epidemiology of invasive fungal infections in children theoklis zaoutis, md, msce assistant...
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Epidemiology of Invasive Epidemiology of Invasive Fungal Infections in ChildrenFungal Infections in Children
Theoklis Zaoutis, MD, MSCETheoklis Zaoutis, MD, MSCE
Assistant Professor of Pediatrics and EpidemiologyUniversity of Pennsylvania School of MedicineDirector, Antimicrobial Stewardship Program
Division of Infectious DiseasesThe Children’s Hospital of Philadelphia
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Invasive Invasive CandidiasisCandidiasis
AspergillosisAspergillosis
ZygomycosesZygomycoses
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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.
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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
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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
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0%
10%
20%
30%
40%
50%
60%
Neonates Oncology BMT SOT Med/Surg
USA
CHOP
Zaoutis T, Coffin SE, et al. PIDJ 2004
Zaoutis, et al. CID 2005
Per
cent
Candidiasis: Incidence
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Candidiasis: Incidence
N
Incidence/100,000 admissions (95% CI)
Children 1665 47 (40-54)
Neonates 433 150 (130-160)
Adults 8949 30 (26-34)
Zaoutis, et al. CID 2005
Zaoutis, et al CID 2007
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Candidiasis: Incidence
N
Incidence/100,000 admissions (95% CI)
Children 1665 47 (40-54)
Neonates 433 150 (130-160)
Adults 8949 30 (26-34)
Meningococcal Disease
0.5 - 5
Zaoutis, et al. CID 2005
Zaoutis, et al CID 2007
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Neonatal Candidiasis: Incidence and Birth Weight
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
>1500 gms 1001-1500 751-1000 401-750
% cases
Stoll BJ, et al Pediatics 2002
Benjamin DK et al. Pediatrics 2005
Benjamim DK, et al. Pediatrics 2003
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Abelson, J. A. et al. Pediatrics 2005;116:61-67
Candidiasis: Incidence over Time
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Fridkin, S. K. et al. Pediatrics 2006;117:1680-1687
Neonatal Candidiasis: Neonatal Candidiasis: Incidence over TimeIncidence over Time
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Fridkin, S. K. et al. Pediatrics 2006;117:1680-1687
Neonatal Candidiasis: Neonatal Candidiasis: Incidence over Time by SpeciesIncidence over Time by Species
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Candidiasis:Species Distribution
0
5
10
15
20
25
30
35
40
45
50
C. albicans C. parapsilosis C. glabrata
Pappas, 2003
Zaoutis, 2005
Abelson, 2005
Pappas, et al CID 2003Zaoutis, T, et al. Diagn Micro Infect Dis 2005Jonathan A. Abelson, et al Pediatrics 2005
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Candidiasis:Species Distribution by Age
Malani PN, et al. Mycoses. 2001,44:446-449.
0%
10%
20%
30%
40%
0-1 2-18 19-40 41-59 60+
C. parapsilosis C. glabrata
Age Groups
Per
cent
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Candida Mortality Rates by SpeciesAdult (N=1447) vs. Pediatric (N=144)
0%
10%
20%
30%
40%
50%
60%
Adults
Pediatrics
Pappas PG, et al. Clin Infect Dis. 2003;37:634-643.
C. Albicans C. TropicalisC. Parapsilosis C. Glabrata
Candidiasis: Mortality by Species
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0
50
100
With Candidemia Without Candidemia
Wey SB et al. Arch Intern Med. 1989;149:2349-2353.
57%
19%
Mo
rta
lity,
%
N = 88
Candidiasis:Attributable Mortality Rate
ADULTS
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Candidiasis: Attributable Mortality and Propensity
MalignancyMalignancy
HyperalimentationHyperalimentation
NeutropeniaNeutropenia
Central CatheterCentral Catheter
Infection/ Infection/ Broad AntibioticsBroad Antibiotics
CANDIDIASISCANDIDIASIS
MORTALITYMORTALITYMORTALITYMORTALITY
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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
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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
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Candidiasis: Attributable Mortality
----------- 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% (6.2-13.8)
Adult 30.6% 16.1% 14.5% (12.1-16.9)
Zaoutis TE, et al Clin Infect Dis 2007
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Candidiasis: Attributable Length of Stay (LOS)
----------- 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)Zaoutis TE, et al Clin Infect Dis 2007
9
Smith PB. PIDJ 2007
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Candidiasis: Attributable Charges (US $)
---------- Charges ---------Attributable
Charges (95% CI)Candidemia Controls
Neonatal < 1000 g
374,481 336,337 39,045
(1,374 - 76,715)
Neonatal > 1000 g 306,194 179,574 122,302 (80,457 - 164,148)
Pediatric 183,645 91,379 92,266 (65,058 - 119,474)
Adult 66,154 26,823 39,331 (33,60 - 45,602)
Zaoutis TE, et al Clin Infect Dis 2007
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Candidemia: DisseminationEye 3-28%
Lung 37%
Liver 5-7%
Kidney 90%
Brain 4-15%
Heart <1%
Spleen 5-7%
Eye 3-8%
Lung 58%
Liver 23%
Kidney 5-16%
Brain 12-19%
Heart 5-8%
Spleen 0-8%
Benjamin DK, et al. Pediatrics 2003
Zaoutis TE, et al. PIDJ 2004
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Risk Factors for Disseminated Candidiasis in
Children with Candidemia
Zaoutis TE, et al (Pediatr Infect Dis J 2004;23: 635–641)
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Candidiasis: Antifungal Therapy
0
10
20
30
40
50
60
70
AMB LAMB FLUC ECHIN VORI
2000-2001
2005-2006
Zaoutis TE. ICAAC 2006
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Candidiasis: Neonatal Antifungal Therapy
0
10
20
30
40
50
60
70
80
90
AMB LAMB FLUC ECHIN VORI
2000-2001
2005-2006
Zaoutis TE. ICAAC 2006
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AspergillusAspergillus
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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
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Invasive Aspergillosis: Incidence
Marr KA et al. Clin Infect Dis. 2002;34:909-917.
