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Epidemiology of Invasive Fungal Infections in Children. Theoklis Zaoutis, MD, MSCE Assistant Professor of Pediatrics and Epidemiology University of Pennsylvania School of Medicine Director, Antimicrobial Stewardship Program Division of Infectious Diseases

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Epidemiology of Invasive Fungal Infections in Children


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    1. Epidemiology of Invasive Fungal Infections in Children Theoklis Zaoutis, MD, MSCE Assistant Professor of Pediatrics and Epidemiology University of Pennsylvania School of Medicine Director, Antimicrobial Stewardship Program Division of Infectious Diseases The Children’s Hospital of Philadelphia

    2. Invasive Candidiasis Aspergillosis Zygomycoses

    3. Anatomic • Primary barriers to defense in children (mucosa and integument) are fragile and easily colonized Physiologic • Greater ability to tolerate more intensive treatments Immunologic • Functional immaturity of phagocytes and T lymphocytes • Congenital immunodeficiencies Anaissie E et al. Clin Mycology. 2003.

    4. Candidiasis: Background • Invasive • Candidemia • Disseminated candidiasis • Third most common bloodstream isolate in US1 • Rate of fungal sepsis increased 207% between 1979-20002 • Fungal sepsis associated with second highest case fatality in children 13%3 1 Wisplinghoff, PIDJ 2003 2 Martin, NEJM 2003 3 Watson, AJRCCM 2003

    5. Infants and Children Immunosuppression Use of broad-spectrum antibiotics Central venous catheters Hyperalimentation Abdominal surgery/perforation Hemodialysis Neonates Gestational age Prolonged rupture of membranes H2 blockers Intubation Third-generation cephalosporins Candidiasis: Risk Factors

    6. Candidiasis: Incidence Percent Zaoutis T, Coffin SE, et al. PIDJ 2004 Zaoutis, et al. CID 2005

    7. Candidiasis: Incidence Zaoutis, et al. CID 2005 Zaoutis, et al CID 2007

    8. Candidiasis: Incidence Zaoutis, et al. CID 2005 Zaoutis, et al CID 2007

    9. Neonatal Candidiasis: Incidence and Birth Weight Stoll BJ, et al Pediatics 2002 Benjamin DK et al. Pediatrics 2005 Benjamim DK, et al. Pediatrics 2003

    10. Candidiasis: Incidence over Time Abelson, J. A. et al. Pediatrics 2005;116:61-67

    11. Neonatal Candidiasis: Incidence over Time Fridkin, S. K. et al. Pediatrics 2006;117:1680-1687

    12. Neonatal Candidiasis: Incidence over Time by Species Fridkin, S. K. et al. Pediatrics 2006;117:1680-1687

    13. Candidiasis: Species Distribution Pappas, et al CID 2003 Zaoutis, T, et al. Diagn Micro Infect Dis 2005 Jonathan A. Abelson, et al Pediatrics 2005

    14. Candidiasis: Species Distribution by Age Percent Age Groups Malani PN, et al. Mycoses. 2001,44:446-449.

    15. Candidiasis: Mortality by Species C. Albicans C. Parapsilosis C. Tropicalis C. Glabrata Pappas PG, et al. Clin Infect Dis. 2003;37:634-643.

    16. Candidiasis: Attributable Mortality Rate N = 88 ADULTS 57% Mortality, % 19% Wey SB et al. Arch Intern Med. 1989;149:2349-2353.

    17. Candidiasis: Attributable Mortality and Propensity Central Catheter Malignancy Hyperalimentation Neutropenia Infection/ Broad Antibiotics MORTALITY MORTALITY CANDIDIASIS

    18. Candidiasis:Attributable Mortality/Propensity Score • Design: • Retrospective Cohort Study with Propensity-Matched Analyses • Propensity Score • Attempt to reconstruct situation similar to random assignment • Propensity of developing candidemia given numerous covariates (clinical and demographic) • Data Sources: • Kids Inpatient Database (KID) 2000 • National Inpatient Sample • Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality Zaoutis TE, et al. Clin Infect Dis 2005

    19. Candidiasis: Propensity Score Covariates • Demographics • Age • Sex • Race • Geographic region • Hospital size • Hospital type • Chronic Conditions • Malignancy • Cardiovascular • Neuromuscular • Gastrointestinal • Respiratory • Renal • Metabolic • Congenital/genetic • Hemat/Immnunologic • Diabetes • Cirrhosis • Procedures • Central catheter • Mechanical ventilation • Hyperalimentation • Bone marrow transplant • Solid organ transplant • GI surgery • Dialysis

    20. Candidiasis: Attributable Mortality Zaoutis TE, et al Clin Infect Dis 2007

    21. Candidiasis: Attributable Length of Stay (LOS) 9 Smith PB. PIDJ 2007 Zaoutis TE, et al Clin Infect Dis 2007

    22. Candidiasis: Attributable Charges (US $) Zaoutis TE, et al Clin Infect Dis 2007

    23. Brain 12-19% Eye 3-8% Lung 58% Heart 5-8% Spleen 0-8% Liver 23% Kidney 5-16% Candidemia: Dissemination Brain 4-15% Eye 3-28% Lung 37% Heart <1% Spleen 5-7% Liver 5-7% Kidney 90% Benjamin DK, et al. Pediatrics 2003 Zaoutis TE, et al. PIDJ 2004

