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
Biomarker Correlates of Survival in Pediatric Patients with Ebola Virus Disease
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.
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.
- Kortepeter MG, Bausch DG, Bray M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J Infect Dis. 2011;204(Suppl 3):S810–6.
- MacNeil A, Farnon EC, Wamala J, Okware S, Cannon DL, Reed Z, Proportion of deaths and clinical features in Bundibugyo Ebola virus infection, Uganda. Emerg Infect Dis. 2010;16:1969–72.
- Fields BN, Knipe DM, Howley PM, editors. Fields’ virology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007.
- Okware SI, Omaswa FG, Zaramba S, Opio A, Lutwama JJ, Kamugisha J, An outbreak of Ebola in Uganda. Trop Med Int Health. 2002;7:1068–75.
- Centers for Disease Control and Prevention. Outbreak of Ebola hemorrhagic fever, Uganda, August 2000–January 2001. 2001 Feb 9. Report nos. 0149–2195/0149–2195.
- Mupere E, Kaducu OF, Yoti Z. Ebola haemorrhagic fever among hospitalised children and adolescents in northern Uganda: epidemiologic and clinical observations. Afr Health Sci. 2001;1:60–5 .
- Rollin PE, Bausch DG, Sanchez A. Blood chemistry measurements and D-Dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. J Infect Dis. 2007;196(Suppl 2):S364–71.
- Hutchinson KL, Rollin PE. Cytokine and chemokine expression in humans infected with Sudan Ebola virus. J Infect Dis. 2007;196(Suppl 2):S357–63.
- Sanchez A, Wagoner KE, Rollin PE. Sequence-based human leukocyte antigen-B typing of patients infected with Ebola virus in Uganda in 2000: identification of alleles associated with fatal and nonfatal disease outcomes. J Infect Dis. 2007;196(Suppl 2):S329–36.
- McElroy AK, Erickson BR, Flietstra TD, Rollin PE, Nichol ST, Towner JS, Ebola hemorrhagic fever: novel biomarker correlates of clinical outcome. J Infect Dis. 2014 Mar 26; [Epub ahead of print].
- Mahanty S, Kalwar R, Rollin PE. Cytokine measurement in biological samples after physicochemical treatment for inactivation of biosafety level 4 viral agents. J Med Virol. 1999;59:341–5.
- Towner JS, Rollin PE, Bausch DG, Sanchez A, Crary SM, Vincent M, Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. J Virol. 2004;78:4330–41.
- Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser A Stat Soc.1995;57:289–300.
- Dinarello C, Porat R. The acute phase response. In: Goldman L, Ausiello DA, editors. Cecil textbook of medicine. 22nd ed. Philadelphia: Saunders;2004. p. 1733–5.
- Page AV, Liles WC. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence. 2013;4:507–16.
- Donald PR, Marais BJ, Barry CE III. Age and the epidemiology and pathogenesis of tuberculosis. Lancet. 2010;375:1852–4.
- Levy JA. The unexpected pleiotropic activities of RANTES. J Immunol. 2009;182:3945–6.
- Makino Y, Cook DN, Smithies O, Hwang OY, Neilson EG, Turka LA, Impaired T cell function in RANTES-deficient mice. Clin Immunol.2002;102:302–9.
- Ng LF, Chow A, Sun YJ, Kwek DJ, Lim PL, Dimatatac F, IL-1beta, IL-6, and RANTES as biomarkers of Chikungunya severity. PLoS ONE.2009;4:e4261.
- Brand HK, Ferwerda G, Preijers F, de Groot R, Neeleman C, Staal FJ, CD4+ T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection. Pediatr Res. 2013;73:187–93.
- John CC, Opika-Opoka R, Byarugaba J, Idro R, Boivin MJ. Low levels of RANTES are associated with mortality in children with cerebral malaria. J Infect Dis. 2006;194:837–45.
- Crawford A, Angelosanto JM, Nadwodny KL, Blackburn SD, Wherry EJ. A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection. PLoS Pathog. 2011;7:e1002098.
- Gupta M, Spiropoulou C, Rollin PE. Ebola virus infection of human PBMCs causes massive death of macrophages, CD4 and CD8 T cell sub-populations in vitro. Virology. 2007;364:45–54.
- Sanchez A, Lukwiya M, Bausch D, Mahanty S, Sanchez AJ, Wagoner KD, Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels. J Virol. 2004;78:10370–7.
- Warfield KL, Olinger G, Deal EM, Swenson DL, Bailey M, Negley DL, Induction of humoral and CD8+ T cell responses are required for protection against lethal Ebola virus infection. J Immunol. 2005;175:1184–91.
- Gupta M, Mahanty S, Greer P, Towner JS, Shieh WJ, Zaki SR, Persistent infection with Ebola virus under conditions of partial immunity. J Virol.2004;78:958–67.
- Sullivan NJ, Hensley L, Asiedu C, Geisbert TW, Stanley D, Johnson J, CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates. Nat Med. 2011;17:1128–31.
- Holven KB, Damas JK, Yndestad A, Waehre T, Ueland T, Halvorsen B, Chemokines in children with heterozygous familiar hypercholesterolemia: selective upregulation of RANTES. Arterioscler Thromb Vasc Biol. 2006;26:200–5.
- Lalani I, Bhol K, Ahmed AR. Interleukin-10: biology, role in inflammation and autoimmunity. Ann Allergy Asthma Immunol. 1997;79:469–83.
- Nash MC, Wade AM, Shah V, Dillon MJ. Normal levels of soluble E-selectin, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) decrease with age. Clin Exp Immunol. 1996;103:167–70.
- van Hinsbergh VW. Endothelium–role in regulation of coagulation and inflammation. Semin Immunopathol. 2012;34:93–106.
- Zegers BJ, Stoop JW, Reerink-Brongers EE, Sander PC, Aalberse RC, Ballieux RE. Serum immunoglobulins in healthy children and adults. Levels of the five classes, expressed in international units per millilitre. Clin Chim Acta. 1975;65:319–29.
- McGregor IA, Rowe DS, Wilson ME, Billewicz WZ. Plasma immunoglobulin concentrations in an African (Gambian) community in relation to season, malaria and other infections and pregnancy. Clin Exp Immunol. 1970;7:51–74 .
- Declerck PJ, Gils A. Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin. Semin Thromb Hemost.2013;39:356–64.
- Rosenthal CJ, Franklin EC. Variation with age and disease of an amyloid A protein-related serum component. J Clin Invest. 1975;55:746–53.
- Cai H, Song C, Endoh I, Goyette J, Jessup W, Freedman SB, Serum amyloid A induces monocyte tissue factor. J Immunol. 2007;178:1852–60.
- Wang X, Chai H, Wang Z, Lin PH, Yao Q, Chen C. Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol. 2008;295:H2399–408.
- Boegehold MA. Endothelium-dependent control of vascular tone during early postnatal and juvenile growth. Microcirculation. 2010;17:394–406.
- Lücke T, Kanzelmeyer N, Kemper MJ, Tsikas D, Das AM. Developmental changes in the L-arginine/nitric oxide pathway from infancy to adulthood: plasma asymmetric dimethylarginine levels decrease with age. Clin Chem Lab Med. 2007;45:1525–30.
- Hawkes M, Elphinstone RE, Conroy AL, Kain KC. Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier. Virulence.2013;4:543–55.
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
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.
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