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.