Aspergillosis in Solid Organ Transplantation

Abstract

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% (1Morgan J Wannemuehler KA Marr KA et al.Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: Interim results of a prospective multicenter surveillance program.Med Mycol. 2005; 43: S49-S58Crossref PubMed Scopus (345) Google Scholar, 2Singh N Arnow PM Bonham A et al.Invasive aspergillosis in liver transplant recipients in the 1990s.Transplantation. 1997; 64: 716-720Crossref PubMed Scopus (156) Google Scholar, 3Singh N Avery RK Munoz P et al.Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients.Clin Infect Dis. 2003; 36: 46-52Crossref PubMed Scopus (160) Google Scholar, 4Gavalda J Len O San JR et al.Risk factors for invasive aspergillosis in solid-organ transplant recipients: A case-control study.Clin Infect Dis. 2005; 41: 52-59Crossref PubMed Scopus (233) Google Scholar). However, currently reported mortality rate in IA among SOT recipients is 22% (5Steinbach WJ Marr KA Anaissie EJ et al.Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry.J Infect. 2012; 65: 453-464Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). An estimated 9.3–16.9% of all deaths in transplant recipients in the first year have been considered attributable to IA (6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar). 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. The net state of immunosuppression including the intensity of immunosuppressive regimen is a major determinant of the development of IA in SOT recipients, regardless of the type of transplant. However, the incidence of IA differs and there are unique risk factors for Aspergillus infections for various types of organ transplant recipients as discussed herein (Table 1). IA is typically acquired by inhalation of the conidia. Less frequently local infections may result in surgical wound infections. Invasive disease may manifest as localized (pulmonary or extrapulmonary disease) or disseminated aspergillosis. In lung transplant recipients, airway disease can manifest as tracheobronchitis or bronchial anastomotic infections.Table 1:Risk factors for invasive aspergillosis in organ transplant recipientsLiver transplant recipients– Retransplantation– Renal failure, particularly requiring renal replacement therapy– Transplantation for fulminant hepatic failure– ReoperationLung transplant recipients– Single lung transplant– Early airway ischemia– Cytomegalovirus infection– Rejection and augmented immunosuppression– Pretransplant Aspergillus colonization– Posttransplant Aspergillus colonization within a year of transplant– Acquired hypogammaglobulinemia (IgG < 400 mg/dL)Heart transplant recipients– Isolation of Aspergillus species in respiratory tract cultures– Reoperation– CMV disease– Posttransplant hemodialysis– Existence of an episode of invasive aspergillosis in the program 2 months before or after heart transplantKidney transplant recipients– Graft failure requiring hemodialysis– High and prolonged duration of corticosteroids Open table in a new tab IA occurs in 1–9.2% of the liver transplant recipients (1Morgan J Wannemuehler KA Marr KA et al.Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: Interim results of a prospective multicenter surveillance program.Med Mycol. 2005; 43: S49-S58Crossref PubMed Scopus (345) Google Scholar,4Gavalda J Len O San JR et al.Risk factors for invasive aspergillosis in solid-organ transplant recipients: A case-control study.Clin Infect Dis. 2005; 41: 52-59Crossref PubMed Scopus (233) Google Scholar,6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar, 7Brown Jr., RS Lake JR Katzman BA et al.Incidence and significance of Aspergillus cultures following liver and kidney transplantation.Transplantation. 1996; 61: 666-669Crossref PubMed Scopus (0) Google Scholar, 8Briegel J Forst H Spill B et al.Risk factors for systemic fungal infections in liver transplant recipients.Eur J Clin Microbiol Infect Dis. 1995; 14: 375-382Crossref PubMed Scopus (95) Google Scholar, 9Kusne S Torre-Cisneros J Manez R et al.Factors associated with invasive lung aspergillosis and the significance of positive Aspergillus culture after liver transplantation.J Infect Dis. 1992; 166: 1379-1383Crossref PubMed Google Scholar). A number of well characterized risk factors have been described for IA after liver transplantation. Retransplantation and renal failure are amongst the most significant risk factors for IA in these patients (4Gavalda J Len O San JR et al.Risk factors for invasive aspergillosis in solid-organ transplant recipients: A case-control study.Clin Infect Dis. 2005; 41: 52-59Crossref PubMed Scopus (233) Google Scholar,10Singh N Paterson DL Aspergillus infections in transplant recipients.Clin Microbiol Rev. 2005; 18: 44-69Crossref PubMed Scopus (511) Google Scholar, 11Fortun J Martin-Davila P Moreno S et al.Risk factors for invasive aspergillosis in liver transplant recipients.Liver Transpl. 