Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7^hi versus IRF7^lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ. The two phenotypes also produced distinct clinical phenotypes. For IRF7^lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7^hi versus IRF7^lo phenotypes with associated differences in clinical phenotypes.

Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases, including asthma. Therapies focusing on repairing vulnerable airways, particularly in early life, present a potentially novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre–school-aged and school-aged wheezing phenotypes, characterized by aberrant migration patterns and reduced integrin α5β1 expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of integrin α5β1, where Akt activation enhanced repair and integrin α5β1 expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K/Akt signaling in primary cultures from children without wheeze reduced α5β1 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib — and its non–COX2-inhibiting analogue, dimethyl-celecoxib — stimulated the PI3K/Akt–integrin α5β1 axis and restored airway epithelial repair in cells from children with wheeze. When compared with published clinical data sets, the identified transcriptomic signature was also associated with viral-induced wheeze exacerbations highlighting the clinical potential of such therapy. Collectively, these results identify airway epithelial restitution via targeting the PI3K–integrin α5β1 axis as a potentially novel therapeutic avenue for childhood wheeze and asthma. We propose that the next step in the therapeutic development process should be a proof-of-concept clinical trial, since relevant animal models to test the crucial underlying premise are unavailable.

Background: A third measles-mumps-rubella vaccine (MMR) dose (MMR3) is recommended in the United States for persons at increased risk for mumps during outbreaks. MMR3 is also likely given to persons who might have received 2 doses of MMR but lack documentation. Since MMR3 safety data are limited, we describe adverse events in persons receiving MMR3 in a nonoutbreak setting. Methods: Young adults with 2 documented MMR doses were administered MMR3. From 2 weeks before until 4 weeks after MMR3 receipt, participants reported daily on 11 solicited, common symptoms potentially associated with MMR. Weekly rate differences in post- vs prevaccination (baseline) were evaluated by Poisson regression. Baseline rates were subtracted from postvaccination rates of significantly different symptoms to estimate the number and percentage of participants with excess risk for symptoms post-MMR3. Descriptive analyses were performed for 3 postvaccination injection-site symptoms. Results: The 662 participants were aged 18–28 years (median = 20 years); 56% were women. Headache, joint problems, diarrhea, and lymphadenopathy rates were significantly higher postvaccination vs baseline. We estimate that 119 participants (18%) reported more symptoms after MMR3 than prevaccination. By symptom, 13%, 10%, 8%, and 6% experienced increased symptoms of headache, joint problems, diarrhea, and lymphadenopathy, respectively, after MMR3. The median onset was Days 3–6 postvaccination; the median duration was 1–2 days. One healthcare visit for a potential vaccination-related symptom (urticaria) was reported. Injection-site symptoms were reported by 163 participants (25%); the median duration was 1–2 days. Conclusions: Reported systemic and local events were mild and transient. MMR3 is safe and tolerable among young adults.

This article discusses recent findings into the mechanisms that determine how viruses trigger asthma exacerbations. Substantial progress has been made in our understanding of the pathogenesis of virus-induced asthma exacerbations. This includes new insights into the role of bacteria, the regulation of interferon responses, and the discovery of innate immune pathways that link viral infections with allergic inflammation. Progress has also been made in elucidating the genetic risk factors for asthma exacerbations, most notably the contribution of the ORMDL3/GSDMB locus on 17q, the mechanisms underlying the farming effect, and the discovery that CDHR3 binds to rhinovirus species C. Asthma exacerbations are heterogeneous conditions that involve the complex interplay between environmental exposures and innate and adaptive immune function in genetically predisposed individuals. Recent insights into the interrelationships between these factors provide new opportunities for therapeutic intervention.

Human rhinovirus (RV)-induced exacerbations of asthma and wheeze are a major cause of emergency room presentations and hospital admissions among children. Previous studies have shown that immune response patterns during these exacerbations are heterogeneous and are characterized by the presence or absence of robust interferon responses. Molecular phenotypes of asthma are usually identified by cluster analysis of gene expression levels. This approach however is limited, since genes do not exist in isolation, but rather work together in networks. Here, we employed personal network inference to characterize exacerbation response patterns and unveil molecular phenotypes based on variations in network structure. We found that personal gene network patterns were dominated by two major network structures, consisting of interferon-response versus FCER1G-associated networks. Cluster analysis of these structures divided children into subgroups, differing in the prevalence of atopy but not RV species. These network structures were also observed in an independent cohort of children with virus-induced asthma exacerbations sampled over a time course, where we showed that the FCER1G-associated networks were mainly observed at late time points (days four–six) during the acute illness. The ratio of interferon- and FCER1G-associated gene network responses was able to predict recurrence, with low interferon being associated with increased risk of readmission. These findings demonstrate the applicability of personal network inference for biomarker discovery and therapeutic target identification in the context of acute asthma which focuses on variations in network structure.

Background: There is evidence that vitamin D (vit D) affects immunity and response to infection. The objective of this study was to determine whether serum vit D predicts influenza vaccine response or upper respiratory illness (URI). Methods: 1101 adults ≥ 50 years old were recruited from 2 communities in WI and TN during the 2008–2009 and 2009–2010 flu seasons. Pre‐and post‐vaccination hemagglutinin antibody inhibition (HAI) titers to vaccine components and serum vit D (1,25(OH) ₂ D) were measured. Seroprotection was defined as HAI ≥ 40; seroconversion as ≥ 4‐fold increase in post‐vaccination HAI. ARI was assessed by self‐report. Results: Mean (± SD) serum vit D was 31 ± 10 ng/mL; 28.5% participants were vitamin D deficient (VDD). Vit D and VDD did not predict seroconversion for any vaccine components in 08–09 (odds ratio [OR]: 95% confidence interval [CI] 1.00: 0.98–1.01, 1.00: 0.98–1.02, and 1.01: 0.99–1.03) for H1N1, H3N2 and B subtypes, respectively (controlling for age, gender, and pre‐vaccination HAI). Vit D did not predict seroconversion in 09–10 or seroprotection or ARI in either year. VDD was related to physician‐attended URI (p = 0.01) but no other disease outcomes in year 1. Conclusions: There was no consistent relationship between vit D and response to influenza vaccination or respiratory illness in our population. Funding Source: CDC 5 U18 IP000183 ‐02, CDC 1 U18 IP000184 ‐01, K23 A1074863‐01A1 (Talbot)