The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Risk factors of invasive fungal infections in lung transplant recipients: A systematic review and meta-analysis

Published:October 03, 2021DOI:


      : Invasive fungal infection (IFI) remains a common complication after lung transplantation, causing significant morbidity and mortality. We have attempted to quantify systematically risk factors of IFI in lung transplant recipients.


      : Studies were retrieved from Ovid MEDLINE, Ovid Embase, Cochrane database of systematic reviews and Cochrane central register of controlled trials. All case-control and cohort studies evaluating the risk factors of IFI in adult lung transplant recipients were screened. Two researchers reviewed and assessed all studies independently. We pooled the estimated effect of each factor associated with IFI by using a random effect model.


      : Eight studies were included in the systematic review and 5 studies were eligible for the meta-analysis. Rates of IFI range from 8% to 33% in lung transplant recipients. Independent risk factors for invasive aspergillosis (IA) in lung transplantation include previous fungal colonization (odds ratio [OR] 2.44; 95% confidence interval [CI] 0.08-0.47), cytomegalovirus infection (OR 1.96; 95% CI 1.08-3.56), and single lung transplantation (OR 1.77; 95% CI 1.08-2.91). Pre-emptive antifungal therapy is a protective factor for IA in lung transplant (OR 0.2; 95% CI 0.08-0.47).


      : Cytomegalovirus infection, previous fungal colonization and single lung transplantation independently increase the risk of IA in lung transplant recipients. Pre-emptive antifungal therapy is a protective factor for IA in the lung transplant population.



