Fungal infections following lung transplantation
- Scott M Palmer, MD, MHS
Scott M Palmer, MD, MHS
- Professor of Medicine
- Duke University Medical Center
- Aimee Zaas, MD, MHS
Aimee Zaas, MD, MHS
- Associate Professor of Medicine
- Duke University Medical Center
- Cameron Wolfe, MBBS (Hons)
Cameron Wolfe, MBBS (Hons)
- Director Biopreparedness
- Duke Preparedness & Response Center
- Division of Infectious Diseases
- Duke University
- Section Editors
- Elbert P Trulock, MD
Elbert P Trulock, MD
- Section Editor — Lung Transplantation
- Professor of Medicine
- Washington University School of Medicine
- Kieren A Marr, MD
Kieren A Marr, MD
- Section Editor — Compromised Host Infections; Fungal Infections
- Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
Lung transplantation is an effective treatment for a wide range of advanced lung diseases. While the survival of lung transplant recipients continues to improve, outcomes after lung transplantation remain inferior to other types of solid organ transplantation . Infectious complications contribute substantially to morbidity and mortality following lung transplantation and account for up to 25 percent of all posttransplant deaths .
Fungal infections are a frequent complication in lung transplant recipients, with attack rates of 11.6 per 1000 patient-years . Aspergillus and Candida species cause the majority of fungal infections in lung transplant recipients; Cryptococcus spp, the agents of mucormycosis, endemic fungi (Histoplasma, Coccidioides, and Blastomyces spp), Scedosporium spp, Fusarium spp, and dematiaceous molds are other important causes (table 1) [3,4].
This topic reviews fungal infections in lung transplant recipients. Bacterial, viral, and mycobacterial infections in lung transplant recipients, as well as the evaluation, treatment, and prophylaxis of infection in solid organ transplant recipients, are reviewed separately. (See "Bacterial infections following lung transplantation" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients" and "Evaluation for infection before solid organ transplantation" and "Infection in the solid organ transplant recipient" and "Prophylaxis of infections in solid organ transplantation".)
RISK OF INFECTION
Lung transplant recipients are at high risk of infectious complications due to the following factors:
●The high level of immunosuppression required to prevent rejection
- Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart-lung transplant report--2005. J Heart Lung Transplant 2005; 24:956.
- Pappas PG MJ, Hajjeh, RA, and the Transplant Associated Infection Surveillance Network (TRANSNET). Prospective surveillance for invasive fungal infections (IFIs) in hematopoetic stem cell (HSCTs) and solid organ transplant (SOTs) recipients in the United States. 43rd Annual Interscience Conference of Antimicrobial Agents and Chemotherapy Chicago, IL 2003.
- Silveira FP, Husain S. Fungal infections in lung transplant recipients. Curr Opin Pulm Med 2008; 14:211.
- Shoham S. Emerging fungal infections in solid organ transplant recipients. Infect Dis Clin North Am 2013; 27:305.
- Husain S, Singh N. Bronchiolitis obliterans and lung transplantation: evidence for an infectious etiology. Semin Respir Infect 2002; 17:310.
- Weigt SS, Elashoff RM, Huang C, et al. Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome. Am J Transplant 2009; 9:1903.
- Weigt SS, Copeland CA, Derhovanessian A, et al. Colonization with small conidia Aspergillus species is associated with bronchiolitis obliterans syndrome: a two-center validation study. Am J Transplant 2013; 13:919.
- Singh 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.
- Peghin M, Monforte V, Martin-Gomez MT, et al. Epidemiology of invasive respiratory disease caused by emerging non-Aspergillus molds in lung transplant recipients. Transpl Infect Dis 2016; 18:70.
- Vazquez R, Vazquez-Guillamet MC, Suarez J, et al. Invasive mold infections in lung and heart-lung transplant recipients: Stanford University experience. Transpl Infect Dis 2015; 17:259.
- Bonnal C, Leleu C, Brugière O, et al. Relationship between Fungal Colonisation of the Respiratory Tract in Lung Transplant Recipients and Fungal Contamination of the Hospital Environment. PLoS One 2015; 10:e0144044.
