IL-25 blockade augments antiviral immunity during respiratory virus infection.

IL-25 is implicated in the pathogenesis of viral asthma exacerbations. However, the effect of IL-25 on antiviral immunity has yet to be elucidated. We observed abundant expression and colocalization of IL-25 and IL-25 receptor at the apical surface of uninfected airway epithelial cells and rhinovirus infection increased IL-25 expression. Analysis of immune transcriptome of rhinovirus-infected differentiated asthmatic bronchial epithelial cells (BECs) treated with an anti-IL-25 monoclonal antibody (LNR125) revealed a re-calibrated response defined by increased type I/III IFN and reduced expression of type-2 immune genes CCL26, IL1RL1 and IL-25 receptor. LNR125 treatment also increased type I/III IFN expression by coronavirus infected BECs. Exogenous IL-25 treatment increased viral load with suppressed innate immunity. In vivo LNR125 treatment reduced IL-25/type 2 cytokine expression and increased IFN-ß expression and reduced lung viral load. We define a new immune-regulatory role for IL-25 that directly inhibits virus induced airway epithelial cell innate anti-viral immunity.

ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma.

BACKGROUND AND OBJECTIVE: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. METHODS: We obtained lower AEC from 145 people from two independent cohorts, aged 2-89 years, Newcastle (n = 115) and Perth (n = 30), Australia. The Newcastle cohort was enriched with people with asthma (n = 37) and COPD (n = 38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC. RESULTS: Increased gene expression of ACE2 was associated with older age (P = 0.03) and male sex (P = 0.03), but not with pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients (P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma (P = 0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface, was increased (P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. CONCLUSION: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications.

Impact of aerosol box on intubation during COVID-19: a simulation study of normal and difficult airways.

PURPOSE: Patients with coronavirus disease (COVID-19) are at risk of requiring mechanical ventilation, and concerns of protecting healthcare workers during aerosol-generating medical procedures has led to the design of the aerosol box. METHODS: We conducted a randomized crossover mannequin-based simulation study to compare airway management with and without the aerosol box. Thirty-five anesthesiology participants and three critical care participants with more than 50 intubations with videolaryngoscopes were recruited. There were four airway simulations with and without the aerosol box (normal, pharyngeal swelling, cervical spine rigidity, and tongue edema). Each participant intubated the mannequin in eight consecutive simulations. The primary outcome of the study was time to intubation. Secondary outcomes included intubation attempts, optimization maneuvers, and personal protective equipment breaches. RESULTS: Mean (standard deviation [SD]) time to intubation overall with the box was 30.9 (23.0) sec, while the time to intubation without the box was 25.1 (12.2) sec (mean difference, 5.8; 95% confidence interval [CI], -2.9 to 14.5). For the normal airway scenario, the mean (SD) time to intubation was 18.6 (3.5) sec for no box and 20.4 (3.3) sec for box (mean difference, 1.8; 95% CI, 0.2 to 3.4). During difficult airway scenarios only, the time to intubation was 34.4 (25.6) sec with the aerosol box and 27.3 (13.2) sec without the aerosol box (mean difference, 7.1; 95% CI, -2.5 to 16.7). There were more intubation attempts, personal protective equipment breaches, and optimization maneuvers during use of the aerosol box. CONCLUSIONS: In this mannequin-based simulation study, the use of the aerosol box increased the time to intubation in some contexts but not others. Further studies in a clinical setting should be conducted to make appropriate modifications to the aerosol box to fully elicit its efficacy and safety prior to implementation in airway guidelines for managing patients with COVID-19.

RéSUMé: OBJECTIF: Les patients atteints de la maladie à coronavirus (COVID-19) courent le risque d'avoir besoin de ventilation mécanique, et les inquiétudes quant à la protection des travailleurs de la santé pendant les interventions médicales générant des aérosols ont motivé la conception d'une boîte pour contenir les aérosols. MéTHODE: Nous avons réalisé une étude de simulation croisée randomisée sur des mannequins afin de comparer la prise en charge des voies aériennes avec et sans boîte pour contenir les aérosols. Trente-cinq anesthésiologistes et trois intensivistes ayant pratiqué plus de 50 intubations avec des vidéolaryngoscopes ont été recrutés. Quatre simulations de voies aériennes avec et sans boîte pour contenir les aérosols ont été évaluées (voies aériennes normales, œdème pharyngé, rigidité de la colonne cervicale et œdème de la langue). Chaque participant a intubé le mannequin dans huit simulations consécutives. Le critère d'évaluation principal de l'étude était le temps nécessaire à l'intubation. Les critères secondaires comprenaient le nombre de tentatives d'intubation, les manœuvres d'optimisation et les bris de stérilité des équipements de protection individuelle. RéSULTATS: Globalement, le temps moyen (écart type [ÉT]) d'intubation avec la boîte était de 30,9 (23,0) sec, alors que le temps d'intubation sans la boîte était de 25,1 (12,2) sec (différence moyenne, 5,8; intervalle de confiance [IC] 95 %, -2,9 à 14,5). Dans la mise en situation simulant des voies aériennes normales, le temps moyen (ÉT) d'intubation était de 18,6 (3,5) sec sans la boîte et 20,4 (3,3) sec avec la boîte (différence moyenne, 1,8; IC 95 %, 0,2 à 3,4). Dans la mise en situation simulant des voies aériennes difficiles seulement, le temps d'intubation était de 34,4 (25,6) sec avec la boîte à aérosol et 27,3 (13,2) sec sans la boîte (différence moyenne, 7,1; IC 95 %, -2,5 à 16,7). Lors de l'utilisation de la boîte pour contenir les aérosols, les tentatives d'intubation étaient plus nombreuses, tout comme les bris de stérilité des équipements de protection individuelle et le nombre de manœuvres d'optimisation. CONCLUSION: Dans cette étude de simulation sur mannequin, l'utilisation de la boîte pour contenir les aérosols a augmenté le temps nécessaire à l'intubation dans certains contextes mais pas dans d'autres. Des études supplémentaires devraient être réalisées dans un cadre clinique pour apporter des modifications adaptées à la boîte pour contenir les aérosols afin d'optimiser son efficacité et la sécurité qu'elle procure avant de l'ajouter aux recommandations de prise en charge des voies aériennes de patients atteints de la COVID-19.