Invasive Aspergillosis: New Approaches against a Dangerous Fungal Infection
Posted April 03, 2007
Invasive aspergillosis is the most common filamentous fungal infection observed in immunocompromised patients and is a leading cause of fungal mortality. The December 14, 2006, symposium at the Academy brought together five leading clinical and research experts to discuss the issue.
David W. Denning of the University Of Manchester and Wythenshawe Hospital, UK, provided an overview of the three main types of aspergillosis, the culprit pathogens, and the challenges facing clinicians and researchers attempting to thwart the disease course. Kieren A. Marr of the Fred Hutchinson Cancer Research Center and University of Washington in Seattle provided an assessment of currently available Aspergillus diagnostics. Thomas J. Walsh of the National Cancer Institute reviewed of environmental interventions to curb aspergillosis and the benefits and limitations of currently available therapies. Jean-Paul Latgé of the Pasteur Institut in Paris and Gordon Brown of the University of Cape Town offered perspectives on the interaction of Aspergillus with the immune system.
The Aspergillus Website
This Web site managed by David Denning includes a wealth of both scientific and medical information, and other resources related to aspergillosis.
Clinical Perspective and Research Challenges
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Sambatakou H, Dupont B, Lode H, Denning DW. Voriconazole treatment for subacute invasive and chronic pulmonary aspergillosis. Am. J. Med. 119: 527.e17-24.
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Diagnostics: State of the Art
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Marr KA, Crippa F, Leisenring W, et al. 2004. Itraconazole versus fluconazole for antifungal prophylaxis in allogeneic HSCT patients. Blood 103: 1527-1533. Full Text
Therapy: State of the Art
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El Saleeby CM, Allison KJ, Knapp KM, et al. 2005. Discordant rise in galactomannan antigenemia in a patient with resolving Aspergillosis, renal failure, and ongoing hemodialysis. J. Clin. Microbiol. 43: 3560-3563. Full Text
Espinel-Ingroff A, Fothergill A, Ghannoum M, et al. 2005. Quality control and reference guidelines for CLSI broth microdilution susceptibility method (M 38-A document) for amphotericin B, itraconazole, posaconazole, and voriconazole. J. Clin. Microbiol. 43: 5243-5246. Full Text
Francesconi A, Kasai M, Petraitiene R, et al. 2006. Characterization and comparison of galactomannan enzyme immunoassay and quantitative real-time PCR assay for detection of Aspergillus fumigatus in bronchoalveolar lavage fluid from experimental invasive pulmonary Aspergillosis. J. Clin. Microbiol. 44: 2475-2480. Full Text
Gil-Lamaignere C, Winn RM, Simitsopoulou M, et al. 2005. Inteferon-γ and granulocyte-macrophage colony-stimulating factor augment the antifungal activity of human polymorphonuclear leukocytes against Scedosporium spp.: comparison with Aspergillus spp. Med. Mycol. 43: 253-260.
Groll AH, Lyman CA, Petraitis V, et al. 2006. Compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations. Antimicrob. Agents Chemother. 50: 3418-23. Full Text
Groll AH, Mickiene D, Petraitis V, et al. 2005. Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits. J. Antimicrob. Chemother. 56: 899-907. Full Text
Groll AH, Stergiopoulou T, Roilides E, Walsh TJ. 2005. Micafungin: pharmacology, experimental therapeutics and clinical applications. Expert. Opin. Investig. Drugs 14: 489-509.
Groll AH, Walsh TJ. 2006. Antifungal efficacy and pharmacodynamics of posaconazole in experimental models of invasive fungal infections. Mycoses 49 Suppl 1: 7-16.
Groll AH, Walsh TJ. 2005. Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev. Anti. Infect. Ther. 3: 467-487.
Hope WW, Walsh TJ, Denning DW. 2005. The invasive and saprophytic syndromes due to Aspergillus spp. Med. Mycol. 43 Suppl 1: S207-238.
Hope WW, Walsh TJ, Denning DW. 2005. Laboratory diagnosis of invasive aspergillosis.Lancet Infect. Dis. 5: 609-622.
La Via WV, Lambert JL, Pelletier MJ, et al. 2006. Measurement of amphotericin B concentration by resonant Raman spectroscopy—a novel technique that may be useful for non-invasive monitoring. Med. Mycol. 44: 169-174.
Maertens J, Raad I, Petrikkos G, et al. 2004. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin. Infect. Dis. 39: 1563-1571.
Marr KA, Balajee SA, McLaughlin L, et al. 2004. Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J. Infect. Dis. 190: 641-649.
Meletiadis J, Petraitis V, Petraitiene R, et al. 2006. Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo correlation. J. Infect. Dis. 194: 1008-18.
Morgan J, Wannemuehler KA, Marr KA, et al. 2005. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med. Mycol. 43 Suppl 1: S49-58.
