American Journal of Transplantation 2014; 14: 1328–1333 Wiley Periodicals Inc.
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Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12691
Epidemiology of Invasive Mold Infections in Lung Transplant Recipients C. T. Doligalski1, K. Benedict2, A. A. Cleveland2, B. Park2, G. Derado3, P. G. Pappas4, J. W. Baddley4, D. W. Zaas5, M. T. Harris6 and B. D. Alexander5,7,* 1
Department of Pharmacy, Tampa General Hospital, Tampa, FL 2 Mycotic Diseases Branch, US Centers for Disease Control and Prevention, Atlanta, GA 3 Division of Foodborne, Waterborne, and Environmental Diseases, US Centers for Disease Control and Prevention, Atlanta, GA 4 Department of Medicine, University of Alabama, Birmingham, AL 5 Department of Medicine, Duke University Hospital, Durham, NC 6 Department of Pharmacy, Duke University Hospital, Durham, NC 7 Department of Pathology, Duke University Hospital, Durham, NC Corresponding author: Barbara D. Alexander, [email protected] 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. Keywords: Epidemiology, infection, lung transplant, mold
sis; IFI, invasive fungal infection; IMI, invasive mold infection; LTR, lung transplant recipient; TRANSNET, Transplant-Associated Infection Surveillance Network Received 26 July 2013, revised 21 January 2014 and accepted for publication 29 January 2014
Background Lung transplantation is a life-saving intervention for patients with end-stage lung disease. In the United States in 2011, 1849 lung and heart/lung transplant procedures were performed (1). Despite important advances in surgical technique, immunosuppressive regimens and the development of novel antifungal agents in recent years, lung transplant recipients (LTRs) remain at substantial risk for development of invasive fungal infections (IFIs) (2). However, few data are available on the overall burden of IFIs in this population. Historical studies have been primarily limited to small retrospective investigations (2–5) from which conflicting results have been reported (6,7) and limited conclusions can be drawn. To better understand the burden of IFIs and their associated outcomes among transplant recipients, the Centers for Disease Control and Prevention and partners formed the Transplant-Associated Infection Surveillance Network (TRANSNET), a multicenter consortium designed to perform prospective surveillance for IFIs among selected major transplant centers in the United States. TRANSNET provides the most comprehensive epidemiologic investigation of IFIs in the solid organ transplant population to date (8). Per overall TRANSNET analysis, the 12-month cumulative incidence (CI) of invasive mycoses in lung and heart– LTRs was 8.6% and invasive mold infections (IMIs) accounted for 70% of all IFIs in this transplant population. This was in contrast to the heart, kidney and liver solid organ transplant populations for which 35%, 21% and 18% of all IFIs, respectively, were caused by molds (8). Given the importance of IMIs in the lung transplant population, we used the TRANSNET prospective data to further describe the epidemiology of IMIs in LTRs.
Methods Study design
Abbreviations: CI, cumulative incidence; EORTC/MSG, European Organization for Research and Treatment of Cancer/Mycoses Study Group; IA, invasive aspergillo1328
The study was conducted in accordance with US Good Clinical Practice regulations and guidelines; human subject approval or waiver was obtained at each institution from which data were reported to TRANSNET.
Invasive Mold in Lung Transplant Surveillance was conducted prospectively among 15 solid organ transplant centers in the United States from March 2001 to March 2006 (8). A standardized case report form was used to collect data on all cases that developed an IFI during the surveillance period, regardless of when the transplant occurred. Data collected on cases included demographic information, transplant date and type, method of diagnosis, comorbid conditions and co-infections, immunosuppressive and antifungal use and 3-month follow-up status. An IMI was defined as proven or probable by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/ MSG) criteria (9). Demographic data, transplant information and limited followup data were also collected on all patients who underwent transplantation at study sites during the surveillance period (incidence cohort). Because lung transplant patients are generally considered at higher risk for IMIs than other organ transplant recipients (8), any combination of solid organ transplants that included lung were included in this analysis (e.g. a patient who was a recipient of both kidney and lung allografts). For patients who developed more than one IMI, only the first IMI was used for incidence calculations.
Statistics All analyses were conducted using SAS version 9.3 (SAS Institute, Inc., Cary, NC). Twelve-month CI of first IMI for lung transplant patients was estimated accounting for the competing risks of death, relapse and re-transplantation; CI estimates were calculated using the ‘‘cmprsk’’ package, v. 2-2-2, in R (v. 2-14-1). Bivariate statistics were calculated using Student’s t-test, chisquared or Fisher’s exact tests, as appropriate. p-Values < 0.05 were considered statistically significant.
