OM-85 is an oral medicine of biological origin: its active principle is an alkaline aqueous soluble extract of 21 bacterial lysates of seven genera isolated originally from human patients suffering from RTIs [
21]. Several studies highlighted the capacity of OM-85 to trigger immunomodulatory and protective immune responses against different pathogens and most recently, sequential experimental studies aiming at dissecting its mode of action both in vitro and in vivo, were shared with the scientific community [
16,
20,
22‐
34]. Focusing on infections of bacterial and viral origins, studies in animal or human cell models revealed new insights on the “what” and the “how” such product can modulate the host immune response [
24,
26,
33,
34]. Recent literature demonstrate the cell activation, which take place in the gut associated lymphoid tissue, and then migrate to the lung associated lymphoid tissue via the lymphatic circulation [
20,
30,
33,
35]. The protective activity of OM-85 against viral infection was further investigated by in situ analysis using human sampling. More precisely, human primary bronchial epithelial cells (BECs) originating from the lung following bronchoscopy using control and disease sampling from donors with RTI [
36]. In this last study, the mechanistic anti-viral effect was confirmed by the production of various anti-viral proteins on the surface of BECs, of which, the anti-viral β-defensin. The first relevant finding of the present post-hoc analysis is that susceptibility to lethality occurred within a tight infectious dose window. Despite the fact that an intermediate/low
S. pneumoniae dose was used, mortality of mice treated with BLANC was higher and concomitant with all morbidity signs. OM-85 treatment appeared to be able to elicit some protective effects; however it was not sufficient to shift the susceptibility to below the threshold of lethality. However, when the mice were exposed firstly to a sublethal influenza infection in the original study [
20], pre-treatment with OM-85 led to a more relevant protection against
S. pneumoniae infection, as shown by improved survival and reduced morbidity. In the original study, OM-85 led to a more relevant protection following a sublethal influenza infection also on
Klebsiella pneumoniae super-infection [
20]. These findings showing an improved resistance to a secondary bacterial infection may be only partially explained by the lower lethality of the
S. pneumoniae dose used. Yet, an important role is played by the non-specific host immune response against influenza virus infection induced by OM-85 [
20]. Indeed and as exemplified earlier in the text, OM-85 can: a) elicit the maturation of dendritic and of B-cells, with upregulation of the surface expression MHC II, CD40, and CD86 [
20,
33], b) polyclonally activate B-cells, with a statistically significant increase in IgG levels in serum, and with a trends toward increased IgA and IgG levels in the airways, and c) anti-I.V. antibodies in serum and BAL [
20]. The protective effect of the non-specific stimulation of the host defences following viral infection was clearly demonstrated by the observation that, in mice treated with OM-85 (but not in those treated with BLANC), 24 h following the super-infection with
S. pneumoniae, bacteremia was no longer detected [
20]. Considering the important findings that a primary viral infection improves the efficacy of OM-85 to incoming bacterial infections in the host, it is fair to admit some limitations of this post-hoc analysis. One being the fact these data originates mostly from animal origin and that the number of mice used was limited due to the complexity of the experimental methodology and the different in vivo conditions. An additional limitation may also originates from the selection of influenza virus and
S. pneumoniae, pathogens classically used to study respiratory co-infections in mice [
37,
38], but not typically involved in recurrent RTIs in children. Notwithstanding these limitations, it is important to stress that the anti-bacterial efficacy of OM-85 was shown against other bacteria [
20,
21]. Concomitantly, the antiviral effects of OM-85 was recently confirmed with mechanistic evidences using human primary lung cells originating from biopsies infected by rhinovirus [
36]. The result of our post-hoc analysis support the clinical efficacy of OM-85 BV in the prevention of recurrent RTIs in children and adolescents, shown by meta-analyses and systematic reviews [
15,
16,
18,
21]. From the translational aspect, these experimental findings support the concept of using immunomodulatory medicine such as OM-85 BV in the clinical setting of respiratory viral and bacterial super-infections that commonly occur in pediatrics. Although viruses (e.g. rhinovirus, adenovirus, parainfluenza and influenza virus) are the main responsible for RTI, bacterial super-infections sustained by respiratory pathogens (e.g.
S. pneumoniae,
H. influenzae, S. pyogenes) are diagnosed in up to 60% of patients with long-lasting (> 10 days) RTI symptoms in this young population [
39]. Synergistic effects between viruses and bacteria (commonly influenza virus and
S. pneumoniae) in the pathogenesis of RTI are also described in the literature [
37‐
40]. Although influenza may be fatal, it is well known that the mortality increases in case of bacterial super-infection [
40]. Therefore the described pre-clinical observations explain the clinical efficacy of OM-85 BV in the prevention of RTIs in children and adolescents, the reduction of symptoms severity and duration, as well as of missed days of school, as it is shown in systematic reviews and meta-analysis [
15,
16,
18,
21]. The reduction of bacterial complications that are associated with higher morbidity, antibiotic prescription, referral visits to a specialist, and hospitalizations, can also contribute to the control of health care costs [
41].