Presentation on theme: "Pediatric Aspergillosis: New Findings and Unique Aspects"— Presentation transcript:
1 Pediatric Aspergillosis: New Findings and Unique Aspects William J. Steinbach, MDAssistant Professor of Pediatrics, Molecular Genetics, and MicrobiologyPediatric Infectious DiseasesDuke University Medical Center
2 Randomized Clinical Trials for Invasive Aspergillosis Voriconazole vs. AmB-deoxycholate277 patients; Eligible patients 12 years oldVoriconazole MITT mean age 48.5 yrs ( yrs)AmB MITT mean age 50.5 yrs ( yrs)Herbrecht R, et al. New Engl J Med 2002;347:ABCD vs. AmB-deoxycholate174 patients; Eligible patients > 2 years oldABCD mean age 48 yrs ( yrs)AmB mean age 44 yrs ( yrs)Bowden R, et al. Clin Infect Dis 2002;35:
3 Other Invasive Aspergillosis Clinical Trials MSG Multicenter Itraconazole76 patients; No age eligibility restrictionPulmonary disease mean age 47.5 yrsExtrapulmonary disease mean age 48.9 yrsDenning DW, et al. Am J Med 1994;97:__________________________________________________________________________________________________________Two doses of L-AmB87 patients; Eligible patients > 1 year oldL-AmB (1 mg/kg/d) mean age 51 yrs ( yrs)L-AmB (4 mg/kg/d) mean age 46 yrs ( yrs)Ellis M, et al. Clin Infect Dis 1998;27:Efficacy and Safety of Voriconazole116 patients; Eligible patients 14 years oldMean age 52 yrs ( yrs)Denning DW, et al. Clin Infect Dis 2002;
4 Treatment Practices in Invasive Aspergillosis Treatment Practices and Outcomes595 PatientsMean age 42.3 yrs ( yrs)Patterson TF, et al. Medicine 2000;79:EORTC Diagnosis and Therapeutic Outcome123 patientsMean age 46 yrs ( yrs)Denning DW, et al. J Infect 1998;37:
5 Epidemiology of Invasive Aspergillosis Risk Factors for mould infection in BMT patientsInfected (n=21) mean age 29 yrs ( yrs)Uninfected (n=209) mean age 28 yrs ( yrs)Yuen K-Y, et al. Clin Infect Dis 1997;25:37-42.________________________________________________________________________________________________Invasive aspergillosis in greater Paris area621 patientsMean age 40.3 yrs (6 days – 89.7 yrs)Cornet M, et al. J Hosp Infect 2002;51:_______________________________________________________________________________________________Early infections in HSCT409 patientsMean age 32 yrs (6mo – 65 yrs)Kruger W, et al. Bone Marrow Transplant 1999;23:__________________________________________________________________________________________________________________Allogeneic HSCT after non-myeloablative conditioning173 patientsMean age 53 yrs ( yrs)Fukuda T, et al. Blood 2003;102:
6 Epidemiology of Invasive Aspergillosis Stratified by Age FHCRC;327 patients with Proven / Probable IA< 19 years 39 cases (13%)19-40 years 99 cases (34%)> 40 years cases (53%)No mention of # of HSCT divided by age, so cannot determine incidence inside age rangeMarr KA, et al. Clin Infect Dis 2002;34:
7 Invasive Aspergillosis in Pediatric HSCT ; 148 pediatric HSCT patientsMean agesAutologous 7.1 yrs ( yrs)Allogeneic 7.7 yrs ( yrs)8 patients with proven invasive aspergillosisAllogeneic (6/73; 8%)Autologous (2/75; 3%)48 patients with suspected IFI not separated between Candida and AspergillusNo IA specific analysesHovi L, et al. Bone Marrow Transplant 2000;26:
8 Invasive Aspergillosis in Pediatric HSCT 510 HSCT in 485 patients ( )Birth – 21 years old584 culture-proven infections in first year post-transplant26 Invasive aspergillosis cases (4.5% of infections)IA post-transplant days0-30 n=10n=13n=3In multivariable analysis IA more likely to have severe GVHD (RR 7.5; 95% CI )Benjamin DK Jr., et al. Pediatr Infect Dis J 2002;21:
9 Invasive Aspergillosis Autopsy by Age Data from 1989, 1993, 1997 Age Range (yrs) Male Female>TotalKume H, et al. Pathol Intl 2003;53:
10 IA Case Fatality Rate by Age 1,941 patients in case series after 1995Mean age 44.2 yrs (3-91 yrs)Age (yrs)No. of patientsNo. of deathsCFR, % 20221568.221 - 30271659.331 - 40523159.641 - 50573052.651 - 60492959.2> 601754.8Unreported1357656.3“There was little variation in mortality by age.”Lin S-J, et al. Clin Infect Dis 2001;32:
