Paediatric Aspergillosis: New Findings and Unique Aspects

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  • 1. 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
  • 2. Randomized Clinical Trials for 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.
  • 3. Other Invasive Aspergillosis Clinical 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.
  • 4. Treatment Practices in Invasive 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.
  • 5. Epidemiology 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.
  • 6. Epidemiology of Invasive Aspergillosis Stratified 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.
  • 7. Invasive Aspergillosis in Pediatric 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.
  • 8. Invasive Aspergillosis in Pediatric 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.
  • 9. Invasive Aspergillosis Autopsy by Age Data from 1989, 1993, 1997
    • Age Range (yrs) Male Female
    • 0 - 9 11 3
    • 10 - 19 21 3
    • 20 - 29 12 6
    • 30 - 39 27 6
    • 40 - 49 33 17
    • 50 - 59 60 32
    • 60 - 69 67 35
    • 70 - 79 40 29
    • > 80 8 2
    • Total 279 133
    • Kume H, et al. Pathol Intl 2003;53:744-50.
  • 10. IA Case Fatality Rate by Age “ 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) Age (yrs) No. of patients No. of deaths 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
  • 11. Pediatric Aspergillosis: Epidemiology
  • 12. Hospital 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.
  • 13. Hospital 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.
  • 14. Species Distribution: Pediatric
    • Species Toronto 1
    • (n=26 isolates)
    • A. fumigatus 4
    • A. flavus 17
    • A. niger 1
    • A. nidulans 1
    • A. terreus 3
    • 1 Walmsley S, et al. Pediatr Infect Dis J 1993;12:673-82.
  • 15. Species Distribution: Pediatric vs. Adult
    • Species Toronto 1 BAMSG 2
    • (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.
  • 16. St. 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.
  • 17. Incidence of Proven Invasive Aspergillosis: St. 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.
  • 18. St. 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.
  • 19. Pediatric Culture Location
    • Location Toronto 1 St. Jude 2
    • (n=39) (n=66)
    • Lung 10 31
    • Sinus / Nose 0 11
    • Skin 15 12
    • Tracheal 1 6
    • Blood 0 4
    • Bone 0 2
    • Heart/Pericardial fluid 0 2
    • Brain 2 2
    • Eye 0 2
    • Pleural fluid 0 1
    • CSF 0 1
    • Liver / Kidney 0 2
    • Esophagus / Bowel 2 0
    • Disseminated 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.
  • 20. Species Distribution: Pediatric vs. Adult
    • Species St. Jude 1 Toronto 2 BAMSG 3
    • (n=39) (n=26) (n=256)
    • A. fumigatus 15 4 171
    • A. flavus 28 17 41
    • A. niger 0 1 14
    • A. nidulans 1 1 2
    • A. terreus 5 3 8
    • Other 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.
  • 21. Species Distribution: Pediatric vs. Adult
    • Species St. Jude 1 Toronto 2 BAMSG 3 VCZ 4
    • (n=39) (n=26) (n=256) (n=110)
    • A. fumigatus 15 4 171 85
    • A. flavus 28 17 41 7
    • A. niger 0 1 14 9
    • A. nidulans 1 1 2 1
    • A. terreus 5 3 8 6
    • Other 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.
  • 22. Neonatal 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
  • 23. Neonatal Primary Cutaneous Aspergillosis – Buttocks lesion Woodruff CA, et al. Pediatr Dermatol 2002;5:439-44.
  • 24. Neonatal 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.
  • 25. Neonatal 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.
  • 26. Species Distribution
    • Species Neonatal 1 St. Jude 2 Toronto 3 BAMSG 4
    • (n=44) (n=39) (n=26) (n=256)
    • A. fumigatus 18 15 4 171
    • A. flavus 6 28 17 41
    • A. niger 3 0 1 14
    • A. nidulans 0 1 1 2
    • A. terreus 0 5 3 8
    • Other Aspergillus 5 0 0 0
    • N/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.
  • 27. Pediatric Aspergillosis: Treatment
  • 28. ABLC in Adults and Children: Open-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.
  • 29. Comparison Adult vs. Pediatric Outcomes
    • 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 0
    • Single (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.
  • 30. Voriconazole 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.
  • 31. Phase II Micafungin: Monotherapy 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 data
    • Ullman AJ, et al. ECCMID 2003, Abstract O-400
  • 32. Pediatric Aspergillosis: Diagnosis
  • 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% children
    • No evidence of air crescent formation within any area of consolidation on CT
    • Thomas KE, et al. Pediatr Radiol 2003;33:453-60.
    • Other pediatric series (higher mean ages):
      • 22% (6/27) with cavitation on CXR
      • Allan BT, et al. Pediatr Radiol 1988;18:118-22.
      • 43% (6/14) with cavitation on CT
      • Taccone A, et al. Pediatr Radiol 1993;23:177-80.
  • 34. Galactomannan 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.
  • 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 samples
    • Adult 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.
  • 36. Galactomannan 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.
  • 37. GM 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 ELISA
    • Mennink-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.
  • 38. Collaborative 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)
  • 39. Pediatric Differences?
    • Potential Aspergillus species differences
    • Radiologic differences
      • Less cavitation on CT
    • Cutaneous presentation
      • 89 cases reviewed, 63% (56/89) in children
    • Walmsley 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