SARS-CoV2 requires angiotensin-converting enzyme 2 (ACE2) to bind to host nasal epithelial cells. However, upon binding of SARS-CoV to ACE2, internalization leads to decreased ACE2 activity. ACE2 can generate biologically active peptides (Ang(1-9) and Ang(1-7)) which are protective against severe COVID-19- induced lung injury. Therefore, although ACE2 expression in the nasal epithelium is a required entry point for viral infection, continued high levels of ACE2 activity may paradoxically provide benefit once the patient is infected. The host factors that regulate ACE2 expression and activity are not fully known and are missing pieces required to expand our understanding of the pathogenesis of this disease. In March 2020 a French health minister suggested that NSAID use might be associated with more severe disease presentation in patients with COVID-19. There is now a desperate attempt to understand whether NSAID use is simply correlated with, or actually causative of, worsened respiratory outcomes. As fever and myalgias are associated with COVID-19, and both are often treated presumptively with NSAIDs, it is imperative that we understand the immunological influence of NSAIDs in this disease. There is also considerable concern regarding the potential for more severe COVID-19-related respiratory disease in patients with Type 2 inflammation, and the subset of patients with aspirin-exacerbated respiratory disease (AERD) have severe upper respiratory inflammation in exactly the anatomic areas of the sinuses where ACE2 expression has been found to be the highest. It is not yet known how the presence of chronic Type 2-driven respiratory inflammation affects ACE2 levels in the respiratory tract or the blood. We have collected nasal epithelial cells (for mRNA assessment of ACE2 expression), and both nasal fluid and serum and plasma (for ELISA measurement of the angiotensin-derived peptides as above) which are banked and are available for immediate analysis. With these, we aim to shed light on two questions that are plaguing the assessment and treatment of patients with COVID-19: 1) Does use of NSAIDs increase risk of severe complications from COVID-19? 2) Are patients with asthma and Type 2 respiratory inflammation at increased risk of severe complications from COVID-19? Completion of these aims would allow us to make recommendations regarding safety of NSAID use in COVID-19. Many patients are currently choosing to stop their regularly prescribed aspirin and NSAIDs out of fear, which we suspect is unfounded. We will also further understand whether patients with severe Type 2 respiratory inflammation have different nasal ACE2 expression and angiotensin peptide levels, compared to healthy controls, which would suggest a differing risk of severe COVID-19 in those patients.

Public Health Relevance

(RELEVANCE) It is not known whether use of NSAIDs is associated with more severe manifestations of COVID-19. In this proposal we seek to understand whether NSAID use changes levels of the ACE2 receptor in the nose and sinuses, where SARS-CoV2 binds and infects, as well as whether NSAIDs change levels of ACE2-related peptides in the blood and nasal fluid that could actually be protective against severe COVID-19. We will do this in patients with severe asthma and inflammation and therefore will also be able to learn whether those patients are at higher risk than the general population. Upon completion of this work, we will be able to make recommendations regarding the safety of NSAID use. Many patients are currently choosing to stop their regularly prescribed aspirin and NSAIDs out of fear, which we suspect is unfounded.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Davidson, Wendy F
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Brigham and Women's Hospital
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Cardet, Juan Carlos; Louisias, Margee; King, Tonya S et al. (2018) Income is an independent risk factor for worse asthma outcomes. J Allergy Clin Immunol 141:754-760.e3
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Tuttle, Katherine L; Buchheit, Kathleen M; Laidlaw, Tanya M et al. (2018) A retrospective analysis of mepolizumab in subjects with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract 6:1045-1047
Pan, Dingxin; Buchheit, Kathleen M; Samuchiwal, Sachin K et al. (2018) COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity. J Allergy Clin Immunol :
Liu, Tao; Barrett, Nora A; Kanaoka, Yoshihide et al. (2018) Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. J Immunol 200:915-927
Eid, Ryan C; Palumbo, Marina L; Laidlaw, Tanya M et al. (2018) A retrospective analysis of esophageal eosinophilia in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract :
Schneider, Thomas R; Johns, Christina B; Palumbo, Marina L et al. (2018) Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial. J Allergy Clin Immunol Pract 6:825-831
Putman, Rachel K; Gudmundsson, Gunnar; Araki, Tetsuro et al. (2017) The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. Eur Respir J 50:
Cahill, Katherine N; Katz, Howard R; Cui, Jing et al. (2017) KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376:1911-1920
Wang, H-B; Akuthota, P; Kanaoka, Y et al. (2017) Airway eosinophil migration into lymph nodes in mice depends on leukotriene C4. Allergy 72:927-936

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