Invasive Pulmonary Aspergillosis

Invasive pulmonary aspergillosis (IPA) is the most common fungal pulmonary infection in severely immunocompromised patients. Aspergillus species are commonly isolated from the soil, plant debris, and the indoor environment, including the hospital. Phagocytosis is the main host defense against Aspergillus conidia and hyphae. The diagnosis of IPA is based on clinical, radiological, and mycological data. Clinical signs have a low specificity. The most typical computed tomographic (CT) findings are nodules with or without the halo sign or the air crescent sign. Sensitivity of microscopy and culture of noninvasive collected samples is low. Galactomannan and nucleic acid detection in serum or in bronchoalveolar lavage (BAL) fluid help to confirm the diagnosis. Crude mortality is high and strongly correlated with the underlying condition, stage of the underlying disease, and extension of the aspergillosis. Optimal therapeutic strategies include the prevention of contamination in patients at high risk, early initiation of antifungal therapy, surgery in some instances, and, importantly, treatment of the underlying condition to restore whenever possible a certain degree of immunocompetence. Voriconazole has demonstrated better efficacy and safety than amphotericin B deoxycholate. The improved survival observed with voriconazole makes it a new reference for the first-line therapy of IA. Lipid formulations of amphotericin B, caspofungin, micafungin, and posaconazole are other therapeutic options in the event of failure of or contraindication to voriconazole. The main indication for surgery is prevention of severe hemoptysis when the lesion is adjacent to a large vessel.

KEYWORDS

Aspergillus - pulmonary infection - amphotericin B - voriconazole - caspofungin - itraconazole - leukemia - hematopoietic stem cell transplantation - galactomannan - chest CT scan

REFERENCES

• 1 Cornet M, Fleury L, Maslo C et al.. Epidemiology of IA in France: a six-year multicentric survey in the Greater Paris area.  J Hosp Infect. 2002;  51 288-296
• 2 Dasbach E J, Davies G M, Teutsch S M. Burden of aspergillosis-related hospitalizations in the United States.  Clin Infect Dis. 2000;  31 1524-1528
• 3 Chandrasekar P H, Weinmann A, Shearer C. Autopsy-identified infections among bone marrow transplant recipients: a clinico-pathologic study of 56 patients. Bone Marrow Transplantation Team.  Bone Marrow Transplant. 1995;  16 675-681
• 4 Ascioglu S, Rex J H, de Pauw B et al.. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus.  Clin Infect Dis. 2002;  34 7-14
• 5 Faure O, Fricker-Hidalgo H, Lebeau B et al.. Eight-year surveillance of environmental fungal contamination in hospital operating rooms and haematological units.  J Hosp Infect. 2002;  50 155-160
• 6 Lass-Florl C, Rath P, Niederwieser D et al.. Aspergillus terreus infections in haematological malignancies: molecular epidemiology suggests association with in-hospital plants.  J Hosp Infect. 2000;  46 31-35
• 7 Burwen D R, Lasker B A, Rao N et al.. IA outbreak on a hematology-oncology ward.  Infect Control Hosp Epidemiol. 2001;  22 45-48
• 8 Loo V G, Bertrand C, Dixon C et al.. Control of construction-associated nosocomial aspergillosis in an antiquated hematology unit.  Infect Control Hosp Epidemiol. 1996;  17 360-364
• 9 Denning D W. IA.  Clin Infect Dis. 1998;  26 781-803
• 10 Anaissie E J, Penzak S R, Dignani M C. The hospital water supply as a source of nosocomial infections: a plea for action.  Arch Intern Med. 2002;  162 1483-1492
• 11 Iwen P C, Rupp M E, Langnas A N et al.. Invasive pulmonary aspergillosis due to Aspergillus terreus: 12-year experience and review of the literature.  Clin Infect Dis. 1998;  26 1092-1097
