The Role of Interferons in Driving Susceptibility to Asthma Following Bronchiolitis: Controversies and Research Gaps

Bronchiolitis is the most common cause of hospitalization in infancy and is associated with a higher risk for the development of childhood asthma. However, not all children hospitalized with bronchiolitis will develop asthma. The mechanisms underlying asthma development following bronchiolitis hospitalization are complex. Immune responses to respiratory viruses may underlie both bronchiolitis severity and long-term sequela (such as asthma). Interferons (IFNs) are important components of innate immune responses to respiratory viruses and could influence both asthma development and asthma exacerbations. However, the nature of the relationship between interferon production and wheezing illnesses is controversial. For example, low peripheral blood IFN responses at birth have been linked with recurrent wheeze and asthma development. In contrast, there is evidence that severe illnesses (e.g., hospitalization for bronchiolitis) are associated with increased IFN responses during acute infection (bronchiolitis hospitalization) and a higher risk for subsequent asthma diagnosis. Furthermore, mechanistic studies suggest that bronchial epithelial cells from asthmatic children have impaired IFN responses to respiratory viruses, which may enable increased viral replication followed by exaggerated secondary IFN responses. This review aims to discuss controversies around the role of IFNs as drivers of susceptibility to asthma development following bronchiolitis hospitalization. Past evidence from both mechanistic and cohort studies are discussed. We will highlight knowledge gaps that can inform future research study design.

Recurrent Wheeze Exacerbations Following Acute Bronchiolitis—A Machine Learning Approach

Introduction: Acute bronchiolitis is one of the most common respiratory infections in infancy. Although most infants with bronchiolitis do not get hospitalized, infants with hospitalized bronchiolitis are more likely to develop wheeze exacerbations during the first years of life. The objective of this prospective cohort study was to develop machine learning models to predict incidence and persistence of wheeze exacerbations following the first hospitalized episode of acute bronchiolitis.Methods: One hundred thirty-one otherwise healthy term infants hospitalized with the first episode of bronchiolitis at a tertiary pediatric hospital in Athens, Greece, and 73 age-matched controls were recruited. All patients/controls were followed up for 3 years with 6-monthly telephone reviews. Through principal component analysis (PCA), a cluster model was used to describe main outcomes. Associations between virus type and the clusters and between virus type and other clinical characteristics and demographic data were identified. Through random forest classification, a prediction model with smallest classification error was identified. Primary outcomes included the incidence and the number of caregiver-reported wheeze exacerbations.Results: PCA identified 2 clusters of the outcome measures (Cluster 1 and Cluster 2) that were significantly associated with the number of recurrent wheeze episodes over 3-years of follow-up (Chi-Squared, p < 0.001). Cluster 1 included infants who presented higher number of wheeze exacerbations over follow-up time. Rhinovirus (RV) detection was more common in Cluster 1 and was more strongly associated with clinical severity on admission (p < 0.01). A prediction model based on virus type and clinical severity could predict Cluster 1 with an overall error 0.1145 (sensitivity 75.56% and specificity 91.86%).Conclusion: A prediction model based on virus type and clinical severity of first hospitalized episode of bronchiolitis could predict sensitively the incidence and persistence of wheeze exacerbations during a 3-year follow-up. Virus type (RV) was the strongest predictor.

Among respiratory symptoms, wheeze associates most strongly with impaired lung function in adults with asthma: a long-term prospective cohort study

BackgroundAsthma is a common disease and a major public health concern. Respiratory symptoms are related to its prognosis, which in turn associates with lung function. Still this association on a long-term basis is not entirely understood.AimTo study the association of the type and number of respiratory symptoms with FEV1 and FEV1 decline in women and men with asthma.MethodA population-based cohort of adults with asthma was examined at study entry between 1986 and 2001 and at follow-up between 2012 and 2014, and n=977 had valid measurements of FEV1 on both occasions. Data regarding respiratory symptoms at study entry (recurrent wheeze, dyspnoea, longstanding cough and productive cough) were analysed in relation to FEV1 and annual decline in FEV1, both unadjusted and adjusted for other potentially associated factors by linear regression.ResultsFor both sexes recurrent wheeze and dyspnoea were associated with lower FEV1 at study entry and follow-up, while productive cough was associated with lower FEV1 only at follow-up. No associations were found between the type of symptoms and annual decline in FEV1. In adjusted analyses, the association between recurrent wheeze and lower FEV1 both at study entry and follow-up remained significant among women. Also, the association between a higher number of symptoms with lower FEV1 both at study entry and follow-up were present for both sexes and remained after adjustment.ConclusionsParticularly recurrent wheeze and a higher number of respiratory symptoms may predict lower lung function also in the long run among women and men with asthma.

