs.

Comparison of the Use of Administrative Data and an Active System for Surveillance of Invasive Aspergillosis

Administrative data, such as International Classification of Diseases, Ninth Revision (ICD-9) codes, are readily available and are an attractive option for surveillance and quality assessment within a single institution or for interinstitutional comparisons. To understand the usefulness of administrative data for the surveillance of invasive aspergillosis, we compared information obtained from a system based on ICD-9 codes with information obtained from an active, prospective surveillance system, which used more extensive case-finding methods (Transplant Associated Infection Surveillance Network). Patients with suspected invasive aspergillosis were identified by aspergillosis-related ICD-9 codes assigned to hematopoietic stem cell transplant recipients and solid organ transplant recipients at a single hospital from April 1, 2001, through January 31, 2005. Suspected cases were classified as proven or probable invasive aspergillosis by medical record review using standard definitions. We calculated the sensitivity and positive predictive value (PPV) of identifying invasive aspergillosis by individual ICD-9 codes and by combinations of codes. The sensitivity of code 117.3 was modest (63% [95% confidence interval {CI}, 38%-84%]), as was the PPV (71% [95% CI, 44%-90%]); the sensitivity of code 117.9 was poor (32% [95% CI, 13%-57%]), as was the PPV (15% [95% CI, 6%-31%]). The sensitivity of codes 117.3 and 117.9 combined was 84% (95% CI, 60%-97%); the PPV of the combined codes was 30% (95% CI, 18%-44%). Overall, ICD-9 codes triggered a review of medical records for 64 medical patients, only 16 (25%) of whom had proven or probable invasive aspergillosis. A surveillance system that involved multiple ICD-9 codes was sufficiently sensitive to identify most cases of invasive aspergillosis; however, the poor PPV of ICD-9 codes means that this approach is not adequate as the sole tool used to classify cases. Screening ICD-9 codes to trigger a medical record review might be a useful method of surveillance for invasive aspergillosis and quality assessment, although more investigation is needed.