The contributions of allergic sensitization and respiratory pathogens to asthma inception(extraction) DIO:org/10.1016/j.jaci.2016.01.002 INTERACTIONS BETWEEN ALLERGY AND INFECTIONS Allergic sensitization, most notably to perennial aeroallergens, has been defined as a pivotal risk factor for the development of asthma. Recently, it has become evident that both the timing of allergic sensitization and the quantity of sensitization are impor-tant prognostic indicators. Simpson et al have identified an atopy phenotype in children they termed multiple early sensitization. In those children sensitized to multiple aeroallergens at an early age, Simpson et al reported a remarkable increase in risk for asthma inception, severe exacerbations leading to hospitalization, and impaired lung function. This link between early-life sensitization to multiple allergens and increased asthma risk has been replicated in additional cohort studies. This observed link between early sensitization to aeroallergens and asthma risk is in part due to synergy between allergic inflammation and viral infections, most commonly rhinovirus. Indeed, children in the COAST study who were sensitized to aeroallergens and wheezed with rhinovirus during the first 3 years of life had the greatest risk for asthma inception. This led to the question of whether viral illnesses in early life lead to allergic sensitization or whether the converse was true. Using a longitudinal multistate Markov model in the COAST study, Jackson et al. identified a sequential relationship whereby allergic sensitization leads to viral wheezing. This relationship was strongest for rhinovirus-induced wheezing, and there was no evidence that viral wheezing led to sensitization. There is also strong evidence to implicate allergic sensitization and exposure as a risk factor for wheezing with common cold infections later in childhood. In emergency department studies detection of a respiratory tract virus, most commonly rhinovirus, with detectable allergen-specific IgE and/or the presence of eosinophilic inflammation were all identified as risk factors for acute wheezing episodes. Notably, viral infections and allergic inflammation synergistically enhanced the risk of wheezing, and higher levels of allergen-specific IgE conferred the greatest risk. This synergism might be particularly notable for patients with rhinovirus C, in whom aeroallergen sensitization was recently reported as a risk factor for recurrent severe exacerbations leading to emergency department visits and hospitalization. MECHANISMS OF ALLERGY-VIRUS INTERACTIONS There are multiple mechanisms by which viral infections are thought to interact with allergic inflammation to lead to lower respiratory airway dysfunction, wheezing, and asthma exacerba- tions. First, underlying allergic inflammation can directly enhance airway responsiveness to rhinovirus infection. Additionally, viral infections can damage the barrier function of the airway epithelium, leading to enhanced absorption of aeroallergens across the airway wall and enhanced inflammation, whereas underlying allergic inflammation might also lead to enhanced viral replication. Of interest, both rhinovirus infections and allergens can enhance airway epithelial cell production of IL-33, a recently identified innate cytokine, which promotes type 2 airway inflammation and remodeling. This steroid- resistant pathway has been reported to be upregulated in children with difficult-to-control asthma. Interestingly, IL-33 polymor- phisms have been linked with intermediate and late-onset wheezing, which are strongly linked to early-life allergic sensiti- zation. Another innate epithelial cytokine, IL-25, is also induced by rhinovirus and is likely to accentuate allergic airway inflammation in the context of rhinovirus infections in allergic subjects. Finally, there is significant evidence that children with allergic asthma have impaired antiviral responses. Indeed, allergen exposure and high-affinity IgE receptor cross-linking has been shown to impair virus-induced type I and III interferon production in peripheral blood cells . The result would be both enhanced viral replication and enhanced type 2 inflammation in the airway. The most direct evidence to support the importance of allergen- virus interactions in patients with virus-induced wheezing and asthma exacerbations comes from a recent clinical trial of omalizumab (anti-IgE) to prevent seasonal virus-induced asthma exacerbations. In this trial virus-induced exacerbations were significantly reduced by omalizumab, and this reduction coincided with an enhanced type I interferon response ex vivo in rhinovirus-stimulated mononuclear cells. Of note, those participants who had larger increases in type I interferon response with omalizumab treatment had the greatest protection from virus-induced exacerbations. CONCLUSION Two key risk factors for the development of childhood asthma are the development of allergic sensitization in early life and wheezing respiratory tract illnesses caused primarily by viruses but also by bacteria either alone or as coinfections accompanying illnesses of viral cause. Therapies directed at these 2 risk factors, either alone or in combination, appear to be essential components to target for development of effective strategies for the primary prevention of asthma in children. All Author: Daniel J. Jackson, MD, James E. Gern, MD,a and Robert F. Lemanske, Jr, MD