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Epidemiology of Invasive Fungal Infections in Children

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Presentation on theme: "Epidemiology of Invasive Fungal Infections in Children"— Presentation transcript:

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 Physiologic Immunologic
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

4 Candidiasis: Background
Invasive Candidemia Disseminated candidiasis Third most common bloodstream isolate in US1 Rate of fungal sepsis increased 207% between 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 Candidiasis: Risk Factors
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

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

7 Candidiasis: Incidence
Incidence/100,000 admissions (95% CI) Children 1665 47 (40-54) Neonates 433 150 ( ) Adults 8949 30 (26-34) Zaoutis, et al. CID 2005 Zaoutis, et al CID 2007

8 Candidiasis: Incidence
Incidence/100,000 admissions (95% CI) Children 1665 47 (40-54) Neonates 433 150 ( ) Adults 8949 30 (26-34) Meningococcal Disease 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:

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

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 1-12 Age Groups Malani PN, et al. Mycoses. 2001,44:

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

16 Candidiasis: Attributable Mortality Rate
ADULTS 57% Mortality, % 19% Wey SB et al. Arch Intern Med. 1989;149:

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
Attributable Risk (95% CI) Candidemia Controls Neonatal < 1000 g 26% 14% 12% (5.5, 18.3) Neonatal > 1000 g 2% 6% - 4 % (-9.8, 1.4) Pediatric 15.8% 5.9% 10% ( ) Adult 30.6% 16.1% 14.5% ( ) Zaoutis TE, et al Clin Infect Dis 2007

21 Candidiasis: Attributable Length of Stay (LOS)
Attributable Days (95% CI) Candidemia Controls Neonatal < 1000 g 85 82 3 (-5, 9) Neonatal > 1000 g 62 46 16 (8,24) Pediatric 44.8 23.7 21.1 (14.4, 27.8) Adult 18.6 8.5 10.1 (8.9,11.3) 9 Smith PB. PIDJ 2007 Zaoutis TE, et al Clin Infect Dis 2007

22 Candidiasis: Attributable Charges (US $)
Attributable Charges (95% CI) Candidemia Controls Neonatal < 1000 g 374,481 336,337 39,045 (1, ,715) Neonatal > 1000 g 306,194 179,574 122,302 (80, ,148) Pediatric 183,645 91,379 92,266 (65, ,474) Adult 66,154 26,823 39,331 (33, ,602) Zaoutis TE, et al Clin Infect Dis 2007

23 Candidemia: Dissemination
Eye 3-28% Brain 4-15% Lung 37% Heart <1% Liver 5-7% Spleen 5-7% Eye 3-8% Lung 58% Liver 23% Kidney 5-16% Brain 12-19% Heart 5-8% Spleen 0-8% Kidney 90% Slide not in original deck Take transcript from Dave Andes and put in notes—blood to metastatic….. Benjamin DK, et al. Pediatrics 2003 Zaoutis TE, et al. PIDJ 2004

24 Risk Factors for Disseminated Candidiasis in Children 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:

30 Invasive Aspergillosis: Incidence in Children by Disease
United States data from 2000 KID database 666 pediatric cases Malignancy = 74% Allogenic BMT 4.5% AML 4.0% Cong immunodeficiency 3.2% Aplastic anemia 1.4% ALL 0.6% Lymphoma 0.4% Autologous BMT 0.3% Solid tumors 0.1% Zaoutis, et al. Pediatrics 2006

31 Invasive Aspergillosis: Risk Factors in Children
Multicenter retrospective study of proven/probable n = 139 Malignancy = 63% Most common isolate: Aspergillus fumigatus Corticosteroid Therapy 69% Neutropenia (>3 days) 59% Immunosuppressive Therapy 43% Malignancy (non BMT) 38% Allogenic BMT 37% GVHD 12% Cong immunodeficiency Solid Organ Transplant 11% 95% of patients had  1 of these risk factors Burgos A, et al. Pediatrics. In press

32 Invasive Aspergillosis: Diagnosis in Children
Pulmonary 59% Nodules 21% Cavity 14% Halo Sign 6.4% Air Crescent sign 1.6% Other infiltrates 20.7% Sinus 10% Cutaneous 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 Invasive Aspergillosis: Case Fatality Rate by Age
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 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:

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

36 Invasive Aspergillosis: Antifungal Therapy
Zaoutis TE. ICAAC 2006

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

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

41 Acknowledgments 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 National Institutes of Health 1K23 AI

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

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

44 Zygomycoses: Emergence
Kontoyiannis D, et al JID 2005

45 Zygomycosis: Challenges
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 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: ; 2. Larkin JA, Montero JA. Infect Med. 2003;20: ; 3. Marty FM et al. N Engl J Med. 2004;350: ; 4. Kontoyiannis DP et al. Clin Infect Dis. 2000;30: Photo courtesy of Deanna A. Sutton, The University of Texas Health Science Center at San Antonio.


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