Results During the 5-year surveillance period, we identified 1173 LTRs under surveillance at 11 of 15 participating transplant centers and 143 (12.2%) developed IMIs. Most patients (107, 74.8%) developed one IMI; 28 (19.6%) developed two IMIs, 5 (3.5%) developed three IMIs and 3 (2.1%) developed four or more. Fifty-three (37.1%) IMIs were classified as ‘‘proven’’ according to EORTC/MSG criteria. The most common pathogen identified was Aspergillus (104, 72.7%); non-Aspergillus infections (39; 27.3%) included: Scedosporium (5, 3.5%), mucormycosis (3, 2.1%) and ‘‘unspecified’’ or ‘‘other’’ mold infections (31, 21.7%; Figure 1). Aspergillus infections were most commonly due to A. fumigatus (n ¼ 54), followed by A. flavus (n ¼ 10), A. niger (n ¼ 9), A. terreus (n ¼ 4), A. versicolor (n ¼ 1), unknown Aspergillus species (n ¼ 8) and multiple unidentified Aspergillus species (n ¼ 18). The 12-month CI of invasive aspergillosis (IA) and non-IA infections was 4.13% and 1.35%, respectively (Figure 2). Median age at time of IMI diagnosis was 55 years; most patients were White (125, 87.4%) and first-time transplant recipients (134, 93.7%). Chronic obstructive pulmonary disease was the most common indication for transplantation (59, 41.3%), followed by pulmonary fibrosis (25, 17.5%) and cystic fibrosis (21, 14.7%). The majority of patients (117, 81.8%) had IMI limited to the pulmonary system; disseminated infection (8, 5.6%) and skin (5, 3.5%), combined pulmonary/sinus (3, 2.1%) and sinus (2, 1.4%) involvement occurred less frequently. Fungemia and bone involvement were rare, with one case of each American Journal of Transplantation 2014; 14: 1328–1333
Figure 1: Infecting mold pathogens in 143 episodes of invasive mold infections occurring in lung transplant recipients. Four Paecilomyces; two each of Acremonium, Penicillium and Phialemonium; one each of Alternaria, Chrysosporium, Cladosporium, Exophiala, Microascus, Ochroconis, Paraphaeosphaeria, Phaeoacremonium, Rhinocladiella, Scopulariopsis, Trichoderma, unidentified basidiomycete and unidentified black mold.
reported. Dyspnea (84, 58.7%), cough (75, 52.4%) and increased sputum production (55, 38.5%) were the most common respiratory symptoms within the first 7 days of IMI diagnosis; less than one-third of patients presented with fever (44, 30.8%). Extrapulmonary symptoms were less common, with less than 5% of IMI-infected patients experiencing central nervous system, sino-nasal or cutaneous symptoms. However, there were significant differences in site of involvement and presentation between IA and non-IA mold infections. Compared with IA infections (Table 1), non-IA mold infections occurred more frequently in men (65.8% vs. 44.7%, p ¼ 0.036) and presented more commonly as a
Figure 2: Twelve-month cumulative incidence by type of first invasive mold infection (top line, invasive aspergillosis; bottom line, non-Aspergillosis invasive mold infection).
