| Aspergillosis |  | | September 4, 2009 |  |
| | From Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children. National Institutes of Health, the Centers for Disease Control and Prevention, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Vol. 58, No. RR-4. September 4, 2009. | | | Epidemiology | | Aspergillus spp. are ubiquitous molds that are widespread in soil and grow on plants and decomposing organic materials (214Long SS. Principles and practice of pediatric infectious diseases. 2nd ed. Orlando, FL: Churchill Livingstone; 2003.); they are infrequent pathogens in HIV-infected children. The most common species causing aspergillosis is A. fumigatus, followed by A. flavus (215Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26: 781-803., 216Herbrecht R, Auvrignon A, Andrès E, et al. Efficacy of amphotericin B lipid complex in the treatment of invasive fungal infections in immunosuppressed paediatric patients. Eur J Clin Microbiol Infect Dis 2001;20:77-82.). Aspergillosis is rare but often lethal in pediatric AIDS patients; the estimated incidence of invasive aspergillosis in pediatric AIDS patients was 1.5%-3% before widespread use of HAART (217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21., 218Drut R, Anderson V, Greco MA, et al. Opportunistic infections in pediatric HIV infection: a study of 74 autopsy cases from Latin America. The Latin American AIDS Pathology Study Group. Pediatr Pathol Lab Med 1997;17:569-76., 219Reik RA, Rodriguez MM, Hensley GT. Infections in children with human immunodeficiency virus/acquired immunodeficiency syndrome: an autopsy study of 30 cases in south Florida, 1990-1993. Pediatr Pathol Lab Med 1995;15:269-81.), and invasive aspergillosis is believed to be much less prevalent during the post-HAART era. Specific risk factors include low CD4 count, neutropenia, corticosteroid use, concurrent malignancy with chemotherapy, broad-spectrum antibiotic exposure, previous pneumonia and respiratory OIs, and HIV-related phagocytic impairment (217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21., 220Denning DW, Follansbee SE, Scolaro M, et al. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324:654-62., 221Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996;33:23-32.,
222Lortholary O, Meyohas MC, Dupont B, et al. Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. French Cooperative Study Group on Aspergillosis in AIDS. Am J Med 1993;95:177-87., 223Walsh TJ, Gonzalez C, Lyman CA, et al. Invasive fungal infections in children: recent advances in diagnosis and treatment. Adv Pediatr Infect Dis 1996:11:187-290., 224Roilides E, Holmes A, Blake C, et al. Defective antifungal activity of monocyte-derived macrophages from human immunodeficiency virus-infected children against Aspergillus fumigatus. J Infect Dis 1993;168:1562-5.). |
| | Clinical Manifestations | | Invasive pulmonary aspergillosis is the most common presentation among HIV-infected children (223Walsh TJ, Gonzalez C, Lyman CA, et al. Invasive fungal infections in children: recent advances in diagnosis and treatment. Adv Pediatr Infect Dis 1996:11:187-290., 225Muller FM, Trusen A, Weig M. Clinical manifestations and diagnosis of invasive aspergillosis in immunocompromised children. Eur J Pediatr 2002;161:563-74., 226Domachowske JB. Pediatric human immunodeficiency virus infection. Clin Microbiol Rev 1996;9:448-68.). Other manifestations include necrotizing tracheobronchitis; pseudomembranous tracheobronchitis; and involvement of CNS, skin, sinuses, middle ear, and mastoid bones (217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21., 218Drut R, Anderson V, Greco MA, et al. Opportunistic infections in pediatric HIV infection: a study of 74 autopsy cases from Latin America. The Latin American AIDS Pathology Study Group. Pediatr Pathol Lab Med 1997;17:569-76., 219Reik RA, Rodriguez MM, Hensley GT. Infections in children with human immunodeficiency virus/acquired immunodeficiency syndrome: an autopsy study of 30 cases in south Florida, 1990-1993. Pediatr Pathol Lab Med 1995;15:269-81., 220Denning DW, Follansbee SE, Scolaro M, et al. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324:654-62., 221Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996;33:23-32., 227Wright M, Fikrig S, Haller JO. Aspergillosis in children with acquired immune deficiency. Pediatr Radiol 1993;23:492-4.). Disseminated aspergillosis has been described rarely (217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21., 228Leibovitz E, Rigaud M, Chandwani S, et al. Disseminated fungal infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1991;10:888-94.). Invasive pulmonary aspergillosis commonly associated with fever, cough, dyspnea, and pleuritic pain. Acute respiratory distress and wheezing or fungal cast production can occur with necrotizing tracheobronchitis, and stridor can occur with laryngotracheitis (214Long SS. Principles and practice of pediatric infectious diseases. 2nd ed. Orlando, FL: Churchill Livingstone; 2003., 217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21., 225Muller FM, Trusen A, Weig M. Clinical manifestations and diagnosis of invasive aspergillosis in immunocompromised children. Eur J Pediatr 2002;161:563-74.). Aspergillus infections of the CNS manifest as single or multiple cerebral abscesses, meningitis, epidural abscess, or
subarachnoid hemorrhage (214Long SS. Principles and practice of pediatric infectious diseases. 2nd ed. Orlando, FL: Churchill Livingstone; 2003.). Cutaneous aspergillosis typically is associated with contaminated adhesive tapes and arm boards used to secure IV devices (214Long SS. Principles and practice of pediatric infectious diseases. 2nd ed. Orlando, FL: Churchill Livingstone; 2003., 217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21.). |
| | Diagnosis | | The organism usually is not recoverable from blood (except A. terreus) but is isolated readily from lung, sinus, brain, and skin biopsy specimens (217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21., 222Lortholary O, Meyohas MC, Dupont B, et al. Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. French Cooperative Study Group on Aspergillosis in AIDS. Am J Med 1993;95:177-87., 229CDC. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. The most recent information is available at http://aidsinfo.nih.gov. MMWR 2004;53 (No. RR-15).). A definitive diagnosis requires relevant clinical signs and symptoms and the histopathologic demonstration of organisms in biopsy specimens obtained from involved sites (e.g., liver or brain). Respiratory tract disease can be presumptively diagnosed in the absence of a tissue biopsy if Aspergillus spp. are recovered from a respiratory sample, compatible signs and symptoms are present, and no alternative diagnosis is identified (90American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006.). A serologic assay to detect galactomannan, a molecule in the cell wall of Aspergillus spp., is available commercially but has not been evaluated widely in infants and children. In addition, the assay has higher false-positive results in children (230Sulahian A, Tabouret M, Ribaud P, et al. Comparison of an enzyme immunoassay and latex agglutination test for detection of galactomannan in the diagnosis of invasive aspergillosis. Eur J Clin Microbiol Infect Dis 1996;15:139-45., 231Herbrecht R, Letscher-Bru V, Oprea C, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 2002;20:1898-906.). Therefore, use
of galactomannan assays for early detection of aspergillosis is not recommended (DIII). Radiologic examination plays an important role in diagnosis and follow-up of invasive pulmonary aspergillosis. Chest radiograph demonstrates either a diffuse interstitial pneumonitis or a localized wedge-shaped dense infiltrate representing pulmonary infarction (214Long SS. Principles and practice of pediatric infectious diseases. 2nd ed. Orlando, FL: Churchill Livingstone; 2003., 217Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21.). Computed tomography (CT) of the chest can be used to identify the halo sign, a macronodule surrounded by a perimeter of ground-glass opacity, which is an early sign of invasive pulmonary aspergillosis (232Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 2007;44:373-9.). Cavitation and air crescent formation shown in chest CT with an aspergilloma appear more frequently in older children and adults than in younger children (233Steinbach WJ. Pediatric aspergillosis: disease and treatment differences in children. Pediatr Infect Dis J 2005;24:358-64., 234Thomas KE, Owens CM, Veys PA, et al. The radiological spectrum of invasive aspergillosis in children: a 10-year review. Pediatr Radiol 2003;33:453-60., 235Allan BT, Patton D, Ramsey NK, et al. Pulmonary fungal infections after bone marrow transplantation. Pediatr Radiol 1988;18:118-22., 236Taccone A, Occhi M, Garaventa A, et al. CT of invasive pulmonary aspergillosis in children with cancer. Pediatr Radiol 1993;23:177-80.). |
