Fungi and Molds following Lung Transplantation

ABSTRACT

The landscape of fungal infections in lung transplant recipients has significantly changed over the course of time. The initial predominance of Candida species has given way to the prominence of Aspergillus species in the current era followed by other mold infections, namely, Scedosporium and Zygomycetes, which are emerging as newer pathogens. Cryptococcus neoformans is another important pathogen responsible for the morbidity in lung transplant recipients. The use of widespread antifungal prophylaxis directed against the mold infections has resulted in delayed onset of invasive aspergillosis in lung transplant recipients. In recent studies cumulative incidence rate of invasive aspergillosis was noted to be 2.4% at 12 months.

Invasive mold infections in lung transplant may present as tracheobronchitis, invasive pulmonary infections, or disseminated disease. Invasive pulmonary infections are now the most common manifestations of mold infections, followed by tracheobronchitis. Pre- or posttransplant Aspergillus colonization, along with preceding cytomegalovirus infections, hypogammaglobulinemia, and single-lung transplants are considered significant risk factors for invasive aspergillosis. Recently posttransplant colonization has been implicated in the development of bronchiolitis obliterans syndrome. The appropriate antimold prophylaxis strategy, by the use of either voriconazole or inhaled amphotericin, remains to be fully determined. Advances in the diagnosis and treatment of invasive aspergillosis have resulted in significant decreases in mortality. The risk factors for other mold infections such as Scedosporium or Zygomycetes are being elucidated. Infections with these organisms, however, carry mortality up to 80%. The current article reviews the changes in the epidemiology of invasive molds and Cryptococcus infections and other emerging fungal pathogens and highlights the controversies surrounding antifungal prophylaxis in lung transplant recipients.

