aspergillosis new and unique aspects小儿感染新的和独特的方面课件

Pediatric Aspergillosis: New Findings and Unique Aspects William J. Steinbach, MD Assistant Professor of Pediatrics, Molecular Genetics, and Microbiology Pediatric Infectious Diseases Duke University Medical Center Randomized Clinical Trials for Invasive Aspergillosis lVoriconazole vs. AmB-deoxycholate 277 patients; Eligible patients 12 years old Voriconazole MITT mean age 48.5 yrs (13 - 79 yrs) AmB MITT mean age 50.5 yrs (12 - 75 yrs) Herbrecht R, et al. New Engl J Med 2002;347:408-15. lABCD vs. AmB-deoxycholate 174 patients; Eligible patients 2 years old ABCD mean age 48 yrs (7 - 81 yrs) AmB mean age 44 yrs (0 - 81 yrs) Bowden R, et al. Clin Infect Dis 2002;35:359-66. Other Invasive Aspergillosis Clinical Trials lMSG Multicenter Itraconazole 76 patients; No age eligibility restriction Pulmonary disease mean age 47.5 yrs Extrapulmonary disease mean age 48.9 yrs Denning DW, et al. Am J Med 1994;97:135-144. _ lTwo doses of L-AmB 87 patients; Eligible patients 1 year old L-AmB (1 mg/kg/d) mean age 51 yrs (14 - 74 yrs) L-AmB (4 mg/kg/d) mean age 46 yrs (15 - 81 yrs) Ellis M, et al. Clin Infect Dis 1998;27:1406-12. _ lEfficacy and Safety of Voriconazole 116 patients; Eligible patients 14 years old Mean age 52 yrs (18 - 79 yrs) Denning DW, et al. Clin Infect Dis 2002;563-71. Treatment Practices in Invasive Aspergillosis lTreatment Practices and Outcomes 595 Patients Mean age 42.3 yrs (0 - 86 yrs) Patterson TF, et al. Medicine 2000;79:250-60. lEORTC Diagnosis and Therapeutic Outcome 123 patients Mean age 46 yrs (9 - 83 yrs) Denning DW, et al. J Infect 1998;37:173-80. Epidemiology of Invasive Aspergillosis lRisk Factors for mould infection in BMT patients Infected (n=21) mean age 29 yrs (1 - 43 yrs) Uninfected (n=209) mean age 28 yrs (0.25 - 54 yrs) Yuen K-Y, et al. Clin Infect Dis 1997;25:37-42. _ lInvasive aspergillosis in greater Paris area 621 patients Mean age 40.3 yrs (6 days 89.7 yrs) Cornet M, et al. J Hosp Infect 2002;51:288-96. _ lEarly infections in HSCT 409 patients Mean age 32 yrs (6mo 65 yrs) Kruger W, et al. Bone Marrow Transplant 1999;23:589-597. _ lAllogeneic HSCT after non-myeloablative conditioning 173 patients Mean age 53 yrs (0 - 72 yrs) Fukuda T, et al. Blood 2003;102:827-33. Epidemiology of Invasive Aspergillosis Stratified by Age lFHCRC; 1985-1999 l327 patients with Proven / Probable IA l 40 years 156 cases (53%) lNo mention of # of HSCT divided by age, so cannot determine incidence inside age range Marr KA, et al. Clin Infect Dis 2002;34:909-17. Invasive Aspergillosis in Pediatric HSCT l1986-1996; 148 pediatric HSCT patients lMean ages Autologous7.1 yrs (1.0 - 17 yrs) Allogeneic7.7 yrs (0.6 - 17 yrs) l8 patients with proven invasive aspergillosis Allogeneic (6/73; 8%) Autologous (2/75; 3%) l48 patients with suspected IFI not separated between Candida and Aspergillus lNo IA specific analyses Hovi L, et al. Bone Marrow Transplant 2000;26:999-1004. Invasive Aspergillosis in Pediatric HSCT l510 HSCT in 485 patients (1990-1998) lBirth 21 years old l584 culture-proven infections in first year post-transplant l26 Invasive aspergillosis cases (4.5% of infections) IA post-transplant days l0-30 n=10 l31-100 n=13 l101-365 n=3 lIn multivariable analysis IA more likely to have severe GVHD (RR 7.5; 95% CI 3.0-18.4) Benjamin DK Jr., et al. Pediatr Infect Dis J 2002;21:227-34. Invasive Aspergillosis Autopsy by Age Data from 1989, 1993, 1997 Age Range (yrs)MaleFemale 0 - 9113 10 - 19213 20 - 29126 30 - 39276 40 - 493317 50 - 596032 60 - 696735 70 - 794029 8082 Total279133 Kume H, et al. Pathol Intl 2003;53:744-50. IA Case Fatality Rate by Age Age (yrs) No. of patients No. of deathsCFR, % 20221568.2 21 - 30271659.3 31 - 40523159.6 41 - 50573052.6 51 - 60492959.2 60311754.8 Unreported1357656.3 “There was little variation in mortality by age.” Lin S-J, et al. Clin Infect Dis 2001;32:358-66. 1,941 patients in case series after 1995 Mean age 44.2 yrs (3-91 yrs) Pediatric Aspergillosis: Epidemiology Hospital for Sick Children, Toronto l39 IA Cases; 1979 1988 l24 Proven, 15 Probable IA lMedian age 10 years (22 days -18 years) 74% with hematologic malignancy or BMT recipient 31/36 patients with ANC 1.5 in at least two sequential samples AdultPediatric Sensitivity88.6%100% Specificity97.5%89.9% lIf the lower cut-off was lowered 1.0, the pediatric specificity was even lower at 88.1%. Sulahian A, et al. Cancer 2001;91:311-8. Galactomannan Assay l 797 episodes (inc. 48 pediatric patients) l FUO group, false-positives: Adults (0.9%) vs. Children (44.0%) (p 0.0001) lOverall specificity: Adults (98.2%) vs. Children (47.6%) (p 0.0001). lOverall positive predictive value: Adult nonallogeneic HSCT recipients (92.1%) Adult allogeneic HSCT patients (42.9%) Children (15.4%) (p 0.0001) Herbrecht R, et al. J Clin Oncol 2002;20:1898-1906. GM Cross-Reactivity lMembrane-associated molecule of Bifidobacterium bifidum spp. pennsylvanicum found to mimic the epitope recognized by EB-A2 and cultures showed in vitro reactivity with Aspergillus sandwich ELISA Mennink-Kersten M, et al. Lancet 2004;363:325-7. lBifidobacterium spp. common in gut microflora Breast-fed neonates 91% total microflora Formula-fed neonates 75% total microflora l 8/14 milk formulas tested were positive for GM lAll breast milk samples were negative for GM Warris A, et al. ICAAC 2001, Abstract J-848. Collaborative Pediatric Groups There has never been a large scale dedicated pediatric invasive aspergillosis study for diagnosis or treatment Childrens Oncology Group (USA) BFM (Germany) Pediatric Differences? lPotential Aspergillus species differences lRadiologic differences Less cavitation on CT lC