Invasive Candidiasis in Children and Neonates

Abstract and Introduction

Abstract

Background: Candida species are the third most common cause of pediatric health care–associated bloodstream infection in the United States and Europe. To our knowledge, this report from the International Pediatric Fungal Network is the largest prospective, multicenter observational study dedicated to pediatric and neonatal invasive candidiasis.

Methods: From 2007 to 2011, we enrolled 196 pediatric and 25 neonatal patients with invasive candidiasis.

Results: Non-albicans Candida species predominated in pediatric (56%) and neonatal (52%) age groups, yet Candida albicans was the most common species in both groups. Successful treatment responses were observed in pediatric (76%) and neonatal patients (92%). Infection with Candida parapsilosis led to successful responses in pediatric (92%) and neonatal (100%) patients, whereas infection with Candida glabrata was associated with a lower successful outcome in pediatric patients (55%). The most commonly used primary antifungal therapies for pediatric invasive candidiasis were fluconazole (21%), liposomal amphotericin B (20%) and micafungin (18%). Outcome of pediatric invasive candidiasis was similar in response to polyenes (73%), triazoles (67%) and echinocandins (73%). The most commonly used primary antifungal therapies for neonatal invasive candidiasis were fluconazole (32%), caspofungin (24%) and liposomal amphotericin B (16%) and micafungin (8%). Outcomes of neonatal candidiasis by antifungal class again revealed similar response rates among the classes.

Conclusions: We found a predominance of non-albicans Candida infection in children and similar outcomes based on antifungal class used. This international collaborative study sets the foundation for large epidemiologic studies focusing on the unique features of neonatal and pediatric candidiasis and comparative studies of therapeutic interventions in these populations.

Introduction

Candida species are the third most common cause of pediatric health care–associated bloodstream infection in the United States and Europe.^[1,2] The attributable mortality from invasive candidiasis in children is 10%, and invasive candidiasis is associated with prolonged hospital stay and increased costs.^[3] Coordinated efforts have succeeded in reducing the incidence and improving the outcomes of invasive candidiasis in adults; however, little work has been done to improve outcomes in children.

Several retrospective analyses of pediatric invasive candidiasis^[3–11] have helped define the epidemiology and risk factors for disease. However, there have been only a limited number of prospective epidemiologic studies of invasive candidiasis that included pediatric patients.^[12–14] Only 2 of those prospective epidemiologic studies were multicenter,^[12,14] and all were conducted in earlier years when antifungal options were limited. Similarly, there are limited open-label,^[15–18] pharmacokinetic^[17,19] or clinical trial data in children with invasive candidiasis.^[20]

The Mycoses Study Group (MSG) was founded to investigate systemic mycoses through clinical trials to move the treatment of invasive fungal infections in adult patients toward an evidence-based format. Although the MSG has occasionally included children during the last 3 decades, their mission does not focus on the growing burden of pediatric fungal disease. Similarly, the European Organization for Research and Treatment of Cancer (EORTC) Infectious Diseases Group has completed a large number of mycoses-related studies. However, most of their epidemiologic and antifungal studies either exclude children or enroll insufficient numbers to make a meaningful contribution. Because most studies worldwide have excluded children, our knowledge of these important infections is limited, and this has resulted in delays in obtaining efficacy data and licensing newer therapies.

Prospective studies of fungal epidemiology and treatment in children require a multiinstitutional design to achieve adequate power and demonstrate comparative effectiveness of therapeutic choices. To address this gap, we organized a unique multinational consortium known as the International Pediatric Fungal Network (PFN; https://pfn.pediatrics.duke.edu). This organization consists of 42 worldwide sites led by pediatric specialists in infectious diseases, hematology/oncology and hematopoietic stem cell transplantation (HSCT) and includes leading authorities on pediatric invasive fungal infections. The mission of this group is to generate prospective, multicenter, primary data needed to advance the field and ultimately develop robust evidence-based strategies to improve the prevention and treatment of pediatric fungal disease. The current study presents initial data from the largest reported prospective multicenter cohort of pediatric and neonatal patients with invasive candidiasis.

Table 1. Demographics of Pediatric Invasive Candidiasis
Characteristic	Pediatric Patients (n = 196)
Age in years (median, IQR)*	5.7 (1.8, 14.9)
Gender
Male	96 (49%)
Female	82 (42%)
Unknown	18 (9%)
Race
White	103 (52%)
Asian	28 (14%)
Black/African American	13 (7%)
Unknown/mixed/other	52 (27%)
Underlying condition
Hematologic malignancy	38 (19%)
ALL	20
AML	9
Non-Hodgkins lymphoma	3
Aplastic anemia	2
Other	4
HSCT recipient†	9
Allogeneic-unrelated	4
Allogeneic-matched	3
Allogeneic-mismatched	1
Allogeneic-unknown	1
Acute GVHD (≥ grade II)	8
Solid tumor malignancy	18 (9%)
Neuroblastoma	5
Brain tumor	3
Bone/soft tissue sarcoma	1
Other	9
Gastrointestinal‡	31 (16%)
Surgery/trauma§	29 (15%)
Primary immunodeficiencies	9 (5%)
Neuromuscular	7 (5%)
Solid organ transplant	6 (3%)
Hematologic (nonmalignant)	5 (3%)
Cardiac	5 (3%)
Pulmonary	4 (2%)
Renal	3 (2%)
HIV/AIDS	1 (1%)
Other	21 (11%)
Unknown	19 (10%)

Table 1. Demographics of Pediatric Invasive Candidiasis

Characteristic

Pediatric Patients (n = 196)

Age in years (median, IQR)*

5.7 (1.8, 14.9)