KEYWORDS

Lung transplantation - Aspergillus - prophylaxis - Scedosporium

REFERENCES

• 1 Christie J D, Edwards L B, Aurora P et al.. The registry of the international society for heart and lung transplantation: twenty-sixth official adult lung and heart-lung transplantation Report-2009.  J Heart Lung Transplant. 2009;  28 1031-1049
• 2 Husain S. Unique characteristics of fungal infections in lung transplant recipients.  Clin Chest Med. 2009;  30 307-313, vii , vii
• 3 Chan K M, Allen S A. Infectious pulmonary complications in lung transplant recipients.  Semin Respir Infect. 2002;  17 291-302
• 4 Solé A, Salavert M. Fungal infections after lung transplantation.  Transplant Rev (Orlando). 2008;  22 89-104
• 5 Solé A, Salavert M. Fungal infections after lung transplantation.  Curr Opin Pulm Med. 2009;  15 243-253
• 6 Yao Z, Liao W. Fungal respiratory disease.  Curr Opin Pulm Med. 2006;  12 222-227
• 7 Grossi P, Farina C, Fiocchi R, Dalla Gasperina D. Italian Study Group of Fungal Infections in Thoracic Organ Transplant Recipients . Prevalence and outcome of invasive fungal infections in 1,963 thoracic organ transplant recipients: a multicenter retrospective study.  Transplantation. 2000;  70 112-116
• 8 Orzechowski Xavier M, Pasqualotto A C, Uchoa Sales MdaP, Bittencourt Severo C, Peixoto Camargo J J, Severo L C. Invasive pulmonary aspergillosis due to a mixed infection caused by Aspergillus flavus and Aspergillus fumigatus .  Rev Iberoam Micol. 2008;  25 176-178
• 9 Vagefi P A, Cosimi A B, Ginns L C, Kotton C N. Cutaneous Aspergillus ustus in a lung transplant recipient: emergence of a new opportunistic fungal pathogen.  J Heart Lung Transplant. 2008;  27 131-134
• 10 Morgan J, Wannemuehler K A, Marr K A 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-S58
• 11 Weigt 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 1903-1911
• 12 Helmi 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;  123 800-808
• 13 Nunley D R, Ohori P, Grgurich W F et al.. Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.  Chest. 1998;  114 1321-1329
• 14 Silveira F P, Husain S. Fungal infections in lung transplant recipients.  Curr Opin Pulm Med. 2008;  14 211-218
• 15 Husain S, Paterson D L, Studer S et al.. Voriconazole prophylaxis in lung transplant recipients.  Am J Transplant. 2006;  6 3008-3016
• 16 Singh N, Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management.  J Heart Lung Transplant. 2003;  22 258-266
• 17 Husain S, Kwak E J, 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;  4 796-802
• 18 Husain S, Paterson D L, Studer S M et al.. Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients.  Transplantation. 2007;  83 1330-1336
• 19 Nunley D R, Gal A A, Vega J D, Perlino C, Smith P, Lawrence E C. Saprophytic fungal infections and complications involving the bronchial anastomosis following human lung transplantation.  Chest. 2002;  122 1185-1191
• 20 Singh N, Paterson D L. Aspergillus infections in transplant recipients.  Clin Microbiol Rev. 2005;  18 44-69
• 21 Cahill B C, Hibbs J R, Savik K et al.. Aspergillus airway colonization and invasive disease after lung transplantation.  Chest. 1997;  112 1160-1164
• 22 Silveira F P, Husain S. Fungal infections in solid organ transplantation.  Med Mycol. 2007;  45 305-320
• 23 Westney G E, Kesten S, De Hoyos A, Chapparro C, Winton T, Maurer J R. Aspergillus infection in single and double lung transplant recipients.  Transplantation. 1996;  61 915-919
• 24 Higgins R, McNeil K, Dennis C et al.. Airway stenoses after lung transplantation: management with expanding metal stents.  J Heart Lung Transplant. 1994;  13 774-778
• 25 Husni 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;  26 753-755
• 26 De Pauw B, Walsh T J, Donnelly J P European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group 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 1813-1821
• 27 Segal B H. Aspergillosis.  N Engl J Med. 2009;  360 1870-1884
• 28 Pfeiffer C D, Fine J P, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis.  Clin Infect Dis. 2006;  42 1417-1427
• 29 Husain S, Clancy C J, Nguyen M H et al.. Performance characteristics of the platelia Aspergillus enzyme immunoassay for detection of Aspergillus galactomannan antigen in bronchoalveolar lavage fluid.  Clin Vaccine Immunol. 2008;  15 1760-1763
• 30 Ostrosky-Zeichner L, Alexander B D, Kett D H et al.. Multicenter clinical evaluation of the (1—>3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans.  Clin Infect Dis. 2005;  41 654-659
• 31 Walsh T J, Anaissie E J, Denning D W Infectious Diseases Society of America et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America.  Clin Infect Dis. 2008;  46 327-360
• 32 Singh N, Limaye A P, 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;  81 320-326
• 33 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;  29 627-628
• 34 Calvo V, Borro J M, Morales P Valencia Lung Transplant Group et al. Antifungal prophylaxis during the early postoperative period of lung transplantation.  Chest. 1999;  115 1301-1304
• 35 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
• 36 Monforte V, Roman A, Gavalda J et al.. Nebulized liposomal amphotericin B (n-LAB) prophylaxis for Aspergillus infection in lung transplantation (LT): pharmacokinetics, safety and efficacy.  J Heart Lung Transplant. 2009;  24 S108-S109
• 37 Minari A, Husni R, Avery R K et al.. The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants.  Transpl Infect Dis. 2002;  4 195-200
• 38 Drew R H, Dodds Ashley E, Benjamin Jr D K, Duane Davis R, Palmer S M, Perfect J R. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients.  Transplantation. 2004;  77 232-237
• 39 Borro J M, 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 3090-3093
• 40 Hamacher J, Spiliopoulos A, Kurt A M, Nicod L P. Geneva Lung Transplantation Group . Pre-emptive therapy with azoles in lung transplant patients.  Eur Respir J. 1999;  13 180-186
• 41 Cadena 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 2085-2091
• 42 Palmer S M, Drew R H, Whitehouse J D et al.. Safety of aerosolized amphotericin B lipid complex in lung transplant recipients.  Transplantation. 2001;  72 545-548