• 12 Grossi P, Farina C, Fiocchi R et al.. Prevalence and outcome of invasive fungal infections in 1,963 thoracic organ transplant recipients: a multicenter retrospective study. Italian Study Group of Fungal Infections in Thoracic Organ Transplant Recipients.  Transplantation. 2000;  70 112-116
• 13 Latge J P. Aspergillus fumigatus and aspergillosis.  Clin Microbiol Rev. 1999;  12 310-350
• 14 Philippe B, Ibrahim-Granet O, Prevost M C et al.. Killing of Aspergillus fumigatus by alveolar macrophages is mediated by reactive oxidant intermediates.  Infect Immun. 2003;  71 3034-3042
• 15 Hebart H, Bollinger C, Fisch P et al.. Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies.  Blood. 2002;  100 4521-4528
• 16 Gerson S L, Talbot G H, Hurwitz S et al.. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia.  Ann Intern Med. 1984;  100 345-351
• 17 Agusti C, Rano A, Filella X et al.. Pulmonary infiltrates in patients receiving long-term glucocorticoid treatment: etiology, prognostic factors, and associated inflammatory response.  Chest. 2003;  123 488-498
• 18 Wald A, Leisenring W, van Burik J A et al.. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation.  J Infect Dis. 1997;  175 1459-1466
• 19 Dimopoulos G, Piagnerelli M, Berre J et al.. Disseminated aspergillosis in intensive care unit patients: an autopsy study.  J Chemother. 2003;  15 71-75
• 20 Rello J, Esandi M E, Mariscal D et al.. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: report of eight cases and review.  Clin Infect Dis. 1998;  26 1473-1475
• 21 Singh N, Arnow P M, Bonham A et al.. IA in liver transplant recipients in the 1990s.  Transplantation. 1997;  64 716-720
• 22 Allam M F, Del Castillo A S, Diaz-Molina C et al.. Invasive pulmonary aspergillosis: identification of risk factors.  Scand J Infect Dis. 2002;  34 819-822
• 23 Lin S J, Schranz J, Teutsch S M. Aspergillosis case-fatality rate: systematic review of the literature.  Clin Infect Dis. 2001;  32 358-366
• 24 Martino R, Lopez R, Sureda A et al.. Risk of reactivation of a recent invasive fungal infection in patients with hematological malignancies undergoing further intensive chemo-radiotherapy: a single-center experience and review of the literature.  Haematologica. 1997;  82 297-304
• 25 Offner F, Cordonnier C, Ljungman P et al.. Impact of previous aspergillosis on the outcome of bone marrow transplantation.  Clin Infect Dis. 1998;  26 1098-1103
• 26 Marr K A, Carter R A, Boeckh M et al.. IA in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors.  Blood. 2002;  100 4358-4366
• 27 Patterson J E, Peters J, Calhoon J H et al.. Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients.  Transpl Infect Dis. 2000;  2 22-28
• 28 Mehrad B, Paciocco G, Martinez F J et al.. Spectrum of Aspergillus infection in lung transplant recipients: case series and review of the literature.  Chest. 2001;  119 169-175
• 29 Minari A, Husni R, Avery R K et al.. The incidence of IA among solid organ transplant recipients and implications for prophylaxis in lung transplants.  Transpl Infect Dis. 2002;  4 195-200
• 30 Gordon S M, Avery R K. Aspergillosis in lung transplantation: incidence, risk factors, and prophylactic strategies.  Transpl Infect Dis. 2001;  3 161-167
• 31 Cahill B C, Hibbs J R, Savik K et al.. Aspergillus airway colonization and invasive disease after lung transplantation.  Chest. 1997;  112 1160-1164
• 32 Fortun J, Martin-Davila P, Moreno S et al.. Risk factors for IA in liver transplant recipients.  Liver Transpl. 2002;  8 1065-1070
• 33 Singh N, Avery R K, Munoz P et al.. Trends in risk profiles for and mortality associated with IA among liver transplant recipients.  Clin Infect Dis. 2003;  36 46-52
