Plasma Levels of IL-8 and Microparticle Tissue Factor Activity Are Associated with Mortality in Patients with Primary Influenza A/H1N1 Infection

Background and Objective: Treatment and triage decisions during influenza remain difficult due to lack of reliable severity of illness predictive score. Influenza A/H1N1 induces the expression and release of tissue-factor bearing microparticles (MP-TF), contributing to a prothrombic milieu. However, there are no studies reporting levels of circulating TF-expressing MPs during the course of human influenza. We sought to determine if MP-TF are an early predictor of mortality in critically ill patients with influenza A/H1N1.

Methods: This was a prospective, multicenter, case-cohort pilot study of three academic intensive care units. We prospectively studied 15 patients with primary influenza A/H1N1 that included 7 survivors and 8 non-survivors. For comparison, 27 healthy, medication-free, age- and gender-matched control subjects were also prospectively studied. Plasma was prepared from blood drawn upon ICU admission in influenza patients. MP-TF activity, thrombin-antithrombin complexes (TATc), and D-dimers were measured as markers of activation of coagulation. Plasma cytokine levels were measured on the same blood samples. Patients were followed for the primary outcome of 28-day mortality.

Results: The average admission APACHE II score of the influenza patients was 25.5±9.3, 60% of patients had shock, and the 28-day mortality rate was 53.3% (n=8/15). Compared to healthy controls, influenza patients had significantly higher plasma fibrinogen, C-reactive protein (CRP) MP-TF activity, TATc, D-dimer and a prolonged prothrombin time. However, of these procoagulant markers, only MP-TF activity predicted influenza related mortality (5.6±1.2 pg/ml in non-survivors vs. 1.8±0.8 pg/mL in survivors, p < 0.05; Table 1 and Fig. 1A). MP-TF activity, TATc levels, and D-dimer did not correlate with APACHE II score, platelet count, fibrinogen levels, CRP, or age or between patients with severe sepsis versus septic shock. Influenza non-survivors also had significantly higher plasma IL-8 levels compared with survivors (71.8±29.1 pg/ml vs. 17.3±3.7 pg/mL, p < 0.05; Figure 1B). MP-TF activity and IL-8 levels were significantly and positively correlated (r² = 0.60, P =0.003; Figure 1C). Other cytokines, TATc, and D-dimer were not different between non-survivors and survivors.

Conclusions: This study demonstrates that plasma IL-8 and MP-TF activity measured upon admission in patients with severe, primary influenza A/H1N1 infection is associated with subsequent mortality. Thus, these biomarkers may serve as very early prognostic markers for patients with influenza A/H1N1.

Figure 1.

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MP-TF activity and IL-8 predict mortality in patients with influenza A/H1N1.

(A) Plasma levels of MP-TF activity and (B) IL-8 levels in survivors and non-survivors. (C) Correlation between MP TF activity and IL-8 levelsin H1N1 influenza-infected patients (*P <0.05).

Figure 1.

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MP-TF activity and IL-8 predict mortality in patients with influenza A/H1N1.

(A) Plasma levels of MP-TF activity and (B) IL-8 levels in survivors and non-survivors. (C) Correlation between MP TF activity and IL-8 levelsin H1N1 influenza-infected patients (*P <0.05).

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