    24. Risk Factors for Disseminated Candidiasis inChildren with Candidemia Zaoutis TE, et al (Pediatr Infect Dis J 2004;23: 635–641)

    25. Candidiasis:Antifungal Therapy Zaoutis TE. ICAAC 2006

    26. Candidiasis:Neonatal Antifungal Therapy Zaoutis TE. ICAAC 2006

    27. Aspergillus

    28. Invasive Aspergillosis: Background • Mould frequency: • 70% of invasive mould infections • Initial sites: • Lungs • Sinuses • Dissemination: • Cerebral infection • Increasing incidence: • 357% since 1980 Hay RJ. In: Aspergillus and Aspergllosis. 1988 Bodey GP, Vartiarian S. Eur J Clin Microbiol Infect Dis. 1989 McNeil MM, et al CID. 2001

    29. Invasive Aspergillosis: Incidence Marr KA et al. Clin Infect Dis. 2002;34:909-917.

    30. Invasive Aspergillosis: Incidence in Children by Disease • United States data from 2000 • KID database • 666 pediatric cases • Malignancy = 74% Zaoutis, et al. Pediatrics 2006

    31. Invasive Aspergillosis: Risk Factors in Children • Multicenter retrospective study of proven/probable • 2000-2005 • n = 139 • Malignancy = 63% • Most common isolate: Aspergillus fumigatus 95% of patients had  1 of these risk factors Burgos A, et al. Pediatrics. In press

    32. Invasive Aspergillosis: Diagnosis in Children Burgos A, et al. Pediatrics. In press

    33. Invasive Aspergillosis: Outcomes • Treatment • Lipid formulations of amphotericin B =57% • Voriconazole = 53% • Caspofungin 9% • Majority received >1 antifungal • Mortality = 53% • Multivariate analysis for predictors of death • Allogeneic BMT, OR=6.14 (2.67, 16.21) • Surgery post diagnosis, OR 0.34 (0.06, 0.85) Burgos A, et al Pediatrics, in press

    34. Age (yrs) No. ofpatients No. 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 Invasive Aspergillosis:Case Fatality Rate by Age • 1,941 patients in case series after 1995 • Mean age 44.2 yrs (3-91 yrs) Lin S-J, et al. Clin Infect Dis 2001;32:358-66.

    35. Invasive Aspergillosis: In-Hospital Mortality (2000) Zaoutis, et al. Pediatrics 2006

    36. Invasive Aspergillosis:Antifungal Therapy Zaoutis TE. ICAAC 2006

    37. Incidence per 1000 Patient Days Aspergillus Invasive aspergillosis 64% 0.7 0.21 Zygomycetes Fusariosis 0.6 0.18 16% 0.5 0.15 Rate of aspergillosis Zygomycosis 0.4 0.12 Rate of zygomycosis 20% 0.3 0.09 0.2 0.06 0.1 0.03 0.0 0.00 2000 2001 2002 2003 Year Invasive Moulds: Changing Spectrum Kontoyiannis DP, et al. J Infect Dis. 2005;191:1350-1360.

    38. Zygomycosis: In Pediatrics • 157 cases in the literature • Malignancy 16%, BMT 6%, 21% neonates • Type of infection • Cutaneous 27% • GI 21% • Associated with neonatal age • Rhinocerebral 18% • Pulmonary 16% • Overall mortality 61% • Disseminated infection and age < 1year had worse outcomes • Surgery and antifungal therapy protective Zaoutis, et al. PIDJ 2007ss

    39. Summary: Pediatric Invasive Fungal Infections • An important cause of morbidity and mortality • Differences between adults an children may be important • Incidence • Species • Diagnosis • Treatment • Outcomes • Large, multi-institutional studies needed

    40. Mentors Thomas J. Walsh Brian Strom Russell Localio Collaborators William Steinbach Danny Benjamin Susan Coffin Chris Feudtner Research Team Kateri Heydon Priya Prasad Sarah Smathers Jaclyn Chu Acknowledgments • National Institutes of Health 1K23 AI0629753-01

    41. Propensity score – matched patients with and without candidemia hospitalized in the United States, 2000.

    42. Propensity score – matched patients with and without candidemia hospitalized in the Untied States, 2000 Zaoutis et al. Clin Infect Dis 2005

    43. Zygomycoses: Emergence Kontoyiannis D, et al JID 2005

    44. One of the more “common” of the uncommon moulds emerging in incidence as a cause of invasive fungal infection1 Difficult to treat 4% response to antifungal treatment in one series2 Diagnosis often comes late Zygomycosis rarely suspected; presentation often mimics other mould infections4 Highly aggressive Onset of symptoms to death was < 4 weeks in 76% of fatal cases in one study4 Significant mortality1 Zygomycosis: Challenges Maxillary sinus, presumably from biopsy. Slide culture preparation mounted in lactophenol cotton blue. Color enhanced. 1. Marr KA et al. Clin Infect Dis. 2002;34:909-917; 2. Larkin JA, Montero JA. Infect Med. 2003;20:201-206; 3. Marty FM et al. N Engl J Med. 2004;350:950-952; 4. Kontoyiannis DP et al. Clin Infect Dis. 2000;30:851-856. Photo courtesy of Deanna A. Sutton, The University of Texas Health Science Center at San Antonio.