Pediatric Aspergillosis: New Findings and Unique Aspects

1
Pediatric AspergillosisNew 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
  2002347408-15.
• ABCD vs. AmB-deoxycholate
• 174 patients Eligible patients gt 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
  200235359-66.

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 199497135-144.
• __________________________________________________
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• Two doses of L-AmB
• 87 patients Eligible patients gt 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
  1998271406-12.
• __________________________________________________
  __________________________________________________
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• 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 2002563-71.

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 200079250-60.
• EORTC Diagnosis and Therapeutic Outcome
• 123 patients
• Mean age 46 yrs (9 - 83 yrs)
• Denning DW, et al. J Infect 199837173-80.

5
Epidemiology of Invasive Aspergillosis

• Risk Factors for mould infection in BMT patients
• Infected (n21) mean age 29 yrs (1 - 43
  yrs)
• Uninfected (n209) mean age 28 yrs (0.25 - 54
  yrs)
• Yuen K-Y, et al. Clin Infect Dis
  19972537-42.
• __________________________________________________
  ______________________________________________
• 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 200251288-96.
• __________________________________________________
  _____________________________________________
• Early infections in HSCT
• 409 patients
• Mean age 32 yrs (6mo 65 yrs)
• Kruger W, et al. Bone Marrow Transplant
  199923589-597.
• __________________________________________________
  __________________________________________________
  ______________
• Allogeneic HSCT after non-myeloablative
  conditioning
• 173 patients
• Mean age 53 yrs (0 - 72 yrs)
• Fukuda T, et al. Blood 2003102827-33.

6
Epidemiology of Invasive Aspergillosis
Stratified by Age

• FHCRC 1985-1999
• 327 patients with Proven / Probable IA
• lt 19 years 39 cases (13)
• 19-40 years 99 cases (34)
• gt 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 200234909-17.

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
  200026999-1004.

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 n10
• 31-100 n13
• 101-365 n3
• 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
  200221227-34.

9
Invasive Aspergillosis Autopsy by AgeData 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
• gt 80 8 2
• Total 279 133
• Kume H, et al. Pathol Intl 200353744-50.

10
IA Case Fatality Rate by Age
1,941 patients in case series after 1995 Mean age
44.2 yrs (3-91 yrs)

There was little variation in mortality by age.
Lin S-J, et al. Clin Infect Dis 200132358-66.
11
Pediatric AspergillosisEpidemiology
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 lt 500 at diagnosis
• Mean duration of ANC lt 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
  199312673-82.

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
  199312673-82.

14
Species DistributionPediatric

• Species Toronto1
• (n26 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
  199312673-82.

15
Species DistributionPediatric vs. Adult

• Species Toronto1 BAMSG2
• (n26 isolates) (n256 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
  199312673-82.
• 2 Perfect JR, et al. Clin Infect Dis
  2001331824-33.

16
St. Jude Childrens 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 lt 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
  1999291210-9.

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Incidence of Proven Invasive AspergillosisSt.
Jude Childrens 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
  1999291210-9.

18
St. Jude Childrens 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
  1999291210-9.

19
Pediatric Culture Location

• Location Toronto1 St. Jude2
• (n39) (n66)
• 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
  199312673-82.
• 2 Abassi s, et al. Clin Infect Dis
  1999291210-9.

20
Species DistributionPediatric vs. Adult

• Species St. Jude1 Toronto2 BAMSG3
• (n39) (n26) (n256)
• 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
  1999291210-9.
• 2 Walmsley S, et al. Pediatr Infect Dis J
  199312673-82.
• 3 Perfect JR, et al. Clin Infect Dis
  2001331824-33.

21
Species DistributionPediatric vs. Adult

• Species St. Jude1 Toronto2 BAMSG3 VCZ4
• (n39) (n26) (n256) (n110)
• 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
  1999291210-9.
• 2 Walmsley S, et al. Pediatr Infect Dis J
  199312673-82.
• 3 Perfect JR, et al. Clin Infect Dis
  2001331824-33.
• 4 Herbrecht R, et al. New Engl J Med
  2002347408-15.

