Tumour necrosis factor receptor-75 and risk of COPD exacerbation in the azithromycin trial

To the Editor: We recently found that azithromycin taken daily for 1 year reduced the frequency of acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) in subjects who were selected as having an increased risk of exacerbations [1]. Since azithromycin has potentially adverse effects, identifying patients most likely to benefit might be useful for targeting therapy. Accordingly, we included a substudy in our trial that was prospectively designed to determine whether plasma levels at entry, or a change in levels at 3 months of any of four blood biomarkers, were associated with improved clinical response to azithromycin as compared to placebo. We chose to study biomarkers of inflammatory pathways likely to be relevant to chronic obstructive pulmonary disease (COPD) including C-reactive protein (CRP), interleukin (IL)-6, IL-8 and soluble tumour necrosis factor receptor 75 (sTNFR75). The parent trial comprised 1142 subjects with COPD randomised to receive azithromycin (250 mg orally each day) or placebo (1:1) for 12 months (ClinicalTrials.gov NCT00325897) [1]. To enrich our population for subjects more likely to have an AECOPDs, we required that subjects used either systemic corticosteroids, visited an emergency room or were hospitalised for AECOPD in the preceding 12 months or were using continuous supplemental oxygen [2]. We required subjects to be free of AECOPDs or other acute illness for ≥4 weeks prior to enrolment and excluded subjects with known congestive heart failure (CHF) and those with clinically defined bronchiectasis. The primary outcome was time to first AECOPD defined as “a complex of respiratory symptoms (increased or new onset) of more than one of the following: cough, sputum, wheezing, dyspnoea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids” [2]. We monitored participants for AECOPDs at follow-up clinic visits …