PDF herunterladen
Semin Respir Crit Care Med 2011; 32(6): 693-702
DOI: 10.1055/s-0031-1295717
© Thieme Medical Publishers

Pulmonary Mucormycosis

Georgios Hamilos1 , George Samonis1 , Dimitrios P. Kontoyiannis2
  • 1Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece
  • 2Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
13. Dezember 2011 (online)

   Lizenzen und Reprints
Preview

ABSTRACT

Mucormycosis (formerly zygomycosis) is a life-threatening opportunistic mycosis that infects a broad range of hosts with qualitative or quantitative defects in innate immunity, including patients with severe neutropenia, recipients of corticosteroids or other immunosuppressive medications, poorly controlled diabetes mellitus, and those with iron overload states. Mucormycosis has recently emerged as breakthrough sinopulmonary infection in hematologic patients and recipients of transplantation being on antifungal prophylaxis with Aspergillus-active antifungals that lack activity against Mucorales. Unlike pulmonary aspergillosis, the prognosis and outcome of pulmonary mucormycosis have not improved significantly over the last decade, mainly because of difficulties in early diagnosis and the limited activity of current antifungal agents against Mucorales. Recent evidence suggests a critical role for iron metabolism and fungal–endothelial cell interactions in pathogenesis of mucormycosis, and holds promise for development of novel therapeutic strategies. Currently, prompt initiation of antifungal therapy with a lipid amphotericin B–based regimen, reversal of underlying host factors, and aggressive surgical approach offers the best chances for survival of patients infected with this devastating mycosis.

KEYWORDS

Mucormycosis - zygomycosis - Rhizopus - Mucor - immunocompromised - hematologic malignancy