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cutaneous infection (14.3% vs. 0%, p ¼ 0.001) while IA was more likely to be limited to the pulmonary system (93.1% vs. 62.9% p < 0.001). Patients with IA were more likely to have dyspnea (65.4% vs. 41%, p ¼ 0.008) and cough (57.7% vs. 38.5%, p ¼ 0.04) while non-IA trended to have more papular or skin nodules (15.4% vs. 0%, p < 0.001). The 3-month mortality for all IMI patients was 21.7%; IMI was noted to be a contributing cause of death in 52% of
cases. There was no significant difference in mortality among the IA group compared with the non-IA group (22% vs. 21%, p ¼ 0.84). IMIs occurred a median of 11 months posttransplant (range: 0–162 months; Figure 3). Early IMI (90 days) accounted for 25% of IMIs; 65% of IMIs occurred within 2 years of transplantation. Median time to IA was slightly less than non-IA IMI (10.5 months vs. 16 months,
Table 1: Characteristics of TRANSNET lung transplant patients who developed invasive mold infection Characteristics, n (%) Age in years, median (range) Male sex Race White Black/African-American Number of months posttransplant to IMI diagnosis, median (range) Underlying disease prompting transplant COPD/emphysema Cystic fibrosis Pulmonary fibrosis Sarcoidosis Other2 Prior transplant Combination transplant3 Anatomical site of IMI involvement Pulmonary only Sinus only Sinus and pulmonary Disseminated Skin Blood only Bone Symptoms present within 7 days of IMI diagnosis Dyspnea Cough Increased sputum production Fever Chest pain Hemoptysis Sino-nasal congestion/pain Papular or nodular skin lesions Central nervous system signs/symptoms Three-month mortality IMI listed as contributing cause of death Assessed at the time of IMI diagnosis Renal insufficiency Diabetes Neutropenia Assessed within 90 days prior to IMI Organ rejection Prophylactic antifungal therapy Amphotericin B, inhaled Fluconazole Itraconazole, oral Itraconazole, intravenous Voriconazole Ketoconazole Empiric antifungal therapy
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IA (n ¼ 104) 55 (20–70) 46 (44.7) 95 (95.0) 5 (5.0) 10.5 (0–162)
Non-IA1 (n ¼ 39) 54 (18–68) 25 (65.8)
p-Value 0.464 0.036 0.231
30 (88.2) 4 (11.8) 16 (0–83)
0.205
41 17 19 4 23 7 3
(39.4) (16.4) (18.3) (3.8) (22.3) (6.7) (2.8)
18 4 6 0 11 2 2
(46.2) (10.3) (15.4) (0) (28.9) (5.1) (5.1)
0.467 0.360 0.686 0.575 0.446 1.000 0.614
95 0 2 4 0 0 1
(93.1) (0) (1.9) (3.9) (0) (0) (1)
22 2 1 4 5 1 0
(62.9) (5.7) (2.9) (11.4) (14.3) (2.9) (0)
90 days posttransplant) with certain non-IA mold infections occurring very late (>1 year) in the posttransplant course. One possible explanation for this shifting epidemiology may be the routine early use of mold-active prophylaxis in LTRs and development of infection after prophylaxis is stopped. The 2004 American Society of Transplantation (AST) guidelines recommended continuing prophylaxis after lung transplantation at least until bronchial anastomosis remodeling is complete, which takes 4–8 months (14). A 2006 survey of 43 1332
international lung transplant centers found that 69% used antifungal prophylaxis during the immediate posttransplant period as the anastomosis was healing, most commonly an aerosolized formulation of amphotericin B alone or in combination with itraconazole (15). While the advent of newer triazole antifungals has altered some center’s prophylaxis strategy, more recent data demonstrate a continued heavy reliance on itraconazole and aerosolized amphotericin B and significant discontinuation rates of newer triazoles due to toxicity (16). Thus, use of mold-active prophylaxis during the early posttransplant period may be influencing the timing of IMIs, resulting in late-onset disease when prophylaxis is no longer routinely used. Alternatively, the shift to later IMI may also be related to increased exposures, as patients resume normal activities of living following the transplant procedure. Consistent with the 2009 AST guidelines (17), prevention strategies should give consideration to the known epidemiology of IMIs in this population, including the infecting pathogens, the mode of transmission/initial site of infection and the usual timing of IMIs following lung transplantation. This approach allows prophylactic therapy to be targeted during windows of highest risk. The majority of experts agree that the historical risk for IFI is substantially high enough during the immediate postlung transplant period to warrant universal antifungal prophylaxis until the anastomosis is healed (18). In addition, based on our data, expert opinion holds that upon completion of initial prophylaxis, patients and caregivers should be particularly vigilant in monitoring patients for late-onset IMIs and avoiding environmental exposures that may lead to inoculation with these pathogens (19). Finally, prophylactic agents should be individualized based on the type of lung transplant performed (e.g. use of systemic rather than aerosolized agents in single LTRs) and therapeutic drug monitoring considered to ensure adequate absorption of orally administered triazoles (20). In summary, IMIs, which tend to appear in the late and very late postlung transplant period, are associated with high mortality. Aspergillus remains the most common mold pathogen; however, non-IA molds are also an important cause of IMIs. Appreciation of the epidemiology of IMIs and assessment of each patient’s individual risks should be used to refine prevention strategies in the lung transplant population.
