Infection prevention and immune modulation by bacterial lysates in patients with asthma: gaining insight into the mechanism of an old therapy

Respiratory tract infections (RTI) are responsible for a large morbidity,
especially in patients with asthma. Asthma is caused by a complex interplay of
genetic predispositions and environmental stimuli. Microorganisms often elicit
exacerbations. Prevention of respiratory tract infections might therefore aid
in controlling asthma symptoms. There are several methods aiming at prevention
of respiratory tract infections, mainly being vaccinations (including their
non-specific immunological effects, e.g. BCG-vaccine), maintenance antibiotics,
probiotics and hygiene measurements. Oral polyvalent bacterial lysates recently
gained renewed attention. These contain bacterial peptides derived from killed
pathogenic respiratory bacteria and have been designed in the *70s. They act as
immune-modulators and follow the route of the natural evoked immune response.
In the intestine, they trigger the gut-associated lymphoid tissue (GALT) system
and modulate the immune system, leading to stimulation of dendritic cells with
activation of B- and T-memory cells. Increased cellular and polyclonal humoral
responses including selective IgA secretion, macrophage activation and
secretion of pro-inflammatory cytokines have been observed in mouse models.
This led to effectively boosted pathogen destruction with a decrease in severe
viral and bacterial infections.
Bacterial lysates have been prescribed for years in many European
countries to prevent RTI and have a long and safe record in adults and
children. However, hardly any large and good quality clinical studies have been
performed till now. Systematic reviews and meta-analyses showed (significantly)
fewer RTI (20-40%) after bacterial lysate therapy. However, patients with
comorbidity who might benefit most, such as asthma or mild immunodeficiency,
were usually not included in these studies. In pre-school children with
asthmatic symptoms, the number of RTI and wheeze episodes significantly
diminished after using bacterial lysates. In older persons with COPD,
bacterial lysates diminished respiratory symptoms and bacterial infections. No
human studies looking at the microbiological and immunological phenomena in
detail with new techniques have been performed yet.
Interestingly, bacterial lysates do not only upregulate the
antimicrobial immune response, the Th1-response, but also seem to downregulate
the Th2-response that is related to allergic diseases. The key inflammatory
cell in this process is the regulatory T-cell (T-reg). 9 This cell has an
important role in maintenance of immunological homeostasis in the body. In an
asthmatic mouse model, significantly lower numbers of inflammatory cells were
found after administering bacterial lysates. Th2-type cytokine levels were
diminished and expansion of Treg-cells was observed. 10
Recently, innate lymphoid cells group 2 (ILC2) were discovered and
these cells have been related with asthmatic symptoms following viral
respiratory tract infection. Induction of ILC2 directly by viruses has been
associated with airway inflammation and hyperreactivity by production of type 2
interleukins. The effect of bacterial lysates on ILC2-activity (either or not
related to activity on Treg-cells) is unknown.
Concluded, treatment by bacterial lysates seems to be promising therapy
for preventing respiratory infections but lacks robust evidence. Even promising
is its supposed modulation of the (asthmatic) inflammatory response by
attenuation of Th2-related inflammation. This intervention study addresses the
clinical effects of bacterial lysate therapy in a prospective controlled
manner, combined with laboratory research into the development of microbial
colonization and immunological aspects related to viral infections and
inflammation.

To diminish the number of asthma exacerbations with the regular use of a
bacterial lysate.

Investigator-initiated double-blind randomized controlled trial.

Broncho-Vaxom is a bacterial lysate that has been used for years in children
and adults with recurrent respiratory tract infections. It has a favorable
after profile. However, for study purposes, it was hardly studies in asthmatic
individuals, till now only in young children. In older subjects with COPD,
bacterial lysates have a positive effect on lung health. We want to investigate
whether this positive effect on lung health can also be observed in asthmatic
patients.
Burden is regarded as low; in winter season participants have to take a pill
daily for 10 days every month. Three-monthly visits will be scheduled as much
as possible together with regular doctor's visits. Venapunctures are taken as
much as possible from adult participants.