| | Prevention Recommendations | | | | Preventing Exposutre | | In HIV-infected children who are severely immunosuppressed or neutropenic, considerations for preventing exposure to Aspergillus might include excluding plants and flowers from rooms, avoiding food items such as nuts and spices that often are contaminated, and minimizing application of nonsterile biomedical devices and adhesive tape (214Long SS. Principles and practice of pediatric infectious diseases. 2nd ed. Orlando, FL: Churchill Livingstone; 2003., 237Allo MD, Miller J, Townsend T, et al. Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med 1987;317:1105-8., 238Bryce EA, Walker M, Scharf S, et al. An outbreak of cutaneous aspergillosis in a tertiary-care hospital. Infect Control Hosp Epidemiol 1996;17:170-2. 106 MMWR September 4, 2009, 239James MJ, Lasker BA, McNeil MM, et al. Use of a repetitive DNA probe to type clinical and environmental isolates of Aspergillus flavus from a cluster of cutaneous infections in a neonatal intensive care unit. J Clin Microbiol 2000;38:3612-8.). Other hospital environmental measures that can help prevent aspergillosis outbreaks include placing suitable barriers between patient-care areas and construction sites; routinely cleaning showerheads, hot water faucets, and air-handling systems; repairing faulty air flow; confining patients to hospital rooms supplied with sterile laminar airflow; and installing highefficiency particulate air filters (90American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006., 240Ruutu P, Valtonen V, Tiitanen L, et al. An outbreak of invasive aspergillosis in a haematologic unit. Scand J Infect Dis 1987;19:347-51., 241Anaissie EJ, Stratton SL, Dignani MC, et al. Pathogenic Aspergillus species recovered from a hospital water system: a 3-year prospective study. Clin Infect Dis 2002;34:780-9., 242Opal S, Asp AA, Cannady PB, et al. Efficacy of infection control measures during a nosocomial outbreak of disseminated aspergillosis associated with hospital construction. J Infect Dis 1986;153:634-7.). |
|
| | Preventing First Episode of Disease | | The use of chemoprophylaxis for aspergillosis is not recommended in HIV-infected children because of the low incidence of invasive disease and the unknown efficacy of prophylaxis in children, combined with the toxicities of likely agents (DIII) (243Morgenstern GR, Prentice AG, Prentice HG, 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;105:901-11., 244Rousey SR, Russler S, Gottlieb M, et al. Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation. Am J Med 1991;91:484-92., 245Siwek GT, Pfaller MA, Polgreen PM, et al. Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis. Diagn Microbiol Infect Dis 2006;55:209-12.). Low-dose amphotericin B, itraconazole, or voriconazole prophylaxis has been employed to prevent aspergillosis, with unknown efficacy. |
| | Discontinuing Primary Prophylaxis | | Not applicable. |
| | Treatment Recommendations | | | | Treatment of Disease | | The recommended treatment for invasive aspergillosis is voriconazole, a second-generation triazole and synthetic derivative of fluconazole (246Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-15., 247Cesaro S, Strugo L, Alaggio R, et al. Voriconazole for invasive aspergillosis in oncohematological patients: a single-center pediatric experience. Support Care Cancer 2003;11:722-7., 248Steinbach WJ. Antifungal agents in children. Pediatr Clin North Am 2005;52:895-915., 249Blyth CC, Palasanthiran P, O' Brien TA. Antifungal therapy in children with invasive fungal infections: a systematic review. Pediatrics 2007;119:772-84.). Data in adults have shown voriconazole to be superior to conventional amphotericin B in treating aspergillosis and to be associated with superior survival (AI) (246Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-15.). However, data regarding fluconazole for children are limited (BII). In a compassionate-use program of voriconazole that included 42 immunocompromised children with invasive aspergillosis, voriconazole treatment elicited a complete (43%) or partial (45%) response (250Pannaraj PS, Walsh TJ, Baker CJ. Advances in antifungal therapy. Pediatr Infect Dis J 2005;24:921-2., 251Walsh TJ, Lutsar I, Driscoll T, et al. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J 2002;21:240-8.). The optimal pediatric dose of voriconazole is not yet known. Children require higher doses (on a mg/kg body weight basis) of voriconazole than do adults to attain similar serum concentrations. The recommended dosage of voriconazole for children is 6-8 mg/kg intravenously or 8 mg/kg orally every 12 hours for two doses, followed by 7 mg/kg intravenously or orally twice daily (AII) (252Scott LJ, Simpson D. Voriconazole: a review of its use in the management of invasive fungal infections. Drugs 2007;67:269-98.). For critically ill patients, parenteral administration is recommended (AIII). Therapy is continued for ≥12 weeks, but treatment duration should be individualized for each patient according to clinical response
(90American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006.). Voriconazole has not been studied in HIV-infected children. Voriconazole is cleared primarily through three key hepatic microsomal CYP450 enzymes - CYP2C19, CYP2C9, and CYP3A4 - with most metabolism mediated through CYP2C19 (253Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 2004;48:2166-72.). As a result of a point mutation in the gene encoding CYP2C19, some persons poorly metabolize voriconazole, and others metabolize it extensively; about 3%-5% of whites and blacks are poor metabolizers, whereas 15%-20% of Asians are poor metabolizers (248Steinbach WJ. Antifungal agents in children. Pediatr Clin North Am 2005;52:895-915., 253Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 2004;48:2166-72.). Drug levels can be as much as fourfold greater in persons who are poor metabolizers than in persons who are homozygous extensive metabolizers. Coadministration of voriconazole with drugs that are potent CYP450 enzyme inducers can significantly reduce voriconazole levels. Voriconazole should be used cautiously with HIV PIs and efavirenz because of potential interactions, and consideration should be given to therapeutic drug monitoring if used concomitantly (CIII). Amphotericin B, either conventional or a lipid formulation has recommendation level (BIII) in children (90American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006., 254Walsh TJ, Seibel NL, Arndt C, et al. Amphotericin B lipid complex in pediatric patients with invasive fungal infections. Pediatr Infect Dis J 1999;18:702-8.). The standard amphotericin B deoxycholate dosage is 1.0-1.5 mg/kg/day. Lipid formulations of amphotericin B allow administration of higher dosage, deliver higher tissue concentrations of drug to reticuloendothelial organs (e.g., lungs, liver, spleen), have fewer infusion-related side effects and less renal toxicity, but are more expensive; dosing of 5 mg/kg/day is recommended. Surgical excision of a localized invasive lesion may be warranted, especially in sinus aspergillosis, certain cases of pulmonary aspergillosis with impingement on great vessels or pericardium, hemoptysis from a single focus, and erosion into the pleural space or ribs (BIII). |
|
| | Management of Treatment Failure | | The efficacy of antifungal therapy in invasive aspergillosis is extremely poor. No data are available to guide recommendations for managing treatment failure. For patients in whom treatment failed or who were unable to tolerate voriconazole, amphotericin B should be considered (BIII). Itraconazole for aspergillosis refractory to primary therapy with voriconazole is not recommended because of similar mechanisms of action and possible cross-resistance (DIII). Caspofungin is approved for adults with invasive aspergillosis who do not improve or do not tolerate standard therapy, and it can be considered for treatment failure in children, although data on this drug are limited in children (CIII). In a pharmacokinetic study in 39 children aged 2-12 years, dosing on a body surface area basis was recommended over a weight-based dosing scheme; 50 mg/m2 body surface area once daily resulted in area-under-the-curve concentrations similar to exposure in adults receiving the standard dosage of 50 mg/ day (256Walsh TJ, Adamson PC, Seibel NL, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005;49:4536-45.). Because of limited bioavailability, caspofungin is available only for IV use. Combination therapy with caspofungin and voriconazole has been studied in a small number of adults and children with invasive aspergillosis (257Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39:797-802., 258Merlin E, Galambrun C, Ribaud P, et al. Efficacy and safety of caspofungin therapy in children with invasive fungal infections. Pediatr Infect Dis J 2006;25:1186-8., 259Cesaro S, Giacchino M, Locatelli F, et al. Safety and efficacy of a caspofungin-based combination therapy for treatment of proven or probable