Acknowledgments This work was supported in part by the Centers for Disease Control (grant no. 5U01C1000286-05) and NIH NIAID K24 AI072522 (BDA).
Disclosure The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of American Journal of Transplantation 2014; 14: 1328–1333
Invasive Mold in Lung Transplant
Transplantation. DWZ discloses affiliation with Pfizer, APT Pharmaceuticals and Merck. BDA discloses research grants from Astellas, Pfizer and Charles River Laboratories, as well as acting as advisor for Bristol-Myers Squibb, bioMerieux and Astellas. All other authors declare no conflicts of interest.
References 1. 2011 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2011. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI. 2. Grossi P, Farina C, Fiocchi R, Dalla Gasperina D. Prevalence and outcome of invasive fungal infections in 1963 thoracic organ transplant recipients: A multicenter retrospective study. Italian Study Group of Fungal Infections in Thoracic Organ Transplant Recipients. Transplantation 2000; 70: 112–116. 3. Iversen M, Burton CM, Vand S, et al. Aspergillus infection in lung transplant patients: Incidence and prognosis. Eur J Clin Microbiol Infect Dis 2007; 26: 879–886. 4. Pugliese F, Ruberto F, Cappannoli A, et al. Incidence of fungal infections in a solid organ recipients dedicated intensive care unit. Transplant Proc 2007; 39: 2005–2007. 5. Radack KP, Alexander BD. Prophylaxis of invasive mycoses in solid organ transplantation. Curr Infect Dis Rep 2009; 11: 427–434. 6. Gavalda J, Len O, San Juan R, et al. Risk factors for invasive aspergillosis in solid-organ transplant recipients: A case control study. Clin Infect Dis 2005; 41: 52–59. 7. Sole´ A, Morant P, Salavert M, Pema´n J, Morales P, Valencia Lung Transplant Group. Aspergillus infections in lung transplant recipients: Risk factors and outcome. Clin Microbiol Infect 2005; 11: 359–365. 8. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: Results of the
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Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010; 50: 1101–1111. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1812–1821. Arthurs SK, Eid AJ, Deziel PJ, et al. The impact of invasive fungal diseases on survival after lung transplantation. Clin Transplant 2010; 24: 341–348. Neofytos D, Fishman JA, Horn D, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis 2010; 12: 220–229. Baddley JW, Andes DR, Marr KA, et al. Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis 2010; 50: 1559–1567. Blot SI, Taccone FS, Van den Abeele AM, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012; 186: 56–64. AST Infectious Disease Community of Practice. Fungal infections. Am J Transplant 2004; 4 (Suppl 10): 110–134. Husain S, Zaldonis D, Kusne S, Kwak EJ, Paterson DL, McCurry KR. Variation in antifungal prophylaxis strategies in lung transplantation. Transpl Infect Dis 2006; 8: 213–218. Neoh CF, Snell GI, Kotsimbos T, et al. Antifungal prophylaxis in lung transplantation—A world-wide survey. Am J Transplant 2011; 11: 361–366. Singh N, Husain S, AST Infectious Diseases Community of Practice. Invasive aspergillosis in solid organ transplant recipients. Am J Transplant 2009; 9: S180–S191. Gordon SM, Avery RK. Aspergillosis in lung transplantation: Incidence, risk factors, and prophylactic strategies. Transpl Infect Dis 2001; 3: 161–167. Avery RK, Michaels MG, AST Infectious Diseases Community of Practice. Strategies for safe living following solid organ transplantation. Am J Transplant 2009; 9 (Suppl 4): S252–S257. Pfeiffer CD, Perfect JR, Alexander BA. Current controversies in the treatment of fungal infections. In: Safdar A, ed. Principles and practice of cancer infectious diseases (current clinical oncology). New York, NY: Humana Press, 2011, pp. 301–316.
