Abstract
OM-85 BV is an immunomodulatory agent used for prevention of exacerbations in persons with chronic lung disease. We conducted a systematic review of OM-85 BV to evaluate its efficacy and safety. A systematic search for relevant articles was performed. Studies were included if they involved persons with chronic obstructive pulmonary disease or chronic bronchitis and were randomized to OM-85 BV or placebo. Investigators extracted data on study design, participant characteristics, and clinical outcomes. Thirteen trials involving 2066 individuals met inclusion criteria. Three trials enrolled an older, more homogenous population with chronic obstructive pulmonary disease. Utilizing quantitative pooled analysis in these studies, with one or more acute exacerbations as the endpoint, we found a non-statistically significant trend in favor of OM-85 BV [relative risk 0.83, 95% confidence interval 0.65–1.05]. Ten trials enrolled a heterogeneous population with chronic bronchitis. In these trials, exacerbation rates were less with OM-85 BV in 4 of 9 trials reporting this outcome. Varied results in the outcomes of hospitalization, symptom scores, and antibiotic or steroid use were found across studies. Withdrawals and adverse events were similar between OM-85 BV and placebo. While OM-85 BV is used to prevent exacerbations in persons with chronic lung disease, consistent evidence across multiple important outcomes does not exist to clearly demonstrate clinical benefit. Further randomized controlled trials enrolling large numbers of persons with well-defined COPD are necessary to confirm the effectiveness of this agent.
Introduction
Acute exacerbations of chronic obstructive pulmonary disease (COPD) represent a serious medical condition throughout the world. Various definitions have been employed in clinical investigations of this disorder, though they generally include some combination of increased dyspnea, cough, wheezing, and change in the quantity/quality of sputum production. The frequency of exacerbations varies widely in individual persons with COPD Citation[[1]], but appear to occur 1–3 times per year Citation[1&2]. In its most severe form, exacerbations result in hospitalization. Aggressive medical therapy is often necessary in these circumstances, and, despite care in intensive care units, death may occur in 11–24% of the most severe cases Citation[3&4].
Few interventions have been shown to prevent exacerbations in COPD. Annual vaccination against influenza provides significant clinical benefit in persons with COPD, conferring protection against need for hospitalization and death Citation[[5]]. Smoking cessation lessens the decline of lung function Citation[[6]] andmay also reduce the risk of hospitalization Citation[[7]]. Pulmonary rehabilitation may decrease the risk of repeated hospitalization for respiratory causes in persons with COPD and appears to lessen the duration of hospitalization Citation[[8]]. Finally, the use of inhaled corticosteroids and long acting bronchodilators have been shown to reduce the rate of acute exacerbations in persons with COPD Citation[9-11]. Additional preventative measures would be helpful in alleviating the medical and economic burdens of this prevalent condition.
OM-85 BV is an immunomodulatory agent widely used in Europe for prevention of exacerbations in adults with COPD and chronic bronchitis. In addition, studies have been performed examining its efficacy in recurrent upper respiratory tract infections in children Citation[12-14] as well as chronic sinusitis in adults Citation[[15]]. In the year 2002, OM-85 BV more than 45 million doses were prescribed in over 50 countries (data from manufacturer). It is composed of the lyophilized extract of eight respiratory pathogens: Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, Klebsiella ozaenae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans, and Neisseria catarrhalis. Putative mechanisms by which OM-85 BV may reduce the frequency of exacerbations include macrophage activation Citation[[16]], up-regulation of adhesion molecules in phagocytic cells Citation[[17]], and increased production of secretory immunoglobulins Citation[[18]]. More recent studies have found OM-85 BV to increase gp130 gene transcription along with increased production of certain gp130-binding cytokines Citation[[19]], up-regulation of T-helper 1 function Citation[[20]], activation of monocyte derived dendritic cells Citation[[21]], and increased production of interferon-gamma production by CD4-positive T cells Citation[[22]].
We conducted a systematic review of randomized, controlled trials of OM-85 BV (OM PHARMA, Geneva, Switzerland) in persons with COPD or chronic bronchitis. Our primary goal was to evaluate the clinical efficacy and adverse effects of this agent.
