key: cord-0918310-x4sfbtxn
authors: van Meel, Evelien R.; Jaddoe, Vincent W. V.; Bønnelykke, Klaus; de Jongste, Johan C.; Duijts, Liesbeth
title: The role of respiratory tract infections and the microbiome in the development of asthma: A narrative review
date: 2017-09-04
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.23795
sha: 8aa5ccc6e4b2c80ebec1b989e6c4554f85ddfbb9
doc_id: 918310
cord_uid: x4sfbtxn

Asthma is a common disease in childhood, and might predispose for chronic obstructive respiratory morbidity in adolescence and adulthood. Various early‐life risk factors might influence the risk of wheezing, asthma, and lower lung function in childhood. Cohort studies demonstrated that lower respiratory tract infections in the first years of life are associated with an increased risk of wheezing and asthma, while the association with lung function is less clear. Additionally, the gut and airway microbiome might influence the risk of wheezing and asthma. The interaction between respiratory tract infections and the microbiome complicates studies of their associations with wheezing, asthma, and lung function. Furthermore, the causality behind these observations is still unclear, and several other factors such as genetic susceptibility and the immune system might be of importance. This review is focused on the association of early‐life respiratory tract infections and the microbiome with wheezing, asthma, and lung function, it is possible influencing factors and perspectives for future studies.

important to understand the development of lower lung function and asthma and allow prevention of disease. Recent studies suggest that early-life respiratory tract infections could lead to airway obstruction and hyperreactivity, 13 and subsequently increased risk of persistent lower lung function and asthma. Also, exposure to microorganisms seems associated with either an increased risk or lower risk of atopic diseases, depending on the type of bacteria, the composition of the microbiome, or both.

In this review, we describe the current knowledge from cohort studies on the role of early-life respiratory tract infections and the microbiome in the development of asthma.

Respiratory tract infections occur most frequently in early childhood, which is also the age with the most rapid development of the immune and respiratory system. [14] [15] [16] The prevalence varies per type of respiratory tract infection. In developed countries, the incidence of pneumonia in children until the age of 5 years is 0.05 episodes per child

year. 17 Symptoms of an upper respiratory tract infection, such as sore throat and rhinorrhea, in children until the age of 5 years are more common, with a reported prevalence of 5.06 episodes per child year in the United States. 18 The diagnosis of early-life respiratory tract infections in studies that examine the relation of respiratory tract infections with wheezing, asthma, or lung function varies largely, and is mainly divided into respiratory tract infections diagnosed in the laboratory or physiciandiagnosed. For laboratory proven respiratory tract infections, nasal samples are taken either during symptoms of an acute respiratory tract infection, [19] [20] [21] [22] [23] [24] [25] [26] [27] or at scheduled time points. 19, 24, 28 These are mainly analyzed for either human rhinovirus (HRV) or respiratory syncytial virus (RSV), the most common viral pathogens, and more rarely for other viruses, such as adenovirus, coronavirus, or influenza virus. The difference in timing of sampling could potentially lead to biased results, since the prevalence of a virus during an acute respiratory infection is most likely not comparable to the prevalence of a virus during an asymptomatic period. Studies that used physician-diagnosed respiratory tract infections in early-life as outcomes used either questionnaires or standardized registries. Some prospective cohort studies used questionnaires in which parents were asked whether their child has had a specific infection in a specific period of time. [29] [30] [31] Alternatively, studies use ICD-codes or hospital (admission) registries to identify children with respiratory tract infections. [32] [33] [34] [35] [36] [37] Such differences in definitions could lead to differences in effect sizes, which is also illustrated by a cohort study that compared RSV infections in children that visited the outpatient clinic, the emergency department or who were hospitalized 34 in relation to asthma diagnosis.

Children with RSV infections in these three different clinical groups had a 1.86-, 2.41-, and 2.82-fold increased risk for asthma, respectively, compared with children without a hospital visit for RSV infections. This is in line with another retrospective cohort study that showed that children with RSV infections who were at the outpatient clinic or prolonged hospitalized had a 1.38 versus 2.59 21 increased odds for recurrent wheeze at the age of 5 years, respectively, compared with those without an RSV infection. The use of questionnaires or registries has the advantage of easily accessible data at relatively low cost, but could possibly lead to misclassification. Viral sampling is more reliable in terms of accurate diagnosis, but whether sampling during symptoms of an acute respiratory tract infection is comparable to sampling at scheduled times is unclear.

