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Pediatric Aspergillosis:Pediatric Aspergillosis:New Findings and Unique AspectsNew Findings and Unique Aspects
William J. Steinbach, MD
Assistant Professor of Pediatrics, Molecular Genetics, and Microbiology
Pediatric Infectious Diseases
Duke University Medical Center
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Randomized Clinical Trials Randomized Clinical Trials for Invasive Aspergillosisfor Invasive Aspergillosis
Voriconazole 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.
ABCD 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.
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Other Invasive Aspergillosis Other Invasive Aspergillosis Clinical TrialsClinical Trials
MSG 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.__________________________________________________________________________________________________________
Two 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.__________________________________________________________________________________________________________
Efficacy 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.
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Treatment Practices in Treatment Practices in Invasive AspergillosisInvasive Aspergillosis
Treatment Practices and Outcomes– 595 Patients– Mean age 42.3 yrs (0 - 86 yrs)
Patterson TF, et al. Medicine 2000;79:250-60.
EORTC Diagnosis and Therapeutic Outcome – 123 patients– Mean age 46 yrs (9 - 83 yrs)
Denning DW, et al. J Infect 1998;37:173-80.
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Epidemiology of Invasive AspergillosisEpidemiology of Invasive Aspergillosis
Risk 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.________________________________________________________________________________________________
Invasive 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._______________________________________________________________________________________________
Early infections in HSCT– 409 patients– Mean age 32 yrs (6mo – 65 yrs)
Kruger W, et al. Bone Marrow Transplant 1999;23:589-597.__________________________________________________________________________________________________________________
Allogeneic HSCT after non-myeloablative conditioning– 173 patients– Mean age 53 yrs (0 - 72 yrs)
Fukuda T, et al. Blood 2003;102:827-33.
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Epidemiology of Invasive AspergillosisEpidemiology of Invasive Aspergillosis
Stratified by AgeStratified by Age FHCRC; 1985-1999 327 patients with Proven / Probable IA
< 19 years 39 cases (13%) 19-40 years 99 cases (34%) > 40 years 156 cases (53%)
No 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.
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Invasive Aspergillosis in Invasive Aspergillosis in Pediatric HSCTPediatric HSCT
1986-1996; 148 pediatric HSCT patients Mean ages
– Autologous 7.1 yrs (1.0 - 17 yrs)– Allogeneic 7.7 yrs (0.6 - 17 yrs)
8 patients with proven invasive aspergillosis – Allogeneic (6/73; 8%)– Autologous (2/75; 3%)
48 patients with suspected IFI not separated between Candida and Aspergillus
No IA specific analyses
Hovi L, et al. Bone Marrow Transplant 2000;26:999-1004.
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Invasive Aspergillosis in Invasive Aspergillosis in Pediatric HSCTPediatric HSCT
510 HSCT in 485 patients (1990-1998) Birth – 21 years old 584 culture-proven infections in first year post-transplant
26 Invasive aspergillosis cases (4.5% of infections)– IA post-transplant days
0-30 n=10 31-100 n=13 101-365 n=3
In 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.
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Invasive Aspergillosis Autopsy by AgeInvasive Aspergillosis Autopsy by AgeData from 1989, 1993, 1997Data from 1989, 1993, 1997
Age Range (yrs) Male Female 0 - 9 11 310 - 19 21 320 - 29 12 630 - 39 27 640 - 49 33 1750 - 59 60 3260 - 69 67 3570 - 79 40 29 > 80 8 2Total 279 133Kume H, et al. Pathol Intl 2003;53:744-50.
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IA Case Fatality Rate by AgeIA Case Fatality Rate by Age
Age (yrs)No. of
patientsNo. ofdeaths CFR, %
20 22 15 68.2
21 - 30 27 16 59.3
31 - 40 52 31 59.6
41 - 50 57 30 52.6
51 - 60 49 29 59.2
> 60 31 17 54.8
Unreported 135 76 56.3
“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)
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Pediatric Aspergillosis:Pediatric Aspergillosis:EpidemiologyEpidemiology
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Hospital for Sick Children, TorontoHospital for Sick Children, Toronto
39 IA Cases; 1979 – 1988 24 Proven, 15 Probable IA Median age 10 years (22 days -18 years)
– 74% with hematologic malignancy or BMT recipient– 31/36 patients with ANC < 500 at diagnosis– Mean duration of ANC < 1000 was 20 days– Hospitalized for a mean of 47 days (0-180) in 6
months preceding diagnosis Survival 23.1% (9/39)
Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.
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Hospital for Sick Children, TorontoHospital for Sick Children, Toronto
Cutaneous– 41% (16/39) cases first suspected as a skin lesion– Skin lesion resolved in 56% (9/16) and in all
coincident with neutropenic recovery; others died
Pulmonary– 41% (16/39) cases first suspected as a fever with
abnormal CXR or chest pain– 94% died, the one survivor had neutropenic
recovery
Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.
