Immunostimulants versus placebo for preventing exacerbations in adults with chronic bronchitis or chronic obstructive pulmonary disease.

backgroundIndividuals with chronic obstructive pulmonary disease (COPD) or chronic bronchitis may experience recurrent exacerbations, which negatively impact prognosis and quality of life, and can impose a significant socioeconomic burden on the individual and wider society. Immunostimulants are a broad category of therapies that may theoretically enhance non-specific immunity against several respiratory insults, thereby reducing exacerbation risk and severity. However, evidence to date for their use in this population is limited.

objectivesTo determine the efficacy of immunostimulants in preventing respiratory exacerbations in adults with chronic obstructive pulmonary disease, chronic bronchitis, or both. SEARCH

methodsWe used standard, extensive Cochrane search methods. The latest literature search was conducted on 25 January 2022.  SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) that compared immunostimulant therapy, administered by any method and with the intention of preventing (rather than treating) exacerbations, with placebo for a minimum treatment duration of one month in adults with chronic bronchitis or COPD, or both. We excluded participants with other respiratory conditions.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were number of participants with no exacerbations during the study period and all-cause mortality, secondary outcomes were respiratory-related mortality, quality of life, number of participants requiring antibiotics, exacerbation duration, respiratory-related hospitalisation duration and adverse events/side effects. We used GRADE to assess certainty of evidence for each outcome. MAIN

resultsThis review included 36 studies involving 6192 participants. Studies were published between 1981 and 2015. Duration ranged from three to 14 months. The mean age of study participants varied between 35.2 and 82 years. Twelve studies examined participants with COPD only. Seventeen studies reported baseline lung function values; most indicated a moderate-to-severe degree of airflow limitation. Nineteen studies indicated inclusion of participants with a mean baseline exacerbation frequency of two or more in the preceding year. Immunostimulants investigated were OM-85, AM3, RU41740 (Biostim), Ismigen, Diribiotine CK, thymomodulin, pidotimod, D53 (Ribomunyl), Lantigen B, Symbioflor, and hyaluronan; routes of administration were oral, sublingual, and subcutaneous. The risk of bias of the included studies was mostly low or unclear. Participants receiving immunostimulants for a mean duration of six months were slightly more likely to be free of exacerbations during that time (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.15 to 1.90; 15 RCTs, 2961 participants; moderate-certainty evidence). The overall number needed to treat with immunostimulants for a mean of six months, to prevent one participant from experiencing an exacerbation, was 11 (95% CI 7 to 29). This outcome was associated with a moderate degree of unexplained heterogeneity (I AUTHORS'

conclusionsIn participants with chronic bronchitis or COPD, we are moderately confident that treatment with immunostimulants is associated with a small reduction in the likelihood of having an exacerbation and a moderate reduction in the requirement for antibiotics. Low numbers of events limit interpretation of the effect of immunostimulants on all-cause and respiratory-related mortality. We are uncertain whether immunostimulants improve quality of life, and whether they are associated with a reduction in exacerbation and respiratory-related hospitalisation durations, although immunostimulants were generally associated with a positive effect direction in the studies that examined these outcomes. Immunostimulants appear to be safe and well-tolerated, and are not associated with an increased risk of adverse events.