- Wahidi MM, Willner DA, Snyder LD, et al. Diagnosis and outcome of early pleural space infection following lung transplantation. Chest 2009; 135:484.
- Minari A, Husni R, Avery RK, et al. The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants. Transpl Infect Dis 2002; 4:195.
- Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005; 18:44.
- Gordon SM, Avery RK. Aspergillosis in lung transplantation: incidence, risk factors, and prophylactic strategies. Transpl Infect Dis 2001; 3:161.
- Sutton DA, Sanche SE, Revankar SG, et al. In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole. J Clin Microbiol 1999; 37:2343.
- Baddley JW, Pappas PG, Smith AC, Moser SA. Epidemiology of Aspergillus terreus at a university hospital. J Clin Microbiol 2003; 41:5525.
- 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.
- Cahill BC, Hibbs JR, Savik K, et al. Aspergillus airway colonization and invasive disease after lung transplantation. Chest 1997; 112:1160.
- Helmi M, Love RB, Welter D, et al. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients. Chest 2003; 123:800.
- Avery RK. Prophylactic strategies before solid-organ transplantation. Curr Opin Infect Dis 2004; 17:353.
- Nunley DR, Ohori P, Grgurich WF, et al. Pulmonary aspergillosis in cystic fibrosis lung transplant recipients. Chest 1998; 114:1321.
- Kramer MR, Denning DW, Marshall SE, et al. Ulcerative tracheobronchitis after lung transplantation. A new form of invasive aspergillosis. Am Rev Respir Dis 1991; 144:552.
- Fernández-Ruiz M, Silva JT, San-Juan R, et al. Aspergillus tracheobronchitis: report of 8 cases and review of the literature. Medicine (Baltimore) 2012; 91:261.
- Mehrad B, Paciocco G, Martinez FJ, et al. Spectrum of Aspergillus infection in lung transplant recipients: case series and review of the literature. Chest 2001; 119:169.
- Morgan 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 Suppl 1:S49.
- Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore) 1999; 78:123.
- Horvath JA, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996; 100:171.
- Perfect JR, Cox GM, Lee JY, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infect Dis 2001; 33:1824.
- Husain S, Kwak EJ, Obman A, et al. Prospective assessment of Platelia Aspergillus galactomannan antigen for the diagnosis of invasive aspergillosis in lung transplant recipients. Am J Transplant 2004; 4:796.
- Husain S, Paterson DL, Studer SM, et al. Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients. Transplantation 2007; 83:1330.
- Luong ML, Clancy CJ, Vadnerkar A, et al. Comparison of an Aspergillus real-time polymerase chain reaction assay with galactomannan testing of bronchoalvelolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in lung transplant recipients. Clin Infect Dis 2011; 52:1218.
- Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63:e1.
- Hadjiliadis D, Howell DN, Davis RD, et al. Anastomotic infections in lung transplant recipients. Ann Transplant 2000; 5:13.
- Palmer SM, Perfect JR, Howell DN, et al. Candidal anastomotic infection in lung transplant recipients: successful treatment with a combination of systemic and inhaled antifungal agents. J Heart Lung Transplant 1998; 17:1029.
- Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347:408.
- Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016; 387:760.
- FDA news release. FDA approves new antifungal drug Cresemba. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437106.htm (Accessed on March 09, 2015).
- Singh 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.
- Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015; 162:81.
- Palmer SM, Alexander BD, Sanders LL, et al. Significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients. Transplantation 2000; 69:2360.
- Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg Infect Dis 2001; 7:375.
- Singh N, Lortholary O, Alexander BD, et al. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis 2005; 40:1756.
- Rakvit A, Meyerrose G, Vidal AM, et al. Cellulitis caused by Cryptococcus neoformans in a lung transplant recipient. J Heart Lung Transplant 2005; 24:642.
- McGuire FR, Grinnan DC, Robbins M. Mucormycosis of the bronchial anastomosis: a case of successful medical treatment and historic review. J Heart Lung Transplant 2007; 26:857.
