Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial

Antiviral Res. 2017 Aug:144:48-56. doi: 10.1016/j.antiviral.2017.05.008. Epub 2017 May 20.

Abstract

Introduction: - Macrolides can ameliorate inflammation in respiratory diseases, providing clinical benefits. Data in influenza is lacking.

Method: - A randomized, open-label, multicenter trial among adults hospitalized for laboratory-confirmed influenza was conducted. Study treatments of oseltamivir and azithromycin (500 mg/day), or oseltamivir alone, both for 5 days, were allocated at 1:1 ratio. The primary outcome was plasma cytokine/chemokine concentration change over time (Day 0-10); secondary outcomes were viral load and symptom score changes. Generalized Estimating Equation (GEE) models were used to analyze longitudinal data.

Results: - Fifty patients were randomized to the oseltamivir-azithromycin or oseltamivir groups, with comparable baseline characteristics (age, 57 ± 18 years; A/H3N2, 70%), complications (72%), and viral load. Pro-inflammatory cytokines IL-6 (GEE: β -0.037, 95%CI-0.067,-0.007, P = 0.016; reduction from baseline -83.4% vs -59.5%), CXCL8/IL-8 (β -0.018, 95%CI-0.037,0.000, P = 0.056; -80.5% vs -58.0%), IL-17 (β -0.064, 95%CI-0.117,-0.012, P = 0.015; -74.0% vs -34.3%), CXCL9/MIG (β -0.010, 95%CI-0.020,0.000, P = 0.043; -71.3% vs -56.0%), sTNFR-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin group. There was a trend toward faster symptom resolution (β -0.463, 95%CI-1.297,0.371). Viral RNA decline (P = 0.777) and culture-negativity rates were unaffected. Additional ex vivo studies confirmed reduced induction of IL-6 (P = 0.017) and CXCL8/IL-8 (P = 0.005) with azithromycin.

Conclusion: - We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infections. Virus control was unimpaired. Clinical benefits of a macrolide-containing regimen deserve further study. [ClinicalTrials.gov NCT01779570].

Keywords: Anti-inflammatory effects; Influenza; Macrolide.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents / administration & dosage*
  • Antiviral Agents / administration & dosage
  • Azithromycin / administration & dosage*
  • Cytokines / blood
  • Female
  • Hospitalization
  • Humans
  • Influenza, Human / drug therapy*
  • Influenza, Human / pathology*
  • Longitudinal Studies
  • Macrolides / administration & dosage*
  • Male
  • Middle Aged
  • Oseltamivir / administration & dosage
  • Plasma / chemistry
  • Severity of Illness Index
  • Treatment Outcome
  • Viral Load

Substances

  • Anti-Inflammatory Agents
  • Antiviral Agents
  • Cytokines
  • Macrolides
  • Oseltamivir
  • Azithromycin

Associated data

  • ClinicalTrials.gov/NCT01779570