      CMV (Cytomegalovirus), COPD (Chronic obstructive disease), EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group), GRADE (Grading of Recommendations Assessment, Development and Evaluation), IA (Invasive aspergillosis), IFI (Invasive fungal infection), ISHLT (International Society of Heart and Lung Transplantation), LTRs (Lung transplant recipients), QUIPS (Quality in Prognosis Study)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Heart and Lung Transplantation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hayes Jr., D
        • Ball AM
        • Mansour HM
        • Martin CA
        • Flynn JD
        Fungal infection in heart-lung transplant recipients receiving single-agent prophylaxis with itraconazole.
        Exp Clin Transplant. 2011; 9: 399-404
        • Chang A
        • Musk M
        • Lavender M
        • et al.
        Epidemiology of invasive fungal infections in lung transplant recipients in Western Australia.
        Transpl Infect Dis. 2019; 21: e13085
        • Hosseini-Moghaddam SM
        • Chaparro C
        • Luong ML
        • et al.
        The effectiveness of culture-directed preemptive anti-aspergillus treatment in lung transplant recipients at one year after transplant.
        Transplantation. 2015; 99: 2387-2393
        • Rabin AS
        • Givertz MM
        • Couper GS
        • et al.
        Risk factors for invasive fungal disease in heart transplant recipients.
        J Heart Lung Transplant. 2015; 34: 227-232
        • Tissot F
        • Pascual M
        • Hullin R
        • et al.
        Impact of targeted antifungal prophylaxis in heart transplant recipients at high risk for early invasive fungal infection.
        Transplantation. 2014; 97: 1192-1197
        • Husain S
        • Bhaskaran A
        • Rotstein C
        • et al.
        A strategy for prevention of fungal infections in lung transplantation: role of bronchoalveolar lavage fluid galactomannan and fungal culture.
        J Heart Lung Transplant. 2018; 37: 886-894
        • Pappas 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: 1101-1111
        • Hosseini-Moghaddam SM
        • Ouedraogo A
        • Naylor KL
        • et al.
        Incidence and outcomes of invasive fungal infection among solid organ transplant recipients: a population-based cohort study.
        Transpl Infect Dis. 2020; 22: e13250
        • Pennington KM
        • Yost KJ
        • Escalante P
        • Razonable RR
        • Kennedy CC.
        Antifungal prophylaxis in lung transplant: a survey of United States' transplant centers.
        Clin Transplant. 2019; 33: e13630
        • Patel TS
        • Eschenauer GA
        • Stuckey LJ
        • Carver PL.
        Antifungal prophylaxis in lung transplant recipients.
        Transplantation. 2016; 100: 1815-1826
        • Bhaskaran A
        • Mumtaz K
        • Husain S.
        Anti-aspergillus prophylaxis in lung transplantation: a systematic review and meta-analysis.
        Curr Infect Dis Rep. 2013; 15: 514-525
        • Pennington KM
        • Baqir M
        • Erwin PJ
        • Razonable RR
        • Murad MH
        • Kennedy CC.
        Antifungal prophylaxis in lung transplant recipients: a systematic review and meta-analysis.
        Transpl Infect Dis. 2020; : e13333
        • Writers AM.
        Long-term use of systemic azole antifungals can result in hepatotoxicity and other serious adverse effects.
        Drugs The Perspect. 2020; 36: 112-115
        • Hamandi B
        • Fegbeutel C
        • Silveira FP
        • et al.
        Voriconazole and squamous cell carcinoma after lung transplantation: a multicenter study.
        Am J Transplant. 2018; 18: 113-124
        • Groll AH
        • Townsend R
        • Desai A
        • et al.
        Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4.
        Transpl Infect Dis. 2017; 19
        • Egli A
        • Fuller J
        • Humar A
        • et al.
        Emergence of Aspergillus calidoustus infection in the era of posttransplantation azole prophylaxis.
        Transplantation. 2012; 94: 403-410
        • Peghin M
        • Monforte V
        • Martin-Gomez MT
        • et al.
        10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation.
        Transpl Int. 2016; 29: 51-62
        • Wilczynski NL
        • Haynes RB
        • Hedges T.
        Developing optimal search strategies for detecting clinically sound causation studies in MEDLINE.
        AMIA Annu Symp Proc. 2003; : 719-723
        • Husni 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: 753-755
        • Chong PP
        • Kennedy CC
        • Hathcock MA
        • Kremers WK
        • Razonable RR.
        Epidemiology of invasive fungal infections in lung transplant recipients on long-term azole antifungal prophylaxis.
        Clin Transplant. 2014; 29: 311-318
        • Peghin M
        • Monforte V
        • Martin-Gomez M
        • et al.
        Epidemiology of invasive respiratory disease caused by emerging non-Aspergillus molds in lung transplant recipients.
        Transpl Infect Dis. 2016; 18: 70-78
        • Sole A
        • Morant P
        • Salavert M
        • et al.
        Aspergillus infections in lung transplant recipients: risk factors and outcome.
        Clin Microbiol Infect. 2005; 11: 359-365
        • Vazquez R
        • Vazquez-Guillamet MC
        • Suarez J
        • Mooney J
        • Montoya JG
        • Dhillon GS.
        Invasive mold infections in lung and heart-lung transplant recipients: Stanford University experience.
        Transpl Infect Dis. 2015; 17: 259-266
        • Singh N
        • Suarez JF
        • Avery R
        • et al.
        Risk factors and outcomes in lung transplant recipients with nodular invasive pulmonary aspergillosis.
        J Infect. 2013; 67: 72-78
        • Echenique IA
        • Angarone MP
        • Gordon RA
        • et al.
        Invasive fungal infection after heart transplantation: a 7-year, single-center experience.
        Transpl Infect Dis. 2017; 19: e12560
        • Luong ML
        • Chaparro C
        • Stephenson A
        • et al.
        Pretransplant Aspergillus colonization of cystic fibrosis patients and the incidence of post-lung transplant invasive aspergillosis.
        Transplantation. 2014; 97: 351-357
        • Aguilar CA
        • Hamandi B
        • Fegbeutel C
        • et al.
        Clinical risk factors for invasive aspergillosis in lung transplant recipients: results of an international cohort study.
        J Heart Lung Transplant. 2018; 37: 1226-1234
        • Monforte V
        • Roman A
        • Gavalda J
        • et al.
        Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors.
        J Heart Lung Transplant. 2001; 20: 1274-1281
        • He X
        • Dai HP
        • Chen QR
        • et al.
        Pneumonia relevant to lung transplantation and pathogen distribution.
        Chin Med J (Engl). 2013; 126: 3209-3214
        • Day LJ
        • Chenoweth CE
        • Hyde KV
        • Lynch JP
        • Iannettoni M
        • Clark NM.
        Aspergillus infections after lung transplantation.
        Infect Dise Clin Pract. 2006; 14: 283-288
        • George 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: 106-113
        • Sawayama Y
        • Itonaga H
        • Fukushima T
        • et al.
        Cytomegalovirus reactivation is associated with increased mortality more than 100 days after allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma.
        Am J Hematol. 2019; 94: E143-E146
        • Atalla A
        • Garnica M
        • Maiolino A
        • Nucci M.
        Risk factors for invasive mold diseases in allogeneic hematopoietic cell transplant recipients.
        Transpl Infect Dis. 2015; 17: 7-13
        • Lopez-Medrano F
        • Fernandez-Ruiz M
        • Silva JT
        • et al.
        Multinational case-control study of risk factors for the development of late invasive pulmonary aspergillosis following kidney transplantation.
        Clin Microbiol Infect. 2018; 24: 192-198
        • Arend SM
        • Westendorp RG
        • Kroon FP
        • et al.
        Rejection treatment and cytomegalovirus infection as risk factors for Pneumocystis carinii pneumonia in renal transplant recipients.
        Clin Infect Dis. 1996; 22: 920-925
        • Hosseini-Moghaddam SM
        • Shokoohi M
        • Singh G
        • et al.
        A Multicenter case-control study of the effect of acute rejection and cytomegalovirus infection on pneumocystis pneumonia in solid organ transplant recipients.
        Clin Infect Dis. 2019; 68: 1320-1326
        • Yong MK
        • Slavin MA
        • Kontoyiannis DP.
        Invasive fungal disease and cytomegalovirus infection: is there an association?.
        Curr Opin Infect Dis. 2018; 31: 481-489
        • Pasupneti S
        • Manouvakhova O
        • Nicolls MR
        • Hsu JL.
        Aspergillus-related pulmonary diseases in lung transplantation.
        Med Mycol. 2017; 55: 96-102
        • Muhlemann K
        • Wenger C
        • Zenhausern R
        • Tauber M G
        Risk factors for invasive aspergillosis in neutropenic patients with hematologic malignancies.
        Leukemia. 2005; 19: 545-550