Azithromycin and risk of COPD exacerbations in patients with and without Helicobacter pylori

Seung Won Ra,On Behalf Of The Canadian Respiratory Research Network ,Sheena Tam,Meilan K Han,Don D Sin,John E Connett,Nick Fishbane,Robert M Reed,Yeni Oh,Richard Albert,Marc A Sze,Fernando J Martinez,Stephen C Lazarus,Shawn D Aaron,S F Paul Man,Gerard J Criner,Prescott G Woodruff,Eun Chong Lee

doi:10.1186/s12931-017-0594-x

Abstract

BackgroundHelicobacter pylori (HP) infection is associated with reduced lung function and systemic inflammation in chronic obstructive pulmonary disease (COPD) patients. Azithromycin (AZ) is active against HP and reduces the risk of COPD exacerbation. We determined whether HP infection status modifies the effects of AZ in COPD patients.MethodsPlasma samples from 1018 subjects with COPD who participated in the Macrolide Azithromycin (MACRO) in COPD Study were used to determine the HP infection status at baseline and 12 months of follow-up using a serologic assay. Based on HP infection status and randomization to either AZ or placebo (PL), the subjects were divided into 4 groups: HP+/AZ, HP-/AZ, HP+/PL, and HP-/PL. Time to first exacerbation was compared across the 4 groups using Kaplan-Meier survival analysis and a Cox proportional hazards model. The rates of exacerbation were compared using both the Kruskal-Wallis test and negative binomial analysis. Blood biomarkers at enrolment and at follow-up visits 3, 12, and 13 (1 month after treatment was stopped) months were measured.ResultsOne hundred eighty one (17.8%) patients were seropositive to HP. Non-Caucasian participants were nearly three times more likely to be HP seropositive than Caucasian participants (37.4% vs 13.6%; p < 0.001). The median time to first exacerbation was significantly different across the four groups (p = 0.001) with the longest time in the HP+/AZ group (11.2 months, 95% CI; 8.4–12.5+) followed by the HP-/AZ group (8.0 months, 95% CI; 6.7–9.7). Hazard ratio (HR) for exacerbations was lowest in the HP+/AZ group after adjustment for age, sex, smoking status, ethnicity, history of peptic ulcer, dyspnea, previous hospital admission, GOLD grade of severity, and forced vital capacity (HR, 0.612; 95% CI, 0.442–0.846 vs HR, 0.789; 95% CI, 0.663–0.938 in the HP-/AZ group). Circulating levels of soluble tumor necrosis factor receptor-75 were reduced only in the HP+/AZ group after 3 months of AZ treatment (−0.87 ± 0.31 μg/L; p = 0.002); levels returned to baseline after discontinuing AZ.ConclusionsAZ is effective in preventing COPD exacerbations in patients with HP seropositivity, possibly by modulating TNF pathways related to HP infection.

Highlights

Helicobacter pylori (HP) infection is associated with reduced lung function and systemic inflammation in chronic obstructive pulmonary disease (COPD) patients
To determine whether AZ and HP status modified common biomarkers of systemic inflammation, we related these parameters to plasma levels of C-reactive protein (CRP) and soluble tumor necrosis factor receptor-75, which had been previously measured at baseline and at the 3, 12 and 13 (1 month after treatment discontinuation) month visits in the Macrolide Azithromycin (MACRO) participants
There were no significant differences in age, sex, smoking status, pack years of smoking, dyspnea grade, hospital admission for COPD or the use of systemic steroids and/or antibiotics past year, lung function, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade of severity of airflow limitation, or baseline levels of biomarkers (CRP and soluble tumor necrosis factor receptor-75 (sTNFR75)) between the 4 groups

Summary

Introduction

Helicobacter pylori (HP) infection is associated with reduced lung function and systemic inflammation in chronic obstructive pulmonary disease (COPD) patients. Persistent systemic inflammation affects ~15 to 20% of patients with chronic obstructive pulmonary disease (COPD), which in turn is associated with an increased risk of exacerbations and mortality [1]. The etiology for this persistent inflammation in COPD, is largely a mystery [2]. Using serum samples from the Lung Health Study (LHS), we recently showed that ~18% of patients in that cohort had serologic evidence for HP infection, which was associated with systemic inflammation and reduced lung function [6]. HP infection may promote persistent low-grade inflammation by up-regulating antigenic stimulation in mucosal surfaces and by skewing the lymphocyte response towards a T helper (Th) lymphocyte 1 bias [7,8,9]

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