Methods
Inclusion Criteria
Studies were included for analysis if they involved persons with COPD or chronic bronchitis and were randomized to OM-85 BV or placebo in a blinded fashion.
Identification of Relevant Trials
We searched Medline using an optimally sensitive search strategy for the years 1966 to 2003 using the Medical Subject Headings chronic obstructive pulmonary disease, chronic bronchitis, emphysema, chronic obstructive airways disease, OM-85, OM-85 BV, broncho-vaxom, broncho-munal, imocur, and ommunal Citation[[23]]. We also searched the Cochrane Library using a similar approach. Reference lists from all identified trials were reviewed for other relevant citations. The manufacturer was contacted for information on additional studies or unpublished data. We did not apply any language restrictions for study inclusion.
Data Abstraction and Study Appraisal
Two study investigators independently reviewed identified studies to determine if inclusion criteria were met. The following data were abstracted from each included study: study and participant characteristics, enrollment criteria, outcomes, adverse events, and number and reason for dropout. Missing or additional information was sought from authors and the manufacturer. Any discrepancy found between the independent reviewers was resolved by discussion and consensus.
Our primary outcome was the comparison of exacerbation rates in persons receiving OM-85 BV in comparison to placebo. Secondary outcomes to be examined included hospitalization frequency or duration, exacerbation-related medication use, health related quality of life or respiratory symptom measures, and adverse events or dropouts in OM-85 BV and placebo populations.
Overall study quality was assessed by examining treatment allocation concealment according to a scale proposed by Schulz et al. Citation[[24]]. This scale graded treatment allocation concealment on a 3-point scale: 1 (poor quality) = concealment inadequate due to predictable assignment to treatment or control groups; 2 (moderate quality) = no/inadequate description on the process of allocation concealment; 3 (best quality) = description to suggest adequate allocation concealment through central randomization or sequentially numbered sealed opaque envelopes.
Statistical Methods
In order to evaluate outcomes in studies enrolling similar populations, the 13 studies included in this analysis were divided into 2 groups according to clinical characteristics of enrolled subjects: 1) COPD, 2) chronic bronchitis (). The 3 trials with entry criteria of COPD were performed more recently and included the necessary data for quantitative pooled analysis of our primary outcome of interest, acute exacerbations Citation[25-27]. Outcomes data for one or more exacerbations during the study period were pooled and analyzed with the Cochrane Collaboration Review Manager (RevMan 4.2) software. Weighted relative risks (RR), comparing study intervention subjects to control subjects, and their 95% confidence intervals, were calculated for the categorical variables. A random-effects model was used, as there was evidence of heterogeneity between the studies, based on the chi-square test for heterogeneity at a significance level of p < 0.10.
Table 1. Description of Randomized Trials of OM-85 BV for Prevention of Exacerbations in Chronic Obstructive Pulmonary Disease (COPD) or Chronic Bronchitis.
The 10 trials that met inclusion criteria for chronic bronchitis differed in terms of dose and schedule of OM-85 BV, populations enrolled, or types of outcome measures reported Citation[28-37]. Additionally, these trials rarely reported sufficient statistical information required for quantitative pooled analysis (e.g., SD, SEM). These factors precludedquantitative analysis or pooling of findings across studies enrolling this heterogeneous population of persons with chronic bronchitis. Therefore, from both a clinical and statistical standpoint we decided that pooling of data would be both inappropriate and unfeasible.
Results
Thirteen studies met inclusion criteria. All studies were performed over a period of 6 months, though the prescribed regimen for OM-85 BV in the treatment population varied substantially between studies (). The concealment of treatment allocation was adequate in only 2 studies (score = 3) Citation[25&26]. The remaining 11 studies noted a random allocation of treatment, however the method of allocation was not further delineated (score = 2). All trials were described as placebo-controlled and double-blinded.