REFERENCES

  • 1 Ribes J A, Vanover-Sams C L, Baker D J. Zygomycetes in human disease.  Clin Microbiol Rev. 2000;  13 (2) 236-301
    Suche in Google Scholar
  • 2 Roden M M, Zaoutis T E, Buchanan W L et al.. Epidemiology and outcome of zygomycosis: a review of 929 reported cases.  Clin Infect Dis. 2005;  41 (5) 634-653
    Suche in Google Scholar
  • 3 Spellberg B, Edwards Jr J, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management.  Clin Microbiol Rev. 2005;  18 (3) 556-569
    Suche in Google Scholar
  • 4 Kontoyiannis D P, Lewis R E. Invasive zygomycosis: update on pathogenesis, clinical manifestations, and management.  Infect Dis Clin North Am. 2006;  20 (3) 581-607 vi
    Suche in Google Scholar
  • 5 Hibbett D S, Binder M, Bischoff J F et al.. A higher-level phylogenetic classification of the fungi.  Mycol Res. 2007;  111 (Pt 5) 509-547
    Suche in Google Scholar
  • 6 Gomes M Z, Lewis R E, Kontoyiannis D P. Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species.  Clin Microbiol Rev. 2011;  24 (2) 411-445
    Suche in Google Scholar
  • 7 Park B J, Pappas P G, Wannemuehler K A et al.. Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001-2006.  Emerg Infect Dis. 2011;  17 (10) 1855-1864
    Suche in Google Scholar
  • 8 Kontoyiannis D P, Lionakis M S, Lewis R E et al.. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases.  J Infect Dis. 2005;  191 (8) 1350-1360
    Suche in Google Scholar
  • 9 Imhof A, Balajee S A, Fredricks D N, Englund J A, Marr K A. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole.  Clin Infect Dis. 2004;  39 (5) 743-746
    Suche in Google Scholar
  • 10 Siwek G T, Dodgson K J, de Magalhaes-Silverman M et al.. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis.  Clin Infect Dis. 2004;  39 (4) 584-587
    Suche in Google Scholar
  • 11 Marty F M, Cosimi L A, Baden L R. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants.  N Engl J Med. 2004;  350 (9) 950-952
    Suche in Google Scholar
  • 12 Trifilio S, Singhal S, Williams S et al.. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.  Bone Marrow Transplant. 2007;  40 (5) 451-456
    Suche in Google Scholar
  • 13 Chamilos G, Luna M, Lewis R E et al.. Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003).  Haematologica. 2006;  91 (7) 986-989
    Suche in Google Scholar
  • 14 Bitar D, Van Cauteren D, Lanternier F et al.. Increasing incidence of zygomycosis (mucormycosis), France, 1997–2006.  Emerg Infect Dis. 2009;  15 (9) 1395-1401
    Suche in Google Scholar
  • 15 Saegeman V, Maertens J, Meersseman W, Spriet I, Verbeken E, Lagrou K. Increasing incidence of mucormycosis in University Hospital, Belgium.  Emerg Infect Dis. 2010;  16 (9) 1456-1458
    Suche in Google Scholar
  • 16 Lamaris G A, Ben-Ami R, Lewis R E, Chamilos G, Samonis G, Kontoyiannis D P. Increased virulence of Zygomycetes organisms following exposure to voriconazole: a study involving fly and murine models of zygomycosis.  J Infect Dis. 2009;  199 (9) 1399-1406
    Suche in Google Scholar
  • 17 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 (6) 1002-1011
    Suche in Google Scholar
  • 18 Kontoyiannis D P, Wessel V C, Bodey G P, Rolston K V. Zygomycosis in the 1990s in a tertiary-care cancer center.  Clin Infect Dis. 2000;  30 (6) 851-856
    Suche in Google Scholar
  • 19 Wingard J R, Carter S L, Walsh T J Blood and Marrow Transplant Clinical Trials Network et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation.  Blood. 2010;  116 (24) 5111-5118
    Suche in Google Scholar
  • 20 Pongas G N, Lewis R E, Samonis G, Kontoyiannis D P. Voriconazole-associated zygomycosis: a significant consequence of evolving antifungal prophylaxis and immunosuppression practices?.  Clin Microbiol Infect. 2009;  15 (Suppl 5) 93-97
    Suche in Google Scholar
  • 21 Chamilos G, Ganguly D, Lande R et al.. Generation of IL-23 producing dendritic cells (DCs) by airborne fungi regulates fungal pathogenicity via the induction of T(H)-17 responses.  PLoS One. 2010;  5 (9) e12955
    Suche in Google Scholar
  • 22 Chamilos G, Lewis R E, Lamaris G, Walsh T J, Kontoyiannis D P. Zygomycetes hyphae trigger an early, robust proinflammatory response in human polymorphonuclear neutrophils through toll-like receptor 2 induction but display relative resistance to oxidative damage.  Antimicrob Agents Chemother. 2008;  52 (2) 722-724
    Suche in Google Scholar