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
20025439-44.
24
Neonatal Aspergillosis

• Review of 44 cases in first 90 days of life
• Primary cutaneous (25 n11)
• Invasive pulmonary (22.7 n10)
• CNS (9.1 n4)
• Gastrointestinal (6.8 n3)
• Misc. single site (4.5 n2)
• Disseminated (31.8 n14)
• Groll AH, et al. Clin Infect Dis 199827437-52.

25
Neonatal Aspergillosis

• Condition Total Cutaneous Pulmonary Dissemina
  ted
• (n44) (n11) (n10) (n14)
• 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 199827437-52.

26
Species Distribution

• Species Neonatal1 St. Jude2 Toronto3 BAMSG4
• (n44) (n39) (n26) (n256)
• 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
  199827437-52.
• 2 Abassi s, et al. Clin Infect Dis
  1999291210-9.
• 3 Walmsley S, et al. Pediatr Infect Dis J
  199312673-82.
• 4 Perfect JR, et al. Clin Infect Dis
  2001331824-33.

27
Pediatric AspergillosisTreatment
28
ABLC in Adults and ChildrenOpen-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
  1998261383-96.
• Patients lt 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
  199918702-8.

29
Comparison Adult vs. Pediatric Outcomes

• Ages CR PR CR PR Stable
  Failure
• All (n130)1 42 17 25 12 45
• Pulm (n74) 38 9 28 16 46
• Diss (n27) 30 15 15 11
  59
• Sinus (n14) 64 36 29 7 29
• Single (n15) 67 40 27 0 33
• Peds (n25)2 56 28 28 8 36
• Pulm (n10) 50 20 30 10 40
• Diss (n7) 29 14 14 14 57
• Sinus (n5) 100 60 40 0 0
• Single (n3) 67 33 33 0 33
• 1 Walsh TJ, et al. Clin Infect Dis
  1998261383-96.
• 2 Walsh TJ, et al. Pediatr Infect Dis J
  199918702-8.

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 (n12) 33
• CNS (n6) 50
• Disseminated (n7) 86
• Sinusitis (n7) 29
• Bone / Liver / Skin (n10) 30
• Stable 7
• Intolerance 10
• Failure 40
• Walsh TJ, et al. Pediatr Infect Dis J
  200221240-8.

31
Phase II MicafunginMonotherapy 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 lt 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 AspergillosisDiagnosis
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
  200333453-60.
• Other pediatric series (higher mean ages)
• 22 (6/27) with cavitation on CXR
• Allan BT, et al. Pediatr Radiol 198818118-22.
• 43 (6/14) with cavitation on CT
• Taccone A, et al. Pediatr Radiol
  199323177-80.

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 200191311-8.

35
Galactomannan Assay

• False-positive antigenemia
• Adult patients 2.5 (10/406)
• Pediatric patients 10.1 (34/338)
• GM gt 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 200191311-8.

36
Galactomannan Assay

• 797 episodes (inc. 48 pediatric patients)
• FUO group, false-positives
• Adults (0.9) vs. Children (44.0) (p lt
  0.0001)
• Overall specificity
• Adults (98.2) vs. Children (47.6) (p lt
  0.0001).
• Overall positive predictive value
• Adult nonallogeneic HSCT recipients (92.1)
• Adult allogeneic HSCT patients (42.9)
• Children (15.4) (p lt 0.0001)
• Herbrecht R, et al. J Clin Oncol
  2002201898-1906.

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
  2004363325-7.
• 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
• Childrens 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
  199312673-82.
• Avoid armboards or change frequently
• Galactomannan sensitivity / false-positivity
• Antifungal PK, dosing, and efficacy?
• Combination Therapy
• Less reported, could be different