key: cord-0857264-o5p8ynl9 authors: Peters, Michael C.; Fahy, John V. title: Reply to Nannini and to Lipworth et al. date: 2020-11-01 journal: Am J Respir Crit Care Med DOI: 10.1164/rccm.202006-2531le sha: e2340e70476c65cf46de2360ca19803dfb43931e doc_id: 857264 cord_uid: o5p8ynl9 nan Reply to Nannini and to Lipworth et al. Dr. Nannini is concerned that IL-6 could be upregulated by overuse of b 2 -agonists (1) . This is unlikely because the SARP-III (Severe Asthma Research Program III) protocol included a bronchodilator medication hold for the blood collection visits. Specifically, short-acting b 2 -agonists were held for 4 hours, and long-acting b 2 -agonists were held for 12 hours (2) , but the halflife of IL-6 in plasma is less than 15 minutes (3, 4) . In addition, participants could only come in for study visits for blood collection if they had been free of an asthma exacerbation in the previous 4 weeks (2). This protocol feature limited the risk that increased b 2 -agonist treatment associated with exacerbations influenced our analysis. Finally, and most importantly, our study focused on plasma IL-6, not airway IL-6, and we have previously reported that patients with IL-6-high asthma do not have high sputum concentrations of IL-6 (5). Instead, the IL-6-high subgroup has clinical features of metabolic dysfunction, including systemic leukocytosis and high frequencies of obesity, hypertension, and diabetes mellitus (5) . Thus, we do not consider that high plasma IL-6 concentrations result from spillover from airway IL-6 but instead result from obesityassociated systemic inflammation, which might drive proneness to exacerbation in these patients (6) . Lipworth and colleagues provide important commentary on the links between IL-6 biology and airway viral infections, including coronavirus disease (COVID-19). We agree that IL-6 is a key component of the cytokine response to viral illness, and we believe it relevant that IL-6-high asthma is characterized by obesity and metabolic dysfunction (1, 5) , because these comorbidities lead to accelerated immune senescence, which has been linked to poor vaccination responses (7) and impairments in cytotoxic T-lymphocyte function (8) . We have reported previously that obesity is associated with decreased airway geneexpression signatures for cytotoxic T lymphocytes (9) , so that high plasma IL-6 levels may be marking patients with impairments in airway T-cell responses to viral airway infections, including COVID-19. It is not known whether triple therapy with beclomethasone, formoterol, and glycopyrronium will address this impairment or decrease susceptibility to airway viral illness. Clinical trials will be necessary to determine that. n NHLBI Severe Asthma Research Program. Evidence for exacerbationprone asthma and predictive biomarkers of exacerbation frequency Baseline features of the severe asthma research program (SARP III) cohort: differences with age For commercial usage and reprints Source and kinetics of interleukin-6 in humans during exercise demonstrated by a minimally invasive model A system model of the effects of exercise on plasma interleukin-6 dynamics in healthy individuals: role of skeletal muscle and adipose tissue National Heart, Lung, and Blood Institute Severe Asthma Research Program. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts Metabolic consequences of obesity as an "outside in" mechanism of disease severity in asthma Obesityinduced chronic inflammation is associated with the reduced efficacy of influenza vaccine Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade A transcriptomic method to determine airway immune dysfunction in T2-high and T2-low asthma Author disclosures are available with the text of this letter at www.atsjournals.org.