Additionally, costs will be higher and logistics are more complex. Thus, in large observational population-based cohort studies, questionnaires or registries are cost-effective methods to assess respiratory tract infections, while smaller studies using viral sampling provide information on specific agents.

In preschool children, asthma is difficult to diagnose and mainly based on the occurrence of wheezing. Previous population-based or high risk cohorts showed that HRV, RSV, or bronchiolitis in the first 1-3 years of life are associated with an up to 13-fold increased risk of preschool wheezing. [20] [21] [22] [23] 28, 30, 38 One cohort study showed that hospitalization for RSV was associated with an increased risk of recurrent wheezing at the age of 18 years. 39 Cohort studies or casecontrol studies that focused on childhood asthma at age 4-13 years showed that HRV, RSV, or bronchiolitis in the first year, the first 2 or the first 3 years of life were associated with an increased risk of asthma with odds ratios ranging from 1.39 to 13.55. 19, 29, [32] [33] [34] [35] [36] [37] 40 Some studies examined a group of, and not individual, respiratory tract infections only. A case-control study showed that hospitalization for any respiratory tract infection in the first year of life was associated with a 1.5-fold increased risk of asthma at the age of 5 years, 35 while a high-risk cohort study demonstrated that wheezy and febrile lower respiratory tract infections in the first year of life were associated with an increased risk of asthma at the age of 5 of 10 years. However, these latter associations seemed only present when the child had allergic sensitization before the age of 2 years. 41, 42 It has also been suggested that the number of respiratory tract infections, rather than a specific infection, is associated with an increased risk of asthma. 43 year of life 46 or at the age of 2-5 years. 47 However, some studies that measured early-life lung function suggest the opposite direction of causality. One prospective cohort study showed that increased bronchial responsiveness in infancy was associated with increased risk of severe bronchiolitis 48 and another showed that children with a lower respiratory system compliance, and higher resistance at the age of 2 months, were at greater risk for hospitalization for an RSV infection and wheeze after the infection. 49 However, the latter study group demonstrated that the association of HRV in the first year of life with wheezing at the age of 4 years remained significant after adjusting for lung function measurements at the age of 2 months. 28 Additionally, another cohort study demonstrated that lower respiratory tract infections in the first year of life were associated with an increased respiratory rate at 1 year of age, and that recurrent lower respiratory tract infections were associated with a lower tidal volume and increased lung clearance index, irrespective of lung function measured at the age of 6 weeks. 50 To examine the direction of causality, further longitudinal studies with detailed information on respiratory tract infections and lung function measures early and later in life are urgently needed to provide more insight in the causal direction of these associations.

The microbiome could be defined as the community of microorganisms living in or on the human body. 51 Two locations of the microbiome are of great interest in relation to wheezing, asthma, and lung function, namely the airway and gut microbiome. Analyses of bacterial communities are mostly performed by 16S rRNA gene sequencing, identifying different bacteria. Challenges in measuring the airway microbiome lie in the relative low density of bacterial communities when compared to the gut microbiome. Additionally, the lower airway microbiome is difficult to sample and carries the risk of contamination of the upper respiratory tract microbiome. 52 When studying the microbiome, it is possible to focus on microbiome diversity or composition, or on specific bacteria. For microbiome diversity, the richness and evenness of species is estimated, for example by using the Shannon index or the Simpson's diversity index. 53 Here, richness reflects the number of different species, while evenness reflects how even these different species are distributed.

Another approach is to model bacterial community compositions, to form distinguishable groups. 54 If specific bacteria are used as the exposure, it is possible to focus on bacterial groups or specific bacteria.

Some of these bacteria might have a beneficial effect on wheezing, asthma, and lung function, such as Bifidobacterium spp, while others might have a negative effect, such as Clostridium difficile. The use of different methods for the determination of the microbiome makes it difficult to compare studies. Also, the question remains whether the focus should be on specific bacteria, or rather on the total composition of the microbiome. Characterizing specific bacteria is used more commonly, and is less complicated in terms of both analysis and interpretation but is likely to be an over simplification of the health effects of the entire microbial composition.

