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

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.

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.

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.

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.

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.

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.

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.

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.

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)

Pediatric Aspergillosis:Pediatric Aspergillosis:EpidemiologyEpidemiology

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

Neonatal Primary Cutaneous Neonatal Primary Cutaneous Aspergillosis – Buttocks lesionAspergillosis – Buttocks lesion

Woodruff CA, et al. Pediatr Dermatol 2002;5:439-44.

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.

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.

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.

Pediatric Aspergillosis:Pediatric Aspergillosis:TreatmentTreatment

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.

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.

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.

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

Pediatric Aspergillosis:Pediatric Aspergillosis:DiagnosisDiagnosis

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.

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.

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.

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.

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.

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)

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