O'Sullivan CE, Kasai M, Francesconi A, et al. 2003. Development and validation of a quantitative real-time PCR Assay using fluorescence resonance energy transfer (FRET) technology for detection of Aspergillus fumigatus in experimental invasive pulmonary aspergillosis. J. Clin. Microbiol. 41: 5676-5682. Full Text
Panicker J, Walsh T, Kamani N. 2006. Recurrent central nervous system blastomycosis in an immunocompetent child treated successfully with sequential liposomal amphotericin B and voriconazole. Pediatr. Infect. Dis. J. 25: 377-379.
Pannaraj PS, Walsh TJ, Baker CJ. 2005. Advances in antifungal therapy. Pediatr. Infect. Dis. J. 24: 921-922.
Peter J, Armstrong D, Lyman CA, Walsh TJ. 2005. Use of fluorescent probes to determine MICs of amphotericin B and caspofungin against Candida spp. and Aspergillus spp. J. Clin. Microbiol. 43: 3788-3792. Full Text
Petraitiene R, Petraitis V, Lyman CA, et al. 2004. Efficacy, safety, and plasma pharmacokinetics of escalating dosages of intravenously administered ravuconazole lysine phosphoester for treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob. Agents Chemother. 48: 1188-1196. Full Text
Petraitis V, Petraitiene R, Lin P, et al. 2005. Efficacy and safety of generic amphotericin B in experimental pulmonary aspergillosis. Antimicrob. Agents Chemother. 49: 1642-5, 2005. Full Text
Petraitis V, Petraitiene R, Solomon J, et al. 2006. Multidimensional volumetric imaging of pulmonary infiltrates for measuring therapeutic response to antifungal therapy in experimental invasive pulmonary aspergillosis. Antimicrob. Agents Chemother. 50: 1510-1517. Full Text
Segal BH, Kwon-Chung J, Walsh TJ, et al. 2006. Immunotherapy for fungal infections. Clin. Infect. Dis. 42: 507-515.
Segal BH, Walsh TJ. 2006. Current approaches to diagnosis and treatment of invasive aspergillosis. Am. J. Respir. Crit. Care Med. 173: 707-717.
Steinbach WJ, Benjamin DK, Kontoyiannis DP, et al. 2004. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin. Infect. Dis. 39: 192-198.
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Wiley JM, Seibel NL, Walsh TJ. 2005. Efficacy and safety of amphotericin B lipid complex in 548 children and adolescents with invasive fungal infections. Pediatr. Infect. Dis. J. 24: 167-174.
Winn RM, Gil-Lamaignere C, Roilides E, et al. 2003. Selective effects of interleukin (IL)-15 on antifungal activity and IL-8 release by polymorphonuclear leukocytes in response to hyphae of Aspergillus species. J. Infect. Dis. 188: 585-590.
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Cell Wall, Antigens, and Virulence
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Beauvais A, Maubon D, Park S, et al. 2005. Two α(1-3) glucan synthases with different functions in Aspergillus fumigatus. Appl. Environ. Microbiol. 71: 1531-1538. Full Text
Braedel S, Radsak M, Einsele H, et al. 2004. Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4. Br. J. Haematol. 125: 392-399.
Chabane S, Sarfati J, Ibrahim-Granet O, et al. 2006. Glycosylphosphatidylinositol-anchored Ecm33p influences conidial cell wall biosynthesis in Aspergillus fumigatus. Appl. Environ. Microbiol. 72: 3259-3267. Full Text
Costachel C, Coddeville B, Latgé JP, Fontaine T. 2005. Glycosylphosphatidylinositol-anchored fungal polysaccharide in Aspergillus fumigatus. J. Biol. Chem. 280: 39,835-39,842. Full Text
Dubourdeau M, Athman R, Balloy V, et al. 2006. Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway Independently of TLR2 and TLR4. J. Immunol. 177: 3994-4001.
Dubourdeau M, Athman R, Balloy V, et al. 2006. Interaction of Aspergillus fumigatus with alveolar macrophage. Med. Mycol. 44: S213-S217.
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Latgé JP, Mouyna I, Tekaia F, et al. 2005. Specific molecular features in the organization and biosynthesis of the cell wall of Aspergillus fumigatus. Med. Mycol. 43: S15-S22.
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Innate Immunity and Dectin-1
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Taylor PR, Brown GD, Reid DM, et al. 2002. The β-glucan receptor, Dectin-1, is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages. J. Immunol. 169: 3876-3882 Full Text
Willment JA, Lin HH, Reid DM, et al. 2003. Dectin-1 expression and function is enhanced on alternatively activated and GM-CSF treated macrophages and negatively regulated by IL-10, dexamethasone and LPS. J. Immunol. 171: 4569-4573. Full Text
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David W. Denning, MD
David Denning is professor of medicine and medical mycology at the University of Manchester, England, and an honorary consultant at Wythenshawe Hospital, also in Manchester. Denning's research interests include the treatment of invasive aspergillosis and the assessment of new antifungal agents. He has authored or coauthored more than 300 peer-reviewed journal articles and has coauthored an undergraduate textbook in medicine. He leads a 20-strong research group in Manchester.