12 Hospital for Sick Children, Toronto 39 IA Cases; 1979 – 198824 Proven, 15 Probable IAMedian age 10 years (22 days -18 years)74% with hematologic malignancy or BMT recipient31/36 patients with ANC < 500 at diagnosisMean duration of ANC < 1000 was 20 daysHospitalized for a mean of 47 days (0-180) in 6 months preceding diagnosisSurvival 23.1% (9/39)Walmsley S, et al. Pediatr Infect Dis J 1993;12:
13 Hospital for Sick Children, Toronto Cutaneous41% (16/39) cases first suspected as a skin lesionSkin lesion resolved in 56% (9/16) and in all coincident with neutropenic recovery; others diedPulmonary41% (16/39) cases first suspected as a fever with abnormal CXR or chest pain94% died, the one survivor had neutropenic recoveryWalmsley S, et al. Pediatr Infect Dis J 1993;12:
14 Species Distribution: Pediatric Species Toronto1(n=26 isolates)A. fumigatus 4A. flavus 17A. niger 1A. nidulans 1A. terreus 31 Walmsley S, et al. Pediatr Infect Dis J 1993;12:
15 Species Distribution: Pediatric vs. Adult Species Toronto1 BAMSG2(n=26 isolates) (n=256 isolates)A. fumigatus (67%)A. flavus (16%)A. niger (5%)A. nidulans (5%)A. terreus (3%)1 Walmsley S, et al. Pediatr Infect Dis J 1993;12:2 Perfect JR, et al. Clin Infect Dis 2001;33:
16 St. Jude Children’s Hospital ; 9,500 children treated66 cases of proven IA (0.7 % incidence)Median age 11.2 yrs (1.3 – 21.6 yrs)ANC < 500 duration for median 14 days (1-402 days)Onset of underlying disease and IA was median 16 months ( months)44 (66%) hospitalized for median of 36 days (1-52 days) before onset of clinical diseaseClinical symptoms median 11 days (0-69 days) before diagnosis of IAAbassi s, et al. Clin Infect Dis 1999;29:
17 Incidence of Proven Invasive Aspergillosis: St Incidence of Proven Invasive Aspergillosis: St. Jude Children’s HospitalMDS 8% (2/25)CGD 7% (1/14)Choriocarcinoma 6% (1/16)Aplastic anemia 4.6% (2/43)AML 4% (26/647)CML 4% (1/24)ALL 1% (29/2659)Neuroblastoma 0.17% (1/583)Lymphoma 0.16% (2/1188)Abassi s, et al. Clin Infect Dis 1999;29:
18 St. Jude Children’s Hospital Survival of 15% at one yearEnd of 1 month 58% survivalEnd of 2 months 25% survivalEnd of 10 months 15% survivalPulmonary disease fared worse than those without pulmonary diseaseMedian time between diagnosis and death was 29 days (3-312 days)Abassi s, et al. Clin Infect Dis 1999;29:
20 Species Distribution: Pediatric vs. Adult Species St. Jude1 Toronto2 BAMSG3(n=39) (n=26) (n=256)A. fumigatusA. flavusA. nigerA. nidulansA. terreusOther Aspergillus1 Abassi s, et al. Clin Infect Dis 1999;29:2 Walmsley S, et al. Pediatr Infect Dis J 1993;12:3 Perfect JR, et al. Clin Infect Dis 2001;33:
21 Species Distribution: Pediatric vs. Adult Species St. Jude1 Toronto2 BAMSG3 VCZ4(n=39) (n=26) (n=256) (n=110)A. fumigatusA. flavusA. nigerA. nidulansA. terreusOther Aspergillus1 Abassi s, et al. Clin Infect Dis 1999;29:2 Walmsley S, et al. Pediatr Infect Dis J 1993;12:3 Perfect JR, et al. Clin Infect Dis 2001;33:4 Herbrecht R, et al. New Engl J Med 2002;347:
22 Neonatal Aspergillosis Invasive candidiasis much more commonIn neonates, IA is more primary cutaneousAge of onset early, can be soon after birthRisk factorsImmature phagocytesCorticosteroidsProlonged hospitalizationSkin traumaTape adhesive / removal from immature thin skinMacerated skin due to prolonged arm boards
23 Neonatal Primary Cutaneous Aspergillosis – Buttocks lesion Woodruff CA, et al. Pediatr Dermatol 2002;5:
24 Neonatal Aspergillosis Review of 44 cases in first 90 days of lifePrimary cutaneous (25%; n=11)Invasive pulmonary (22.7%; n=10)CNS (9.1%; n=4)Gastrointestinal (6.8%; n=3)Misc. single site (4.5%; n=2)Disseminated (31.8%; n=14)Groll AH, et al. Clin Infect Dis 1998;27:
28 ABLC in Adults and Children: Open-Label Use ; ABLC given for proven/probable IFIAll patients analyzed556 cases, 291 evaluable for efficacyOverall mean age 37.2 yrs (21 days – 93 years)130 cases of IA (CR + PR = 42%)Walsh TJ, et al. Clin Infect Dis 1998;26:Patients < 18years old111 treatment episodes of pediatric IFI54 evaluated for efficacyOverall median age 11 years (21 days – 16 years)25 cases of IA (CR + PR = 56%)Walsh TJ, et al. Pediatr Infect Dis J 1999;18:702-8.