• 43 Corcoran T E, Venkataramanan R, Mihelc K M et al.. Aerosol deposition of lipid complex amphotericin-B (Abelcet) in lung transplant recipients.  Am J Transplant. 2006;  6 2765-2773
• 44 Maurer J R, Tullis D E, Grossman R F, Vellend H, Winton T L, Patterson G A. Infectious complications following isolated lung transplantation.  Chest. 1992;  101 1056-1059
• 45 Bassetti M, Righi E, Costa A et al.. Epidemiological trends in nosocomial candidemia in intensive care.  BMC Infect Dis. 2006;  6 21
• 46 Singh N. Antifungal prophylaxis for solid organ transplant recipients: seeking clarity amidst controversy.  Clin Infect Dis. 2000;  31 545-553
• 47 Zenati M, Dowling R D, Dummer J S et al.. Influence of the donor lung on development of early infections in lung transplant recipients.  J Heart Transplant. 1990;  9 502-508, discussion 508–509
• 48 Danziger-Isakov L A, Worley S, Arrigain S et al.. Increased mortality after pulmonary fungal infection within the first year after pediatric lung transplantation.  J Heart Lung Transplant. 2008;  27 655-661
• 49 Speich R, van der Bij W. Epidemiology and management of infections after lung transplantation.  Clin Infect Dis. 2001;  33(Suppl 1) S58-S65
• 50 Hadjiliadis D, Howell D N, Davis R D et al.. Anastomotic infections in lung transplant recipients.  Ann Transplant. 2000;  5 13-19
• 51 Park K Y, Park C H. Candida infection in a stent inserted for tracheal stenosis after heart lung transplantation.  Ann Thorac Surg. 2005;  79 1054-1056
• 52 Wahidi M M, Willner D A, Snyder L D, Hardison J L, Chia J Y, Palmer S M. Diagnosis and outcome of early pleural space infection following lung transplantation.  Chest. 2009;  135 484-491
• 53 van Hal S J, Stark D, Harkness J, Marriott D. Candida dubliniensis meningitis as delayed sequela of treated C. dubliniensis fungemia.  Emerg Infect Dis. 2008;  14 327-329
• 54 Moudgal V, Little T, Boikov D, Vazquez J A. Multiechinocandin- and multiazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis.  Antimicrob Agents Chemother. 2005;  49 767-769
• 55 Saag M S, Graybill R J, Larsen R A Infectious Diseases Society of America et al. Practice guidelines for the management of cryptococcal disease.  Clin Infect Dis. 2000;  30 710-718
• 56 Husain S, Wagener M M, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome.  Emerg Infect Dis. 2001;  7 375-381
• 57 Kanj S S, Welty-Wolf K, Madden J et al.. Fungal infections in lung and heart-lung transplant recipients: report of 9 cases and review of the literature.  Medicine (Baltimore). 1996;  75 142-156
• 58 Singh N, Alexander B D, Lortholary O et al.. Pulmonary cryptococcosis in solid organ transplant recipients: clinical relevance of serum cryptococcal antigen.  Clin Infect Dis. 2008;  46 e12-e18
• 59 Singh N, Lortholary O, Dromer F Cryptococcal Collaborative Transplant Study Group et al. Central nervous system cryptococcosis in solid organ transplant recipients: clinical relevance of abnormal neuroimaging findings.  Transplantation. 2008;  86 647-651
• 60 Singh N, Dromer F, Perfect J R, Lortholary O. Cryptococcosis in solid organ transplant recipients: current state of the science.  Clin Infect Dis. 2008;  47 1321-1327
• 61 Berenguer J, Rodríguez-Tudela J L, Richard C Scedosporium Prolificans Spanish Study Group et al. Deep infections caused by Scedosporium prolificans: a report on 16 cases in Spain and a review of the literature.  Medicine (Baltimore). 1997;  76 256-265
• 62 Guerrero A, Torres P, Duran M T, Ruiz-Díez B, Rosales M, Rodriguez-Tudela J L. Airborne outbreak of nosocomial Scedosporium prolificans infection.  Lancet. 2001;  357 1267-1268
• 63 Alvarez M, Lopez Ponga B, Rayon C et al.. Nosocomial outbreak caused by Scedosporium prolificans (inflatum): four fatal cases in leukemic patients.  J Clin Microbiol. 1995;  33 3290-3295
• 64 Husain S, Muñoz P, Forrest G et al.. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome.  Clin Infect Dis. 2005;  40 89-99
• 65 Musk M, Chambers D, Chin W, Murray R, Gabbay E. Successful treatment of disseminated Scedosporium infection in 2 lung transplant recipients: review of the literature and recommendations for management.  J Heart Lung Transplant. 2006;  25 1268-1272
• 66 Raj R, Frost A E. Scedosporium apiospermum fungemia in a lung transplant recipient.  Chest. 2002;  121 1714-1716
• 67 Tamm M, Malouf M, Glanville A. Pulmonary Scedosporium infection following lung transplantation.  Transpl Infect Dis. 2001;  3 189-194
• 68 Martino P, Gastaldi R, Raccah R, Girmenia C. Clinical patterns of Fusarium infections in immunocompromised patients.  J Infect. 1994;  28(Suppl 1) 7-15
• 69 Nucci M, Anaissie E. Fusarium infections in immunocompromised patients.  Clin Microbiol Rev. 2007;  20 695-704
• 70 Sampathkumar P, Paya C V. Fusarium infection after solid-organ transplantation.  Clin Infect Dis. 2001;  32 1237-1240
• 71 Guinvarc'h A, Guilbert L, Marmorat-Khuong A et al.. Disseminated Fusarium solani infection with endocarditis in a lung transplant recipient.  Mycoses. 1998;  41 59-61
• 72 Arney K L, Tiernan R, Judson M A. Primary pulmonary involvement of Fusarium solani in a lung transplant recipient.  Chest. 1997;  112 1128-1130
• 73 Singh N, Aguado J M, Bonatti H et al.. Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome.  J Infect Dis. 2009;  200 1002-1011
• 74 Mantadakis E, Samonis G. Clinical presentation of zygomycosis.  Clin Microbiol Infect. 2009;  15(Suppl 5) 15-20
• 75 Sun H Y, Aguado J M, Bonatti H Zygomycosis Transplant Study Group et al. Pulmonary zygomycosis in solid organ transplant recipients in the current era.  Am J Transplant. 2009;  9 2166-2171
• 76 Almyroudis N G, Sutton D A, Linden P, Rinaldi M G, Fung J, Kusne S. Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature.  Am J Transplant. 2006;  6 2365-2374
• 77 Spellberg B, Walsh T J, Kontoyiannis D P, Edwards Jr J, Ibrahim A S. Recent advances in the management of mucormycosis: from bench to bedside.  Clin Infect Dis. 2009;  48 1743-1751
• 78 van Burik J A, Hare R S, Solomon H F, Corrado M L, Kontoyiannis D P. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases.  Clin Infect Dis. 2006;  42 e61-e65
• 79 Spellberg B, Andes D, Perez M et al.. Safety and outcomes of open-label deferasirox iron chelation therapy for mucormycosis.  Antimicrob Agents Chemother. 2009;  53 3122-3125