• Ashley Fraser and Phillippa Poole.
• Auckland DHB, Auckland, New Zealand.
• Cochrane Db Syst Rev. 2022 Nov 14; 11 (11): CD013343CD013343.

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 (I2 = 53%). Type of immunostimulant, baseline lung function, baseline exacerbation frequency, treatment duration, and follow-up duration did not modify the effect size, although due to heterogeneity and limited study and participant numbers within some subgroups, the validity of the subgroup treatment effect estimates were uncertain. Immunostimulants probably result in little to no difference in all-cause mortality (OR 0.64, 95% CI 0.37 to 1.10; 5 RCTs, 1558 participants; moderate-certainty evidence) and respiratory-related mortality (OR 0.40, 95% CI 0.15 to 1.07; 2 RCTs, 735 participants; low-certainty evidence) compared to placebo; however, the effects were imprecise and data quality limited the certainty of these results.  There was a small improvement in health-related quality of life, as measured by the St George's Respiratory Questionnaire (SGRQ), with immunostimulant compared to placebo (mean difference -4.59, 95% CI -7.59 to -1.59; 2 RCTs, 617 participants; very-low certainty evidence). The effect estimate just met the minimum clinically important difference (MCID) score of 4 units; however, the CI width means the possibility of a non-meaningful difference cannot be excluded. The pooled result from five studies indicated that immunostimulants likely reduce the number of participants requiring antibiotics over a mean duration of six months (OR 0.34, 95% CI 0.18 to 0.63; 542 participants; moderate-certainty evidence). This outcome had a low-to-moderate degree of heterogeneity (I2 = 38%), but the direction of effect was consistent across all studies. There was no evidence of a difference in the odds of experiencing an adverse event with immunostimulant compared to placebo, over a mean duration of six months (OR 1.01, 95% CI 0.84 to 1.21; 20 RCTs, 3780 participants; high-certainty evidence). The CI limits for the associated risk ratio (RR) did not cross thresholds for appreciable harm or benefit (RR 1.02, 95% CI 0.92 to 1.13). An additional seven studies reported no events rates in either study arm. Meta-analyses were not performed for the outcomes of exacerbation duration and respiratory-related hospitalisation duration, due to high levels of heterogeneity across the included studies (exacerbation duration: I2 = 92%; respiratory-related hospitalisation duration: I2 = 83%). Results from an effect direction plot and binomial probability test for exacerbation duration indicated that a significant proportion of studies (94% (95% CI 73% to 99%); P = 0.0002) favoured intervention, possibly indicating that immunostimulants are efficacious in reducing the mean exacerbation duration compared to placebo. However, the degree of uncertainty associated with this estimate remained high due to data quality and heterogeneity. Three studies reported mean duration of respiratory-related hospitalisation, two of which demonstrated a direction of effect that favoured immunostimulant over placebo.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.Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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