  • 23 Gil-Lamaignere C, Simitsopoulou M, Roilides E, Maloukou A, Winn R M, Walsh T J. Interferon- gamma and granulocyte-macrophage colony-stimulating factor augment the activity of polymorphonuclear leukocytes against medically important zygomycetes.  J Infect Dis. 2005;  191 (7) 1180-1187
    Suche in Google Scholar
  • 24 Chamilos G, Lewis R E, Hu J et al.. Drosophila melanogaster as a model host to dissect the immunopathogenesis of zygomycosis.  Proc Natl Acad Sci USA. 2008;  105 (27) 9367-9372
    Suche in Google Scholar
  • 25 Boelaert J R, de Locht M, Van Cutsem J et al.. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.  J Clin Invest. 1993;  91 (5) 1979-1986
    Suche in Google Scholar
  • 26 Ibrahim A S, Gebermariam T, Fu Y et al.. The iron chelator deferasirox protects mice from mucormycosis through iron starvation.  J Clin Invest. 2007;  117 (9) 2649-2657
    Suche in Google Scholar
  • 27 Ibrahim A S, Gebremariam T, Lin L et al.. The high affinity iron permease is a key virulence factor required for Rhizopus oryzae pathogenesis.  Mol Microbiol. 2010;  77 (3) 587-604
    Suche in Google Scholar
  • 28 Artis W M, Patrusky E, Rastinejad F, Duncan Jr R L. Fungistatic mechanism of human transferrin for Rhizopus oryzae and Trichophyton mentagrophytes: alternative to simple iron deprivation.  Infect Immun. 1983;  41 (3) 1269-1278
    Suche in Google Scholar
  • 29 Artis W M, Fountain J A, Delcher H K, Jones H E. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability.  Diabetes. 1982;  31 (12) 1109-1114
    Suche in Google Scholar
  • 30 Reed C, Ibrahim A, Edwards Jr J E, Walot I, Spellberg B. Deferasirox, an iron-chelating agent, as salvage therapy for rhinocerebral mucormycosis.  Antimicrob Agents Chemother. 2006;  50 (11) 3968-3969
    Suche in Google Scholar
  • 31 Ibrahim A S, Spellberg B, Avanessian V, Fu Y, Edwards Jr J E. Rhizopus oryzae adheres to, is phagocytosed by, and damages endothelial cells in vitro.  Infect Immun. 2005;  73 (2) 778-783
    Suche in Google Scholar
  • 32 Liu M, Spellberg B, Phan Q T et al.. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice.  J Clin Invest. 2010;  120 (6) 1914-1924
    Suche in Google Scholar
  • 33 Lee F Y, Mossad S B, Adal K A. Pulmonary mucormycosis: the last 30 years.  Arch Intern Med. 1999;  159 (12) 1301-1309
    Suche in Google Scholar
  • 34 Chamilos G, Marom E M, Lewis R E, Lionakis M S, Kontoyiannis D P. Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer.  Clin Infect Dis. 2005;  41 (1) 60-66
    Suche in Google Scholar
  • 35 McAdams H P, Rosado de Christenson M, Strollo D C, Patz Jr E F. Pulmonary mucormycosis: radiologic findings in 32 cases.  AJR Am J Roentgenol. 1997;  168 (6) 1541-1548
    Suche in Google Scholar
  • 36 Wahba H, Truong M T, Lei X, Kontoyiannis D P, Marom E M. Reversed halo sign in invasive pulmonary fungal infections.  Clin Infect Dis. 2008;  46 (11) 1733-1737
    Suche in Google Scholar
  • 37 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 (1) 112-116
    Suche in Google Scholar
  • 38 Hosseini-Moghaddam S M, Husain S. Fungi and molds following lung transplantation.  Semin Respir Crit Care Med. 2010;  31 (2) 222-233
    Suche in Google Scholar
  • 39 Glazer M, Nusair S, Breuer R, Lafair J, Sherman Y, Berkman N. The role of BAL in the diagnosis of pulmonary mucormycosis.  Chest. 2000;  117 (1) 279-282
    Suche in Google Scholar
  • 40 Frater J L, Hall G S, Procop G W. Histologic features of zygomycosis: emphasis on perineural invasion and fungal morphology.  Arch Pathol Lab Med. 2001;  125 (3) 375-378
    Suche in Google Scholar
  • 41 Kontoyiannis D P, Chamilos G, Hassan S A, Lewis R E, Albert N D, Tarrand J J. Increased culture recovery of Zygomycetes under physiologic temperature conditions.  Am J Clin Pathol. 2007;  127 (2) 208-212
    Suche in Google Scholar
  • 42 Rickerts V, Mousset S, Lambrecht E et al.. Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect invasive mold infections from biopsy specimens.  Clin Infect Dis. 2007;  44 (8) 1078-1083
    Suche in Google Scholar
  • 43 Bialek R, Konrad F, Kern J et al.. PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue.  J Clin Pathol. 2005;  58 (11) 1180-1184
    Suche in Google Scholar
  • 44 Lass-Flörl C, Resch G, Nachbaur D et al.. The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients.  Clin Infect Dis. 2007;  45 (7) e101-e104
    Suche in Google Scholar