Gender

Male

96 (49%)

Female

82 (42%)

Unknown

18 (9%)

Race

White

103 (52%)

Asian

28 (14%)

Black/African American

13 (7%)

Unknown/mixed/other

52 (27%)

Underlying condition

Hematologic malignancy

38 (19%)

ALL

AML

Non-Hodgkins lymphoma

Aplastic anemia

Other

HSCT recipient†

Allogeneic-unrelated

Allogeneic-matched

Allogeneic-mismatched

Allogeneic-unknown

Acute GVHD (≥ grade II)

Solid tumor malignancy

18 (9%)

Neuroblastoma

Brain tumor

Bone/soft tissue sarcoma

Other

Gastrointestinal‡

31 (16%)

Surgery/trauma§

29 (15%)

Primary immunodeficiencies

9 (5%)

Neuromuscular

7 (5%)

Solid organ transplant

6 (3%)

Hematologic (nonmalignant)

5 (3%)

Cardiac

5 (3%)

Pulmonary

4 (2%)

Renal

3 (2%)

HIV/AIDS

1 (1%)

Other

21 (11%)

Unknown

19 (10%)

Authors and Disclosures

Table 2. Candida Species Recovered and Sites of Isolation from 196 Pediatric Patients and 25 Neonates
	Pediatric (n = 201 Isolates)	Neonatal (n = 26 Isolates)
Species
Candida albicans	87 (44%)	12 (48%)
Candida parapsilosis	45 (22%)	7 (28%)
Candida glabrata	21 (11%)	1 (4%)
Candida lusitaniae	8 (4%)	0
Candida krusei	6 (3%)	0
Candida guillermondii	3 (2%)	0
Candida dubliniensis	3 (2%)	0
Other*	28 (14%)	6 (24%)
Sites†
Blood	136	21
Soft tissue	7	0
GI tract	5	0
Lung	2	1
Cerebrospinal fluid	2	1
Kidney	1	1
Heart	1	0
Liver	1	1
Spleen	1	0
Eye	1	0
Bone/Joint	0	1
Other	20	5

Table 3. Outcomes of Pediatric and Neonatal Candidiasis
Outcome	Pediatric(n = 196 Patients)	Neonatal(n = 25 Patients)
Success, complete response	132 (67%)	20 (80%)
Success, partial response	17 (9%)	3 (12%)
Failure, stable response	4 (2%)	0
Failure, progression of disease	4 (2%)	0
Failure, death	38 (19%)	2 (8%)
Unknown	1 (1%)	0

William J. Steinbach, MD,* Emmanuel Roilides, MD,† David Berman, DO,‡ Jill A. Hoffman, MD,§ Andreas H. Groll, MD,¶ Ibrahim Bin-Hussain, MD,∥ Debra L. Palazzi, MD,** Elio Castagnola, MD,†† Natasha Halasa, MD, MPH,‡‡ Aristea Velegraki, MD,§§ Christopher C. Dvorak, MD,¶¶Arunaloke Charkabarti, MD,∥ ∥ Lillian Sung, MD, PhD,*** Lara Danziger-Isakov, MD,††† Catherine Lachenauer, MD,‡‡‡ Antonio Arrieta, MD,§§§ Katherine Knapp, MD,¶¶¶ Mark J. Abzug, MD,∥ ∥ ∥ Christine Ziebold, MD, PhD,**** Thomas Lehrnbecher, MD, PhD,†††† Lena Klingspor, MD, PhD,‡‡‡‡ Adilia Warris, MD, PhD,§§§§ Kateri Leckerman, MS,¶¶¶¶ Teresa Martling, BS,* Thomas J. Walsh, MD,∥ ∥ ∥ ∥Daniel K. Benjamin, Jr., MD, PhD,* Theoklis E. Zaoutis, MD, MSCE,¶¶¶¶ and the International Pediatric Fungal Network

Duke University, Durham, NC; †3rd Department of Pediatrics, Aristotle University and Hippokration Hospital, Thessaloniki, Greece; ‡All Children's Hospital, St. Petersburg, FL; §Children's Hospital Los Angeles, Los Angeles, CA; ¶Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany; ∥King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia; **Baylor College of Medicine and Texas Children's Hospital, Houston, TX; ††"G. Gaslini" Children's Hospital, Genoa, Italy; ‡‡Vanderbilt University, Nashville, TN; §§Microbiology Department, Medical School, University of Athens, Athens, Greece; ¶¶University of California-San Francisco, San Francisco, CA; ∥∥Postgraduate Institute of Medical Education and Research, Chandigarh, India; ***Hospital for Sick Children, Toronto, Ontario, Canada; †††Cleveland Clinic, Cleveland, OH; ‡‡‡Children's Hospital Boston, Boston, MA; §§§Children's Hospital–Orange County, Orange, CA; ¶¶¶St. Jude Children's Hospital, Memphis, TN; ∥∥∥University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO; ****University of Iowa Children's Hospital, Iowa City, IA; ††††Johann Wolfgang Goethe University, Frankfurt, Germany; ‡‡‡‡Karolinska University Hospital, Stockholm, Sweden; §§§§Department of Pediatrics, Radboud University Nijmegen Medical Center, the Netherlands; ¶¶¶¶Children's Hospital of Philadelphia, Philadelphia, PA; and ∥∥∥∥Weill Cornell Medical Center, New York, NY.

Address for correspondence
William J. Steinbach, MD, Division of Pediatric Infectious Diseases, Department of Pediatrics, Department of Molecular Genetics and Microbiology, 427 Jones Building, Research Drive, Duke University Medical Center, Durham, NC 27710. E-mail: bill.steinbach@duke.edu.