3.2 Delayed viral clearance, RSV and HRV infection and recurrent
wheezing
Respiratory virus clearance requires a complex response initiated by
resident respiratory tract cells and innate immune cells and ultimately
resolved by adaptive immune cells [30]. This viral clearance that is
largely dependent on the interplay between infecting agents and host
immune response, may be influenced by nasopharyngeal microbiota
composition in infants with RSV bronchiolitis. A 17-center prospective
cohort study of infants aged less
than 1 year, with RSV bronchiolitis, found that those with a
nasopharyngeal Haemophilus -dominant microbiota profile at time of
hospitalization were more likely than those with a mixed profile to have
delayed viral clearance, also after adjustment for 11 factors, including
viral load (figure 2B) [23]. Nasopharyngeal microbiota composition
at the time of hospitalization was also described as associated to an
increased risk of recurrent wheezing. In children < 2
year of age, with severe bronchiolitis due to RSV and/or HRV enrichment
of Haemophilus influenzae and Moraxella catarrhalis was
found in their nasopharynx (figure 2B) [31]. Haemophilus
influenzae was detected in most RSV-only infected and co-infected
samples, but not in HRV-only samples, whilst Moraxella spp were
detected in co-infection and were more common among children with
wheezing upon admission [31]. No enrichment of Haemophilus
influenzae in HRV-only and of Moraxella spp in RSV- or HRV-only
was reported. It is therefore possible that specific bacterial species
increase the likelihood of one viral infection or another, and play a
role in the onset of wheezing (figure 2B). This may be the case of the
association of Moraxella spp enrichment with HRV infection. In 17
U.S.A. centers, nasal swabs were collected in infants hospitalized for
bronchiolitis and repeated 3 weeks and 1 year after hospitalization
[32]. The viral etiology of bronchiolitis was not reported. An
increase in relative abundance of Moraxella orStreptococcus spp, at 3 weeks, and of Streptococcus spp,
at 1-year follow-up was associated
with increased risk of recurrent wheezing in the study subjects
[32]. In a similar study performed in Beijing Children’s Hospital;
74 infants aged 6 months or less, hospitalized for an initial episode of
severe RSV bronchiolitis, were included and followed until age 3 years
[33]. A higher relative
abundance of Haemophilus , Moraxella and Klebsiellawas detected in nasotracheal aspiration in the 26 infants (35.1%) who
later developed recurrent wheezing. In these infants, higher abundance
of Haemophilus or of Moraxella was respectively associated
with elevated CXCL8 levels or of IL-6 and IL-10 (figure 2B). Resolving
the conundrum of the differential role of Moraxella , as having an
apparent protective role on the severity of RSV infection in the acute
phase, yet being consistently identified as a risk pathogen for
recurrent wheezing, will advance our comprehension on both its role and
that of other nasopharyngeal microbial species’ in the course, severity
and complications of different respiratory conditions. A different
nasopharyngeal microbiota composition was observed as associated with a
reduced risk of wheeze after RSV infection. A population-based birth
cohort of 118 previously healthy term infants was evaluated during the
first confirmed RSV acute respiratory infection in a Tennessee-based
study [34]. Of the 113 (95.8%) children who had 2-year outcome
data, 46 (40.7%) had at least one parental reported wheezing episode.
There was no association between the nasopharyngeal microbiome taxonomic
composition, diversity and richness assessed both during the first RSV
infection and the subsequent wheeze development. However, detection
as well as relative abundance ofLactobacillus in nasopharyngeal aspirate was consistently higher
in infants who did not develop wheezing. Lactobacillus also
ranked first among the different genera in a model distinguishing infant
with and without subsequent wheeze [34]. Increasing evidence
supports that dysbiosis, in the first years of life may also have a role
in the development of allergy and asthma
because of the “gut-lung axis”
interaction. Therefore, probiotics were suggested as a possible
therapeutic approach in prevention of wheezing episodes [35].
However, in a randomized double-blind study conducted in 131 young
children (6-24 months old) with at least two wheezing episodes and a
first-degree family history of atopic disease, 6 months treatment with
oral Lactobacillus rhamnosus showed no clinical efficacy on
asthma-related events and only mild effects on allergic sensitization
which persisted 6 months after its cessation [36]. In a similar
study of 160 children and adolescents (6–18 years old), with asthma
diagnosis, 3 months of treatment with other species of probiotics,Lactobacillus paracasei , Lactobacillus fermentum , as well
as their combination decreased IgE levels, and improved asthma control
based on the Childhood Asthma Control Test, Pediatric Asthma Quality of
Life Questionnaire scores, and improved peak expiratory flow
rates[37]. Further studies are needed to confirm these inconsistent
findings and, importantly, to investigate the possible long-term benefits
of some probiotics in infants and young children at high risk for
allergic sensitization, recurrent wheezing and asthma.