• 34 Panackal A A, Dahlman A, Keil K T et al.. Outbreak of IA among renal transplant recipients.  Transplantation. 2003;  75 1050-1053
• 35 Groll A H, Kurz M, Schneider W et al.. Five-year-survey of IA in a paediatric cancer centre: epidemiology, management and long-term survival.  Mycoses. 1999;  42 431-442
• 36 Denning D W, Marinus A, Cohen J et al.. An EORTC multicentre prospective survey of IA in haematological patients: diagnosis and therapeutic outcome. EORTC Invasive Fungal Infections Cooperative Group.  J Infect. 1998;  37 173-180
• 37 Lortholary O, Ascioglu S, Moreau P et al.. IA as an opportunistic infection in nonallografted patients with multiple myeloma: a European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the Intergroupe Francais du Myelome.  Clin Infect Dis. 2000;  30 41-46
• 38 Shetty D, Giri N, Gonzalez C E et al.. IA in human immunodeficiency virus-infected children.  Pediatr Infect Dis J. 1997;  16 216-221
• 39 Wallace J M, Lim R, Browdy B L et al.. Risk factors and outcomes associated with identification of Aspergillus in respiratory specimens from persons with HIV disease. Pulmonary Complications of HIV Infection Study Group.  Chest. 1998;  114 131-137
• 40 Mylonakis E, Barlam T F, Flanigan T et al.. Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases.  Chest. 1998;  114 251-262
• 41 Mouy R, Veber F, Blanche S et al.. Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease.  J Pediatr. 1994;  125 998-1003
• 42 Chudwin D S, Wara D W, Cowan M J et al.. Aspergillus pneumonia in chronic granulomatous disease: recurrence and long-term outcome.  Acta Paediatr Scand. 1982;  71 915-917
• 43 Lundin J, Hagberg H, Repp R et al.. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome.  Blood. 2003;  101 4267-4272
• 44 Kim W U, Kim S I, Yoo W H et al.. Adult respiratory distress syndrome in systemic lupus erythematosus: causes and prognostic factors: a single center, retrospective study.  Lupus. 1999;  8 552-557
• 45 Garrett D O, Jochimsen E, Jarvis W. Invasive Aspergillus spp. infections in rheumatology patients.  J Rheumatol. 1999;  26 146-149
• 46 Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy.  N Engl J Med. 2001;  344 1099-1100
• 47 De Rosa F G, Shaz D, Campagna A C et al.. Invasive pulmonary aspergillosis soon after therapy with infliximab, a tumor necrosis factor-alpha-neutralizing antibody: a possible healthcare-associated case?.  Infect Control Hosp Epidemiol. 2003;  24 477-482
• 48 Karim M, Alam M, Shah A A et al.. Chronic IA in apparently immunocompetent hosts.  Clin Infect Dis. 1997;  24 723-733
• 49 Patterson T F, Kirkpatrick W R, White M et al.. IA: disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group.  Medicine (Baltimore). 2000;  79 250-260
• 50 Brenier-Pinchart M P, Lebeau B, Devouassoux G et al.. Aspergillus and lung transplant recipients: a mycologic and molecular epidemiologic study.  J Heart Lung Transplant. 1998;  17 972-979
• 51 Helmi M, Love R B, 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;  123 800-808
• 52 Subira M, Martino R, Rovira M et al.. Clinical applicability of the new EORTC/MSG classification for invasive pulmonary aspergillosis in patients with hematological malignancies and autopsy-confirmed IA.  Ann Hematol. 2003;  82 80-82
• 53 Hauggaard A, Ellis M, Ekelund L. Early chest radiography and CT in the diagnosis, management and outcome of invasive pulmonary aspergillosis.  Acta Radiol. 2002;  43 292-298
• 54 Greene R E, Schlamm H T, Stark P et al.. Radiological findings in acute invasive pulmonary aspergillosis: utility and reliability of halo sign and air-crescent sign for diagnosis and treatment of IPA in high-risk patients. Proceedings of the 13th European Congress of Clinical Microbiology and Infectious Diseases May 10-13, 2003 Glasgow, Scotland;