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Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12691
Epidemiology of Invasive Mold Infections in Lung Transplant Recipients C. T. Doligalski1, K. Benedict2, A. A. Cleveland2, B. Park2, G. Derado3, P. G. Pappas4, J. W. Baddley4, D. W. Zaas5, M. T. Harris6 and B. D. Alexander5,7,* 1
Department of Pharmacy, Tampa General Hospital, Tampa, FL 2 Mycotic Diseases Branch, US Centers for Disease Control and Prevention, Atlanta, GA 3 Division of Foodborne, Waterborne, and Environmental Diseases, US Centers for Disease Control and Prevention, Atlanta, GA 4 Department of Medicine, University of Alabama, Birmingham, AL 5 Department of Medicine, Duke University Hospital, Durham, NC 6 Department of Pharmacy, Duke University Hospital, Durham, NC 7 Department of Pathology, Duke University Hospital, Durham, NC Corresponding author: Barbara D. Alexander, [email protected] 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. Keywords: Epidemiology, infection, lung transplant, mold
sis; IFI, invasive fungal infection; IMI, invasive mold infection; LTR, lung transplant recipient; TRANSNET, Transplant-Associated Infection Surveillance Network Received 26 July 2013, revised 21 January 2014 and accepted for publication 29 January 2014
Background Lung transplantation is a life-saving intervention for patients with end-stage lung disease. In the United States in 2011, 1849 lung and heart/lung transplant procedures were performed (1). Despite important advances in surgical technique, immunosuppressive regimens and the development of novel antifungal agents in recent years, lung transplant recipients (LTRs) remain at substantial risk for development of invasive fungal infections (IFIs) (2). However, few data are available on the overall burden of IFIs in this population. Historical studies have been primarily limited to small retrospective investigations (2–5) from which conflicting results have been reported (6,7) and limited conclusions can be drawn. To better understand the burden of IFIs and their associated outcomes among transplant recipients, the Centers for Disease Control and Prevention and partners formed the Transplant-Associated Infection Surveillance Network (TRANSNET), a multicenter consortium designed to perform prospective surveillance for IFIs among selected major transplant centers in the United States. TRANSNET provides the most comprehensive epidemiologic investigation of IFIs in the solid organ transplant population to date (8). Per overall TRANSNET analysis, the 12-month cumulative incidence (CI) of invasive mycoses in lung and heart– LTRs was 8.6% and invasive mold infections (IMIs) accounted for 70% of all IFIs in this transplant population. This was in contrast to the heart, kidney and liver solid organ transplant populations for which 35%, 21% and 18% of all IFIs, respectively, were caused by molds (8). Given the importance of IMIs in the lung transplant population, we used the TRANSNET prospective data to further describe the epidemiology of IMIs in LTRs.
Methods Study design
Abbreviations: CI, cumulative incidence; EORTC/MSG, European Organization for Research and Treatment of Cancer/Mycoses Study Group; IA, invasive aspergillo1328
The study was conducted in accordance with US Good Clinical Practice regulations and guidelines; human subject approval or waiver was obtained at each institution from which data were reported to TRANSNET.
Invasive Mold in Lung Transplant Surveillance was conducted prospectively among 15 solid organ transplant centers in the United States from March 2001 to March 2006 (8). A standardized case report form was used to collect data on all cases that developed an IFI during the surveillance period, regardless of when the transplant occurred. Data collected on cases included demographic information, transplant date and type, method of diagnosis, comorbid conditions and co-infections, immunosuppressive and antifungal use and 3-month follow-up status. An IMI was defined as proven or probable by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/ MSG) criteria (9). Demographic data, transplant information and limited followup data were also collected on all patients who underwent transplantation at study sites during the surveillance period (incidence cohort). Because lung transplant patients are generally considered at higher risk for IMIs than other organ transplant recipients (8), any combination of solid organ transplants that included lung were included in this analysis (e.g. a patient who was a recipient of both kidney and lung allografts). For patients who developed more than one IMI, only the first IMI was used for incidence calculations.
Statistics All analyses were conducted using SAS version 9.3 (SAS Institute, Inc., Cary, NC). Twelve-month CI of first IMI for lung transplant patients was estimated accounting for the competing risks of death, relapse and re-transplantation; CI estimates were calculated using the ‘‘cmprsk’’ package, v. 2-2-2, in R (v. 2-14-1). Bivariate statistics were calculated using Student’s t-test, chisquared or Fisher’s exact tests, as appropriate. p-Values < 0.05 were considered statistically significant.