Proximity to Major Roads and Risks of Childhood Recurrent Wheeze and Asthma in a Severe Bronchiolitis Cohort

Air pollution exposures have been suggested as risk factors for childhood respiratory diseases. We investigated proximity to major roads, an indicator of air pollution exposure, and its associations with childhood recurrent wheeze and asthma. We used data from a multicenter prospective cohort study of 921 infants hospitalized for bronchiolitis and recruited from 14 U.S. states. Primary exposure was residential proximity to the nearest major road at birth through age 3 years. Residential distance from nearest major road was divided into four categories: <100, 100–200, 201–300, and >300 m. Outcomes were parent-reported recurrent wheeze by age 3 years and asthma by age 5 years. Associations between residential proximity to major roads and respiratory outcomes were investigated using multivariable Cox proportional hazards modeling and logistic regression, adjusted for confounders. Out of 920 participants with home address data, pooled estimates identified 241 (26%) participants resided within 300 m of a major road, 296 (32%) developed recurrent wheeze by age 3, and 235 out of 858 participants (27%) developed asthma by 5 years. Participants who resided close to a major road had the highest risk of recurrent wheeze (adjusted hazards ratio for <100 m, 1.59, 95%CI: 1.08–2.33) and asthma (adjusted odds ratio for 201–300 m, 1.62, 95%CI: 1.16–2.25), compared to those residing >300 m from a major road. Proximity to major roads is associated with increased risks of recurrent wheeze and asthma in young children.

Small airway dysfunction is an independent dimension of wheezing disease in preschool children

Background. Whether small airway dysfunction (SAD), which is prevalent in asthma, helps to characterize wheezing phenotypes is undetermined. The objective was to assess whether SAD parameters obtained from impedance measurement and asthma probability are linked. Methods. One hundred and thirty-nine preschool children (mean age 4.7 years, 68% boys) suffering from recurrent wheeze underwent impulse oscillometry that allowed calculating peripheral resistance and compliance of the respiratory system (markers of SAD) using the extended RIC model (central and peripheral Resistance, Inertance and peripheral Compliance of the respiratory system). Children were classified using the probability-based approach of GINA guidelines (few, some, most having asthma). A principal component analysis (PCA) that determined the dimensions of wheezing disease evaluated the links between SAD and asthma probability. Results. Forty-seven children belonged to the few, 28 to the some and 64 to the most having asthma groups. Whereas their anthropometrics and measured parameters were similar, the most having asthma group exhibited the lowest mean value of airway inertance after bronchodilator probably due to airway inhomogeneities. PCA characterized nine independent dimensions including a peripheral resistance (constituted by baseline peripheral resistance, AX, R5-20Hz, X5Hz), a central resistance (baseline central resistance, R20Hz) and an airway size dimension (post-bronchodilator inertance and central resistance). PCA showed that the SAD markers were independent from clinical dimensions (control and asthma probability were two other dimensions) and did not help to define wheezing phenotypes. Conclusions. Lung function parameters obtained from impulse oscillometry and asthma probability were belonging to independent dimensions of the wheezing disease.

Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze

BackgroundPrenatal vitamin D3 supplementation has been linked to reduced risk of early life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional SNP rs12936231 of the child, which regulates the expression of ORMDL3, and for which the high-risk CC-genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.MethodsWe determined the rs12936231 genotype of mother-child pairs from two randomised-controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010, n=563) to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0–3 years between groups who received high-dose prenatal vitamin D3 supplementation versus placebo.ResultsOffspring of mothers with low-risk GG-genotype or GC-genotype who received high-dose vitamin D3 supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared to the placebo group (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.37–0.77; p<0.001 for VDAART and HR, 0.56; 95% CI, 0.35–0.92; p=0.021 for COPSAC2010), whereas no difference was observed among the offspring of mothers with high-risk CC-genotype (HR, 1.05; 95% CI, 0.61–1.84; p=0.853 for VDAART and HR, 1.11; 95% CI, 0.54–2.28; p=0.785 for COPSAC2010).ConclusionMaternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

Maternal Metabolome in Pregnancy and Childhood Asthma or Recurrent Wheeze in the Vitamin D Antenatal Asthma Reduction Trial

The in utero environment during pregnancy has important implications for the developing health of the child. We aim to examine the potential impact of maternal metabolome at two different timepoints in pregnancy on offspring respiratory health in early life. In 685 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial, we assessed the prospective associations between maternal metabolites at both baseline (10–18 weeks gestation) and third trimester (32–38 weeks gestation) and the risk of child asthma or recurrent wheeze by age three using logistic regression models accounting for confounding factors. Subgroup analyses were performed by child sex. Among 632 metabolites, 19 (3.0%) and 62 (9.8%) from baseline and third trimester, respectively, were associated with the outcome (p-value < 0.05). Coffee-related metabolites in the maternal metabolome appeared to be of particular importance. Caffeine, theophylline, trigonelline, quinate, and 3-hydroxypyridine sulfate were inversely associated with asthma risk at a minimum of one timepoint. Additional observations also highlight the roles of steroid and sphingolipid metabolites. Overall, there was a stronger relationship between the metabolome in later pregnancy and offspring asthma risk. Our results suggest that alterations in prenatal metabolites may act as drivers of the development of offspring asthma.