Three of the trials enrolled an older adult population with evidence of airflow obstruction that suggested a more uniform population of individuals with COPD Citation[25-27]. The entry criteria for these trials included spirometric evidence of airflow obstruction Citation[[26]], clinical evidence of chronic bronchitis Citation[[27]], or both Citation[[25]]. These studies included a total of 1054 study participants with a mean age of nearly 70 years and mean FEV1 < 60% of predicted normal (). Two of the trials were performed in Europe Citation[[25]]Citation[[27]], the other being completed in Canada Citation[[26]]. One of the trials was completed in June, 1999 and is not published Citation[[25]]. In all three trials, the primary study outcome was a comparison of exacerbation rates in persons receiving OM-85 BV compared to placebo.
Table 2. Baseline Characteristics of OM-85 BV Trials.
Ten of the trials enrolled persons with a clinical diagnosis of chronic bronchitis () Citation[28-37]. With the exception of 1 trial Citation[[34]], no clear definition for the diagnosis of “chronic bronchitis” was provided. The populations studied in these trials were younger, with at least 3 trials including persons less than 18 years of age Citation[[30]]Citation[[34]]Citation[[36]]. Overall, these studies included 1012 study participants with a mean age of 51 years (). Spirometric data was reported in only 4 trials, and these trials noted a mild reduction in mean FEV1. These trials were performed throughout Eastern and Western Europe, with one trial performed in Egypt Citation[[28]]. Four were reported in languages other than English Citation[[33]]Citation[35-37], and one trial was presented only in abstract form Citation[[34]]. The major outcomes for these trials were either exacerbation frequency or measures of symptomatic severity comparing persons receiving OM-85 BV to those receiving placebo.
Outcomes: Exacerbations
All 3 trials with entry criteria of COPD reported outcomes on rates of exacerbations. The efficacy of OM-85 BV in reducing rates of exacerbation was variable. The mean number of exacerbations over the 6-month trial duration was consistent among all 3 trials, ranging from 0.6–0.8 in OM-85 BV and 0.6–1.1 in placebo. One of the trials reported a statistically significant reduction in the rate of exacerbations with the use of OM-85 BV () Citation[[27]]. Soler et al. noted a trend towards reduction in rates of exacerbation with use of OM-85 BV (p = 0.08). With quantitative pooled analysis of one or more acute exacerbations as the endpoint, we found a non-statistically significant trend in favor of OM-85 BV [relative risk 0.83, 95% confidence interval 0.65–1.05] ().
Table 3. Outcome Data on Exacerbations and Hospitalizations from Randomized Trials of OM-85 BV.
Nine of the 10 trials with entry criteria of chronic bronchitis provided information on exacerbation rates or duration (). The mean number of exacerbations in these 10trials was higher, compared to the 3 trials with entry criteria of COPD (range 1.3–5.7 OM-85 BV, 3.1–7.8 placebo). Three trials reported a statistically significant reduction in the mean number of exacerbations with the use of OM-85 BV when compared to placebo Citation[[28]]Citation[32&33]. In another 3 trials, a reduced mean number of exacerbations were noted in the treatment population when compared to controls, however, no statistical comparison of the 2 populations was performed Citation[[29]]Citation[[34]]Citation[[36]]. One trial reported only a reduction in the mean duration of exacerbations in those receiving OM-85 BV compared to placebo, without providing data on the mean number of exacerbations Citation[[31]]. Finally, 2 trials found no statistical difference in treatment and control populations with regard to exacerbation rate Citation[[30]]Citation[[35]].
Outcomes: Hospitalizations
Two of three trials with entry criteria of COPD reported data on hospitalization (). The populations studied in these two trials had clinically important differences that preclude direct comparison of hospitalization frequency or duration. The most recent trial, performed by Soler andcolleagues, excluded persons with more severe obstructive lung disease, defined as a predicted FEV1 < 50% Citation[[25]]. In contrast, Collet et al. studied an older population with more advanced lung disease Citation[[26]]. There were few hospitalizations in either treatment or control populations in the Soler et al. trial, without statistically significant differences between study populations. Despite finding no difference in the frequency of exacerbations between OM-85 BV and placebo groups, Collet and colleagues found a statistically significant reduction in the duration of hospitalization due to respiratory causes. The third trial, performed by Orcel et al., enrolled an institutionalized, elderly population and provided no information on hospitalization at outside facilities Citation[[27]].