• 55 Herbrecht R, Denning D W, Patterson T F et al.. Voriconazole versus amphotericin B for primary therapy of IA.  N Engl J Med. 2002;  347 408-415
• 56 von Eiff M, Roos N, Schulten R et al.. Pulmonary aspergillosis: early diagnosis improves survival.  Respiration. 1995;  62 341-347
• 57 Westney G E, Kesten S, De Hoyos A et al.. Aspergillus infection in single and double lung transplant recipients.  Transplantation. 1996;  61 915-919
• 58 Caillot D, Casasnovas O, Bernard A et al.. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery.  J Clin Oncol. 1997;  15 139-147
• 59 Brown M J, Worthy S A, Flint J D et al.. IA in the immunocompromised host: utility of computed tomography and bronchoalveolar lavage.  Clin Radiol. 1998;  53 255-257
• 60 Burt M E, Flye M W, Webber B L et al.. Prospective evaluation of aspiration needle, cutting needle, transbronchial, and open lung biopsy in patients with pulmonary infiltrates.  Ann Thorac Surg. 1981;  32 146-153
• 61 Pagano L, Girmenia C, Mele L et al.. Infections caused by filamentous fungi in patients with hematologic malignancies: a report of 391 cases by GIMEMA Infection Program.  Haematologica. 2001;  86 862-870
• 62 Andreas S, Heindl S, Wattky C et al.. Diagnosis of pulmonary aspergillosis using optical brighteners.  Eur Respir J. 2000;  15 407-411
• 63 Kontoyiannis D P, Sumoza D, Tarrand J et al.. Significance of aspergillemia in patients with cancer: a 10-year study.  Clin Infect Dis. 2000;  31 188-189
• 64 Girmenia C, Nucci M, Martino P. Clinical significance of Aspergillus fungaemia in patients with haematological malignancies and IA.  Br J Haematol. 2001;  114 93-98
• 65 Maertens J, Verhaegen J, Demuynck H et al.. Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for IA.  J Clin Microbiol. 1999;  37 3223-3228
• 66 Maertens J, Verhaegen J, Lagrou K et al.. Screening for circulating galactomannan as a noninvasive diagnostic tool for IA in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation.  Blood. 2001;  97 1604-1610
• 67 Sulahian A, Tabouret M, Ribaud P et al.. Comparison of an enzyme immunoassay and latex agglutination test for detection of galactomannan in the diagnosis of IA.  Eur J Clin Microbiol Infect Dis. 1996;  15 139-145
• 68 Verweij P E, Stynen D, Rijs A J et al.. Sandwich enzyme-linked immunosorbent assay compared with Pastorex latex agglutination test for diagnosing IA in immunocompromised patients.  J Clin Microbiol. 1995;  33 1912-1914
• 69 Herbrecht R, Letscher-Bru V, Oprea C et al.. Aspergillus galactomannan detection in the diagnosis of IA in cancer patients.  J Clin Oncol. 2002;  20 1898-1906
• 70 Siemann M, Koch-Dorfler M, Gaude M. False-positive results in premature infants with the Platelia Aspergillus sandwich enzyme-linked immunosorbent assay.  Mycoses. 1998;  41 373-377
• 71 Gangneux J P, Lavarde D, Bretagne S et al.. Transient Aspergillus antigenaemia: think of milk.  Lancet. 2002;  359 1251
• 72 Ansorg R, van den Boom R, Rath P M. Detection of Aspergillus galactomannan antigen in foods and antibiotics.  Mycoses. 1997;  40 353-357
• 73 Becker M J, Lugtenburg E J, Cornelissen J J et al.. Galactomannan detection in computerized tomography-based broncho-alveolar lavage fluid and serum in haematological patients at risk for invasive pulmonary aspergillosis.  Br J Haematol. 2003;  121 448-457
• 74 Bretagne S, Costa J M, Marmorat-Khuong A et al.. Detection of Aspergillus species DNA in bronchoalveolar lavage samples by competitive PCR.  J Clin Microbiol. 1995;  33 1164-1168
• 75 Raad I, Hanna H, Huaringa A et al.. Diagnosis of invasive pulmonary aspergillosis using polymerase chain reaction-based detection of Aspergillus in BAL.  Chest. 2002;  121 1171-1176
