Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation.Objectives: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway.Methods: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirusinfected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade.

Selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on (1) patient empowerment, preferences, and age; (2) prominent symptoms, symptom severity, and multimorbidity; (3) efficacy and safety of treatment 1 ; (4) speed of onset of action of treatment; (5) current treatment; (6) historic response to treatment; (7) effect on sleep and work productivity 2,3 ; (8) self-management strategies; and (9) resource use. 4,5 An algorithm was devised 5 and digitalized 6 to step up or step down allergic rhinitis treatment based on control. However, its

Respiratory virus infections are major triggers of acute exacerbations of asthma in both adults and children, implicated in around 80% of paediatric (1) and 75% of adult (2) asthma attacks. They are therefore major causes of asthma morbidity and mortality (3). Of viruses detected in asthma exacerbations, two thirds are rhinoviruses (1). Influenza viruses are also implicated in asthma exacerbations during annual influenza epidemics (2,4,5).Current therapy of asthma exacerbations is of limited efficacy (6-8), new approaches are therefore required.Background: Respiratory viruses, predominantly rhinoviruses are the major cause of asthma exacerbations. Impaired production of interferon-b in rhinovirus infected bronchial epithelial cells (BECs) and of the newly discovered interferon-ks in both BECs and bronchoalveolar lavage cells, is implicated in asthma exacerbation pathogenesis. Thus replacement of deficient interferon is a candidate new therapy for asthma exacerbations. Rhinoviruses and other respiratory viruses infect both BECs and macrophages, but their relative capacities for a-, b-and k-interferon production are unknown. Methods: To provide guidance regarding which interferon type is the best candidate for development for treatment/prevention of asthma exacerbations we investigated respiratory virus induction of a-, b-and k-interferons in BECs and peripheral blood mononuclear cells (PBMCs) by reverse transferase-polymerase chain reaction and enzyme-linked immunosorbent assay. Results: Rhinovirus infection of BEAS-2B BECs induced interferon-a mRNA expression transiently at 8 h and interferon-b later at 24 h while induction of interferon-k was strongly induced at both time points. At 24 h, interferon-a protein was not detected, interferon-b was weakly induced while interferon-k was strongly induced. Similar patterns of mRNA induction were observed in primary BECs, in response to both rhinovirus and influenza A virus infection, though protein levels were below assay detection limits. In PBMCs interferon-a, interferon-b and interferon-k mRNAs were all strongly induced by rhinovirus at both 8 and 24 h and proteins were induced: interferon-a>-b>-k. Thus respiratory viruses induced expression of a-, b-and k-interferons in BECs and PBMCs. In PBMCs interferon-a>-b>-k while in BECs, interferon-k>-b>-a. Conclusions: We conclude that interferon-ks are likely the principal interferons produced during innate responses to respiratory viruses in BECs and interferonas in PBMCs, while interferon-b is produced by both cell types.