- Manchikalapati P, Canon CL, Jhala N, Eloubeidi MA. Gastrointestinal zygomycosis complicating heart and lung transplantation in a patient with Eisenmenger's syndrome. Dig Dis Sci 2005; 50:1181.
- Miller R, Assi M, AST Infectious Diseases Community of Practice. Endemic fungal infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:250.
- Kauffman CA. Endemic mycoses after hemopoietic stem cell or solid organ transplantation. In: Transplant Infections, 2nd ed, Bowden RA, Ljungman P, Paya CV (Eds), Lippincott Williams and Wilkins, Philadelphia 2003. p.524.
- Sepkowitz KA. Opportunistic infections in patients with and patients without Acquired Immunodeficiency Syndrome. Clin Infect Dis 2002; 34:1098.
- Sepkowitz KA, Brown AE, Armstrong D. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. More patients, same risk. Arch Intern Med 1995; 155:1125.
- Gerrard JG. Pneumocystis carinii pneumonia in HIV-negative immunocompromised adults. Med J Aust 1995; 162:233.
- Radisic M, Lattes R, Chapman JF, et al. Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case-control study. Transpl Infect Dis 2003; 5:84.
- Dummer JS, Montero CG, Griffith BP, et al. Infections in heart-lung transplant recipients. Transplantation 1986; 41:725.
- Gryzan S, Paradis IL, Zeevi A, et al. Unexpectedly high incidence of Pneumocystis carinii infection after lung-heart transplantation. Implications for lung defense and allograft survival. Am Rev Respir Dis 1988; 137:1268.
- Schaenman JM. Is universal antifungal prophylaxis mandatory in lung transplant patients? Curr Opin Infect Dis 2013; 26:317.
- Neoh CF, Snell GI, Kotsimbos T, et al. Antifungal prophylaxis in lung transplantation--a world-wide survey. Am J Transplant 2011; 11:361.
- Drew RH, Dodds Ashley E, Benjamin DK Jr, et al. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients. Transplantation 2004; 77:232.
- Palmer SM, Drew RH, Whitehouse JD, et al. Safety of aerosolized amphotericin B lipid complex in lung transplant recipients. Transplantation 2001; 72:545.
- Solé A. Invasive fungal infections in lung transplantation: role of aerosolised amphotericin B. Int J Antimicrob Agents 2008; 32 Suppl 2:S161.
- Monforte V, Ussetti P, López R, et al. Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety. J Heart Lung Transplant 2009; 28:170.
- Singh N, Husain S, AST Infectious Diseases Community of Practice. Aspergillosis in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:228.
- Reichenspurner 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.
- Borro JM, Solé 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.
- Monforte V, Ussetti P, Gavaldà J, et al. Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation. J Heart Lung Transplant 2010; 29:523.
- Husain S, Paterson DL, Studer S, et al. Voriconazole prophylaxis in lung transplant recipients. Am J Transplant 2006; 6:3008.
- Gordon SM, LaRosa SP, Kalmadi S, et al. Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clin Infect Dis 1999; 28:240.
- Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc 2007; 82:1052.
- Lehto JT, Koskinen PK, Anttila VJ, et al. Bronchoscopy in the diagnosis and surveillance of respiratory infections in lung and heart-lung transplant recipients. Transpl Int 2005; 18:562.
- Martin SI, Fishman JA, AST Infectious Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:272.
- RISK OF INFECTION
- TIMELINE OF INFECTION
- EVALUATION FOR INFECTION
- Risk factors
- Clinical manifestations
- - Tracheobronchial aspergillosis
- - Pulmonary aspergillosis
- - Other sites
- - Galactomannan, beta-D-glucan, and PCR
- - Tracheobronchial aspergillosis
- - Pulmonary and disseminated aspergillosis
- OTHER FUNGAL INFECTIONS
- Endemic fungi
- Pneumocystis jirovecii
- Invasive fungal infections
- - Approach to prophylaxis
- - Efficacy
- Nebulized amphotericin B
- Pneumocystis pneumonia
- SUMMARY AND RECOMMENDATIONS
- Clinical manifestations and diagnosis
- Treatment of aspergillosis
- Antifungal prophylaxis