Only 2 of 10 trials with entry criteria of chronic bronchitis reported information on hospitalization (). Magyar and colleagues found a reduced mean duration of hospitalization in persons receiving OM-85 BV compared to placebo (18.9 vs. 29.5 days), however this difference was not statistically different Citation[[33]]. The only other trial reporting information on hospitalization did not find a significant difference between treatment and control populations Citation[[35]].
Outcomes: Antibiotic and Steroid Use
Data on the use of antibiotics or steroids was reported in two of three trials with entry criteria of COPD (). Soler et al. found no difference between treatment and control populations with regard to mean days of antibiotic use or the number of subjects receiving at least one prescription for corticosteroids Citation[[25]]. Orcel and colleagues found a statistically significant reduction in the use of antibiotics and corticosteroids in those receiving OM-85 BV compared to placebo, this despite relatively little overall use of these medications Citation[[27]].
Table 4. Outcome Data of Antibiotic and Steroid Use from Randomized Trials of OM-85 BV.
Eight of 10 trials with entry criteria of chronic bronchitis reported data on antibiotic therapy (). Four trials found a significant reduction in the cumulative use of antibiotics in the OM-85 BV group when compared to placebo Citation[[28]]Citation[[30]]Citation[33&34]. Another trial, performed by Xinogalos et al. Citation[[29]], found a reduction in antibiotic use in those receiving OM-85 BV in 2 of 6 monthly follow-up visits, without a significant difference in other assessment time points. Ahrens et al. did not perform a statistical comparison of antibiotic use between treatment and control populations, though they found fewer mean days of antibiotic use in those receiving OM-85 BV compared to placebo Citation[[36]]. The remaining 2 trials did not find any difference in antibiotic therapy between treatment and control populations Citation[[32]]Citation[[35]]. Only 2 trials with entry criteria of chronic bronchitis reported on corticosteroid use () Citation[[33]]Citation[[35]]. Neither trial found a significant difference between treatment and control groups.
Outcomes: Symptom Scores
In the trials with entry criteria of COPD, there was no significant difference in measures of symptomatic change or health-related quality-of-life between OM-85 BV and placebo study populations (data not shown). Soler et al., using defined, categorical measures of 4 clinical signs or symptoms, found a similar reduction in symptom score when comparing treatment and control groups Citation[[25]]. Collet and colleagues examined changes in a general health status measure (i.e., Short-form 36), and found little change over the course of the trial in both study populations Citation[[26]]. Orcel et al., without providing data, noted a similar reduction in respiratory signs and symptoms in those receiving OM-85 BV and placebo Citation[[27]].
Nine of 10 trials with entry criteria of chronic bronchitis reported information on clinical signs and symptoms of acute exacerbations of chronic bronchitis (data not shown). Generally, these clinical measures included 3–5 symptoms graded on a numerical scale of severity (e.g., 0 = absent, 1 = mild, 2 = moderate, 3 = severe). In four of these trials, a total symptom score was generated by adding individual measures of symptom severity. Two of these trials found a statistically significant improvement in symptom scores when comparing OM-85 BV to placebo study groups Citation[29&30], while two trials found no significant difference between treatment and control groups Citation[34&35]. Without providing a composite symptom score, Tag El Din et al. also noted significantly different and improved clinical symptoms when comparing OM-85 BV to placebo populations Citation[[28]]. Djuric and colleagues found mixed results, with two of four symptoms improving in treatment compared to control populations Citation[[32]]. The three remaining trials generally found no significant difference in symptomatic measures between study populations Citation[[31]]Citation[[33]]Citation[[37]].
Discontinuations and Adverse Events
Data on withdrawals from treatment, perhaps the best indicator of tolerability, was provided in 11 of 13 trials (). In trials with entry criteria of COPD, similar numbers withdrew from OM-85 BV (14.5%) and placebo (15.4%). Likewise, in trials with entry criteria of chronic bronchitis there was no evidence of adverse tolerability in those receiving OM-85 BV compared to placebo with withdrawal rates of 9.2% and 14.0%, respectively. Ten of 13 trials provided at least some information on specific adverse events or side effects. Generally, the adverse events were mild and similar in frequency between treatment and control populations. The most common reported adverse events were headache and gastrointestinal symptoms.
