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Weily Soong,1 Bradley E Chipps,2 Sean O’Quinn,3 Jennifer Trevor,4 Warner W Carr,5 Laura Belton,6 Frank Trudo,7 Christopher S Ambrose3 1Alabama Allergy & Asthma Center, Birmingham, AL, USA; 2Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 3BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 4University of Alabama at Birmingham, Birmingham, AL, USA; 5Allergy & Asthma Associates of Southern California, Mission Viejo, CA, USA; 6Biostatistics, AstraZeneca, Cambridge, UK; 7BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USACorrespondence: Weily SoongAlabama Allergy & Asthma Center, 504 Brookwood Boulevard, Birmingham, AL, 35209, USATel +1 205 871-9661Fax +1 205 870-1621Email wsoong@alabamaallergy.comBackground: Health-related quality of life (HRQoL) and productivity of patients with confirmed severe asthma (SA) have not been well characterized in large, real-world populations.Purpose: To characterize SA impact on HRQoL, work productivity, and activity impairment in a large, real-world cohort in the United States (US).Methods: CHRONICLE is an observational study of specialist-treated adults (≥ 18 years) in the US with SA receiving biologics or maintenance systemic corticosteroids (mSCS), or those persistently uncontrolled by high-dosage inhaled corticosteroids with additional controllers (HD ICS+). At enrollment, patients completed the St. George’s Respiratory Questionnaire (SGRQ) and Work Productivity and Activity Impairment (WPAI) questionnaire. Results were analyzed for those enrolled between February 2018 and February 2020.Results: Among patients who completed enrollment questionnaires (n = 1109), mean age was 54 years and most were women (70%). Among SGRQ respondents (n = 960), mean (SD) total score was 43 (23); 51% reported good/very good health. Among WPAI respondents (n = 1057; 566 employed), mean (SD) overall work impairment was 21% (25). Patients receiving biologics (vs mSCS, HD ICS+ only) had better SGRQ total scores (38 vs 59, 48) and lower work impairment (17% vs 34%, 27%). Patients with better SGRQ activity scores relative to symptom scores had better SGRQ impacts scores, total scores, and reported better overall health.Conclusion: SA significantly affects HRQoL, work productivity, and activity. The SGRQ is a valuable research instrument for evaluating HRQoL in SA. Due to its association with HRQoL and overall health, activity impairment should be a focus when monitoring patients’ disease control.Study Registration: ClinicalTrials.gov Identifier: NCT03373045.Keywords: real-world, St. George’s Respiratory Questionnaire, SGRQ, WPAI, symptoms, activity

Asthma is an inflammatory disease of the airways that may result from exposure to allergens or other environmental irritants, resulting in bronchoconstriction, wheezing, and shortness of breath. The structural changes of the airways associated with asthma, broadly referred to as airway remodeling, is a pathological feature of chronic asthma that contributes to the clinical manifestations of the disease. Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation, and fibroblast activation. These pathological changes in the airway are orchestrated by crosstalk of different cell types within the airway wall and submucosa. Environmental exposures to dust, chemicals, and cigarette smoke can initiate the cascade of pro-inflammatory responses that trigger airway remodeling through paracrine signaling and mechanostimulatory cues that drive airway remodeling. In this review, we explore three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial cells; (2) amplification by immune cells; and (3) mesenchymal effector functions. Furthermore, we explore the role of inflammaging in the dysregulated and persistent inflammatory response that perpetuates airway remodeling in elderly asthmatics.

Chronic inflammation involving both innate and adaptive immune cells is implicated in the pathogenesis of asthma. Intercellular communication is essential for driving and resolving inflammatory responses in asthma. Emerging studies suggest that extracellular vesicles (EVs) including exosomes facilitate this process. In this report, we have used a range of approaches to show that EVs contain markers of mitochondria derived from donor cells which are capable of sustaining a membrane potential. Further, we propose that these participate in intercellular communication within the airways of human subjects with asthma. Bronchoalveolar lavage fluid of both healthy volunteers and asthmatics contain EVs with encapsulated mitochondria; however, the % HLA-DR+ EVs containing mitochondria and the levels of mitochondrial DNA within EVs were significantly higher in asthmatics. Furthermore, mitochondria are present in exosomes derived from the pro-inflammatory HLA-DR+ subsets of airway myeloid-derived regulatory cells (MDRCs), which are known regulators of T cell responses in asthma. Exosomes tagged with MitoTracker Green, or derived from MDRCs transduced with CellLight Mitochondrial GFP were found in recipient peripheral T cells using a co-culture system, supporting direct exosome-mediated cell-cell transfer. Importantly, exosomally transferred mitochondria co-localize with the mitochondrial network and generate reactive oxygen species within recipient T cells. These findings support a potential novel mechanism of cell-cell communication involving exosomal transfer of mitochondria and the bioenergetic and/or redox regulation of target cells., Graphical abstract fx1, Highlights • BAL and MDRC-derived exosomes contain mitochondria. • Airway exosomes contain mtDNA. • MDRC-derived exosomes transfer mitochondria to CD4+ T cells. • Exosomal mitochondria co-localize with host cell mitochondria.