Introduction
Chronic obstructive pulmonary disease (COPD) is a highly prevalent respiratory disorder that affects an estimated 210 million individuals worldwide [1]. In Korea, the 2012 Korea National Health and Nutrition Examination Survey reported a prevalence of 15.5% among individuals aged ≥40 years, and 57.6% among men aged ≥70 years [2]. The Global Burden of Disease Study by the World Health Organization ranked COPD as the sixth leading cause of death globally in 1990, rising to third in 2020. It is projected to become the fourth leading cause of death by 2030. The disease burden, as measured by disability-adjusted life years, has also shown a steady increase over recent decades [3]. Beyond its clinical impact, COPD imposes a substantial economic burden, through increased healthcare utilization and productivity loss [4].
COPD is characterized by persistent, irreversible airflow limitation due to an abnormal inflammatory response that affects the small airways and alveolar structures [1]. This inflammation is triggered by exposure to noxious particles or gases, such as cigarette smoke, and involves the activation of inflammatory cells, including macrophages, neutrophils, and lymphocytes. T-cell-mediated inflammatory responses play a central role in this process, and can persist even after cessation of exposure to causative agents, Therefore, T-cell-driven inflammation is considered a key factor in COPD pathogenesis [5,6].
OM-85 is an oral immunomodulatory agent composed of lyophilized bacterial lysates from 21 different bacterial strains. It has demonstrated the ability to reduce inflammation, while enhancing host immunity against respiratory infections [7-11]. Several studies have shown that OM-85 reduces the frequency of acute exacerbations in COPD, consequently lowering the use of antibiotics and systemic corticosteroids [12-20]. However, most prior investigations emphasized exacerbation prevention, with comparatively limited attention to symptom control and health-related quality of life (HRQoL). Symptom relief is a core treatment goal in COPD, because it directly improves daily functioning, and in contemporary guidance is recognized—alongside future risk reduction—as a primary target of therapy [1]. Importantly, higher day-to-day symptom burden is associated with worse HRQoL and greater disease impact [21], and specific symptom profiles (e.g., prominent morning symptoms) independently predict a higher risk of future exacerbations [22]. Broader syntheses similarly link greater symptom intensity to increased exacerbation risk and healthcare utilization [23]. Thus, improving symptoms and HRQoL is not merely palliative; it may also mitigate downstream clinical risk by reducing susceptibility to infection-triggered worsening, supporting activity and self-management, and stabilizing disease trajectories [1,21-23].
Against this background, the present study evaluated the efficacy of OM-85 for symptom control in patients with COPD, and explored whether symptom improvement is associated with the incidence of acute exacerbations. We hypothesized that OM-85 would yield clinically meaningful gains in symptoms and HRQoL—in particular, among patients with higher baseline symptom burden—and that symptom responders would show a lower risk of subsequent exacerbation events.
Materials and Methods
1. Population
This prospective, observational, single-arm study was conducted from June 1, 2022, to December 31, 2023, at four South Korean university hospitals: Chonnam National University Hospital, Chosun University Hospital, Chonbuk National University Hospital, and Wongkang University Hospital. Eligible participants were adults aged ≥18 years with a diagnosis of COPD, confirmed by post-bronchodilator forced expiratory volume in 1 second/forced vital capacity <−0.70 within the past year. Patients who had been prescribed and had taken OM-85 for a defined period were enrolled. Exclusion criteria included known hypersensitivity to OM-85 or its components, drug contraindications, or refusal to provide informed consent.
2. Protocol and sample size
OM-85 (Broncho-Vaxom, Aju Pharm Co. Ltd., Seoul, Korea), a lyophilized bacterial lysate, was administered as a 7 mg capsule once daily in the morning while fasting. The study period included a 3-month treatment phase, followed by a 3-month observation phase. During both phases, patients were evaluated monthly for symptoms, quality of life, acute exacerbations, and adverse events (AEs) (Supplementary Table S1).
The sample size was calculated based on a previous Korean epidemiological investigation reporting that approximately 60% of COPD patients experience persistent respiratory symptoms [24]. It was hypothesized that treatment with OM-85 would lead to a ≥12% improvement in symptom rates from baseline. To detect this effect with 80% power at a two-sided α of 0.05, the minimum required sample size was 540 participants. Allowing for a 10% attrition rate, the final target sample size was adjusted to 600 participants. Each of the four participating institutions aimed to recruit 150 patients.
