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Pediatric Aspergillosis: New Findings and Unique Aspects William J. Steinbach, MD Assistant Professor of Pediatrics, Molecular Genetics, and Microbiology.

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Presentation on theme: "Pediatric Aspergillosis: New Findings and Unique Aspects William J. Steinbach, MD Assistant Professor of Pediatrics, Molecular Genetics, and Microbiology."— Presentation transcript:

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: ________________________________________________________________________________________________ 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; patients with Proven / Probable IA < 19 years 39 cases (13%) 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:

7 Invasive Aspergillosis in Pediatric HSCT ; 148 pediatric HSCT patients Mean ages – Autologous7.1 yrs ( yrs) – Allogeneic7.7 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= n= 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)MaleFemale > 8082 Total Kume H, et al. Pathol Intl 2003;53:

10 IA Case Fatality Rate by Age Age (yrs) No. of patients No. of deathsCFR, % > Unreported There was little variation in mortality by age. Lin S-J, et al. Clin Infect Dis 2001;32: ,941 patients in case series after 1995 Mean age 44.2 yrs (3-91 yrs)

11 Pediatric Aspergillosis: Epidemiology

12 Hospital for Sick Children, Toronto 39 IA Cases; 1979 – 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 SpeciesToronto 1 (n=26 isolates) A. fumigatus4 A. flavus17 A. niger1 A. nidulans 1 A. terreus3 1 Walmsley S, et al. Pediatr Infect Dis J 1993;12:

15 Species Distribution: Pediatric vs. Adult SpeciesToronto 1 BAMSG 2 (n=26 isolates)(n=256 isolates) A. fumigatus4171 (67%) A. flavus1741 (16%) A. niger114 (5%) A. nidulans 12 (5%) A. terreus38 (3%) 1 Walmsley S, et al. Pediatr Infect Dis J 1993;12: Perfect JR, et al. Clin Infect Dis 2001;33:

16 St. Jude Childrens 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. Jude Childrens Hospital MDS8% (2/25) CGD7% (1/14) Choriocarcinoma6% (1/16) Aplastic anemia4.6% (2/43) AML4% (26/647) CML4% (1/24) ALL1% (29/2659) Neuroblastoma0.17% (1/583) Lymphoma0.16% (2/1188) Abassi s, et al. Clin Infect Dis 1999;29:

18 St. Jude Childrens Hospital Survival of 15% at one year – End of 1 month58% survival – End of 2 months25% survival – End of 10 months15% 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 LocationToronto 1 St. Jude 2 (n=39)(n=66) Lung1031 Sinus / Nose011 Skin1512 Tracheal 16 Blood04 Bone02 Heart/Pericardial fluid02 Brain22 Eye02 Pleural fluid01 CSF01 Liver / Kidney02 Esophagus / Bowel20 Disseminated90 1 Walmsley S, et al. Pediatr Infect Dis J 1993;12: Abassi s, et al. Clin Infect Dis 1999;29:

20 Species Distribution: Pediatric vs. Adult SpeciesSt. Jude 1 Toronto 2 BAMSG 3 (n=39) (n=26) (n=256) A. fumigatus A. flavus A. niger A. nidulans A. terreus Other Aspergillus Abassi s, et al. Clin Infect Dis 1999;29: Walmsley S, et al. Pediatr Infect Dis J 1993;12: Perfect JR, et al. Clin Infect Dis 2001;33:

21 Species Distribution: Pediatric vs. Adult SpeciesSt. Jude 1 Toronto 2 BAMSG 3 VCZ 4 (n=39) (n=26) (n=256) (n=110) A. fumigatus A. flavus A. niger A. nidulans A. terreus Other Aspergillus Abassi s, et al. Clin Infect Dis 1999;29: Walmsley S, et al. Pediatr Infect Dis J 1993;12: Perfect JR, et al. Clin Infect Dis 2001;33: 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 TotalCutaneousPulmonaryDisseminated (n=44)(n=11)(n=10)(n=14) Prematurity 43.2%90.9%20%28.6% CGD 13.6%050%7.1% Prior neutropenia 2.3%007.1% Groll AH, et al. Clin Infect Dis 1998;27:

26 Species Distribution SpeciesNeonatal 1 St. Jude 2 Toronto 3 BAMSG 4 (n=44)(n=39) (n=26)(n=256) A. fumigatus A. flavus A. niger A. nidulans A. terreus Other Aspergillus N/A Groll AH, et al. Clin Infect Dis 1998;27: Abassi s, et al. Clin Infect Dis 1999;29: Walmsley S, et al. Pediatr Infect Dis J 1993;12: 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 AgesCR + 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% 033% 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: 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 – 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 patients10.1% (34/338) GM > 1.5 in at least two sequential samples AdultPediatric – Sensitivity88.6%100% – Specificity97.5%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: 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 1993;12: – Avoid armboards or change frequently Galactomannan sensitivity / false-positivity Antifungal PK, dosing, and efficacy? Combination Therapy – Less reported, could be different


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