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Species Distribution:Species Distribution:PediatricPediatric
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;12:673-82.
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Species Distribution:Species Distribution:Pediatric vs. AdultPediatric vs. Adult
Species Toronto1 BAMSG2
(n=26 isolates) (n=256 isolates)
A. fumigatus 4 171 (67%)A. flavus 17 41 (16%)A. niger 1 14 (5%)A. nidulans 1 2 (5%)A. terreus 3 8 (3%)1 Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.2 Perfect JR, et al. Clin Infect Dis 2001;33:1824-33.
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St. Jude Children’s HospitalSt. Jude Children’s Hospital
1962-1996; 9,500 children treated 66 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
(0- 180 months)– 44 (66%) hospitalized for median of 36 days (1-52 days)
before onset of clinical disease – Clinical symptoms median 11 days (0-69 days) before
diagnosis of IA
Abassi s, et al. Clin Infect Dis 1999;29:1210-9.
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Incidence of Incidence of Proven Proven Invasive Aspergillosis:Invasive Aspergillosis:
St. Jude Children’s HospitalSt. Jude Children’s Hospital
MDS 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;29:1210-9.
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St. Jude Children’s HospitalSt. Jude Children’s Hospital Survival of 15% at one year
– End of 1 month 58% survival– End of 2 months 25% survival– End of 10 months 15% survival
Pulmonary disease fared worse than those without pulmonary disease
Median time between diagnosis and death was 29 days (3-312 days)
Abassi s, et al. Clin Infect Dis 1999;29:1210-9.
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Pediatric Culture LocationPediatric Culture LocationLocation Toronto1 St. Jude2
(n=39) (n=66)
Lung 10 31Sinus / Nose 0 11Skin 15 12Tracheal 1 6Blood 0 4Bone 0 2Heart/Pericardial fluid 0 2Brain 2 2Eye 0 2Pleural fluid 0 1CSF 0 1Liver / Kidney 0 2Esophagus / Bowel 2 0Disseminated 9 0
1 Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.2 Abassi s, et al. Clin Infect Dis 1999;29:1210-9.
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Species Distribution:Species Distribution:Pediatric vs. AdultPediatric vs. Adult
Species St. Jude1 Toronto2 BAMSG3
(n=39) (n=26) (n=256)
A. fumigatus 15 4 171A. flavus 28 17 41A. niger 0 1 14A. nidulans 1 1 2A. terreus 5 3 8Other Aspergillus 0 0 0
1 Abassi s, et al. Clin Infect Dis 1999;29:1210-9.2 Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.3 Perfect JR, et al. Clin Infect Dis 2001;33:1824-33.
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Species Distribution:Species Distribution:Pediatric vs. AdultPediatric vs. Adult
Species St. Jude1 Toronto2 BAMSG3 VCZ4
(n=39) (n=26) (n=256) (n=110)
A. fumigatus 15 4 171 85 A. flavus 28 17 41 7A. niger 0 1 14 9A. nidulans 1 1 2 1A. terreus 5 3 8 6Other Aspergillus 0 0 0 2
1 Abassi s, et al. Clin Infect Dis 1999;29:1210-9.2 Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.3 Perfect JR, et al. Clin Infect Dis 2001;33:1824-33.4 Herbrecht R, et al. New Engl J Med 2002;347:408-15.
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Neonatal AspergillosisNeonatal Aspergillosis
Invasive candidiasis much more common In neonates, IA is more primary cutaneous Age of onset early, can be soon after birth Risk factors
– Immature phagocytes– Corticosteroids– Prolonged hospitalization– Skin trauma
Tape adhesive / removal from immature thin skin Macerated skin due to prolonged arm boards
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Neonatal Primary Cutaneous Neonatal Primary Cutaneous Aspergillosis – Buttocks lesionAspergillosis – Buttocks lesion
Woodruff CA, et al. Pediatr Dermatol 2002;5:439-44.
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Neonatal AspergillosisNeonatal Aspergillosis
Review of 44 cases in first 90 days of life– Primary 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;27:437-52.
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Neonatal AspergillosisNeonatal Aspergillosis
Condition Total Cutaneous Pulmonary Disseminated
(n=44) (n=11) (n=10) (n=14)
Prematurity 43.2% 90.9% 20% 28.6%
CGD 13.6% 0 50% 7.1%
Prior neutropenia 2.3% 0 0 7.1%
Groll AH, et al. Clin Infect Dis 1998;27:437-52.
