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

Invasive Invasive CandidiasisCandidiasis

AspergillosisAspergillosis

ZygomycosesZygomycoses

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.

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

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

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

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

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

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

Abelson, J. A. et al. Pediatrics 2005;116:61-67

Candidiasis: Incidence over Time

Fridkin, S. K. et al. Pediatrics 2006;117:1680-1687

Neonatal Candidiasis: Neonatal Candidiasis: Incidence over TimeIncidence over Time

Fridkin, S. K. et al. Pediatrics 2006;117:1680-1687

Neonatal Candidiasis: Neonatal Candidiasis: Incidence over Time by SpeciesIncidence over Time by Species

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

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

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

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

Candidiasis: Attributable Mortality and Propensity

MalignancyMalignancy

HyperalimentationHyperalimentation

NeutropeniaNeutropenia

Central CatheterCentral Catheter

Infection/ Infection/ Broad AntibioticsBroad Antibiotics

CANDIDIASISCANDIDIASIS

MORTALITYMORTALITYMORTALITYMORTALITY

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

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

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

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

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

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

Risk Factors for Disseminated Candidiasis in

Children with Candidemia

Zaoutis TE, et al (Pediatr Infect Dis J 2004;23: 635–641)

Candidiasis: Antifungal Therapy

0

10

20

30

40

50

60

70

AMB LAMB FLUC ECHIN VORI

2000-2001

2005-2006

Zaoutis TE. ICAAC 2006

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

AspergillusAspergillus

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

Invasive Aspergillosis: Incidence

Marr KA et al. Clin Infect Dis. 2002;34:909-917.

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%

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

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%

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

• 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.

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

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

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

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

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

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

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.

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

Zygomycoses:Emergence

Kontoyiannis D, et al JID 2005

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.