30 Voriconazole for Pediatric Aspergillosis Compassionate Use; 58 IFI including 42 IAMean age 8.2 yrs (9 mo – 15 yrs)Therapeutic responseComplete or partial response 43%Pulmonary IA (n=12) 33%CNS (n=6) 50%Disseminated (n=7) 86%Sinusitis (n=7) 29%Bone / Liver / Skin (n=10) 30%Stable 7%Intolerance 10%Failure 40%Walsh TJ, et al. Pediatr Infect Dis J 2002;21:240-8.
31 Phase II Micafungin: Monotherapy or Combination Failing, likely to fail, or intolerant of OLT283 patients enrolledMean age 37 yrs (9 wks – 84 yrs)63 (22.3%) were < 16 yrsMedian duration of therapyAdults 34 daysChildren 37 daysHope to see pediatric-specific outcome dataUllman AJ, et al. ECCMID 2003, Abstract O-400
33 Pediatric Radiology 27 consecutive patients; 10 yr review Mean age 5 yrs (7 mo – 18 yrs)In adult series, approx. 50% with cavitation and air crescent formation in 40%Central cavitation of small nodules in 25% childrenNo evidence of air crescent formation within any area of consolidation on CTThomas KE, et al. Pediatr Radiol 2003;33:Other pediatric series (higher mean ages):22% (6/27) with cavitation on CXRAllan BT, et al. Pediatr Radiol 1988;18:43% (6/14) with cavitation on CTTaccone A, et al. Pediatr Radiol 1993;23:
34 Galactomannan Assay Prospective study from 1995-1998 450 adult allogeneic HSCT patients (3883 samples)347 children with hematologic malignancies (2376 samples)First positive resultsAdult patients: median of 74 days post-transplantPediatric patients: median of 36 daysSulahian A, et al. Cancer 2001;91:311-8.
35 Galactomannan Assay False-positive antigenemia Adult patients 2.5% (10/406)Pediatric patients 10.1% (34/338)GM > 1.5 in at least two sequential samplesAdult PediatricSensitivity 88.6% 100%Specificity 97.5% 89.9%If 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.
36 Galactomannan Assay 797 episodes (inc. 48 pediatric patients) FUO group, false-positives:Adults (0.9%) vs. Children (44.0%) (p < )Overall specificity:Adults (98.2%) vs. Children (47.6%) (p < ).Overall positive predictive value:Adult nonallogeneic HSCT recipients (92.1%)Adult allogeneic HSCT patients (42.9%)Children (15.4%) (p < )Herbrecht R, et al. J Clin Oncol 2002;20:
37 GM Cross-ReactivityMembrane-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 ELISAMennink-Kersten M, et al. Lancet 2004;363:325-7.Bifidobacterium spp. common in gut microfloraBreast-fed neonates 91% total microfloraFormula-fed neonates 75% total microflora8/14 milk formulas tested were positive for GMAll breast milk samples were negative for GMWarris A, et al. ICAAC 2001, Abstract J-848.
38 Collaborative Pediatric Groups There has never been a large scale dedicated pediatric invasive aspergillosis study for diagnosis or treatmentChildren’s Oncology Group (USA)BFM (Germany)
39 Pediatric Differences? Potential Aspergillus species differencesRadiologic differencesLess cavitation on CTCutaneous presentation89 cases reviewed, 63% (56/89) in childrenWalmsley S, et al. Pediatr Infect Dis J 1993;12:Avoid armboards or change frequentlyGalactomannan sensitivity / false-positivityAntifungal PK, dosing, and efficacy?Combination TherapyLess reported, could be different
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