Ahead of Print -Biomarker Correlates of Survival in Pediatric Patients with Ebola Virus Disease - Volume 20, Number 10—October 2014 - Emerging Infectious Disease journal - CDC

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Ahead of Print -Biomarker Correlates of Survival in Pediatric Patients with Ebola Virus Disease - Volume 20, Number 10—October 2014 - Emerging Infectious Disease journal - CDC

Volume 20, Number 10—October 2014

Research

Biomarker Correlates of Survival in Pediatric Patients with Ebola Virus Disease

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• Materials and Methods
• Results
• Discussion
• Suggested Citation

Figures

• Figure 1
• Figure 2
• Figure 3
• Figure 4

Tables

• Table 1
• Table 2
• Table 3

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Anita K. McElroy , Bobbie R. Erickson, Timothy D. Flietstra, Pierre E. Rollin, Stuart T. Nichol, Jonathan S. Towner, and Christina F. Spiropoulou

Author affiliations: Emory University, Atlanta, Georgia, USA (A.K. McElroy); Centers for Disease Control and Prevention, Atlanta (A.K. McElroy, B.R. Erickson, T.D. Flietstra, P.E. Rollin, S.T. Nichol, J.S. Towner, C.F. Spiropoulou)

Suggested citation for this article

Abstract

Outbreaks of Ebola virus disease (EVD) occur sporadically in Africa and are associated with high case-fatality rates. Historically, children have been less affected than adults. The 2000–2001 Sudan virus–associated EVD outbreak in the Gulu district of Uganda resulted in 55 pediatric and 161 adult laboratory-confirmed cases. We used a series of multiplex assays to measure the concentrations of 55 serum analytes in specimens from patients from that outbreak to identify biomarkers specific to pediatric disease. Pediatric patients who survived had higher levels of the chemokine regulated on activation, normal T-cell expressed and secreted marker and lower levels of plasminogen activator inhibitor 1, soluble intracellular adhesion molecule, and soluble vascular cell adhesion molecule than did pediatric patients who died. Adult patients had similar levels of these analytes regardless of outcome. Our findings suggest that children with EVD may benefit from different treatment regimens than those for adults.

Outbreaks of Ebola virus disease (EVD) occur sporadically in sub-Saharan Africa and are associated with exceptionally high case-fatality rates (CFRs). The disease onset is nonspecific and is characterized by abrupt onset of fever, fatigue, headache, myalgia, and gastrointestinal distress 3–13 days after exposure to the virus (1). The term hemorrhagic fever has been used to describe this disease process because hemorrhagic manifestations develop in many patients during the course of illness. The Ebolavirus genus includes 5 different viruses that result in different CFRs: Ebola virus (EBOV; CFR 57%–90%), Sudan virus (SUDV; CFR 41%–65%), and Bundibugyo virus (CFR 40%) cause fatal infections, but neither Tai Forest virus nor Reston virus has been associated with human fatalities (2,3).

Pediatric patients have been underrepresented in EVD studies because total numbers of affected children in any given EVD outbreak, whether associated with EBOV, SUDV, or Bundibugyo virus, are usually low because of outbreak dynamics and societal structure. For example, nosocomial EVD infections mostly occur in adults working on hospital wards, and children are not usually caregivers for EVD patients. However, the 2000–2001 SUDV outbreak in the Gulu district of Uganda, the largest recorded EVD outbreak to that point, resulted in 425 cases; 145 cases were in patients <21 years of age, and 55 of these cases were laboratory confirmed (4,5). The CFR for pediatric patients in this outbreak was lower than for adults (6), but the reasons for this increased survival were unknown. The relatively large number of pediatric cases in this outbreak enabled closer investigation of factors associated with increased survival of pediatric patients with EVD.

Samples collected during the Gulu outbreak have been invaluable for advancing understanding of EVD pathophysiology. Studies using these samples found associations between fatal outcomes and elevated liver enzyme levels, renal dysfunction, cytokine dysregulation, and genetic factors (7–9). Recently, we analyzed serum biomarkers by using samples from the Gulu outbreak and identified associations between cytokines/chemokines, acute-phase reactants, makers of coagulopathy, and markers of endothelial function and patient death, hemorrhage, and viremia (10). In this study, we used a series of multiplex assays to measure the concentrations of 55 serum analytes in specimens from patients from the Gulu outbreak to identify biomarkers that had age-specific associations with survival, hemorrhagic manifestations, or both.

Dr McElroy is an instructor at Emory University in the Department of Pediatrics, a pediatric infectious disease physician, and an infectious disease researcher who performs her research work as an affiliate of CDC. Her primary research interests are in understanding the pathogenesis of emerging viral diseases, with a focus on host immune responses.

Acknowledgments

We thank Tatyana Klimova for editing this manuscript.

A.K.M is supported by the PIDS/St. Jude Fellowship Award and the Atlanta Pediatric Scholars Award (National Institutes of Health K12 HD072245). This work was performed while she held a National Institutes of Health Loan Repayment Award.

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Figures

• Figure 1. Viral loads for Ebola virus disease patients infected with Sudan virus during outbreak in Uganda, 2000–2001. A) Relative TCID50, of pediatric patients (1–21 years of age) compared with those...
• Figure 2. Biomarkers associated with age-dependent survival outcomes for patients with Ebola virus disease: black, adult fatal; white, adult nonfatal; dark gray, pediatric fatal; light gray, pediatric nonfatal. A) Interleukin 10;...
• Figure 3. Biomarkers associated with age-dependent hemorrhagic manifestations (heme) for patients with Ebola virus disease: black, adult heme; white, adult nonheme; dark gray, pediatric heme; light gray, pediatric nonheme. A) Serum...
• Figure 4. Biomarkers associated with age but not survival outcome or hemorrhage for patients with Ebola virus disease: black, adult; white, pediatric. A) Macrophage colony-stimulating factor; B) total IgG; C) tissue...

Tables

• Table 1. Demographics and clinical data for pediatric and adult patients included in analysis of Ebola virus disease outbreak in Uganda, 2000–2001
• Table 2. Characteristics of patients with laboratory-confirmed Ebola virus disease during outbreak in Uganda, 2000–2001
• Table 3. Biomarkers that demonstrated an association with age in analysis of Ebola virus disease, Uganda, 2000–2001

Suggested citation for this article: McElroy AK, Erickson BR, Flietstra TD, Rollin PE, Nichol ST, Towner JS, et al. Biomarker correlates of survival in pediatric patients with Ebola virus disease. Emerg Infect Dis [Internet]. 2014 Oct [date cited]. http://dx.doi.org/10.3201/eid2010.140430

DOI: 10.3201/eid2010.140430

Medline indexes "J R Stat Soc Ser A Stat Soc" but cannot find a listing for reference 13 "Benjamini, Hochberg, 1995". Please check the reference for accuracy.

CrossRef reports the last page should be "484" not "83" in reference 29 "Lalani, Bhol, Ahmed, 1997".