Denning is a founder of the antifungal discovery and development company, F2G Ltd and the molecular diagnostic company Myconostica Ltd. He manages The Aspergillus Website. He also consults for the pharmaceutical industry with regard to antifungal drug development.
Denning earned his medical degree at Guy's Hospital, University of London, in 1980. He received clinical training in internal medicine and infectious diseases in Glasgow and London, including at the Medical Research Council (MRC) Clinical Research Center in London. He completed a fellowship in diagnostic microbiology and infectious diseases at the Santa Clara Valley Medical Center and Stanford University, California.
Kieren A. Marr, MD
Kieran Marr is professor of medicine and director of transplant infectious diseases and the ID Clinical Research Center, Oregon Health and Sciences University. Before relocation to Portland, Oregon this year, she was an associate member in the Program of Infectious Diseases and associate professor in the Department of Medicine at the University of Washington, Seattle. She runs a laboratory that focuses on immunity to pathogenic fungi, and her clinical research focuses on algorithms to prevent infection in transplant recipients. She sits on numerous advisory boards, has published more than 100 per review articles on infection in transplant recipients, and is an editor of two text books in the field.
Thomas J. Walsh, MD
Thomas Walsh is a senior investigator and chief of the Immunocompromised Host Section in the Pediatric Oncology Branch of the National Cancer Institute. He obtained his MD from the Johns Hopkins University, and received additional postdoctoral training in pathology, pharmacology, immunology, and medical mycology. Boarded in infectious diseases and oncology, Walsh directs a combined laboratory and clinical translational research program dedicated to the molecular detection, immunomodulation, and pharmacotherapeutics of invasive fungal infections in children and adults with cancer and HIV infection.
Jean-Paul Latgé, PhD
Jean-Paul Latgé is professor at the Pasteur Institute in Paris and is the head of the Aspergillus Unit and the vice-chair of the Department of Parasitology and Mycology. The focus of the research of the Aspergillus Unit is on the biology of Aspergillus fumigatus and the study of Invasive Aspergillosis, now the most important mold infection worldwide. Expertise is mainly in the fields of fungal biochemistry, molecular biology, and immunology. Main achievements concern: (1) the chemical characterization of several antigens and development of the unique commercially available kit for the detection of invasive aspergillosis; (2) the analysis of the molecular epidemiology of invasive aspergillosis with its incidence on the prophylaxis of the disease; (3) the isolation and biochemical characterization of a dozen of proteins of A. fumigatus putatively involved in pathogenesis, cloning and disruption of the encoding genes and testing for pathogenicity in a murine model of pulmonary aspergillosis; (4) the study of the host-A. fumigatus interactions with special emphasis on the analysis of the innate and specific immunity and the identification of genes differentially expressed in vivo; (5) the structural analysis of the cell wall of hyphae and conidia of A. fumigatus and the characterization of synthases and glycosyltransferases involved in the cell wall assembly of A. fumigatus; (6) the development of large-scale biological studies, including comparative genomics, proteome and transcriptome analysis.
Gordon D. Brown, PhD
Gordon Brown was born in South Africa and completed a PhD in microbiology at the University of Cape Town. In 1999, after two years with the late Albert Beyers at the University of Stellenbosch, he moved to the Sir William Dunn School of Pathology at the University of Oxford, where he spent the next five years working with Siamon Gordon on pattern recognition receptors. In 2004, he moved back to the University of Cape Town as a Wellcome Trust Senior Research fellow. His primary research interests are macrophage receptors and their role in immunity.
Marilynn Larkin is a medical editor, journalist, and videographer based in New York City. Her work has frequently appeared in, among others, The Lancet, The Lancet Infectious Diseases, and Reuters Health's professional newswire. She is currently head of publications for The Society for Biomolecular Screening.
Ms. Larkin has served as editor of clinical publications for neurologists, anesthesiologists, HIV providers, and long-term care professionals. She also developed physician/patient education videos and continuing medical education symposia for several medical communications companies.
Prior to her work for physician audiences, she covered health, nutrition, fitness, psychology, and travel for women's and general interest magazines. She is also author of five medical books for general readers, and of Reporting on Health Risk, a handbook for journalists.
In 2004, Ms. Larkin started her own fitness consulting company (www.mlarkinfitness.com), and developed a class, Posture-cize, that helps people improve their posture, increase productivity, and reduce injury.