Table 5. Withdrawals from Treatment and Adverse Events for OM-85 BV Trials: Number of Subjects Reporting.
Discussion
We report the first systematic review evaluating the efficacy and safety of OM-85 BV in persons with COPD or chronic bronchitis. Interpretation of the available evidence is complicated by variation in the populations recruited forenrollment and the assessment of outcomes. This heterogeneity, as well as the failure of most studies to routinely report statistical data such as standard deviations, precluded pooling of study results for a quantitative estimate of efficacy for most endpoints of interest.
More homogeneous populations were generated by grouping the studies according to clinically relevant entry criteria of COPD or chronic bronchitis. The trials with entry criteria of COPD were performed most recently and had the highest methodological quality of the studies reviewed. It should be noted that even in these 3 studies, only Collet et al. required spirometric evidence of airflow obstruction for inclusion Citation[[26]]. While Orcel et al. found moderate airflow obstruction in their population (mean FEV1 55%), both they and Soler et al. included persons with a clinical diagnosis of chronic bronchitis Citation[[25]]Citation[[27]]. Presumably, a portion of both of these study populations included persons without airflow obstruction. Exacerbation rates across these trials were similar, suggesting a similarly stringent definition of exacerbation in all three studies. In these trials, we found varying findings in the most important clinical outcomes of exacerbation rate and/or hospitalization. One trial found a significant reduction in exacerbations with the use of OM-85 BV, with another finding a trend towards improvement. Sufficient information was provided on acute exacerbations in these trials to perform a pooled analysis. While the frequency of one or more acute exacerbations was less in those who received OM-85 BV in these trials, this difference did not reach the level of statistical significance. Of interest, Collet et al. also found a reduction in hospitalization due to respiratory causes with OM-85 BV Citation[[26]]. Neither of the 2 remaining articles was likely to find a difference in hospitalization either due to mild respiratory disease Citation[[25]] or institutionalization of their study population Citation[[27]]. However, these data should be viewed with caution as hospitalization was a secondary endpoint in the Collet study.
The trials with entry criteria of chronic bronchitis suffered from a number of methodological flaws. The study populations were poorly defined and likely represented a number of different pulmonary conditions including asthma. While all study participants were enrolled with “chronic bronchitis,” in only one study was this definition provided Citation[[34]]. Furthermore, treatment allocation, a validated measure of treatment quality, was not described in any study. Exacerbation rates in these trials were higher, and more variable, than in the trials with entry criteria of COPD. This suggests a less stringent definition of acute exacerbation of chronic bronchitis was employed, though no definition was provided in any of these trials. Overall, exacerbation rates were found to be statistically less with use of OM-85 BV in 4 of the 9 trials reporting this outcome Citation[[28]]Citation[31-33]. Four of 9 trials also found improved respiratory symptoms in those treated with OM-85 BV compared to placebo Citation[28-30]Citation[[32]]. However, none of these trials utilized a standardized, validated measure of respiratory symptoms Citation[38&39]. A significant reduction in antibiotic use among persons receiving OM-85 BV was reported in 4 of 8 trials Citation[[28]]Citation[[30]]Citation[33&34].
Consensus panels have called for clinical research aimed at identifying interventions to reduce the frequency and severity of exacerbations in persons with COPD Citation[40&41]. Decreasing acute exacerbations in COPD would be helpful in reducing the morbidity, mortality, and expense of this common disease. The available evidence suggests that the putative immunomodulatory agent OM-85 BV is well tolerated. However, consistent results across important clinical outcomes, such as exacerbation and hospitalization rates, are lacking to determine whether it is effective. Further randomized, controlled trials enrolling large numbers of persons with well-defined COPD are necessary to confirm the effectiveness of this agent. The measured outcomes of such trials should be rigorously defined and clinically important: exacerbation rate, all-cause and disease-specific hospitalization, respiratory health related quality of life measures, and cost effectiveness analyses.
Acknowledgment
This study was funded through an unrestricted grant from OM PHARMA, Geneva, Switzerland.
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