aspergillosis in pediatric hematological patients. BMC Infect Dis 2007;7(Apr 18):28.). For salvage therapy, an additional antifungal agent might be added to current therapy, or combination antifungal drugs from different classes other than the initial regimen can be used (BIII) (257Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39:797-802., 259Cesaro S, Giacchino M, Locatelli F, et al. Safety and efficacy of a caspofungin-based combination therapy for treatment of proven or probable aspergillosis in pediatric hematological patients. BMC Infect Dis 2007;7(Apr 18):28., 260Singh 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;81:320-6., 261Johnson MD, Perfect JR. Combination antifungal therapy: what can and should we expect? Bone Marrow Transplant 2007;40:297-306., 262Baddley JW, Pappas PG. Combination antifungal therapy for the treatment of invasive yeast and mold infections. Curr Infect Dis Rep 2007;9:448-56., 263Raad II, Hanna HA, Boktour M, et al. Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Leukemia 2008;22:496-503., 264Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 2006;53:337-49.). |
| | Discontinuing Secondary Prophylaxis | | Not applicable. |
| | Recommendations for treatment of opportunistic infections in HIV-exposed and HIV-infected infants and children, United States*†: Aspergillosis complex | | | Preferred therapies and duration | Alternative therapies | Other options or issues |
|---|
Excerpted from Table 4 * HIV=human immunodeficiency virus; PCP=Pneumocystis pneumonia; TB=tuberculosis; IV=intravenous; IV=intravenous; IM=intramuscularly; CSF=cerebrospinal fluid;CNS=central nervous system; TMP/SMX=trimethoprim-sulfamethoxazole; HAART=highly active antiretroviral therapy; CMV=cytomegalovirus. HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HCV=hepatitis C virus; IRIS=immune reconstitution inflammatory syndrome; PCR=polymerase chain reaction; HSV=herpes simplex virus; HPV=human papillomavirus † Information in these guidelines might not represent Food and Drug Administration (FDA) approval or approved labeling for products or indications. Specifically, the terms safe and effective might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box). | | Fungal infections | Voriconazole, 6-8 mg/kg body weight per dose IV or 8 mg/kg body weight (max 400 mg) per dose orally twice daily on day 1, followed by 7 mg/kg body weight (max 200 mg) per dose IV or orally twice daily (AI) Treatment duration: ≥12 wks, but treatment duration should be individualized for each patient according to clinical response | Amphotericin B deoxycholate, 1.0-1.5 mg/kg body weight IV once daily (AIII) Lipid formulations of amphotericin B, 5 mg/kg body weight IV once daily (AIII) Caspofungin, 70 mg/m2 body surface area (max 70 mg) IV as loading dose, then 50 mg/m2 body surface area (max 50 mg) IV once daily (CIII) | Potential for significant pharmacokinetic interactions between protease inhibitors or non-nucleoside reverse transcriptase inhibitors with voriconazole and should be used cautiously in these situations. Consider therapeutic drug monitoring and dosage adjustment if necessary. |
|
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| | American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006. | | | 214.
| | Long SS. Principles and practice of pediatric infectious diseases. 2nd ed. Orlando, FL: Churchill Livingstone; 2003. | | | 215.
| | Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26: 781-803. | | | 216.
| | Herbrecht R, Auvrignon A, Andrès E, et al. Efficacy of amphotericin B lipid complex in the treatment of invasive fungal infections in immunosuppressed paediatric patients. Eur J Clin Microbiol Infect Dis 2001;20:77-82. | | | 217.
| | Shetty D, Giri N, Gonzalez CE, et al. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:216-21. | | | 218.
| | Drut R, Anderson V, Greco MA, et al. Opportunistic infections in pediatric HIV infection: a study of 74 autopsy cases from Latin America. The Latin American AIDS Pathology Study Group. Pediatr Pathol Lab Med 1997;17:569-76. | | | 219.
| | Reik RA, Rodriguez MM, Hensley GT. Infections in children with human immunodeficiency virus/acquired immunodeficiency syndrome: an autopsy study of 30 cases in south Florida, 1990-1993. Pediatr Pathol Lab Med 1995;15:269-81. | | | 220.
| | Denning DW, Follansbee SE, Scolaro M, et al. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324:654-62. | | | 221.
| | Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996;33:23-32. | | | 222.