Results During the 5-year surveillance period, we identified 1173 LTRs under surveillance at 11 of 15 participating transplant centers and 143 (12.2%) developed IMIs. Most patients (107, 74.8%) developed one IMI; 28 (19.6%) developed two IMIs, 5 (3.5%) developed three IMIs and 3 (2.1%) developed four or more. Fifty-three (37.1%) IMIs were classified as ‘‘proven’’ according to EORTC/MSG criteria. The most common pathogen identified was Aspergillus (104, 72.7%); non-Aspergillus infections (39; 27.3%) included: Scedosporium (5, 3.5%), mucormycosis (3, 2.1%) and ‘‘unspecified’’ or ‘‘other’’ mold infections (31, 21.7%; Figure 1). Aspergillus infections were most commonly due to A. fumigatus (n ¼ 54), followed by A. flavus (n ¼ 10), A. niger (n ¼ 9), A. terreus (n ¼ 4), A. versicolor (n ¼ 1), unknown Aspergillus species (n ¼ 8) and multiple unidentified Aspergillus species (n ¼ 18). The 12-month CI of invasive aspergillosis (IA) and non-IA infections was 4.13% and 1.35%, respectively (Figure 2). Median age at time of IMI diagnosis was 55 years; most patients were White (125, 87.4%) and first-time transplant recipients (134, 93.7%). Chronic obstructive pulmonary disease was the most common indication for transplantation (59, 41.3%), followed by pulmonary fibrosis (25, 17.5%) and cystic fibrosis (21, 14.7%). The majority of patients (117, 81.8%) had IMI limited to the pulmonary system; disseminated infection (8, 5.6%) and skin (5, 3.5%), combined pulmonary/sinus (3, 2.1%) and sinus (2, 1.4%) involvement occurred less frequently. Fungemia and bone involvement were rare, with one case of each American Journal of Transplantation 2014; 14: 1328–1333
Figure 1: Infecting mold pathogens in 143 episodes of invasive mold infections occurring in lung transplant recipients. Four Paecilomyces; two each of Acremonium, Penicillium and Phialemonium; one each of Alternaria, Chrysosporium, Cladosporium, Exophiala, Microascus, Ochroconis, Paraphaeosphaeria, Phaeoacremonium, Rhinocladiella, Scopulariopsis, Trichoderma, unidentified basidiomycete and unidentified black mold.
reported. Dyspnea (84, 58.7%), cough (75, 52.4%) and increased sputum production (55, 38.5%) were the most common respiratory symptoms within the first 7 days of IMI diagnosis; less than one-third of patients presented with fever (44, 30.8%). Extrapulmonary symptoms were less common, with less than 5% of IMI-infected patients experiencing central nervous system, sino-nasal or cutaneous symptoms. However, there were significant differences in site of involvement and presentation between IA and non-IA mold infections. Compared with IA infections (Table 1), non-IA mold infections occurred more frequently in men (65.8% vs. 44.7%, p ¼ 0.036) and presented more commonly as a
Figure 2: Twelve-month cumulative incidence by type of first invasive mold infection (top line, invasive aspergillosis; bottom line, non-Aspergillosis invasive mold infection).
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cutaneous infection (14.3% vs. 0%, p ¼ 0.001) while IA was more likely to be limited to the pulmonary system (93.1% vs. 62.9% p < 0.001). Patients with IA were more likely to have dyspnea (65.4% vs. 41%, p ¼ 0.008) and cough (57.7% vs. 38.5%, p ¼ 0.04) while non-IA trended to have more papular or skin nodules (15.4% vs. 0%, p < 0.001). The 3-month mortality for all IMI patients was 21.7%; IMI was noted to be a contributing cause of death in 52% of
cases. There was no significant difference in mortality among the IA group compared with the non-IA group (22% vs. 21%, p ¼ 0.84). IMIs occurred a median of 11 months posttransplant (range: 0–162 months; Figure 3). Early IMI (90 days) accounted for 25% of IMIs; 65% of IMIs occurred within 2 years of transplantation. Median time to IA was slightly less than non-IA IMI (10.5 months vs. 16 months,
Table 1: Characteristics of TRANSNET lung transplant patients who developed invasive mold infection Characteristics, n (%) Age in years, median (range) Male sex Race White Black/African-American Number of months posttransplant to IMI diagnosis, median (range) Underlying disease prompting transplant COPD/emphysema Cystic fibrosis Pulmonary fibrosis Sarcoidosis Other2 Prior transplant Combination transplant3 Anatomical site of IMI involvement Pulmonary only Sinus only Sinus and pulmonary Disseminated Skin Blood only Bone Symptoms present within 7 days of IMI diagnosis Dyspnea Cough Increased sputum production Fever Chest pain Hemoptysis Sino-nasal congestion/pain Papular or nodular skin lesions Central nervous system signs/symptoms Three-month mortality IMI listed as contributing cause of death Assessed at the time of IMI diagnosis Renal insufficiency Diabetes Neutropenia Assessed within 90 days prior to IMI Organ rejection Prophylactic antifungal therapy Amphotericin B, inhaled Fluconazole Itraconazole, oral Itraconazole, intravenous Voriconazole Ketoconazole Empiric antifungal therapy
