A critical analysis of the effect of OM-85 for the prevention of recurrent respiratory tract infections or wheezing/asthma from systematic reviews with meta-analysis

Abstract

Acute respiratory tract infections (RTIs) are one of the most common causes of pediatric consultations/hospitalizations and a major trigger for asthma exacerbations. Some consensus statements have recommended the use of immunostimulants to boost natural defenses against severe or repeated infections. One of the most common immunostimulants is OM-85; while several randomized clinical trials (RCTs) have evaluated its efficacy in preventing acute RTIs and wheezing/asthma exacerbations, results have been conflicting. Similarly, various systematic reviews with meta-analyses (SRMs) on OM-85 have used different strategies, populations, and outcomes; moreover, SRM conclusions are limited when the original studies are highly heterogeneous or have a low quality, hindering the generalizability of the findings. Here we summarize the evidence on the effect of OM-85 to prevent acute RTIs, wheezing/asthma episodes, or loss of asthma control in children, by including and critically evaluating all SRMs published to date. We searched for SRMs on OM-85 in three publication databases, and found nine SRMs (seven for RTI, and two for wheezing/asthma). Among those, one had a high confidence evaluation of quality (AMSTAR-2 tool) and found a reduction in the total number of acute RTIs among the OM-85 group. Overall, no strong recommendations can be derived from the existing literature, mainly due to the high heterogeneity among included RCTs and SRMs. Further, large, high-quality RCTs are needed to confirm the true efficacy of OM-85 for the prevention of acute RTIs, asthma development, and asthma exacerbations.

INTRODUCTION

Respiratory tract infections (RTIs) are one of the most common causes of pediatric consultations and hospitalizations.¹ Although most upper RTIs (URTIs) such as rhinitis, otitis media, pharyngitis, and tonsillitis are self-limiting, they can contribute to lower RTIs (LRTIs) such as bronchiolitis, bronchitis, and pneumonia.² Most RTIs are caused by viruses, and risk may be related to congenital factors, waning immunity, trace element deficiencies, and social determinants of health including the living environment.^{3, 4} Recurrent RTIs are associated with vast health and economic burdens, resulting in a decline in the quality of life of patients and families.⁵

Viral RTIs are a major trigger for asthma exacerbation, especially important given the rising rates of severe acute asthma exacerbations, which constitute a significant cause of morbidity for children.⁶ Some studies have reported that bacterial RTIs may trigger asthma exacerbations just as frequently as viruses.⁷ In addition, RTIs are associated with preschool wheezing affecting up to 30% of children, and nearly 15–25% of children experience recurrent wheezing before school age.⁸ Viral RTIs are associated with a high level of inflammation and may contribute to airway remodeling⁹ and to significantly increased risk of preschool recurrent wheezing and asthma later in life,^10–12 which may in turn have irreversible effects on lung function.

Some consensus documents and statements recommend the use of immunostimulants to boost the body’s natural defenses against infections and reduce the probability of reinfection in susceptible children.^13–15 Bacterial lysates used in clinical studies generally include polyvalent chemical or mechanical bacterial lysates (PCBL or PMBL, respectively). OM-85 (brand names Broncho-Vaxom, OM-85 BV, Broncho Munal, Ommunal, Imoccur, Vaxoral and Paxoral) is a PCBL in which bacteria are cultured in batches, inactivated by heat, and subjected to alkaline lysis after being harvested; the lysates of 21 bacteria are then mixed and lyophilized.¹⁶

Several randomized clinical trials (RCTs) have been performed to determine the efficacy of OM-85 in preventing acute RTIs, acute wheezing episodes, and/or asthma exacerbations, with some yielding conflicting results. Similarly, systematic reviews and meta-analyses have been published using different strategies, populations, and outcomes. Systematic reviews and meta-analyses can provide convincing and reliable evidence when the results of the studies they include show clinically important effects of similar magnitude. However, their conclusions are less clear when the original studies included are highly heterogeneous or have a low quality, hindering the generalizability of the findings.

This review aims to summarize and critically evaluate evidence on the effect of OM-85 preventing RTIs or wheezing/asthma episodes in children, by including all systematic reviews with meta-analysis published to date, while reinforcing the incorporation of double-blinded RCTs, quality evaluation, and the use of the I² statistic for measured heterogeneity.

METHODS

We identified the published studies in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) (up to May 2023) database, using the terms: ((OM-85) OR (Bronchovaxom)) AND ((Child*)) limited to meta-analyses or systematic reviews of studies in humans. Studies published solely in abstract form were excluded because the methods and results could not be fully analyzed. To be included, studies had to meet all the following criteria: (a) systematic review of RCTs with meta-analysis without language restriction (only the latest version was considered); (b) inclusion of children (1–18 years) or in a mixed population (adults and children) only if data exclusively on children was presented separately; (c) recurrent RTIs or wheezing/asthma (acute exacerbations or asthma control) as outcomes; and (d) comparison between OM-85 versus placebo or other therapies. Reviews done exclusively on laboratory or experimental data were excluded, as were any systematic reviews without meta-analysis, consensus documents, or other guidelines.

Data extraction and assessment of risk of bias: Titles, abstracts, and citations were independently analyzed by two authors (J.C.R. and K.N.T.). Disagreements were discussed and resolved by consensus or, if unable to reach consensus, by arbitration by the third author (E.F.). Based on the full text form, all the studies were evaluated for inclusion criteria, type of intervention, population included, study design, and outcomes. After obtaining full reports about potentially relevant trials, eligibility was assessed. The pooled estimate of the principal and secondary outcomes with their 95% confidence interval (CI), I² statistic, and number needed to treat (NNT) are presented only if they were available. The methodological quality of the systematic reviews was assessed using AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews). AMSTAR-2 evaluates 16 domains (7 of them critical), and rates overall confidence in four categories: high (no or one non-critical weakness), moderate (more than one non-critical weakness), low (one critical flaw with or without non-critical weaknesses) and critically low (more than one critical flaw with or without non-critical weaknesses).¹⁷ Disagreements were discussed and resolved by consensus as above.

RESULTS

Figure 1 shows the study selection flowchart. Thirteen systematic reviews from databases retrieved for further evaluation, among which 9 systematic reviews with meta-analysis were included (7 related to RTIs and 2 to wheezing/asthma). The reasons for excluding the other studies are shown in Figure 1. Using the AMSTAR-2 tool to evaluate the quality of the systematic review (Table 1), only 1 out of 9 systematic reviews had a “high confidence”, 1 a “low confidence”, and 7 had “critical low confidence”. The main findings of each systematic review are summarized on Table 2.

Figure 1:

Flow chart for identification of usable systematic reviews of randomized clinical trials (SRCTs)

Table 1:

Quality assessment of the nine systematic reviews.

AMSTAR-2 Question	De La Torre 2005	Steurer-Stey 2007	Schaad 2010	Del-Rio-Navarro 2012	Yin 2018	de Boer 2020	Cao 2021	Zhang 2022	Yao 2023
1	Y	Y	Y	Y	Y	Y	Y	Y	Y
2	Y	PY	Y	Y	Y	Y	PY	PY	Y
3	Y	Y	Y	Y	Y	Y	Y	Y	Y
4	PY	Y	Y	Y	PY	Y	PY	PY	Y
5	N	Y	N	Y	Y	Y	N	Y	Y
6	N	Y	N	Y	Y	Y	N	Y	Y
7	N	N	N	Y	N	N	N	N	N
8	Y	Y	Y	Y	Y	Y	PY	Y	Y
9	N	Y	Y	Y	Y	Y	PY	Y	Y
10	N	Y	Y	N	N	N	N	N	N
11	PY	Y	Y	Y	Y	Y	Y	Y	Y
12	N	Y	Y	Y	Y	Y	N	Y	Y
13	N	Y	Y	Y	Y	Y	N	Y	PY
14	N	Y	Y	Y	N	Y	N	N	Y
15	N	N	N	Y	N	N	Y	N	Y
16	N	N	Y	Y	Y	Y	Y	Y	Y
Overall quality	Critical low	Critical low	Critical low	High	Critical low	Critical low	Critical low	Critical low	Low

Quality assessment based on AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews-2): https://pubmed.ncbi.nlm.nih.gov/28935701/

Y=yes, PY=partial yes, N=no.

AMSTAR-2 Questions:

1. Did the research questions and inclusion criteria for the review include the components of PICO?
2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?
3. Did the review authors explain their selection of the study designs for inclusion in the review?
4. Did the review authors use a comprehensive literature search strategy?
5. Did the review authors perform study selection in duplicate?
6. Did the review authors perform data extraction in duplicate?
7. Did the review authors provide a list of excluded studies and justify the exclusions?
8. Did the review authors describe the included studies in adequate detail?
9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?
10. Did the review authors report on the sources of funding for the studies included in the review?
11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?
12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?
13. Did the review authors account for RoB in individual studies when interpreting/discussing the results of the review?
14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?
15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?
16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?

Table 2.

Main findings of the nine systematic reviews.

Author/year	De la Torre 2005	Steurer-Stey 2007	Schaad 2010	Del-Rio-Navarro 2012	Yin 2018	de Boer 2020	Cao 2021	Zhang 2022	Yao 2023
Publication years of included RCTs	1982 – 2003	1982 – 2003	1982 – 2007	1984 – 2003	1984 – 2017	2007 – 2018	1984 – 2020	1984 −2019	2009 – 2021
Region/country of origin of included RCTs	Europe, Mexico	Europe, Mexico	Europe, China	Europe, Mexico	Europe, China	Turkey, China	Europe, Mexico, China, Brazil, Australia, Turkey, Lebanon	Europe, Mexico	China
Outcome(s)	RTI	RTI	RTI	RTI	RTI	Wheeze episodes, Asthma exacerbation	RTI	RTI	Asthma symptoms Asthma exacerbation
Statistics	Globally, MD: −1.20, 95%CI [−1.7, −0.69]. Mexico, MD: −1.55, 95%CI [−2.0, 1.10]	RR: 0.82, 95%CI [0.65, 1.02]	MD: −1.15, 95%CI [−1.55, −0.75]	MD: −1.20, 95%CI [−1.75, −0.66]	MD: −2.33, 95%CI [−2.75, −1.90]	Wheeze episodes, MD: −2.35, 95%CI [−3.03, −1.67] Asthma exacerbation, MD: −0.90, 95%CI [−0.57, −1.23]	MD: −1.16, 95%CI [−1.66, −0.65]	MD: −0.21, 95%CI [−0.16, 0.26]	Asthma symptoms, RR:1.22, 95%CI [1.17, 1.27] Asthma exacerbation, MD: −1.78, 95%CI [−1.99, −1.75]
Heterogeneity	NR	NR	Test for heterogeneity: P=0.001 for ≥1 RTIs; P<0.00001 for ≥3 RTIs	I2=86.49%, P <0.00001	I2 = 98%, P <0.00001	Wheeze episodes: I2=0%, p=0.65 Asthma exacerbation: I2=0%, p=0.78	I2 = 92%	NR	I2= 95%
Conclusion	P	NP	P	P	P	P	P	P	P

CI=confidence interval. MD=mean difference. RR=risk ratio. RTI=respiratory tract infection.

P=Protective, NP= not protective, NR= Not reported

Respiratory tract infections.

In 2005, de la Torre et al.¹⁸ performed a systematic review and meta-analysis (SR-MA) on the efficacy of immunostimulants marketed in Mexico (RCTs control by placebo) for preventive acute RTI. The main outcome was number of RTI, or if it was not available the frequency/total number of infections or clinical store or days with symptoms was considered. Twelve studies were conducted with OM-85, but only 8 had sufficient data for the meta-analysis. Compared with placebo, after 6 months OM-85 significantly decreased the number of acute RTIs, both among studies done globally (n=669, weighted mean difference [WMD] = −1.20 acute RTIs per 6 months [95% confidence interval = −1.7 to −0.69], p<0.05) and those only in Mexico (n=349, WMD = −1.55 [−2.0 to −1.10], p<0.05). Similarly, OM-85 significantly decreased the percentage of children who experienced an acute RTI (global WMD = −39.28% [−52.58 to −25.98]; WMD for studies in Mexico = −46.85% [−54.98 to −38.72]). However, no data on study heterogenicity was present in the meta-analysis.

Steurer-Stey et al. in 2007¹⁹ studied the effectiveness of oral purified bacterial extracts (OM-85, IRS-19, or LW-50020) compared with placebo in the prevention (prophylaxis) of acute RTIs in children. Secondary outcomes measured in their SR-MA were symptom duration and improvement as assessed by the observers and the patients, rate of hospitalization due to infections, reduction of antibiotic requirements, school absences, and adverse effects. Eleven out of the thirteen RCTs were on OM-85; 9 of them acknowledged sponsorships by a manufacturer, and in one RCT, one author was collaborator of a manufacturer. There were no language restrictions. The methodological quality of the trials included in the review was poor to moderate. In two studies of children not in daycare (n=240), there was no significant effect of OM-85 (vs. placebo) on the number of patients with less than three infections over 6 months of follow-up (RR:0.82, 95%CI [0.65–1.02]). Based on two studies (n=199), the number of patients without infections over 4–6 months was similar between groups (RR: 0.64, 95%CI [0.26–1.57]). Two studies (n=253) reporting on the number of antibiotic courses indicated a benefit for the OM-85 intervention arm (WMD: 2.0 fewer events per study follow-up time [95% CI, 1.7–2.3]).

In 2010, Schaad²⁰ assessed the efficacy of OM-85 BV compared with a placebo in the prevention of recurrent RTIs in children. This study was partially funded by OM Pharma, Switzerland. The primary outcome was the proportion of patients with recurrent RTIs (defined as ≥3 RTIs per 6 months). Secondary endpoints were the proportion of patients with ≥1 RTI, and the mean number of RTIs during 6 months of follow-up. Eight studies (n=851 children) were included, all of which were at least partially industry sponsored. Although the data were heterogeneous, 32% of the patients in the OM-85 BV treated group had recurrent RTIs vs. 58.2% of the placebo (p<0.001). After eliminating the outlier studies, 20.2% fewer patients had recurrent RTIs in the OM-85 BV group than in the placebo (p<0.001). For the secondary endpoints, most children had at least one RTI during the study period in both OM-85 BV and placebo groups. Although the data were heterogeneous, there was a significant difference between the groups: 27.3% of patients in the OM-85 BV treated group were “RTI free”, compared with 11.1% in the placebo group (p<0.001). There was also a significant reduction in the number of RTI during 6 months of follow-up OM-85 BV compared to placebo (OR: 0.33 [95% CI: 0.23, 0.49] for one or more RTIs and OR:0.33 [0.25,0.45) for 3 or more RTIs, both results with heterogeneity), as well as the number of RTIs during 6 months of follow-up (WMD = −1.15 [95% CI: −1.55, −0.75]); although the data were ordinals and not all trials were suitable for analysis because of differences in variance.

Del Rio-Navarro et al. published a review in 2006 that was updated in 2012,²¹ assessing the safety and efficacy of immunostimulants administered to children to prevent acute RTIs. The main outcome was the number of RTIs by group (immunostimulant or placebo) and the percent change in the rate of acute RTIs. Secondary outcomes were the percent reduction in acute RTIs and the incidence of adverse events. Among thirty-five placebo-controlled trials, nine used OM-85 (n=852). OM-85 reduced both the total number of ARTIs (MD = −1.20 events per study follow-up time [95% CI −1.75 to −0.66]) with high heterogeneity (I²=86.49%); and the number of RTIs as a percentage of baseline (MD = −35.9% [95% CI −49.46 to −22.35]) with high heterogeneity (I²= 75%).

More recently, Yin and colleagues²² conducted a meta-analysis to assess the efficacy and safety of Broncho-Vaxom compared with placebo or “routine therapies” in pediatric recurrent RTIs using Chinese databases and RCTs published up to January 2017. Fifty-three RCTs (n=4851 children) were included, of which 42 RCTs were published in Chinese and 11 in English. In general, the description of the methodology was not clear in most of the studies included in the review. Only 13 RCTs used a placebo as a comparator, while the rest used routine treatment. The primary outcome was the number of participants experiencing RTIs. The secondary outcomes included the duration of antibiotic course, infections, fever, cough, and wheezing. Compared to the control group, Broncho-Vaxom treatment was significantly associated with a reduction in the frequency of RTIs (WMD = −2.33 events/study, 95% CI [−2.75, −1.90], P < 0.00001, I² = 98%), shorter time of antibiotics (WMD = −4.10 days, 95% CI (−4.52, −3.67), P < 0.00001, I²=77%), shorter duration of infection (WMD = −3.13 days, 95% CI (−3.91, −2.35), P < 0.00001, I²= 94%), shorter febrile time (WMD = −2.91 days, 95% CI (−3.75, −2.07), P < 0.00001, I²= 98%), shorter length of cough (WMD = −5.26 days, 95% CI (−6.41, −4.12), P < 0.00001, I²= 83), and shorter wheezing duration (WMD = −3.37 days, 95% CI (−4.52, −2.22), P < 0.00001, I²=94%). The adverse event rate was higher in the Broncho-Vaxom group compared with the control [RR = 1.39, 95% CI (1.02, 1.88), P = 0.04]. However, no separate data for RCTs using a placebo or “routine therapies” as a control group was presented for any of the outcomes.

In 2021 Cao et al.²³ performed a systematic review of the efficacy and safety of OM-85 in children with recurrent RTIs, including 14 studies published in English studies up to May 2020 (n=1859 patients with recurrent RTIs). Of note, two publications included were retrospective studies and another did not use a placebo as a comparator. This SR-MA reported that OM-85 was significantly related to lower frequency of RTIs (WMD: −1.16 events/study; 95% CI [−1.66 to −0.65], P < .001, I² = 92%) (10 trials, n=1325 children, but included one retrospective study); lower total duration of RTIs (WMD: −hours; 95% CI [−23.00 to −16.01], P < .001, I² = 0%) in 3 RCTs (n=302 participants); lower incidence of RTIs (OR: 0.40; 95% CI [0.21–0.77], P = 0.006, I² = 72%) in 4 RTCs (n=774, but included one retrospective study); lower number of antibiotic courses (WMD events/study: −1.40; 95% CI [−2.63 to −0.17], P = 0.03, I² = 96%) in 4 RCTs (n= 749); and lower antibiotic use (OR: 0.38; 95% CI [0.29–0.52], P < .001, I² = 14%) in 4 RCTS (n=779 participants, including one retrospective study). However, OM-85 was not significantly related to higher or lower adverse event rate (OR: 1.02; 95% CI [0.52–2.03], P = 0.94, I² = 0%); or to wheezing attack frequency (WMD: −0.25 events/study; 95% CI [−0.59 to 0.08], P = 0.14, I² = 90%).

Most recently, Zhang and colleagues²⁴ published a systematic review assessing whether immunostimulants are effective in susceptible children suffering from recurrent RTI, using a modeling analysis based on literature aggregate data by constructing a quantitative pharmacodynamic model. The factors potentially affecting the slope of the cumulative number of RTIs were explored by covariate modeling. Age, sex, site of RTI (all or upper), baseline RTIs, preventing time, and dosage form were selected as candidate covariables. Using modeling-based meta-analysis (MBMA) the authors accounted for the site of the RTI and the different time points of the intervention. A total of 14 RCTs in English were included; 9 on OM-85 (n=1011), and 5 on pidotimod. The authors present data separately for each treatment vs. placebo. The estimated final model showed that the incidence of RTI per month was 0.65, 95% CI [0.55–0.75] in the placebo group, and OM-85 BV reduced the incidence of RTI by −0.21, 95% CI [−0.26 to −0.16]. Over a 6-month follow-up period (median observation duration), the cumulative number of RTI of OM-85 BV was 2.64 [95%CI, 2.43–2.85], significantly lower than that of the placebo (4.00; 95%CI [3.46–4.54]). The cumulative number of upper RTI at 6 months of OM-85 BV treatment was 1.62 (95%CI [1.42–1.83]), which was also significantly lower than that of placebo (2.98; 95%CI [2.45–3.52]). The incidence of drug-related adverse events of OM-85 BV was higher than that of the placebo (RR: 1.31; 95%CI [0.54–3.19], I²= 13,9%).

Wheezing/asthma exacerbations or asthma control

In 2020 De Boer et al.²⁵ published a systematic review of bacterial lysate therapy (including bronchovaxom, ismigen, and MV130) as an add-on therapy for the prevention of acute wheezing episodes and asthma exacerbations in children and adolescents. The primary outcome measurement was the difference in episode frequency after the use of bacterial lysates. Studies published in English, French, or German up to September 2019, were included. The authors found 22 original studies, including 10 clinical studies and 12 laboratory studies. Among the 10 clinical studies, 5 were excluded for various reasons, and the other 5 were included in the meta-analysis. However, only two small double-blinded RCT used OM-85 (Razi et al.²⁶ and Sly et al.²⁷), while the others used another bacterial lysate or were non-double-blind RCTs, limiting the results of this systematic review. In the Razi et. al. trial (n=75 infants) the number of wheezing episodes in one year was significantly lower in the group that received OM-85 in addition to standard care with ICS, compared to the placebo add-on group (3.6±1.6 vs 5.8±2.7, p<0.01). In the Sly et al. study (n=59 infants), after 6 months of treatment there were fewer wheezing episodes in the OM-85 vs. placebo group (9 vs. 17, p=0.04).

Most recently, Yao et al²⁸ performed a meta-analysis on 36 RCTs (n=3030) evaluating OM-85 add-on therapy in patients with asthma; 33 were published in Chinese and 3 in English, and 31 trials were done in children. The intervention group included subjects who received at least one course of OM-85, alone or combined with conventional symptomatic treatment of asthma, whereas the control group received asthma conventional therapy or a placebo. While no separate data was presented in terms of intervention or placebo group, the proportion of improvement in asthma symptoms in children was 22% higher in the OM-85 group than among controls (RR=1.22 (95%CI: 1.17–1.27), I²=0%). Similarly, the number of asthma exacerbations during treatment was lower in the OM-85 group than in controls, but with high study heterogeneity (SMD: −1.78 (95%CI: −1.99 to −1.57, I²= 95%). Finally, children in the OM-85 group showed greater improvement in FEV₁% (SMD: 0.90, 95% CI: −0.68 to 1.13, I²=52.2%) than controls.

DISCUSSION

This critical appraisal of the evidence on the effectiveness of OM-85 to prevent RTIs or acute wheezing/asthma episodes in children, including 9 meta-analyses, shows evidence that OM-85 reduces the incidence of RTIs, asthma symptoms, and acute asthma exacerbations.

However, out of seven systematic reviews with meta-analysis on RTIs, only one early review found insignificant benefits of OM-85 BV in the prevention of acute RTI.¹⁹ One early systematic reviews¹⁸ did not report I² for measured heterogeneity and, thus, the robustness of evidence is not entirely clear. The 2012 Cochrane review²¹ found a reduction in the total number of acute RTIs among the OM-85 groups, but no strong recommendations were given due to high heterogeneity in the data. Similarly, Yin et al.²² found that the use of Broncho-Vaxom was beneficial, but all outcomes had high heterogeneity and no separate analysis was done on the different comparators (i.e., placebo or “routine therapy”). In contrast, Cao et al.²³ reported only two out of seven outcomes favored OM-85 without significant heterogeneity: a decrease in 19.5 hours the total duration of the RTI event, and 62% less antibiotic use than the control group. Finally, Zhang et al.²⁴ constructed a quantitatively pharmacodynamic regression model using aggregated data from literature and found that the OM-85 BV could reduce the incidence of RTIs by 0.21 times per month; that is, ~1.26 fewer RTIs every half-year. Among these seven systematic review on RTIs, only one review²¹ had “high confidence” (i.e., ≤1 non-critical weakness, providing an accurate and comprehensive summary of the results of the available studies that address the question of interest) and six^{18–20, 22–24} “critical low confidence” (i.e., >1 critical flaw and should not be relied on to provide an accurate and comprehensive summary of existing studies).

Two meta-analyses were conducted on the efficacy of OM-85 in preventing wheezing/asthma exacerbations or improved asthma symptoms. De Boer et al.²⁵ supported the benefit of OM-85, although their meta-analysis was based on one small double-blinded RCT (n=75) where the number of wheezing episodes a year decreased compared to controls (3.6±1.6 vs 5.8±2.7), plus one study on a different bacterial lysate. They did report a second RCT on OM-85 that showed significant improvements, but for unclear reasons that study was not part of the pooled analysis. Yao et al²⁸ reported 22% of improvement in asthma symptoms in the OM-85 groups vs. controls, but no separate data was presented in terms of intervention or placebo group. The number of asthma exacerbations during treatment was lower in the OM-85 group than in controls, but with high heterogeneity (I²= 95%). And children in the OM-85 group showed greater improvement in FEV₁% (I²=52.2%) than controls. Among those two systematic reviews^25,28 on wheezing/asthma exacerbations or asthma control, one²⁵ had “critical low confidence” and one²⁸ had “low confidence” (i.e., the review has one critical flaw and may not provide an accurate and comprehensive summary of the available studies that address the question of interest). One systematic review²⁹ we did not include, because not separately data exclusively on pediatric population was presented, was done on 12 RCTs (10 RCTs was in children, accounting for 84% participants) showed asthma symptoms control was 22% higher and FEV1 improved more in the OM-85 group compared to controls (placebo or routine therapy, without analyze separately).

Among the meta-analyses we reviewed that reported I² as a measure of heterogeneity, most had large values. The I² was designed as an approach to evaluate the proportion of total variation between studies that is likely due to a true variance in the effects, rather than due to sampling error or random chance.³⁰ Heterogeneity may arise from differences in study design (e.g., different populations or ways to measure an outcome) or from true variability in the effect. The high heterogeneity in most meta-analyses included here precludes drawing strong conclusions, but it is important to examine some potential sources of such heterogeneity. As shown in Table 3, the original studies reported were conducted in several countries over a span of many years. The older meta-analyses, published around 2005–2012, included original trials conducted in Europe and Mexico and published between 1982 and 2007; on the other hand, several meta-analyses published in 2018–2023 included original trials from China, and one (Cao et al.²³) included original trials from Brazil, Australia, and Lebanon. Yet, we did not observe marked differences in the range pooled effects or I² statistics by broad year or geography; most meta-analysis reported high I² regardless of time frame, language, and region of the world they covered in their included original trials. Specifically for event rates, part of the heterogeneity may have arisen due to different timeframes of the original trials that were not necessarily standardized or comparable (e.g., an effect of 2 fewer episodes over 3 months of follow-up will be different than the same 2 fewer events over a full year). Based on the existing data, we are unable to examine whether this heterogeneity is due to other study characteristics (e.g., populations may look relatively similar in terms of age or sex, but perhaps certain trials captured individuals with immunologic or other susceptibilities that were not captured in their summary reports) or due to truly variable effects of OM-85.

Table 3.

Description of the randomized clinical trials (RCTs) on OM-85 included in the nine systematic reviews.

RCTs:			De la Torre 2005	Steurer Stey 2007	Schaad 2010	Del Rio Navarro 2012	Yin 2018	de Boer 2020	Cao 2021	Zhang 2022	Yao 2023
Author	Country	Year
MartinDuPan	Switzerland	1982	X	X	X
Ahrens	Switzerland	1984	X		X	X	X
Maestroni	Switzerland	1984	X	X	X	X	X		X	X
Schaad	Switzerland	1986	X	X	X	X	X
Zagar	Yugoslavia	1988	X	X	X	X	X		X	X
Paupe	France	1991	X	X	X		X		X
Collet	France	1993	X	X	X
Tarango	Mexico	1997								X
Field	Mexico	1998			X
Gomez-Barreto	Mexico	1998	X	X	X	X	X
Jara-Perez	Mexico	2000	X	X	X	X	X		X	X
Tingxi Zhang	China	2000					X
Gutierrez-Tarango	Mexico	2001	X	X	X	X	X		X	X
Schaad	Switzerland Germany	2002	X	X	X	X	X		X	X
DelRioNavarro	Mexico	2003	X	X	X	X	X		X	X
Jie Gao	China	2006					X
Chen ZG	China	2007			X			X
Lihua Huan	China	2007					X
Junhui Yuan	China	2007					X
Huiyu Zhang	China	2007					X
Jinsong Li	China	2008					X
Yu Tan	China	2008					X
Yongli Wu	China	2008					X
Ying Liao	China	2009					X
Haiying Mo	China	2009					X
Aiqi Zhang	China	2009					X
Xin Zhao	China	2009					X
Chen Zhuanggui	China	2009						X			X
Razi	Turkey	2010					X	X	X	X
Hua Fu	China	2010					X
Yuan Gao	China	2010					X
Min Song	China	2010					X
Guoying Ye	China	2010					X
Mingxia Chao	China	2011					X
Beiling Hu	China	2011					X
Aiping Liang	China	2011					X
Yujing Zhang	China	2011					X				X
Hu Peiling	China	2011									X
Xiongxiong Huang	China	2012					X
Huiqun Ji	China	2012					X
Juhong Li	China	2012					X
Zhihong Lou	China	2012					X
Yuping Zhao	China	2012					X
Diqian Zhuang	China	2012					X
Manfeng Zuo	China	2012					X
Guolin Chen	China	2013					X
Guie Li	China	2013					X
Lancui Lu	China	2013					X
Jiayi Liao	China	2014					X	X
Ya Shen	China	2014					X
Ling Su	China	2014					X
Lu Yanming	China	2015						X			X
Shenfeng Gu	China	2015					X
Fei Liu	China	2015					X
Wei Zhang	China	2015					X				X
Hongwen Zhu	China	2015					X
Shaoxiong Zhuang	China	2015					X
Cheng Yang	China	2015									X
Shiyan Luo	China	2016					X
Yincun Ye	China	2016					X
Liming Yin	China	2016					X
Bitar	Lebanon	2016							X
Cao Jian	China	2016
Lv Yanqin	China	2016									X
Hao Lixia	China	2016									X
R-F Han	China	2016						X			X
Jingyang Li	China	2017					X
Su Huixia	China	2017
Tang Yuqi	China	2017									X
Yang Feng	China	2017									X
Yang Xing	China	2017									X
Chen	China	2017							X
Li Xia	China	2017									X
Li Xianqing	China	2017									X
Zhang Tian	China	2018									X
Cai Weiwei	China	2019
Hou Jie	China	2019
Wu Huanting	China	2019
Esposito (J Trans Med)	Italy	2019							X	X
Esposito (Int J Envir Resp…)	Italy	2019							X
Sly PD	Australia	2019						X	X
Zhang Hua	China	2019									X
Souza	Brazil	2020							X
Cai Jierong	China	2020						X			X
Mao Chengli	China	2020									X
Qian Donglin	China	2020									X
Li Yi	China	2020									X
Yang Sibo	China	2020									X
Wu Xiaoxu	China	2020									X
Yang Liwei	China	2020									X
Wang Pingsheng	China	2021									X
Total RCTs			12	11	14	9	53	8	14	9	24

The working mechanisms of OM-85 have not been fully characterized. Based on evidence obtained in vitro, in animal models, and many studies in humans, four (non-mutually exclusive) cellular mechanisms may be involved: gut-associated lymphoid tissue (GALT)-mediated activation of dendritic cells, T-lymphocytes, and B-lymphocytes; migration of GALT-generated immune cells into the upper and lower respiratory tract; increased production of immunoglobulins resulting in decreased susceptibility to pathogens; and prevention (or early correction) of an imbalance in T1/T2-mediated immunological responses.^31–33 Yao et al.²⁸ examined some immunological measurements and found that OM-85 add-on therapy did present immunomodulatory effects such as increased numbers of T-lymphocytes, increased IgA concentration in serum and sputum, elevated levels of T1 inflammatory cytokines, and decreased intensity of T2-mediated inflammatory responses.

Conclusions: Based in this updated extensive review, it is not feasible to reach clear recommendations on the efficacy of OM-85 for acute RTIs, asthma development, or acute exacerbations in children. While it has been over thirteen years since the publication of the Cochrane review²¹ on the topic, we agree with the need and recommendation for large, high-quality, multicenter, double-blind, placebo-controlled RCTs evaluating the safety and efficacy of immunostimulants for these outcomes. At least five large RCTs are being conducted in the US and Europe (NCT02148796 and NCT05857930 in US; and NCT05677763, NCT05063149 and NCT05710081 in Europe); these trials will hopefully yield adequate evidence of the real effectiveness of OM-85 on preventing respiratory tract infections or asthma/recurrent wheezing, and we look forward to the publication of their results.

KEY MESSAGE.

In this extensive review, we summarize the evidence on the effect of OM-85 to prevent acute respiratory tract infections, wheezing/asthma episodes, or loss of asthma control in children, by including and critically evaluating all systematic review with metanalysis published to date. We found nine systematic reviews, among those only one had a high confidence evaluation of quality reporting a reduction in the total number of acute respiratory tract infections in the OM-85 group, but with high heterogeneity. Therefore, no strong recommendations can be derived from the existing literature. Further, large, high-quality randomized clinical trials are needed to confirm the true efficacy of OM-85.