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| | Roilides E, Holmes A, Blake C, et al. Defective antifungal activity of monocyte-derived macrophages from human immunodeficiency virus-infected children against Aspergillus fumigatus. J Infect Dis 1993;168:1562-5. | | | 225.
| | Muller FM, Trusen A, Weig M. Clinical manifestations and diagnosis of invasive aspergillosis in immunocompromised children. Eur J Pediatr 2002;161:563-74. | | | 226.
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| | Wright M, Fikrig S, Haller JO. Aspergillosis in children with acquired immune deficiency. Pediatr Radiol 1993;23:492-4. | | | 228.
| | Leibovitz E, Rigaud M, Chandwani S, et al. Disseminated fungal infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1991;10:888-94. | | | 229.
| | CDC. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. The most recent information is available at http://aidsinfo.nih.gov. MMWR 2004;53 (No. RR-15). | | | 230.
| | 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 invasive aspergillosis. Eur J Clin Microbiol Infect Dis 1996;15:139-45. | | | 231.
| | Herbrecht R, Letscher-Bru V, Oprea C, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 2002;20:1898-906. | | | 232.
| | Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 2007;44:373-9. | | | 233.
| | Steinbach WJ. Pediatric aspergillosis: disease and treatment differences in children. Pediatr Infect Dis J 2005;24:358-64. | | | 234.
| | Thomas KE, Owens CM, Veys PA, et al. The radiological spectrum of invasive aspergillosis in children: a 10-year review. Pediatr Radiol 2003;33:453-60. | | | 235.
| | Allan BT, Patton D, Ramsey NK, et al. Pulmonary fungal infections after bone marrow transplantation. Pediatr Radiol 1988;18:118-22. | | | 236.
| | Taccone A, Occhi M, Garaventa A, et al. CT of invasive pulmonary aspergillosis in children with cancer. Pediatr Radiol 1993;23:177-80. | | | 237.
| | Allo MD, Miller J, Townsend T, et al. Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med 1987;317:1105-8. | | | 238.
| | Bryce EA, Walker M, Scharf S, et al. An outbreak of cutaneous aspergillosis in a tertiary-care hospital. Infect Control Hosp Epidemiol 1996;17:170-2. 106 MMWR September 4, 2009 | | | 239.
| | James MJ, Lasker BA, McNeil MM, et al. Use of a repetitive DNA probe to type clinical and environmental isolates of Aspergillus flavus from a cluster of cutaneous infections in a neonatal intensive care unit. J Clin Microbiol 2000;38:3612-8. | | | 240.
| | Ruutu P, Valtonen V, Tiitanen L, et al. An outbreak of invasive aspergillosis in a haematologic unit. Scand J Infect Dis 1987;19:347-51. | | | 241.
| | Anaissie EJ, Stratton SL, Dignani MC, et al. Pathogenic Aspergillus species recovered from a hospital water system: a 3-year prospective study. Clin Infect Dis 2002;34:780-9. | | | 242.
| | Opal S, Asp AA, Cannady PB, et al. Efficacy of infection control measures during a nosocomial outbreak of disseminated aspergillosis associated with hospital construction. J Infect Dis 1986;153:634-7. | | | 243.
| | Morgenstern GR, Prentice AG, Prentice HG, 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;105:901-11. | | | 244.
| | Rousey SR, Russler S, Gottlieb M, et al. Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation. Am J Med 1991;91:484-92. | | | 245.
| | Siwek GT, Pfaller MA, Polgreen PM, et al. Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis. Diagn Microbiol Infect Dis 2006;55:209-12. | | | 246.
| | Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-15. | | | 247.
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