The composition of the airway microbiome changes in the first years of life. Nasopharyngeal samples in healthy subjects around the age of 2 months are mostly dominated by Staphylococcus and

Corynebacterium, but this frequency decreases with increasing age.

In contrast, Alloicoccus and Moraxella colonization is low at the age of 2 months, but is increased at the age of 12 months. 55 Interestingly, when an acute respiratory illness had occurred in between the two sample periods, a transition to Moraxella or a stable colonization with Moraxella was most commonly present. Other than respiratory illness, exposure to pets, daycare attendance, siblings, and antibiotic use in the 4 weeks prior to sampling were associated with nasopharyngeal colonization, showing mostly higher rates of Haemophilus and Moraxella colonization. Additionally, a prospective cohort study collected samples of the hypopharyngeal microbiome at the age of 1 week, 1 month, and 3 months, and showed that the microbiome at the age of 1 week represented over 60% of the microbiome at 3 months. 56 Thus, although various factors can influence the airway microbiome, it is also likely that the microbiome formation in later life is determined by early colonization.

Various airway microbiota have been linked to later life asthma and wheezing. A prospective high-risk cohort study showed that Streptococcus colonization at the age of 2 months was associated with an increased risk of chronic wheeze at the age of 5 years, 55 and that that the bacterial concentration and diversity were higher in adults with suboptimally controlled asthma, 59 compared with children or adults without asthma. To date, it is not clear whether differences in the microbiome of the airways and lungs precede asthma, or whether the disease itself is the cause of these changes.

The composition of the gut microbiome changes during the first years of life, mostly as an effect of the changing diet in the same period. 60 The introduction of supplementary feeding, the introduction of solids and the start of weaning 61 are important time periods in which the microbial composition changes. These time periods should be taken into account when deciding at which age to sample feces for measuring the gut microbiome, or when interpreting results of different studies.

Previously published human studies have linked the gut microbiome with the development of atopic diseases such as asthma. A prospective cohort study showed that C. difficile colonization at the age of 1 month was associated with an increased risk of recurrent wheeze until the age of 2 years, but also with eczema and atopic sensitization at the same age. 62 However, only the presence of C. difficile, not the concentration in the feces was associated with these outcomes. Other bacteria, such as bifobacteria, B. fragilis species, E. coli, and lactobacilli were not associated with recurrent wheeze. A birth cohort study characterized the bacterial composition at the age of 1 month and 6 months within three distinct groups. 54 The group with a lower abundance of bacteria such as Bifidobacteria and Lactobacillus, but a higher abundance of fungi such as Candida had the highest risk of asthma, predominantly multisensitized atopy at the age of 2 years, and asthma at the age of 4 years. No difference was observed between the three groups in the risk of atopy at the age of 2 years, defined as an IgE level above 0.35 IU mL −1 . A comparison of stool samples at the age of 4 years between non-wheeze, non-sensitized controls, and wheezy-sensitized cases showed no difference in the microbiome composition. 63 Both a prospective cohort and a substudy of an RCT showed that the gut microbiome until the age of 1 month is also associated with asthma development at the age of 6 or 7 years. 64, 65 The microbiome at the age of 12 months however was not associated with asthma. In summary, previous studies support the hypothesis that mostly the microbiome in early life is important for the development of wheezing and asthma at a later age. 64 

It is likely that respiratory tract infections and the airway microbiome influence each other. Respiratory tract infections could have an effect on the microbiome both during, and after the infection. 66 Additionally, it is possible that the microbiome colonization of the airway could increase the risk of a subsequent respiratory tract infection. 67 Hypopharyngeal colonization with S. pneumoniae, H. influenza, or M. catharralis in the first 3 years of life is associated with an increased risk of pneumonia and bronchitis at the age of 4 years, providing evidence for the latter. It has also been shown that early Streptococcus colonization is associated with an increased risk of a lower respiratory tract infection at an earlier age, while Moraxella colonization is associated with an upper respiratory tract infection at an earlier age. 55 These findings suggest that respiratory tract infections might not only influence the airway microbiome, but also vice versa. This further complicates the relationship of either with wheezing, asthma, and lung function, and the understanding of this association.

