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 ( yrs)
AmB MITT mean age 50.5 yrs ( yrs)
Herbrecht R, et al. New Engl J Med 2002;347:
ABCD vs. AmB-deoxycholate
174 patients; Eligible patients > 2 years old
ABCD 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 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:
__________________________________________________________________________________________________________
Two doses of L-AmB
87 patients; Eligible patients > 1 year old
L-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 Voriconazole
116 patients; Eligible patients  14 years old
Mean age 52 yrs ( yrs)
Denning DW, et al. Clin Infect Dis 2002;

4. Treatment Practices in Invasive Aspergillosis
Treatment Practices and Outcomes
595 Patients
Mean age 42.3 yrs ( yrs)
Patterson TF, et al. Medicine 2000;79:
EORTC Diagnosis and Therapeutic Outcome
123 patients
Mean age 46 yrs ( yrs)
Denning DW, et al. J Infect 1998;37:

5. Epidemiology of Invasive Aspergillosis
Risk Factors for mould infection in BMT patients
Infected (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 area
621 patients
Mean age 40.3 yrs (6 days – 89.7 yrs)
Cornet M, et al. J Hosp Infect 2002;51:
_______________________________________________________________________________________________
Early infections in HSCT
409 patients
Mean age 32 yrs (6mo – 65 yrs)
Kruger W, et al. Bone Marrow Transplant 1999;23:
__________________________________________________________________________________________________________________
Allogeneic HSCT after non-myeloablative conditioning
173 patients
Mean 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 range
Marr KA, et al. Clin Infect Dis 2002;34:

7. Invasive Aspergillosis in Pediatric HSCT
; 148 pediatric HSCT patients
Mean ages
Autologous 7.1 yrs ( yrs)
Allogeneic 7.7 yrs ( 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:

8. Invasive Aspergillosis in Pediatric HSCT
510 HSCT in 485 patients ( )
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
n=13
n=3
In 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
>
Total
Kume H, et al. Pathol Intl 2003;53:

10. IA Case Fatality Rate by Age
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 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:

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:

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:

14. Species Distribution: Pediatric
Species Toronto1
(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:

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 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 ( 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:

17. Incidence of Proven Invasive Aspergillosis: St
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:

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:

19. Pediatric Culture Location
Location Toronto1 St. Jude2
(n=39) (n=66)
Lung
Sinus / Nose
Skin
Tracheal
Blood
Bone
Heart/Pericardial fluid 0 2
Brain
Eye
Pleural fluid
CSF
Liver / Kidney
Esophagus / Bowel 2 0
Disseminated
1 Walmsley S, et al. Pediatr Infect Dis J 1993;12:
2 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. fumigatus
A. flavus
A. niger
A. nidulans
A. terreus
Other Aspergillus
1 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. fumigatus
A. flavus
A. niger
A. nidulans
A. terreus
Other Aspergillus
1 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 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:

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:

25. Neonatal Aspergillosis
Condition Total Cutaneous Pulmonary Disseminated
(n=44) (n=11) (n=10) (n=14)
Prematurity % 90.9% 20% 28.6%
CGD % 0 50% 7.1%
Prior neutropenia % %
Groll AH, et al. Clin Infect Dis 1998;27:

26. Species Distribution Species Neonatal1 St. Jude2 Toronto3 BAMSG4
(n=44) (n=39) (n=26) (n=256)
A. fumigatus
A. flavus
A. niger
A. nidulans
A. terreus
Other Aspergillus
N/A
1 Groll AH, et al. Clin Infect Dis 1998;27:
2 Abassi s, et al. Clin Infect Dis 1999;29:
3 Walmsley S, et al. Pediatr Infect Dis J 1993;12:
4 Perfect JR, et al. Clin Infect Dis 2001;33:

27. Pediatric Aspergillosis: Treatment

28. ABLC in Adults and Children: Open-Label Use
; 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:
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% % % % 45%
Pulm (n=74) 38% % % % 46%
Diss (n=27) 30% % % % %
Sinus (n=14) 64% 36% % % %
Single (n=15) 67% % % %
Peds (n=25)2 56% 28% % % %
Pulm (n=10) 50% 20% % % 40%
Diss (n=7) 29% 14% 14% % 57%
Sinus (n=5) 100% 60% 40%
Single (n=3) 67% 33% 33% %
1 Walsh TJ, et al. Clin Infect Dis 1998;26:
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:
Other pediatric series (higher mean ages):
22% (6/27) with cavitation on CXR
Allan BT, et al. Pediatr Radiol 1988;18:
43% (6/14) with cavitation on CT
Taccone 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 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 < )
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-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:
Avoid armboards or change frequently
Galactomannan sensitivity / false-positivity
Antifungal PK, dosing, and efficacy?
Combination Therapy
Less reported, could be different