• 76 Spiess B, Buchheidt D, Baust C et al.. Development of a LightCycler PCR assay for detection and quantification of Aspergillus fumigatus DNA in clinical samples from neutropenic patients.  J Clin Microbiol. 2003;  41 1811-1818
• 77 Kami M, Fukui T, Ogawa S et al.. Use of real-time PCR on blood samples for diagnosis of IA.  Clin Infect Dis. 2001;  33 1504-1512
• 78 Einsele H, Hebart H, Roller G et al.. Detection and identification of fungal pathogens in blood by using molecular probes.  J Clin Microbiol. 1997;  35 1353-1360
• 79 Hebart H, Loffler J, Meisner C et al.. Early detection of Aspergillus infection after allogeneic stem cell transplantation by polymerase chain reaction screening.  J Infect Dis. 2000;  181 1713-1719
• 80 Hebart H, Loffler J, Reitze H et al.. Prospective screening by a panfungal polymerase chain reaction assay in patients at risk for fungal infections: implications for the management of febrile neutropenia.  Br J Haematol. 2000;  111 635-640
• 81 Einsele H, Quabeck K, Muller K D et al.. Prediction of invasive pulmonary aspergillosis from colonisation of lower respiratory tract before marrow transplantation.  Lancet. 1998;  352 1443
• 82 Nash G, Irvine R, Kerschmann R L et al.. Pulmonary aspergillosis in acquired immune deficiency syndrome: autopsy study of an emerging pulmonary complication of human immunodeficiency virus infection.  Hum Pathol. 1997;  28 1268-1275
• 83 Franquet T, Serrano F, Gimenez A et al.. Necrotizing aspergillosis of large airways: CT findings in eight patients.  J Comput Assist Tomogr. 2002;  26 342-345
• 84 Denning D W. Therapeutic outcome in IA.  Clin Infect Dis. 1996;  23 608-615
• 85 Boutboul F, Alberti C, Leblanc T et al.. IA in allogeneic stem cell transplant recipients: increasing antigenemia is associated with progressive disease.  Clin Infect Dis. 2002;  34 939-943
• 86 Groll A H, Shah P M, Mentzel C et al.. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.  J Infect. 1996;  33 23-32
• 87 Ribaud P, Chastang C, Latge J P et al.. Survival and prognostic factors of IA after allogeneic bone marrow transplantation.  Clin Infect Dis. 1999;  28 322-330
• 88 Yeghen T, Kibbler C C, Prentice H G et al.. Management of invasive pulmonary aspergillosis in hematology patients: a review of 87 consecutive cases at a single institution.  Clin Infect Dis. 2000;  31 859-868
• 89 Subira M, Martino R, Franquet T et al.. Invasive pulmonary aspergillosis in patients with hematologic malignancies: survival and prognostic factors.  Haematologica. 2002;  87 528-534
• 90 Caillot D, Couaillier J F, Bernard A et al.. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia.  J Clin Oncol. 2001;  19 253-259
• 91 Withington S, Chambers S T, Beard M E et al.. IA in severely neutropenic patients over 18 years: impact of intranasal amphotericin B and HEPA filtration.  J Hosp Infect. 1998;  38 11-18
• 92 Oren I, Haddad N, Finkelstein R et al.. Invasive pulmonary aspergillosis in neutropenic patients during hospital construction: before and after chemoprophylaxis and institution of HEPA filters.  Am J Hematol. 2001;  66 257-262
• 93 Cornet M, Levy V, Fleury L et al.. Efficacy of prevention by high-efficiency particulate air filtration or laminar airflow against Aspergillus airborne contamination during hospital renovation.  Infect Control Hosp Epidemiol. 1999;  20 508-513
• 94 Morgenstern G R, Prentice A G, Prentice H G et al.. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. U.K. Multicentre Antifungal Prophylaxis Study Group.  Br J Haematol. 1999;  105 901-911
• 95 Kibbler C C. Antifungal prophylaxis with itraconazole oral solution in neutropenic patients.  Mycoses. 1999;  42(suppl 2) S121-S124