2002; 8: 1065-1070Crossref PubMed Scopus (133) Google Scholar, 12Singh N Paterson DL Gayowski T Wagener MM Marino IR Preemptive prophylaxis with a lipid preparation of amphotericin B for invasive fungal infections in liver transplant recipients requiring renal replacement therapy.Transplantation. 2001; 71: 910-913Crossref PubMed Google Scholar). Retransplantation confers 30-fold higher risk and renal dysfunction, particularly the requirement of any form of renal replacement therapy, e.g. hemodialysis or continuous venovenous hemofiltration is associated with a 15- to 25-fold greater risk of IA in liver transplant recipients (3Singh N Avery RK Munoz P et al.Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients.Clin Infect Dis. 2003; 36: 46-52Crossref PubMed Scopus (160) Google Scholar,11Fortun J Martin-Davila P Moreno S et al.Risk factors for invasive aspergillosis in liver transplant recipients.Liver Transpl. 2002; 8: 1065-1070Crossref PubMed Scopus (133) Google Scholar). Most Invasive fungal infections in these high-risk patients occur within the first month posttransplant; the median time to onset of IA after renal replacement therapy and retransplantation was 13 and 28 days, respectively in one study (9Kusne S Torre-Cisneros J Manez R et al.Factors associated with invasive lung aspergillosis and the significance of positive Aspergillus culture after liver transplantation.J Infect Dis. 1992; 166: 1379-1383Crossref PubMed Google Scholar,13Singh N Limaye AP Forrest G et al.Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective, multicenter, observational study.Transplantation. 2006; 81: 320-326Crossref PubMed Scopus (289) Google Scholar). Other factors associated with IA in liver transplant recipients include transplantation for fulminant hepatic failure, cytomegalovirus (CMV) infection and prolonged intensive unit care stay (7Brown Jr., RS Lake JR Katzman BA et al.Incidence and significance of Aspergillus cultures following liver and kidney transplantation.Transplantation. 1996; 61: 666-669Crossref PubMed Scopus (0) Google Scholar, 8Briegel J Forst H Spill B et al.Risk factors for systemic fungal infections in liver transplant recipients.Eur J Clin Microbiol Infect Dis. 1995; 14: 375-382Crossref PubMed Scopus (95) Google Scholar, 9Kusne S Torre-Cisneros J Manez R et al.Factors associated with invasive lung aspergillosis and the significance of positive Aspergillus culture after liver transplantation.J Infect Dis. 1992; 166: 1379-1383Crossref PubMed Google Scholar,14Osawa M Ito Y Hirai T et al.Risk factors for invasive aspergillosis in living donor liver transplant recipients.Liver Transpl. 2007; 13: 566-570Crossref PubMed Scopus (33) Google Scholar, 15George MJ Snydman DR Werner BG et al.The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland.Am J Med. 1997; 103: 106-113Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 16Collins LA Samore MH Roberts MS et al.Risk factors for invasive fungal infections complicating orthotopic liver transplantation.J Infect Dis. 1994; 170: 644-652Crossref PubMed Google Scholar; Table 2).Table 2:Recommendations for prophylaxis for invasive aspergillosis in solid organ transplant recipientsOrganRisk factorsAntifungal prophylaxisDurationLiver II-2RetransplantationLipid formulation of amphotericin B (3–5 mg/kg/day) OR an echinocandinInitial hospital stay or for 4 weeks posttransplantRenal failure, particularly requiring renal replacement therapyReoperation involving thoracic or abdominal cavityLungPresence of one of these risk factors (II-2)Inhaled amphotericin B 6 mg/q8 or 25 mg/dayORPreferably guided by interval airway inspection, respiratory surveillance fungal cultures, and clinical risk factors.Pretransplant Aspergillus colonizationPosttransplant Aspergillus colonization within a year of transplantPresence of more than one of these risk factors (II-3,III)Induction with alemtuzumab or ThymoglobulinInhaled Abelcet 50 mgORInhaled