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Species DistributionSpecies Distribution
Species Neonatal1 St. Jude2 Toronto3 BAMSG4
(n=44) (n=39) (n=26) (n=256)
A. fumigatus 18 15 4 171A. flavus 6 28 17 41A. niger 3 0 1 14A. nidulans 0 1 1 2A. terreus 0 5 3 8Other Aspergillus 5 0 0 0N/A 12 0 0 0
1 Groll AH, et al. Clin Infect Dis 1998;27:437-52.2 Abassi s, et al. Clin Infect Dis 1999;29:1210-9.3 Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.4 Perfect JR, et al. Clin Infect Dis 2001;33:1824-33.
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Pediatric Aspergillosis:Pediatric Aspergillosis:TreatmentTreatment
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ABLC in Adults and Children:ABLC in Adults and Children:Open-Label UseOpen-Label Use
1990-1995; ABLC given for proven/probable IFI All patients analyzed
– 556 cases, 291 evaluable for efficacy– Overall mean age 37.2 yrs (21 days – 93 years)– 130 cases of IA (CR + PR = 42%)
Walsh TJ, et al. Clin Infect Dis 1998;26:1383-96.
Patients < 18years old– 111 treatment episodes of pediatric IFI– 54 evaluated for efficacy– Overall 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.
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Comparison Adult vs. Pediatric Comparison Adult vs. Pediatric OutcomesOutcomes
Ages CR + PR CR PR Stable Failure
All (n=130)1 42% 17% 25% 12% 45%Pulm (n=74) 38% 9% 28% 16% 46%Diss (n=27) 30% 15% 15% 11% 59%Sinus (n=14) 64% 36% 29% 7% 29%Single (n=15) 67% 40% 27% 0 33%
Peds (n=25)2 56% 28% 28% 8% 36%Pulm (n=10) 50% 20% 30% 10% 40%Diss (n=7) 29% 14% 14% 14% 57%Sinus (n=5) 100% 60% 40% 0 0Single (n=3) 67% 33% 33% 0 33%
1 Walsh TJ, et al. Clin Infect Dis 1998;26:1383-96.2 Walsh TJ, et al. Pediatr Infect Dis J 1999;18:702-8.
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Voriconazole for Pediatric AspergillosisVoriconazole for Pediatric Aspergillosis
Compassionate Use; 58 IFI including 42 IA Mean age 8.2 yrs (9 mo – 15 yrs) Therapeutic response
– Complete 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.
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Phase II Micafungin:Phase II Micafungin:Monotherapy or CombinationMonotherapy or Combination
Failing, likely to fail, or intolerant of OLT 283 patients enrolled Mean age 37 yrs (9 wks – 84 yrs) 63 (22.3%) were < 16 yrs Median duration of therapy
– Adults 34 days– Children 37 days
Hope to see pediatric-specific outcome dataUllman AJ, et al. ECCMID 2003, Abstract O-400
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Pediatric Aspergillosis:Pediatric Aspergillosis:DiagnosisDiagnosis
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Pediatric RadiologyPediatric 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% children No evidence of air crescent formation within any area of
consolidation on CTThomas KE, et al. Pediatr Radiol 2003;33:453-60.
Other pediatric series (higher mean ages):– 22% (6/27) with cavitation on CXRAllan BT, et al. Pediatr Radiol 1988;18:118-22.
– 43% (6/14) with cavitation on CTTaccone A, et al. Pediatr Radiol 1993;23:177-80.
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Galactomannan AssayGalactomannan Assay
Prospective study from 1995-1998 – 450 adult allogeneic HSCT patients
(3883 samples)– 347 children with hematologic malignancies
(2376 samples)
First positive results– Adult patients: median of 74 days post-transplant– Pediatric patients: median of 36 days
Sulahian A, et al. Cancer 2001;91:311-8.
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Galactomannan Assay 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 Pediatric
– Sensitivity 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.
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Galactomannan AssayGalactomannan Assay
797 episodes (inc. 48 pediatric patients)
FUO group, false-positives: – Adults (0.9%) vs. Children (44.0%) (p < 0.0001)
Overall specificity:– Adults (98.2%) vs. Children (47.6%) (p < 0.0001).
Overall 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.
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GM Cross-ReactivityGM Cross-Reactivity Membrane-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 microflora– Breast-fed neonates 91% total microflora– Formula-fed neonates 75% total microflora
8/14 milk formulas tested were positive for GM All breast milk samples were negative for GM
Warris A, et al. ICAAC 2001, Abstract J-848.
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Collaborative Pediatric GroupsCollaborative Pediatric Groups
There has never been a large scale dedicated pediatric invasive aspergillosis study for diagnosis or treatment
– Children’s Oncology Group (USA)– BFM (Germany)
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Pediatric Differences?Pediatric Differences?
Potential Aspergillus species differences Radiologic differences
– Less cavitation on CT Cutaneous presentation
– 89 cases reviewed, 63% (56/89) in childrenWalmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.
– Avoid armboards or change frequently Galactomannan sensitivity / false-positivity Antifungal PK, dosing, and efficacy? Combination Therapy
– Less reported, could be different