3. Outcomes
The primary outcomes of this study were the change in respiratory symptoms and quality of life during treatment. HRQoL indices were assessed using the modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT), while quality of life was measured using the St. George’s Respiratory Questionnaire (SGRQ). The SGRQ was analyzed in three domains (symptoms, activity, and impacts), and SGRQ% refers to the percentage score calculated according to the official SGRQ scoring algorithm, with higher scores indicating greater impairment in health status. For responder analyses, the minimal clinically important difference (MCID) was defined as a reduction of ≥2 points from baseline for the CAT, and ≥4 points for the SGRQ. The secondary outcome was the incidence of acute exacerbations, defined as a sudden worsening of respiratory symptoms—such as dyspnea, cough, or sputum volume and purulence—beyond normal daily variation, requiring additional treatment, which treatment included antibiotics, systemic corticosteroids, or both [1].
4. Safety assessment
Safety was assessed by monitoring AEs, defined as any undesirable medical occurrence following the administration of the investigational product, regardless of the causal relationship. This included new symptoms, worsening of preexisting conditions, or abnormal laboratory findings. Adverse drug reactions (ADRs) were defined as harmful and unintended responses for which a causal link to OM-85 could not be excluded. Serious AEs/ADRs were defined as lifethreatening events, hospitalizations or their prolongation, permanent disability, or other medically significant conditions. A suspected serious adverse reaction was defined as a serious ADR differing in nature or severity from known product characteristics, and which could not be excluded as being related to the investigational product.
Causality was assessed based on timing, alternative explanations (e.g., comorbidities or concomitant medications), and response to drug discontinuation or readministration. Events were categorized as unlikely, possible, probable, or definite. The severity of each AE was graded according to the general principles of the Common Terminology Criteria for Adverse Events (CTCAE), as follows:
• Mild: transient and easily tolerated, with no interference in daily activities, and no need for medical intervention.
• Moderate: symptoms causing some interference with daily activities and requiring minimal medical intervention, but not lifethreatening.
• Severe: medically significant symptoms that are potentially lifethreatening, or result in hospitalization or disability.
5. Statistical analysis
Continuous variables were expressed as the mean±-standard deviation, while categorical variables were presented as the count (%). For between-group comparisons, t-tests were used for continuous variables, and Pearson’s chi-squared or Fisher’s exact test for categorical variables. Repeated-measures analysis of variance (ANOVA) was used to evaluate within-subject changes over time for continuous outcomes, while a generalized estimating equation approach was applied for nominal variables.
Binary logistic regression was performed to identify factors associated with the outcome. Variables with a p-value <0.2 in the univariable analysis were initially considered for inclusion. In addition, clinically important factors previously reported to be associated with the outcome were included, regardless of their univariable significance. A backward selection method was applied to derive the final multivariable model. A p-value <0.05 was considered statistically significant.
6. Ethics statement
This study was conducted in accordance with the principles of the Declaration of Helsinki, and was approved by the Institutional Review Boards and Ethics Committees of all participating institutions, including Chonnam National University Hospital (IRB No. BCRE22159). Written informed consent was obtained from all participants prior to their enrollment.
Results
Although the target sample size was 600, the enrollment rate was slower than anticipated, and the recruitment of additional centers was not feasible. Consequently, the study was terminated earlier than planned. A total of 332 patients were initially enrolled; of these, four withdrew informed consent and five were lost to followup with no subsequent records, resulting in a final study population of 323 patients included in the analysis.
Among these 323 patients, the mean age was 73.3± 7.8 years, and 83.9% (n=266) were male. A history of smoking was reported in 277 patients (85.8%), while 104 (32.2%) had a previous history of tuberculosis (TB), which included all individuals with a history of previous TB treatment, as well as those with imaging findings suggestive of old TB lesions. Common comorbidities included cardiovascular disease in 153 patients (47.4%), and diabetes mellitus in 75 patients (23.2%). Most patients (94.4%) were receiving inhaled bronchodilator therapy: 67 (20.7%) with long-acting muscarinic antagonists (LAMA) alone, 193 (59.8%) with combination therapy of a long-acting beta-2 agonist (LABA) and a LAMA, and 36 (11.1%) with an inhaled corticosteroid and LABA. Among the participants, 44.6% (n=144) had mMRC dyspnea grade ≥2, 39.0% (n=126) had CAT score ≥10, and 57.6% (n=186) of patients had SGRQ score ≥25. A previous history of AE in the previous 6 months was reported in 9.1% (29/319) of patients (Table 1).
