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The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary
2016; Elsevier BV; Volume: 35; Issue: 3 Linguagem: Inglês
10.1016/j.healun.2016.01.007
ISSN1557-3117
AutoresShahid Husain, Amparó Solé, Barbara D. Alexander, Saima Aslam, Robin K. Avery, Christian Benden, Eliane M. Billaud, Daniel C. Chambers, Lara Danziger‐Isakov, Savitri Fedson, Kate Gould, Aric L. Gregson, Paolo Grossi, Denis Hadjiliadis, Peter Hopkins, Me‐Linh Luong, Debbie Marriott, Vı́ctor Monforte, Patricia Muñóz, Alessandro C. Pasqualotto, Antonio Román, Fernanda P. Silveira, Jeffrey Teuteberg, S. Weigt, Aimee K. Zaas, Andreas Zuckerman, Orla Morrissey,
Tópico(s)Antifungal resistance and susceptibility
ResumoThe field of cardiothoracic transplantation (CT) has evolved significantly, but infections remain an important cause of morbidity and mortality, particularly fungal infections (FIs). The higher mortality associated with FIs has prompted the institution of center-specific anti-fungal prophylactic strategies.1Dummer J.S. Lazariashvilli N. Barnes J. Ninan M. Milstone A.P. A survey of anti-fungal management in lung transplantation.J Heart Lung Transplant. 2004; 23: 1376-1381Google Scholar, 2Husain S. Zaldonis D. Kusne S. Kwak E.J. Paterson D.L. McCurry K.R. Variation in antifungal prophylaxis strategies in lung transplantation.Transpl Infect Dis. 2006; 8: 213-218Google Scholar, 3Neoh C.F. Snell G.I. Kotsimbos T. et al.Antifungal prophylaxis in lung transplantation—a world-wide survey.Am J Transplant. 2011; 11: 361-366Google Scholar, 4Munoz P. Valerio M. Palomo J. et al.Targeted antifungal prophylaxis in heart transplant recipients.Transplantation. 2013; 96: 664-669Google Scholar, 5Delgado A. Nailor M.D. Initial posaconazole prophylactic dosing and serum levels in heart transplant patients.Conn Med. 2012; 76: 413-415Google Scholar In the absence of existing clinical trials, the International Society for Heart and Lung Transplantation (ISHLT) Infectious Diseases Council has committed to convening an international and multidisciplinary panel of experts in the field to address the issue. The panel members are recognized leaders in the field of heart and lung transplantation and mechanical circulatory support devices (MCSDs), and were selected from established transplant centers worldwide by the chairs. The panel members approved the most relevant questions to be addressed in the areas of epidemiology, diagnosis, prophylaxis, and treatment of FIs, including therapeutic drug monitoring (TDM) of anti-fungal agents in adult and pediatric heart, lung, and MCSD patients. The panel was subsequently divided into working groups, each headed by their respective chairs, for epidemiology, diagnosis, prophylaxis, treatment, TDM, and pediatrics. A comprehensive literature search was performed by the panel chairs and was disseminated to the working groups. The working groups reviewed the existing literature to answer the identified questions based on the published evidence or, in the absence of published evidence, to provide guidance based on prevailing expert knowledge and experience. Each group reviewed, evaluated, and summarized the relevant evidence and then presented its findings at a workshop held at the annual ISHLT meeting in Montreal on April 23, 2013. The recommendations were graded according to ISHLT Standards and Guidelines Committee documents. Disagreements were resolved by iterative discussion and consensus. Subsequently, each group chair prepared an article with input from the members of the group and submitted it to the cochairs. The articles were modified based on the feedback of the cochairs. The executive summaries for each topic were generated from the articles by the cochairs and were submitted to the ISHLT Standards and Guidelines Committee. Each panel member disclosed his or her potential conflicts of interest. The panel recommendations do not include management of Pneumocystis jiroveci, Cryptococcus, and endemic mycoses in CT recipients (Table 1 and Table 2).Table 1Important Definitions Used in the DocumentTermDefinitionColonizationPresence of fungus in the respiratory secretions (sputum or bronchoalveolar lavage [BAL]) detected by the culture, polymerase chain reaction (PCR) or biomarker (galactomannan [GM]/cryptococcal antigen) in the absence of symptoms, radiologic, and endobronchial changes.6Husain S. Mooney M.L. 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: 361-374Google ScholarInvasive fungal disease (IFD)Presence of fungus in the respiratory secretions (sputum or BAL) detected by the culture, PCR, or biomarker (GM/cryptococcal antigen) in the presence of symptoms, radiologic, and endobronchial changes, or presence of histologic changes consistent with fungal invasion of the tissue.6Husain S. Mooney M.L. 