Ambisome 25mgORVoriconazole 200 mg bidORItraconazole 200 mg bidOnce every 2 days for 2 weeks and then once per week for at least 13 weeksSingle lung transplantAspergillus colonization following cytomegalovirus infectionThree times/week for 2 months, followed by weekly administration for 6 months and twice per month afterwardsRejection and augmentedImmunosuppression (particularly useof monoclonal antibody posttransplant with Aspergillus colonization)4 months or longerAcquired hypogammaglobulinemia (IgG < 400 mg/dL)Heart II-3Isolation of Aspergillus species in respiratory tract cultures ReoperationItraconazole 200 mg bid50–150 daysCMV diseaseORPosttransplant hemodialysisvoriconazole 200 mg bidExistence of an episode of IA in program 2 months before or after heart transplant Open table in a new tab Historically IA in liver transplant recipients has occurred in the early posttransplant period; the median time to onset after transplantation was 17 days in one study (2Singh N Arnow PM Bonham A et al.Invasive aspergillosis in liver transplant recipients in the 1990s.Transplantation. 1997; 64: 716-720Crossref PubMed Scopus (156) Google Scholar) and 16 days in another (17Selby R Ramirez CB Singh R et al.Brain abscess in solid organ transplant recipients receiving cyclosporine-based immunosuppression.Arch Surg. 1997; 132: 304-310Crossref PubMed Google Scholar). More recently, however, Aspergillus infections have been shown to occur in the late posttransplant period, i.e. more than 90 days after transplantation. In a study that compared a cohort of patients with IA from 1998 to 2002 with those from 1990 to 1995, median onset to IA was 60 days posttransplant; 55% of the infections in the later compared with 23% in the earlier cohort occurred after 90 days of transplantation (3Singh N Avery RK Munoz P et al.Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients.Clin Infect Dis. 2003; 36: 46-52Crossref PubMed Scopus (160) Google Scholar). Improved outcome in the early postoperative period due to technical surgical advances, and delayed onset of posttransplant risk factors such as CMV infection, allograft dysfunction due to recurrent hepatitis C virus hepatitis are proposed to have led to delayed occurrence of IA in liver transplant recipients in the current era (3Singh N Avery RK Munoz P et al.Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients.Clin Infect Dis. 2003; 36: 46-52Crossref PubMed Scopus (160) Google Scholar). CMV and hepatitis C virus infection are independent risk factors for late-onset IA in liver transplant recipients (2Singh N Arnow PM Bonham A et al.Invasive aspergillosis in liver transplant recipients in the 1990s.Transplantation. 1997; 64: 716-720Crossref PubMed Scopus (156) Google Scholar,7Brown Jr., RS Lake JR Katzman BA et al.Incidence and significance of Aspergillus cultures following liver and kidney transplantation.Transplantation. 1996; 61: 666-669Crossref PubMed Scopus (0) Google Scholar,11Fortun J Martin-Davila P Moreno S et al.Risk factors for invasive aspergillosis in liver transplant recipients.Liver Transpl. 2002; 8: 1065-1070Crossref PubMed Scopus (133) Google Scholar). Mortality in liver transplant recipients with IA has ranged from 83% to 88% (6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar,18Denning DW. Therapeutic outcome in invasive aspergillosis.Clin Infect Dis. 1996; 23: 608-615Crossref PubMed Google Scholar). Requirement of dialysis and CMV infection are independent predictors of mortality in SOT recipients, including liver transplant recipients with IA (13Singh N Limaye AP Forrest G et al.Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective, multicenter, observational study.Transplantation. 2006; 81: 320-326Crossref PubMed Scopus (289) Google Scholar). More recent studies have reported improved outcomes with mortality ranging from 33.3% to 65% (3Singh N Avery RK Munoz P et al.Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients.Clin Infect Dis. 2003; 36: 46-52Crossref PubMed Scopus (160) Google Scholar,19Fortun J Martin-Davila P Moreno S et al.Prevention of invasive fungal infections in liver transplant recipients: The role of prophylaxis with lipid formulations of amphotericin B in high-risk patients.J Antimicrob Chemother. 2003; 52: 813-819Crossref PubMed Scopus (80) Google Scholar). Mortality, however, remains high in patients who develop IA after liver retransplantation (82.4%), particularly in those undergoing retransplantation after 30 days of primary transplant (100%; Ref. 13Singh N Limaye AP Forrest G et al.Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective, multicenter, observational study.Transplantation. 2006; 81: 320-326Crossref PubMed Scopus (289) Google Scholar). IA has been reported in approximately 0.7% and in up to 4% of the renal transplant recipients (6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar,7Brown Jr., RS Lake JR Katzman BA et al.Incidence and significance of Aspergillus cultures following liver and kidney transplantation.Transplantation. 1996; 61: 666-669Crossref PubMed Scopus (0) Google Scholar,20Altiparmak MR Apaydin S Trablus S et al.Systemic fungal infections after renal transplantation.Scand J Infect Dis. 2002; 34: 284-288Crossref PubMed Scopus (0) Google Scholar, 21Cofan F Ricart MJ Oppenheimer F et al.Study of kidney rejection following simultaneous kidney-pancreas transplantation.Nephron. 1996; 74: 58-63Crossref PubMed Scopus (6) Google Scholar, 22Weiland D Ferguson RM Peterson PK Snover DC Simmons RL Najarian JS Aspergillosis in 25 renal transplant patients. Epidemiology, clinical presentation, diagnosis, and management.Ann Surg. 1983; 198: 622-629Crossref PubMed Scopus (119) Google Scholar, 23Gustafson TL Schaffner W Lavely GB Stratton CW Johnson HK Hutcheson Jr., RH Invasive aspergillosis in renal transplant recipients: Correlation with corticosteroid therapy.J Infect Dis. 1983; 148: 230-238Crossref PubMed Google Scholar, 24Peterson PK Ferguson R Fryd DS Balfour Jr., HH Rynasiewicz J Simmons RL Infectious diseases in hospitalized renal transplant recipients: A prospective study of a complex and evolving problem.Medicine (Baltimore). 1982; 61: 360-372Crossref PubMed Google Scholar, 25Gallis HA Berman RA Cate TR Hamilton JD Gunnells JC Stickel DL Fungal infection following renal transplantation.Arch Intern Med. 1975; 135: 1163-1172Crossref PubMed Google Scholar). High doses and prolonged duration of corticosteroids, graft failure requiring hemodialysis and potent immunosuppressive therapy have been shown to be risk factors for IA after renal transplantation (6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar,23Gustafson TL Schaffner W Lavely GB Stratton CW Johnson HK Hutcheson Jr., RH Invasive aspergillosis in renal transplant recipients: Correlation with corticosteroid therapy.J Infect Dis. 1983; 148: 230-238Crossref PubMed Google Scholar,26Panackal AA Dahlman A Keil KT et al.Outbreak of invasive aspergillosis among renal transplant recipients.Transplantation. 2003; 75: 1050-1053Crossref PubMed Google Scholar). Despite a relatively lower overall incidence as compared to other organ transplant recipients, IA is a significant contributor to morbidity in renal transplant recipients. Mortality in renal transplant recipients with IA has ranged from 67% to 75% (4Gavalda J Len O San JR et al.Risk factors for invasive aspergillosis in solid-organ transplant recipients: A case-control study.Clin Infect Dis. 2005; 41: 52-59Crossref PubMed Scopus (233) Google Scholar,6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar). Earlier studies had reported the overall incidence of IA in lung transplant patients ranges from 4% to 23.3% (27Husain S Paterson DL Studer S et al.Voriconazole prophylaxis in lung transplant recipients.Am J Transplant. 2006; 6: 3008-3016Crossref PubMed Scopus (181) Google Scholar). In a recently concluded multicenter prospective study, the first year cumulative incidence of fungal infections in lung transplant was 8.6% (28Pappas PG Alexander BD Andes DR et al.Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Crossref PubMed Scopus (1035) Google Scholar). This incidence of all fungal infections was in parallel with the reported incidence in donor mismatch allogeneic bone marrow transplant recipients (29Kontoyiannis DP Marr KA Park BJ et al.Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.Clin Infect Dis. 2010; 50: 1091-1100Crossref PubMed Scopus (1053) Google Scholar). These data highlight the highest risk status of fungal infections in lung transplant recipients despite widespread use of antifungal prophylaxis. IA is the predominant fungal infection in lung transplant recipients (30Neofytos D Fishman JA Horn D et al.Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.Transpl Infect Dis. 2010; Crossref Scopus (330) Google Scholar). The median time to onset of IA in lung transplant recipients from 2002 to 2005 was 508 days posttransplant (30Neofytos D Fishman JA Horn D et al.Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.Transpl Infect Dis. 2010; Crossref Scopus (330) Google Scholar). In lung transplant recipients, the continuous exposure of the organ to the environment, coupled with impaired defenses due to decreased mucociliary clearance and blunted cough reflex, contributes to the vulnerability to IA (31Chan KM. Approach towards infectious pulmonary complications in lung tramnsplant recipients.in: Singh N Aguado JM Infectious complications in transplant aptients.1st Ed. Kluwer Academic Publishers, Norwell, MA2001: 149-175Crossref Google Scholar). Other risk factors that confer an increased risk of IA in lung transplant recipients are relative ischemia at the anastomosis (32Higgins R McNeil K Dennis C et al.Airway stenoses after lung transplantation: Management with expanding metal stents.J Heart Lung Transplant. 1994; 13: 774-778PubMed Google Scholar), receipt of single lung transplant (33Westney GE Kesten S De Hoyos A Chapparro C Winton T Maurer JR Aspergillus infection in single and double lung transplant recipients.Transplantation. 1996; 61: 915-919Crossref PubMed Scopus (154) Google Scholar), hypogammaglobulinemia (34Goldfarb NS Avery RK Goormastic M et al.Hypogammaglobulinemia in lung transplant recipients.Transplantation. 2001; 71: 242-246Crossref PubMed Google Scholar), CMV infection (35Husni RN Gordon SM Longworth DL et al.Cytomegalovirus infection is a risk factor for invasive aspergillosis in lung transplant recipients.Clin Infect Dis. 1998; 26: 753-755Crossref PubMed Google Scholar) and pre/postcolonization of the airways with Aspergillus (36Cahill BC Hibbs JR Savik K et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Abstract Full Text Full Text PDF PubMed Google Scholar, 37Nunley DR Ohori P Grgurich WF et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Abstract Full Text Full Text PDF PubMed Google Scholar, 38Helmi M Love RB Welter D Cornwell RD Meyer KC Aspergillus infection in lung transplant recipients with cystic fibrosis: Risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). The presence of bronchiolitis obliterans syndrome as a risk factor for IA is not well determined. However, one study failed to find a higher rate of IA in lung transplant recipients with bronchiolitis obliterans syndrome (39Valentine VG Bonvillain RW Gupta MR et al.Infections in lung allograft recipients: Ganciclovir era.J Heart Lung Transplant. 2008; 27: 528-535Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The mortality of IA in lung transplant recipients varies according to the clinical presentation, ranging from 23% to 29% in patients with tracheobronchitis to as high as 67–82% in patients with invasive pulmonary disease (10Singh N Paterson DL Aspergillus infections in transplant recipients.Clin Microbiol Rev. 2005; 18: 44-69Crossref PubMed Scopus (511) Google Scholar). Recent data would suggest that overall mortality of 20% among patients with IA (30Neofytos D Fishman JA Horn D et al.Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.Transpl Infect Dis. 2010; Crossref Scopus (330) Google Scholar). The overall 12 months cumulative incidence of fungal infection in heart transplant recipients was 3.4% in a large prospective cohort study (28Pappas PG Alexander BD Andes DR et al.Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Crossref PubMed Scopus (1035) Google Scholar). The incidence of IA in heart transplant recipients ranges from 1% to 14% (40Munoz P Singh N Bouza E Treatment of solid organ transplant patients with invasive fungal infections: Should a combination of antifungal drugs be used?.Curr Opin Infect Dis. 2006; 19: 365-370Crossref PubMed Scopus (0) Google Scholar). The risk factors for the development of IA include the isolation of Aspergillus fumigatus from bronchoalveolar lavage (BAL), reoperation, CMV disease, posttransplant hemodialysis, (41Berenguer J Munoz P Parras F Fernandez-Baca V Hernandez-Sampelayo T Bouza E Treatment of deep mycoses with liposomal amphotericin B.Eur J Clin Microbiol Infect Dis. 1994; 13: 504-507Crossref PubMed Scopus (33) Google Scholar, 42Munoz P Rodriguez C Bouza E et al.Risk factors of invasive aspergillosis after heart transplantation: Protective role of oral itraconazole prophylaxis.Am J Transplant. 