Table 2 summarizes symptom-related outcomes at 3 and 6 months following OM-85 administration. No statistically significant change was observed in the mMRC dyspnea scale. The mean SGRQ score decreased from 34.74±22.08 at baseline, to 33.78±22.25 at 3 months (p=0.234), and 32.72±23.48 at 6 months (p=0.074), showing a trend toward improvement over time without statistical significance. Although CAT scores were significantly reduced at both 3 and 6 months compared to baseline (from 9.81±7.79 to 8.97±7.58 at 3 months, p=0.001; and to 8.69±7.35 at 6 months, p=0.001), the magnitude of change did not reach the MCID of 2 points required to be considered a CAT responder.
Multivariable logistic regression analysis was performed to identify risk factors for acute exacerbation in all patients receiving OM-85. Regardless of treatment response, a baseline CAT score ≥10 was a significant COPD-related factor associated with acute exacerbation (Supplementary Table S2). In a separate analysis assessing factors associated with increased AE frequency after treatment—defined as a higher frequency of AE during the study period compared to before—a baseline CAT score ≥10 was also a significant predictor (Supplementary Table S3).
Therefore, a subgroup analysis for patients with baseline CAT score ≥10 was conducted to assess the association between OM−85 response and exacerbation risk.
Compared to patients with baseline CAT <10, those with CAT ≥10 had a significantly lower body mass index (22.16±3.36 vs. 23.10±3.25, p=0.014), a higher prevalence of asthmatic components (24.6% vs. 6.1%, p<0.001), and were more likely to receive phosphodiesterase-4 inhibitors (9.5% vs. 3.6%, p=0.026). Use of LAMA monotherapy was more common in the CAT <10 group (26.9% vs. 11.1%, p<0.001). Other baseline characteristics, including age, sex, smoking status, comorbidities, pulmonary function, and history of exacerbation, did not differ significantly between the groups (Supplementary Table S4).
Table 3 presents the comparison of clinical outcomes according to baseline CAT scores. Both groups showed improvement over time (p for time effect <0.001), with a significantly greater reduction over time in the CAT ≥10 group (p for interaction <0.001). Although no significant time-by-group interaction was observed for responder rates (p=0.749), the CAT ≥10 group consistently demonstrated a higher proportion of responders compared to the CAT <10 group (p<0.001).
Also, SGRQ scores were significantly higher in the CAT ≥10 group across all time points (p for group effect <0.001), while both groups showed improvement over time (p for time effect=0.014), with a significantly greater reduction over time in the CAT ≥10 group (p for interaction <0.001). A significant time-by-group interaction was also observed for SGRQ responder rates (p=0.032), indicating that the proportion of responders in the CAT ≥10 group increased more markedly over time.
The frequency of acute exacerbations was significantly higher in the CAT ≥10 group compared to the CAT <10 group (p for group effect=0.004), with both groups showing a significant decrease over time (p for time effect=0.001). However, there was no significant time-by-group interaction (p=0.966), indicating a similar pattern of reduction in both groups (Table 3).
In the multivariable analysis of factors associated with increased frequency of AE, no variable reached statistical significance. However, SGRQ response at 6 months showed a negative association with the outcome, with a trend toward significance (odds ratio, 0.246; 95% confidence interval, 0.050 to 1.207; p=0.084) (Table 4).
In the safety assessment, 23 AEs were reported in 23 patients (7.1%) comprising 10 mild, 10 moderate, and three severe cases. Causality assessment indicated that three mild cases (palpitations, decreased appetite, and tingling sensation) were possibly related to OM-85, while one moderate case (urticaria) was deemed probably related. All three severe cases were assessed as either unrelated, or unlikely to be related, to OM-85 (Table 5).