Several factors could be of influence in the associations of respiratory tract infections or the microbiome with wheezing, asthma, and lung function. The difference between the influencing factors is of importance in the matter of possible prevention or treatment strategies.

Mode of delivery has been suggested as a possible intermediate factor in the relationship between the microbiome and risk of asthma. [68] [69] [70] [71] [72] [73] Children born through a caesarian section are likely to have a lower gut microbiome diversity, especially in the first 3 months of life. Mode of delivery might also influence the airway microbiome, although the association of mode of delivery with the airway microbiome has been studied less. Antibiotic use could be related to both the associations of respiratory tract infections with wheezing, asthma, and lung function, and to the associations of the microbiome with these outcomes.

Respiratory tract infections could lead to increased antibiotic use, which thereby has as an intermediate effect on wheezing, asthma, and lung function. 74, 75 The use of antibiotics could also have an effect on the composition of the gut microbiome, and therefore act as a confounder in the associations of the microbiome with asthma or wheezing. [76] [77] [78] Confounding by indication or reverse causation can complicate studies on the effect of the microbiome. For example, it has been suggested that the use of antibiotics is a results of confounding by indication, meaning that only respiratory tract infections themselves have an effect on wheezing, asthma, and lung function, and that a observed adverse effect of antibiotic use on these outcomes is solely because of the direct relation between the use of antibiotics and respiratory tract infections. 75 

An explaining factor for the associations of respiratory tract infections with wheezing, asthma and lung function is genetic susceptibility. The 17q21 locus, the strongest known susceptibility locus for asthma, was demonstrated to be associated with HRV wheezing in early life as well, but not with RSV wheezing illness. 79 Similarly, CDHR3 gene variation increases risk of childhood asthma with severe exacerbations, 80 with an increased susceptibility to rhinovirus C infections as a possible underlying mechanism. 81 Genetic differences in immune response to infections are also of interest. Some single nucleotide polymorphisms (SNPs) have been identified to be associated with respiratory tract infections and asthma or airway hyperreactivity, including picornavirus with atopic asthma and airway hyperreactivity, and RSV with atopic asthma and airway hyperreactivity. 82 A cohort study of children with RSV demonstrated that genes coding for the Interleukin (IL) pathway, specifically IL4 which might promote allergic inflammation and asthma, are associated with both RSV infection and wheezing, suggesting a potential role for genetic differences in immune responses to infections. 83 The immune system could also be an explaining factor in the associations of the microbiome with asthma and wheezing. The gut-associated lymphoid tissue is an important factor in the immune system, and plays a role in the development of the gastro-intestinal immune system. 84 Additionally, the birth cohort study that demonstrated that one of three distinct groups of bacterial composition of the gut microbiome was associated with a higher risk of asthma and atopy, also showed that this same group was associated with CD4 + cell dysfunction. Specifically, CD4 + IL4 + cells are upregulated, as is the concentration of IL-4 released, which could contribute to airway inflammation. 54 This could possibly mean that the risk of asthma and wheezing due to differences in the gut microbiome might be mediated by differences in the immune system. The immune system could be a true underlying causal factor in these associations, meaning that the immune system could influence both the risk of respiratory tract infections or alter the microbiome, and influence the risk of wheezing, asthma, and lung function separately. Alternatively, the immune system might be a mediating factor in the association of respiratory tract infections or the microbiome with wheezing, asthma, and lung function. Further studies on the role of the immune system are needed to disentangle these associations.

The associations between respiratory tract infections and wheezing, asthma, and lung function might be modified by some factors such as the atopic status characterized by sensitization or parental asthma or atopy. In a prospective cohort study, associations of wheezy or febrile lower respiratory tract infections was only found if children were sensitized by the age of 2 years, defined as a positive skin prick test for either food or inhalant allergens. 41, 42 Some differences in the effect estimates for bronchiolitis with asthma were also found when children with and without atopic parents were compared, although for both groups the effect estimates were significant (odds ratios 3.11 vs 1.66). 40 The role of genetics, the immune system and atopy in the associations of the microbiome or respiratory tract infections with wheezing, asthma, and lung function should be explored further. 

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