title: The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: results of two international observational cohort studies.
abstract: BACKGROUND
  Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies.
  
  
  METHODS
  Among patients with RT-PCR-confirmed influenza A(H1N1)pdm09 virus infection, odds ratios (ORs) estimated by logistic regression were used to summarize the associations of biomarkers measured at enrollment with worsened disease outcome or death after 14 days of follow-up for those seeking outpatient care (FLU 002) or after 60 days for those hospitalized with influenza complications (FLU 003). Biomarkers that were significantly associated with progression in both studies (p<0.05) or only in one (p<0.002 after Bonferroni correction) were identified.
  
  
  RESULTS
  In FLU 002 28/528 (5.3%) outpatients had influenza A(H1N1)pdm09 virus infection that progressed to a study endpoint of complications, hospitalization or death, whereas in FLU 003 28/170 (16.5%) inpatients enrolled from the general ward and 21/39 (53.8%) inpatients enrolled directly from the ICU experienced disease progression. Higher levels of 12 of the 25 markers were significantly associated with subsequent disease progression. Of these, 7 markers (IL-6, CD163, IL-10, LBP, IL-2, MCP-1, and IP-10), all with ORs for the 3(rd) versus 1(st) tertile of 2.5 or greater, were significant (p<0.05) in both outpatients and inpatients. In contrast, five markers (sICAM-1, IL-8, TNF-α, D-dimer, and sVCAM-1), all with ORs for the 3(rd) versus 1(st) tertile greater than 3.2, were significantly (p≤.002) associated with disease progression among hospitalized patients only.
  
  
  CONCLUSIONS
  In patients presenting with varying severities of influenza A(H1N1)pdm09 virus infection, a baseline elevation in several biomarkers associated with inflammation, coagulation, or immune function strongly predicted a higher risk of disease progression. It is conceivable that interventions designed to abrogate these baseline elevations might affect disease outcome.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. rdavey@niaid.nih.gov
authors.forename: Richard T
authors.initials: RT
authors.lastname: Davey
authors.forename: Ruth
authors.initials: R
authors.lastname: Lynfield
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Dwyer
authors.forename: Marcello H
authors.initials: MH
authors.lastname: Losso
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.forename: Deborah
authors.initials: D
authors.lastname: Wentworth
authors.forename: H Clifford
authors.initials: HC
authors.lastname: Lane
authors.forename: Robin
authors.initials: R
authors.lastname: Dewar
authors.forename: Adam
authors.initials: A
authors.lastname: Rupert
authors.forename: Julia A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Pett
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Uyeki
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Bruguera
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.forename: Nathan
authors.initials: N
authors.lastname: Cummins
authors.forename: Jens
authors.initials: J
authors.lastname: Lundgren
authors.forename: James D
authors.initials: JD
authors.lastname: Neaton
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics; D007251:Influenza, Human / Q000097:blood* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011379:Prognosis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators