Bacterial lysate add-on therapy to reduce exacerbations in severe asthma: A double-blind placebo-controlled trial

Abstract

Background: Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune-modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown.

Aims: To reduce asthma exacerbations by add-on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune-modulatory effects of this treatment.

Methods: Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year were included. The intervention regimen consisted of OM-85/placebo for 10 consecutive days per month for 6 months during two winter seasons. Primary end-point was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent.

Results: Seventy-five participants were included (38 OM-85; 37 placebo). Exacerbation frequencies were not different between the groups after 18 months (incidence rate ratio 1.07, 95%CI [0.68-1.69], p = 0.77). With the use of OM-85, FEV1% increased by 3.81% (p = 0.04) compared with placebo. Nasopharyngeal swabs taken during RTIs detected a virus less frequently in patients using OM-85 compared to placebo (30.5% vs. 48.0%, p = 0.02). In subjects with type 2 inflammation adherent to the protocol (22 OM-85; 20 placebo), a non-statistically significant decrease in exacerbations in the OM-85 group was observed (IRR = 0.71, 95%CI [0.39-1.26], p = 0.25). Immune-modulatory effects included an increase in several plasma cytokines in the OM-85 group, especially IL-10 and interferons. Peripheral blood T- and B cell subtyping, including regulatory T cells, did not show differences between the groups.

Conclusion: Although OM-85 may have immune-modulatory effects, it did not reduce asthma exacerbations in this heterogeneous severe adult asthma group. Post hoc analysis showed a potential clinical benefit in patients with type 2 inflammation.

Keywords: asthma; bacterial lysates; exacerbations; immune modulation; type 2 inflammation.

FIGURE 1

Study outline: Visits were scheduled every 3 months and at the time of an exacerbation. ACQ, asthma control questionnaire; AQLQ, asthma quality of life questionnaire; LF, lung function; NP, nasopharyngeal swab

FIGURE 2

Flow diagram of inclusion. N, number; OCS, oral corticosteroids; T2, type 2 inflammation

FIGURE 3

Clinical outcomes after OM‐85 and placebo treatment: (1) Cumulative mean number of exacerbations per patients during the study: (A) patients included in the intention to treat analysis (mean exacerbations at 18 months: 1.87 ± 1.71 vs. 1.81 ± 1.91, IRR 1.07. 95% CI [0.68–1.69]. p = 0.77); (B) patients with type 2 inflammation included in the per protocol analysis (mean exacerbations at 18 months: 1.50 ± 1.50 vs. 2.18 ± 1.94 IRR 0.71CI [0.39–1.26]. p = 0.25). 2) Percentage of forced expiratory volume in 1 second trend in time: (C) patients included in intention to treat analysis (ED between groups in time 3.81%, 95%CI [0.17;7.46], p = 0.04) and (D) patients with type 2 inflammation included in the per protocol (ED between groups in time 5.38%, 95%CI [0.67;10.09], p = 0.03

FIGURE 4

Plasma cytokine fold‐change ratios between baseline and 12 months for both the OM‐85 and placebo group (shown as mean fold‐changes). Significant differences (p < 0.005) after Mann‐Whitney U test shown as *for intention to treat (ITT) and #for patients with type 2 inflammation being adherent to the study protocol (PPT2)