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Invasive Aspergillosis: Incidence in Children by Disease
• United States data from 2000
• KID database
• 666 pediatric cases
• Malignancy = 74%
Zaoutis, et al. Pediatrics 2006
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%
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Invasive Aspergillosis: Risk Factors in Children
• Multicenter retrospective study of proven/probable
• 2000-2005
• n = 139
• Malignancy = 63%
• Most common isolate: Aspergillus fumigatus
Burgos A, et al. Pediatrics. In press
Corticosteroid Therapy 69%
Neutropenia (>3 days) 59%
Immunosuppressive Therapy
43%
Malignancy (non BMT) 38%
Allogenic BMT 37%
GVHD 12%
Cong immunodeficiency
12%
Solid Organ Transplant 11%
95% of patients had 1 of these risk factors
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Invasive Aspergillosis: Diagnosis in Children
Burgos A, et al. Pediatrics. In press
Pulmonary 59%
Nodules 21%
Cavity 14%
Halo Sign 6.4%
Air Crescent sign 1.6%
Other infiltrates 20.7%
Sinus 10%
Cutaneous 10%
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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
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• 1,941 patients in case series after 1995
• Mean age 44.2 yrs (3-91 yrs)
Age (yrs)No. of
patients
No. ofdeath
s 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
Lin S-J, et al. Clin Infect Dis 2001;32:358-66.
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Invasive Aspergillosis:In-Hospital Mortality (2000)
0
5
10
15
20
25
30
35
40
45
BMT ALL AML LYM AA SOT
IA
NO IA
Zaoutis, et al. Pediatrics 2006
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Invasive Aspergillosis: Antifungal Therapy
0
10
20
30
40
50
60
70
80
AMB LAMB ECHIN VORI
2000-2001
2005-2006
Zaoutis TE. ICAAC 2006
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Invasive Moulds:Changing Spectrum
Invasive aspergillosis
64% 16%
20%
Fusariosis
Zygomycosis
Kontoyiannis DP, et al. J Infect Dis. 2005;191:1350-1360.
Incidence per 1000 Patient Days
Rat
e o
f as
per
gil
losi
s R
ate of zyg
om
ycosis
2000 2001 2002 20030.0
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
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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
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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
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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 AI0629753-01
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Demographic characteristic With candidemia
(n=1118)
Without Candidemia
(n=2062)
P
Age, median years (IQR) 1 (0-7) 1 (0-7) .49 Female Sex 523 (470 906 (44) .41 Race .41 White 464 (42) 722 (35) Hispanic 211 (19) 400 (19) Asian or Pacific Islander 216 (19) 406 (20) Native American 23 (2) 45 (2) Other 53 (5) 126 (6) Unknown 149 (13) 357 (17) Hospital region .65 Northeast 188 (17) 379 (18) Midwest 155 (14) 227 (11) South 505 (45) 892 (43) West 270 (24) 564 (27) NACHRI hospital type .06 Children’s general hospital 424 (38) 660 (32) Children’s unit in a general hospital 385 (34) 621 (30) Not a children’s hospital 294 (26) 726 (35) Hospital Size .54 Small 209 (19) 346 (17) Medium 305 (34) 621 (30) Large 598 (53) 1091 (53)
Propensity score – matched patients with and without candidemia hospitalized in the United States, 2000.
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Pediatric patients Demographic or clinical characteristic With
candidemia
(n=1118)
Without Candidemia
(n=2062)
P
Chronic condition Malignancy Solid tumor 102 (9) 183 (9) .87 Leukemia or lymphoma 91 (8) 185 (9) .55 Cardiovascular 108 (10) 236 (11) .27 Neuromuscular 104 (9) 302 (5) .02 Gastrointestinal 63 (6) 121 (6) .87 Respiratory 140 (13) 265 (13) .89 Renal 37 (3) 75 94) .80 Metabolic 34 (3) 67 (3) .84 Congenital or genetic defects 66 (6) 119 (6) .96 Hematological/immunological deficiencies
32 (3) 73 (4) .39
Perinatal conditions 286 (26) 486 (24) .52 Diabetes mellitus 6 (<1) 10 (<1) .91 Cirrhosis NA NA NA Vascular catheterization 645 (58) 1319 (64) .03 Inpatient procedure Mechanical ventilation 411 (37) 782 (38) .74 Gastrointestinal procedure 344 (31) 682 (33) .46 Enteral or parenteral nutrition 314 (28) 510 (55) .31 Solid-organ transplantation 27 (2) 31 (2) .22 Bone marrow transplantation 25 (2) 15 (<1) .12 Hemodialysis 35 (3) 62 (3) .89 Peritoneal dialysis 29 (3) 22 (1) .04 Orthopedic procedure 47 (4) 86 (40 .97
Propensity score – matched patients with and without candidemia hospitalized in the Untied States, 2000
Zaoutis et al. Clin Infect Dis 2005
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Zygomycoses:Emergence
Kontoyiannis D, et al JID 2005
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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
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.
Maxillary sinus, presumably from biopsy. Slide culture preparation mounted in lactophenol cotton blue. Color enhanced.
Photo courtesy of Deanna A. Sutton, The University of Texas Health Science Center at San Antonio.