• 96 Nucci M, Biasoli I, Akiti T et al.. A double-blind, randomized, placebo-controlled trial of itraconazole capsules as antifungal prophylaxis for neutropenic patients.  Clin Infect Dis. 2000;  30 300-305
• 97 Herbrecht R, Neuville S, Letscher-Bru V et al.. Fungal infections in patients with neutropenia: challenges in prophylaxis and treatment.  Drugs Aging. 2000;  17 339-351
• 98 Harousseau J L, Dekker A W, Stamatoullas-Bastard A et al.. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B.  Antimicrob Agents Chemother. 2000;  44 1887-1893
• 99 Glasmacher A, Hahn A, Molitor E et al.. Itraconazole for antifungal prophylaxis in neutropenic patients: a meta-analysis of 2181 patients. American Society for Microbiology, Washington DC. Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract J-681 p. 378 2001 Chicago, IL;
• 100 Tollemar J, Ringden O, Andersson S et al.. Randomized double-blind study of liposomal amphotericin B (Ambisome) prophylaxis of invasive fungal infections in bone marrow transplant recipients.  Bone Marrow Transplant. 1993;  12 577-582
• 101 Schwartz S, Behre G, Heinemann V et al.. Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial.  Blood. 1999;  93 3654-3661
• 102 Tiphine M, Letscher-Bru V, Herbrecht R. Amphotericin B and its new formulations: pharmacologic characteristics, clinical efficacy, and tolerability.  Transpl Infect Dis. 1999;  1 273-283
• 103 Bowden R, Chandrasekar P, White M H et al.. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of IA in immunocompromised patients.  Clin Infect Dis. 2002;  35 359-366
• 104 Wingard J R, Kubilis P, Lee L et al.. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis.  Clin Infect Dis. 1999;  29 1402-1407
• 105 Leenders A C, Daenen S, Jansen R L et al.. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections.  Br J Haematol. 1998;  103 205-212
• 106 Linden P K, Coley K, Fontes P et al.. IA in liver transplant recipients: outcome comparison of therapy with amphotericin B lipid complex and a historical cohort treated with conventional amphotericin B.  Clin Infect Dis. 2003;  37 17-25
• 107 Barrett J P, Vardulaki K A, Conlon C et al.. A systematic review of the antifungal effectiveness and tolerability of amphotericin B formulations.  Clin Ther. 2003;  25 1295-1320
• 108 Wingard J R, White M H, Anaissie E et al.. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group.  Clin Infect Dis. 2000;  31 1155-1163
• 109 Johnson L B, Kauffman C A. Voriconazole: a new triazole antifungal agent.  Clin Infect Dis. 2003;  36 630-637
• 110 Denning D W, Ribaud P, Milpied N et al.. Efficacy and safety of voriconazole in the treatment of acute IA.  Clin Infect Dis. 2002;  34 563-571
• 111 Caillot D, Bassaris H, McGeer A et al.. Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS.  Clin Infect Dis. 2001;  33 e83-e90
• 112 Caillot D. Intravenous itraconazole followed by oral itraconazole for the treatment of amphotericin-B-refractory invasive pulmonary aspergillosis.  Acta Haematol. 2003;  109 111-118
• 113 Denning D W, Lee J Y, Hostetler J S et al.. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for IA.  Am J Med. 1994;  97 135-144
• 114 Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients.  J Am Acad Dermatol. 1990;  23 607-614
• 115 Maertens J, Raad I, Sable C A et al.. Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin in adults with IA refractory or intolerant to amphotericin B, AMB lipid formulations, or azoles. American Society for Microbiology, Washington DC. Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract J-1103 371 2000 Toronto, Canada;
• 116 Salerno C T, Ouyang D W, Pederson T S et al.. Surgical therapy for pulmonary aspergillosis in immunocompromised patients.  Ann Thorac Surg. 1998;  65 1415-1419