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IA (n ¼ 104) 55 (20–70) 46 (44.7) 95 (95.0) 5 (5.0) 10.5 (0–162)
Non-IA1 (n ¼ 39) 54 (18–68) 25 (65.8)
p-Value 0.464 0.036 0.231
30 (88.2) 4 (11.8) 16 (0–83)
0.205
41 17 19 4 23 7 3
(39.4) (16.4) (18.3) (3.8) (22.3) (6.7) (2.8)
18 4 6 0 11 2 2
(46.2) (10.3) (15.4) (0) (28.9) (5.1) (5.1)
0.467 0.360 0.686 0.575 0.446 1.000 0.614
95 0 2 4 0 0 1
(93.1) (0) (1.9) (3.9) (0) (0) (1)
22 2 1 4 5 1 0
(62.9) (5.7) (2.9) (11.4) (14.3) (2.9) (0)
90 days posttransplant) with certain non-IA mold infections occurring very late (>1 year) in the posttransplant course. One possible explanation for this shifting epidemiology may be the routine early use of mold-active prophylaxis in LTRs and development of infection after prophylaxis is stopped. The 2004 American Society of Transplantation (AST) guidelines recommended continuing prophylaxis after lung transplantation at least until bronchial anastomosis remodeling is complete, which takes 4–8 months (14). A 2006 survey of 43 1332
international lung transplant centers found that 69% used antifungal prophylaxis during the immediate posttransplant period as the anastomosis was healing, most commonly an aerosolized formulation of amphotericin B alone or in combination with itraconazole (15). While the advent of newer triazole antifungals has altered some center’s prophylaxis strategy, more recent data demonstrate a continued heavy reliance on itraconazole and aerosolized amphotericin B and significant discontinuation rates of newer triazoles due to toxicity (16). Thus, use of mold-active prophylaxis during the early posttransplant period may be influencing the timing of IMIs, resulting in late-onset disease when prophylaxis is no longer routinely used. Alternatively, the shift to later IMI may also be related to increased exposures, as patients resume normal activities of living following the transplant procedure. Consistent with the 2009 AST guidelines (17), prevention strategies should give consideration to the known epidemiology of IMIs in this population, including the infecting pathogens, the mode of transmission/initial site of infection and the usual timing of IMIs following lung transplantation. This approach allows prophylactic therapy to be targeted during windows of highest risk. The majority of experts agree that the historical risk for IFI is substantially high enough during the immediate postlung transplant period to warrant universal antifungal prophylaxis until the anastomosis is healed (18). In addition, based on our data, expert opinion holds that upon completion of initial prophylaxis, patients and caregivers should be particularly vigilant in monitoring patients for late-onset IMIs and avoiding environmental exposures that may lead to inoculation with these pathogens (19). Finally, prophylactic agents should be individualized based on the type of lung transplant performed (e.g. use of systemic rather than aerosolized agents in single LTRs) and therapeutic drug monitoring considered to ensure adequate absorption of orally administered triazoles (20). In summary, IMIs, which tend to appear in the late and very late postlung transplant period, are associated with high mortality. Aspergillus remains the most common mold pathogen; however, non-IA molds are also an important cause of IMIs. Appreciation of the epidemiology of IMIs and assessment of each patient’s individual risks should be used to refine prevention strategies in the lung transplant population.
Acknowledgments This work was supported in part by the Centers for Disease Control (grant no. 5U01C1000286-05) and NIH NIAID K24 AI072522 (BDA).
Disclosure The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of American Journal of Transplantation 2014; 14: 1328–1333
Invasive Mold in Lung Transplant
Transplantation. DWZ discloses affiliation with Pfizer, APT Pharmaceuticals and Merck. BDA discloses research grants from Astellas, Pfizer and Charles River Laboratories, as well as acting as advisor for Bristol-Myers Squibb, bioMerieux and Astellas. All other authors declare no conflicts of interest.
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