  • 45 Tedder M, Spratt J A, Anstadt M P, Hegde S S, Tedder S D, Lowe J E. Pulmonary mucormycosis: results of medical and surgical therapy.  Ann Thorac Surg. 1994;  57 (4) 1044-1050
    Suche in Google Scholar
  • 46 Chamilos G, Lewis R E, Kontoyiannis D P. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis.  Clin Infect Dis. 2008;  47 (4) 503-509
    Suche in Google Scholar
  • 47 Perfect J R. Treatment of non-Aspergillus moulds in immunocompromised patients, with amphotericin B lipid complex.  Clin Infect Dis. 2005;  40 (Suppl 6) S401-S408
    Suche in Google Scholar
  • 48 Walsh T J, Hiemenz J W, Seibel N L et al.. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases.  Clin Infect Dis. 1998;  26 (6) 1383-1396
    Suche in Google Scholar
  • 49 Walsh T J, Goodman J L, Pappas P et al.. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study.  Antimicrob Agents Chemother. 2001;  45 (12) 3487-3496
    Suche in Google Scholar
  • 50 Revankar S G, Hasan M S, Smith J W. Cure of disseminated zygomycosis with cerebral involvement using high dose liposomal amphotericin B and surgery.  Med Mycol. 2007;  45 (2) 183-185
    Suche in Google Scholar
  • 51 Cornely O A, Maertens J, Bresnik M AmBiLoad Trial Study Group et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial).  Clin Infect Dis. 2007;  44 (10) 1289-1297
    Suche in Google Scholar
  • 52 Lewis R E, Albert N D, Liao G, Hou J, Prince R A, Kontoyiannis D P. Comparative pharmacodynamics of amphotericin B lipid complex and liposomal amphotericin B in a murine model of pulmonary mucormycosis.  Antimicrob Agents Chemother. 2010;  54 (3) 1298-1304
    Suche in Google Scholar
  • 53 Safdar A, O’Brien S, Kouri I F. Efficacy and feasibility of aerosolized amphotericin B lipid complex therapy in caspofungin breakthrough pulmonary zygomycosis.  Bone Marrow Transplant. 2004;  34 (5) 467-468
    Suche in Google Scholar
  • 54 Dannaoui E, Meis J F, Loebenberg D, Verweij P E. Activity of posaconazole in treatment of experimental disseminated zygomycosis.  Antimicrob Agents Chemother. 2003;  47 (11) 3647-3650
    Suche in Google Scholar
  • 55 Dannaoui E, Meletiadis J, Mouton J W, Meis J F, Verweij P E. Eurofung Network . In vitro susceptibilities of zygomycetes to conventional and new antifungals.  J Antimicrob Chemother. 2003;  51 (1) 45-52
    Suche in Google Scholar
  • 56 Greenberg R N, Mullane K, van Burik J A et al.. Posaconazole as salvage therapy for zygomycosis.  Antimicrob Agents Chemother. 2006;  50 (1) 126-133
    Suche in Google Scholar
  • 57 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 (7) e61-e65
    Suche in Google Scholar
  • 58 Lekakis L J, Lawson A, Prante J et al.. Fatal rhizopus pneumonia in allogeneic stem cell transplant patients despite posaconazole prophylaxis: two cases and review of the literature.  Biol Blood Marrow Transplant. 2009;  15 (8) 991-995
    Suche in Google Scholar
  • 59 Ibrahim A S, Bowman J C, Avanessian V et al.. Caspofungin inhibits Rhizopus oryzae 1,3-beta-D-glucan synthase, lowers burden in brain measured by quantitative PCR, and improves survival at a low but not a high dose during murine disseminated zygomycosis.  Antimicrob Agents Chemother. 2005;  49 (2) 721-727
    Suche in Google Scholar
  • 60 Ibrahim A S, Gebremariam T, Fu Y, Edwards Jr J E, Spellberg B. Combination echinocandin-polyene treatment of murine mucormycosis.  Antimicrob Agents Chemother. 2008;  52 (4) 1556-1558
    Suche in Google Scholar
  • 61 Reed C, Bryant R, Ibrahim A S et al.. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis.  Clin Infect Dis. 2008;  47 (3) 364-371
    Suche in Google Scholar
  • 62 John B V, Chamilos G, Kontoyiannis D P. Hyperbaric oxygen as an adjunctive treatment for zygomycosis.  Clin Microbiol Infect. 2005;  11 (7) 515-517
    Suche in Google Scholar
  • 63 Grigull L, Beilken A, Schmid H et al.. Secondary prophylaxis of invasive fungal infections with combination antifungal therapy and G-CSF-mobilized granulocyte transfusions in three children with hematological malignancies.  Support Care Cancer. 2006;  14 (7) 783-786
    Suche in Google Scholar
  • 64 Ma L J, Ibrahim A S, Skory C et al.. Genomic analysis of the basal lineage fungus Rhizopus oryzae reveals a whole-genome duplication.  PLoS Genet. 2009;  5 (7) e1000549
    Suche in Google Scholar

Dimitrios P. KontoyiannisM.D. 

Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center

1515 Holcombe Blvd., Houston, TX 77030

eMail: dkontoyi@mdanderson.org