Discussion
In this multicenter, real-world observational study, a 3-month course of OM-85 was associated with significant improvements in symptom burden and HRQoL in patients with COPD. Critically, these clinically meaningful benefits, as measured by CAT and SGRQ scores exceeding the MCID, were most pronounced in the subgroup of patients with a high baseline symptom load (CAT score ≥10) population. In addition, among patients with a baseline CAT score ≥10, those who were SGRQ responders at 6 months tended to have a lower incidence of increased frequency of acute exacerbation, suggesting a potential association. These findings suggest that the potential therapeutic value of OM-85 in COPD management may be greatest when targeted toward this more symptomatic population. Our study’s emphasis on symptom-focused outcomes provides a unique perspective within the broader landscape of OM-85 research. The existing literature presents a mixed picture; while several meta-analyses and trials have reported benefits in reducing exacerbation frequency [13,16], other studies have shown modest or no significant effects [17,19,20]. This discrepancy may be partly explained by differences in study design and patient populations. Many previous trials focused primarily on exacerbation prevention as the primary endpoint, and often enrolled patients with milder or more heterogeneous baseline symptoms. In contrast, our results highlight that by prioritizing patients with a greater initial symptom burden, it is possible to observe significant improvements in quality of life. This underscores the importance of patient selection, and suggests that to better identify those most likely to benefit from OM-85, future trials should consider stratifying patients by symptom severity.
The sustained clinical improvements observed in our study, which persisted for 3 months post-treatment, are supported by the well-established immunomodulatory mechanisms of OM-85. As an oral bacterial lysate, OM-85 has been shown to stimulate a multifaceted immune response. Mechanistically, it enhances innate immunity by promoting the maturation of dendritic cells and the activation of macrophages [25,26], bolsters mucosal defense by increasing secretory immunoglobulin A production [11], and modulates T-cell-mediated adaptive immunity [8,27]. These integrated immune adaptations provide a strong biological rationale for why OM-85 could produce durable clinical benefits, offering a plausible mechanism that should be tested in controlled settings.
While our study was not powered to definitively assess exacerbation prevention, our findings align with previous research that suggests a link between symptom control and exacerbation risk [28-30]. A baseline CAT score ≥10 was a significant predictor of acute exacerbations, and although not reaching statistical significance, an improvement in SGRQ score at 6 months showed a trend toward being protective against an increased frequency of exacerbations (p=0.084). This observation supports the potential dual role of OM-85, a hypothesis that warrants investigation in larger, randomized controlled trials.
With respect to safety, OM-85 was generally well-tolerated, consistent with its established safety profile in prior large-scale studies [10,16]. The AEs reported were infrequent, and mostly mild. However, the occurrence of some clinically important respiratory events, though not definitively linked to the treatment, suggests that prudent clinical monitoring remains advisable.
These findings are consistent with the established safety profile of OM-85 from prior large-scale studies [10,16], and support its use as a safe adjunctive therapy for symptom control in COPD patients, with appropriate monitoring.
Despite the encouraging real-world data presented, our study has several notable limitations that warrant discussion. The primary constraint is its observational, single-arm design, which lacks a control group. This inherent limitation prevents us from definitively concluding that the observed clinical improvements are solely attributable to OM-85, as other contributing factors may have influenced the outcomes. Furthermore, the absence of strict criteria for OM-85 prescription and broad enrollment criteria introduce the possibility of selection bias. Attending physicians’ preferences may have influenced who received the treatment, potentially favoring patients with a history of frequent respiratory infections.
Second, the study was underpowered due to early termination, which limits the generalizability of the results. Notably, only a small proportion of patients had a previous history of acute exacerbations at baseline, thereby making it difficult to directly assess the preventive effect of OM-85 on acute exacerbations. To address this limitation, we performed an indirect analysis by evaluating factors negatively associated with the increase in acute exacerbation frequency during the study period among patients with a positive history of acute exacerbations prior to enrollment. However, this approach inherently limited our ability to directly assess the preventive effect of OM-85 on acute exacerbations.
Third, heterogeneity in baseline characteristics—such as Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, exacerbation history, and prior treatment—along with incomplete clinical data, may have introduced bias and affected patient classification, thereby limiting the interpretation of treatment outcomes. Broad enrollment criteria may also have led to selection bias, particularly due to variations in prescribing practices among physicians.
Finally, reliance on questionnaire-based outcomes (e.g., CAT, SGRQ, mMRC) without objective clinical parameters, such as pulmonary function tests or biomarkers, may limit the objectivity of the results.
In conclusion, in this multicenter, single-arm observational study, OM-85 was associated with improvements in symptom burden and HRQoL, with clinically meaningful gains confined to patients with higher baseline symptoms (i.e., CAT ≥10). The regimen was generally well tolerated over the 3-month course, though prudent monitoring is advised, given occasional clinically important respiratory events. No preventive effect on acute exacerbations was demonstrated. These hypothesis- generating findings support considering OM-85 as an adjunctive option for symptom control in selected COPD patients, and warrant confirmation in adequately powered, prospective randomized trials.
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