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.

Figure 1. Biomarker study designs.

The respective study designs and distribution of patients with and without severe disease outcomes in the outpatient case-control study FLU 002 (A) and in the hospitalization cohort study FLU 003 (B).

Figure 2. Biomarkers significantly related to disease progression.

The biomarkers found to be significantly associated with disease progression in both studies (A) and in FLU 003 only (B) are shown. Odds ratios (3^rd/1^st tertile) and 95% confidence intervals are depicted.

Figure 3. Mortality by tertiles of IL-6 in the FLU 003 study.

A Kaplan-Meier graph of cumulative mortality (%) for FLU 003 participants according to baseline levels of IL-6 as grouped into tertiles.

Figure 4. Relationship of functional categories of biomarkers to disease progression in FLU 002 and FLU 003.

The odds ratios and 95% confidence intervals for the risk of disease progression in FLU 002 (in blue) and FLU 003 (in red) are depicted according to four functional categorizations of the 25 biomarkers analyzed in these two studies.