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: 361-374Google ScholarUniversal anti-fungal prophylaxisRefers to an anti-fungal medication started in the post-operative period in all patients, before any post-transplant isolation of a fungal pathogen.Targeted anti-fungal prophylaxisRefers to an anti-fungal medication started in the post-operative period, before any post-transplant isolation of a fungal pathogen or serologic marker of fungus, which is prescribed only to patients deemed at higher risk for IFD (e.g., cystic fibrosis patients and those with pre-transplant fungal colonization/infection or on augmented immunosuppression).Preemptive anti-fungal therapyRefers to an anti-fungal medication started after post-transplant isolation of a fungal pathogen or serologic marker of fungus in the absence of any evidence for IFD.Attack rateRefers to the cumulative incidence of IFD over time in a colonized transplant recipient. Open table in a new tab Table 2International Society for Heart and Lung Transplantation Standards and Guidelines Committee Grading CriteriaClass IEvidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effectiveClass IIConflicting evidence and/or divergence of opinion about the usefulness/efficacy of the treatment or procedureClass IIaWeight of evidence/opinion is in favor of usefulness/efficacyClass IIbUsefulness/efficacy is less well established by evidence/opinionClass IIIEvidence or general agreement that the treatment or procedure is not useful or effective and in some cases may be harmfulLevel of evidence AData derived from multiple randomized clinical trials or meta-analysesLevel of evidence BData derived from a single randomized clinical trial or large non-randomized studiesLevel of evidence CConsensus of opinion of the experts and/or small studies, retrospective studies, registries Open table in a new tab All information on fungal colonization in lung transplant (LT) candidates has been obtained from observational studies, most of them from single centers. Therefore, confidence about the exact prevalence of fungal colonization in LT candidates is limited. The data are more robust in the cystic fibrosis (CF) population due to these patients’ ability to produce sputum. Studies have included colonization at any time pre-transplant, and there is a distinct lack of data regarding colonization rates at different times pre-transplant (e.g., little or no comparison of colonization rates in the months preceding transplant vs at the time of transplant). In addition, the frequency of sampling might influence the identification of fungal pathogens before LT. In a study examining explanted lungs, the overall prevalence was 5% (14 of 304),7Vadnerkar A. Clancy C.J. Celik U. et al.Impact of mold infections in explanted lungs on outcomes of lung transplantation.Transplantation. 2010; 89: 253-260Google Scholar whereas in studies with greater proportions of CF patients, 8% to 59% of patients were colonized with fungi, of which most of the isolates were Aspergillus species.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 11Kanj S.S. Tapson V. Davis R.D. Madden J. Browning I. Infections in patients with cystic fibrosis following lung transplantation.Chest. 1997; 112: 924-930Google Scholar The data on non-CF populations have been scarce, and studies have reported a prevalence of 0% to 52%.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar Multicenter studies with diverse geographic distributions, representative pre-transplant diagnoses, and standardized sampling techniques are needed to more accurately determine the prevalence of fungal colonization in LT candidates. Multiple studies have assessed the presence of fungal colonization in LT recipients (LTRs). Studies have focused primarily on colonization by molds, particularly Aspergillus species. Although these studies have differed, all have been case series of patients after LT.12Husain S. Paterson D.L. Studer S. et al.Voriconazole prophylaxis in lung transplant recipients.Am J Transplant. 2006; 6: 3008-3016Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 16Cahill B.C. Hibbs J.R. Savik K. et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Google Scholar, 17Cadena J. Levine D.J. Angel L.F. et al.Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness.Am J Transplant. 2009; 9: 2085-2091Google Scholar, 18Calvo V. Borro J.M. Morales P. et al.Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.Chest. 1999; 115: 1301-1304Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 20Shitrit D. Ollech J.E. Ollech A. et al.Itraconazole prophylaxis in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction.J Heart Lung Transplant. 2005; 24: 2148-2152Google Scholar, 21Dhar D. Dickson J.L. Carby M.R. Lyster H.S. Hall A.V. Banner N.R. Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy.Transpl Int. 2012; 25: 758-764Google Scholar The rates of fungal colonization ranged from 20% to 50%, and the numbers of patients in each of the series ranged from 32 to 455 patients.12Husain S. Paterson D.L. Studer S. et al.Voriconazole prophylaxis in lung transplant recipients.Am J Transplant. 2006; 6: 3008-3016Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 16Cahill B.C. Hibbs J.R. Savik K. et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Google Scholar, 17Cadena J. Levine D.J. Angel L.F. et al.Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness.Am J Transplant. 2009; 9: 2085-2091Google Scholar, 18Calvo V. Borro J.M. Morales P. et al.Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.Chest. 1999; 115: 1301-1304Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 20Shitrit D. Ollech J.E. Ollech A. et al.Itraconazole prophylaxis in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction.J Heart Lung Transplant. 2005; 24: 2148-2152Google Scholar, 21Dhar D. Dickson J.L. Carby M.R. Lyster H.S. Hall A.V. Banner N.R. Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy.Transpl Int. 2012; 25: 758-764Google Scholar Most of the larger series had rates of colonization greater than 30% and closer to 40%, suggesting that a rate of fungal colonization of 30% is likely the most accurate. In all series, the presence of CF greatly increased the rate of fungal colonization in LTRs. Patients with CF as their underlying diagnosis had rates from 42% to 76%. By contrast, the rates for non-CF patients ranged from 21% to 40%, and the rate was lowest among the non-CF patients in largest series (299 patients).7Vadnerkar A. Clancy C.J. Celik U. et al.Impact of mold infections in explanted lungs on outcomes of lung transplantation.Transplantation. 2010; 89: 253-260Google Scholar, 8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 11Kanj S.S. Tapson V. Davis R.D. Madden J. Browning I. Infections in patients with cystic fibrosis following lung transplantation.Chest. 1997; 112: 924-930Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 22Husni R.N. Gordon S.M. Longworth D.L. et al.Cytomegalovirus infection is a risk factor for invasive aspergillosis in lung transplant recipients.Clin Infect Dis. 1998; 26: 753-755Google Scholar These studies demonstrate that the presence of CF results in higher rates of post-transplant fungal colonization. In another study, the Aspergillus species were most commonly responsible for colonization.23Sole A. Morant P. Salavert M. Peman J. Morales P. Aspergillus infections in lung transplant recipients: risk factors and outcome.Clin Microbiol Infect. 2005; 11: 359-365Abstract Full Text Full Text PDF Scopus (151) Google Scholar Of all the Aspergillus species, A fumigatus was the most common (59%), followed by A flavus (35%). The incidence of invasive fungal disease (IFD) is much lower than that of fungal colonization after LT,9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar with rates ranging from 3% to 14%. The rate in the largest series was closer to the lower percentage limit (e.g., 6.6% in 1 series with 335 patients and 8.6% in a large, multicenter trial).7Vadnerkar A. Clancy C.J. Celik U. et al.Impact of mold infections in explanted lungs on outcomes of lung transplantation.Transplantation. 2010; 89: 253-260Google Scholar, 8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 11Kanj S.S. Tapson V. Davis R.D. Madden J. Browning I. Infections in patients with cystic fibrosis following lung transplantation.Chest. 1997; 112: 924-930Google Scholar, 12Husain S. Paterson D.L. Studer S. et al.Voriconazole prophylaxis in lung transplant recipients.Am J Transplant. 2006; 6: 3008-3016Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 16Cahill B.C. Hibbs J.R. Savik K. et al.Aspergillus airway colonization and invasive disease after lung transplantation.Chest. 1997; 112: 1160-1164Google Scholar, 17Cadena J. Levine D.J. Angel L.F. et al.Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness.Am J Transplant. 2009; 9: 2085-2091Google Scholar, 18Calvo V. Borro J.M. Morales P. et al.Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.Chest. 1999; 115: 1301-1304Google Scholar, 24Borro J.M. Sole A. de la Torre M. et al.Efficiency and safety of inhaled amphotericin B lipid complex (Abelcet) in the prophylaxis of invasive fungal infections following lung transplantation.Transplant Proc. 2008; 40: 3090-3093Google Scholar, 25Singh N. Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management.J Heart Lung Transplant. 2003; 22: 258-266Google Scholar, 26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar, 27Reichenspurner H. Gamberg P. Nitschke M. et al.Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis.Transplant Proc. 1997; 29: 627-628Google Scholar When the rarer but potentially severe invasive infection with Mucorales was examined, the rate was lower again, between 0.28% and 1.4%.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar, 28Silveira F.P. Husain S. Fungal infections in lung transplant recipients.Curr Opin Pulm Med. 2008; 14: 211-218Google Scholar In this setting, a pre-transplant diagnosis of CF was once again associated with an increased risk of post-transplant IFD.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar A paucity of studies have examined the incidence/prevalence of IFD after heart transplantation. The incidence in available studies has ranged from 0.12 per patient-year to 0.4 per 100 patient-years.21Dhar D. Dickson J.L. Carby M.R. Lyster H.S. Hall A.V. Banner N.R. Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy.Transpl Int. 2012; 25: 758-764Google Scholar, 27Reichenspurner H. Gamberg P. Nitschke M. et al.Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis.Transplant Proc. 1997; 29: 627-628Google Scholar A multicenter study at 15 transplant centers in the United States suggested that the cumulative incidence of IFD after heart transplantation was 3.4% during the first year.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar Candida species accounted for 49% of the infections, and Aspergillus species accounted for 23%. More than 50% of the infections occurred in the first 90 days.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar Overall, IFD after heart transplantation is rare; when it occurs, it is usually during the first year after transplant, likely at a time when immunosuppression levels are higher. The presence of another case of invasive aspergillosis (IA) in the same institution in the preceding 3 months has been identified as a risk factor for early IA after heart transplantation; therefore, it is important that centers know their own epidemiology.19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar This area requires further study. Multiple case series have addressed this question, although no well-controlled trials have been performed to date.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 13Luong M.L. Hosseini-Moghaddam S.M. Singer L.G. et al.Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.Am J Transplant. 2012; 12: 1929-1935Google Scholar, 14Mitsani D. Nguyen M.H. Shields R.K. et al.Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.Antimicrob Agents Chemother. 2012; 56: 2371-2377Google Scholar, 15Weigt S.S. Elashoff R.M. Huang C. et al.Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.Am J Transplant. 2009; 9: 1903-1911Google Scholar, 25Singh N. Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management.J Heart Lung Transplant. 2003; 22: 258-266Google Scholar, 29Egli A. Fuller J. Humar A. et al.Emergence of Aspergillus calidoustus infection in the era of posttransplantation azole prophylaxis.Transplantation. 2012; 94: 403-410Google Scholar, 30Silveira F.P. Kwak E.J. Paterson D.L. Pilewski J.M. McCurry K.R. Husain S. Post-transplant colonization with non-Aspergillus molds and risk of development of invasive fungal disease in lung transplant recipients.J Heart Lung Transplant. 2008; 27: 850-855Google Scholar These studies have included patients who have undergone heart-lung transplant, single LT, and bilateral LT, and all have demonstrated that invasive infections tend to occur during the first 6 months after transplant. Surveillance and interaction with the health care team is always more common during the first year after transplant, and thus, sampling bias might have played a role in the findings. However, immunosuppression is highest during the same time period, and patients are more frequently treated for rejection, potentially increasing their susceptibility to IFD. In a multicenter center study that assessed IFD during the first year post-transplant after solid organ transplantation (SOT), most infections occurred in the first 3 months after transplant for both lung and heart transplants. Approximately 66% occurred during that interval, with total incidences in the first year of 8.6% and 4.0% for lung and heart transplant recipients, respectively.26Pappas P.G. Alexander B.D. Andes D.R. et al.Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Google Scholar This is in contrast to a previously reported literature review where a median time to onset of IA was 3.2 months.25Singh N. Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management.J Heart Lung Transplant. 2003; 22: 258-266Google Scholar The increase in the time to onset of IA in LTRs may be attributed to the widespread use of anti-fungal prophylaxis.3Neoh C.F. Snell G.I. Kotsimbos T. et al.Antifungal prophylaxis in lung transplantation—a world-wide survey.Am J Transplant. 2011; 11: 361-366Google Scholar Another study found that invasive candidiasis (IC) occurred at 52 days (range, 0–5,727 days) in LTR and at 66.5 days (range, 2–4,645 days) in heart transplant recipients, whereas IA was noted at 504 days (range, 3–4,417 days) in LTRs and at 382 days (range, 31–1,309) in heart transplant recipients.31Neofytos D. Fishman J.A. Horn D. et al.Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.Transpl Infect Dis. 2010; 12: 220-229Google Scholar A study of heart transplant recipients reported IA which occurred during the first 3 months after transplantation (early IA) accounted for 23 cases (median, 35 days [range 19–88 days] after transplantation); in the remaining 8 cases, IA occurred a median of 125.5 days (range, 91–301 days) after transplantation (late IA).32Munoz P. Ceron I. Valerio M. et al.Invasive aspergillosis among heart transplant recipients: a 24-year perspective.J Heart Lung Transplant. 2014; 33: 278-288Google Scholar Multiple studies, mostly single-center case series and cohort studies, have addressed the risk factors for IFD after LT. There has been a paucity of studies regarding the same question in heart transplantation. The main risk factor is a pre-transplant diagnosis of CF, which appears to result in increased rates of IFD after LT.8Helmi M. Love R.B. Welter D. Cornwell R.D. Meyer K.C. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.Chest. 2003; 123: 800-808Google Scholar, 9Nunley D.R. Ohori P. Grgurich W.F. et al.Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.Chest. 1998; 114: 1321-1329Google Scholar, 10Iversen M. Burton C.M. Vand S. et al.Aspergillus infection in lung transplant patients: incidence and prognosis.Eur J Clin Microbiol Infect Dis. 2007; 26: 879-886Google Scholar, 19Tofte N. Jensen C. Tvede M. Andersen C.B. Carlsen J. Iversen M. Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.Scand J Infect Dis. 2012; 44: 835-841Google Scholar, 22Husni R.N. Gordon S.M. Longworth D.L. et al.Cytomegalovirus infection is a risk factor for invasive aspergillosis in lung transplant recipients.Clin Infect Dis. 1998; 26: 753-755Google Scholar Other important risk factors for IFD after LT include the presence of fungal colonization
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