2004; 4: 636-643Crossref PubMed Scopus (97) Google Scholar, 43Munoz P Alcala L Sanchez CM et al.The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients is highly predictive of invasive aspergillosis.Transplantation. 2003; 75: 326-329Crossref PubMed Scopus (0) Google Scholar). Overall mortality in heart transplant recipients with IA at 1 year was 66.7% in one study (40Munoz P Singh N Bouza E Treatment of solid organ transplant patients with invasive fungal infections: Should a combination of antifungal drugs be used?.Curr Opin Infect Dis. 2006; 19: 365-370Crossref PubMed Scopus (0) Google Scholar). A substantial delay in establishing an early diagnosis remains a major impediment to the successful treatment of IA. Diagnostic criteria have been established to facilitate the diagnosis of IA. The European Organization of Research and Treatment and Mycosis Study Group had put forth the criteria for the diagnosis of fungal infections in immunocompromised host (44De PB 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: 1813-1821Crossref PubMed Scopus (0) Google Scholar). However, they lack complete applicability in lung transplant recipients owing to the unique clinical syndromes and lack of sensitivity of certain diagnostic tests (serum galactomannan) in lung transplants. The International Society for Heart and Lung Transplantation has developed a working formulation for the diagnosis of invasive fungal infections in lung transplant recipients. This definition excludes the “possible” category from EORTC/MSG criteria and defines the clinical syndromes of colonization, tracheobronchitis/bronchial anastomotic infection with the inclusion of Aspergillus PCR in the microbiological diagnostic criteria. These definitions may be more specific in the epidemiological and intervention studies in lung transplant recipients (45Husain S Mooney ML Danziger-Isakov L et al.A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients.J Heart Lung Transplant. 2011; 30: 361-374Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Among the diagnostic modalities, cultures of the respiratory tract secretions lack sensitivity and the Aspergillus may only be detected in clinical samples in late stages of the disease. On the other hand, a positive culture with Aspergillus from respiratory tract samples does not always indicate invasive disease. The significance of a positive culture from an airway sample also varies with the type of organ transplant. Isolation of Aspergillus spp. from the respiratory tract of liver transplant recipients is an infrequent event (∼1.5%). However, it has a high positive predictive value, ranging from 41% to 72% for the subsequent development of IA (6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar). Aspergillus spp. can be detected in airway samples of ∼25–30% of the lung transplant recipients (3Singh N Avery RK Munoz P et al.Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients.Clin Infect Dis. 2003; 36: 46-52Crossref PubMed Scopus (160) Google Scholar,36Cahill BC Hibbs JR Savik K et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Abstract Full Text Full Text PDF PubMed Google Scholar,46Mehrad B Paciocco G Martinez FJ Ojo TC Iannettoni MD Lynch III, JP Spectrum of Aspergillus infection in lung transplant recipients: Case series and review of the literature.Chest. 2001; 119: 169-175Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). Although positive airway cultures have a low positive predictive value for the diagnosis of IA in lung transplant recipients, they portend a higher risk for subsequent invasive infection (6Paterson DL Singh N Invasive aspergillosis in transplant recipients.Medicine (Baltimore). 1999; 78: 123-138Crossref PubMed Scopus (329) Google Scholar). Recovery of Aspergillus spp. from an airway sample in lung transplant recipients warrants a bronchoscopic examination to exclude the presence of tracheobronchitis because radiographic and imaging studies may be nonrevealing at this stage. In heart transplant recipients, the positive predictive value of culturing Aspergillus from respiratory tract samples for the diagnosis of IA was 60–70% (43Munoz P Alcala L Sanchez CM et al.The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients is highly predictive of invasive aspergillosis.Transplantation. 2003; 75: 326-329Crossref PubMed Scopus (0) Google Scholar). The positive predictive value of recovering A. fumigatus for the diagnosis of IA was 78–91%, whereas it was 0% for other including A. versioclor, A. terreus, A. gla