Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized
Nelson Lee1, Chun-Kwok Wong2, Martin C W Chan3
1Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong; Stanley Ho Center for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong.
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].
Insights
Adding azithromycin to oseltamivir significantly reduced inflammation in hospitalized influenza patients. This macrolide treatment did not impair viral control, suggesting potential clinical benefits for severe flu.
Area of Science:
- Infectious Diseases
- Pharmacology
- Immunology
Background:
- Macrolides are known to reduce inflammation in respiratory conditions.
- Clinical data on macrolide use in influenza patients is limited.
- Influenza can cause significant inflammation and complications.
Purpose of the Study:
- To investigate the anti-inflammatory effects of adjunctive azithromycin in adults hospitalized with influenza.
- To assess the impact of azithromycin on cytokine levels, viral load, and symptom scores in influenza patients.
Main Methods:
- A randomized, open-label, multicenter trial was conducted.
- Adults with confirmed influenza received either oseltamivir plus azithromycin or oseltamivir alone for 5 days.
- Plasma cytokine/chemokine concentrations, viral load, and symptom scores were analyzed over time using Generalized Estimating Equation models.
Main Results:
- The oseltamivir-azithromycin group showed significantly faster declines in pro-inflammatory cytokines IL-6, IL-17, and CXCL9/MIG compared to oseltamivir alone.
- Faster reduction in other inflammatory markers including CXCL8/IL-8, sTNFR-1, IL-18, and CRP was observed.
- There was a trend towards faster symptom resolution, but viral RNA decline and culture-negativity rates were unaffected.
- Ex vivo studies confirmed azithromycin's ability to reduce IL-6 and CXCL8/IL-8 induction.
Conclusions:
- Adjunctive macrolide treatment with azithromycin demonstrates significant anti-inflammatory effects in adults with severe influenza.
- This regimen did not compromise viral clearance, suggesting a potential for improved clinical outcomes.
- Further research is warranted to explore the clinical benefits of macrolide-containing regimens for influenza.
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