Dupilumab use is associated with protection from COVID-19 mortality: A retrospective analysis

Abstract We previously found that type 2 immunity promotes COVID-19 pathogenesis in a mouse model. To test relevance to human disease we used electronic health record databases and determined that patients on dupilumab (anti-IL-4R monoclonal antibody that blocks IL-13 and IL-4 signaling) at the time of COVID-19 infection had lower mortality.

A C C E P T E D M A N U S C R I P T 2 Abstract: 1 We previously found that type 2 immunity promotes COVID-19 pathogenesis in a 2 mouse model. To test relevance to human disease we used electronic health record 3 databases and determined that patients on dupilumab (anti-IL-4R monoclonal antibody 4 that blocks IL-13 and IL-4 signaling) at the time of COVID-19 infection had lower 5 mortality. inflammation, such as with the corticosteroid dexamethasone [1] or the monoclonal 4 antibody against IL-6, tocilizumab [2]. However, while these therapeutic options have 5 been observed to reduce mortality in patients, protection is not complete. This was 6 exemplified by mortality due to the delta variant being 12.6% during the fall 2021 surge warranted. Additionally, the emergence of novel variants such as omicron, for which the 10 vaccine is increasingly less effective, highlights the need for development of better 11 therapeutic options in treating this disease. 12 Recently, we have uncovered a causal role of Interleukin (IL)-13 in promoting 13 severe outcomes caused by infection with SARS-CoV-2, suggesting that type 2 immune 14 responses are pathogenic during COVID-19 [4,5] IL-13 is often associated with 15 promoting pathology in asthma, allergies, and atopic dermatitis. In the lung, pulmonary 16 responses potentiated by IL-13 include airway hyperreactivity, mucus production, 17 smooth muscle contractility, recruitment of immune cells, and long-term airway 18 remodeling [6][7][8]. In acute settings this results in airway restriction causing breathing 19 difficulty and wheezing, and long-term can result in decreased lung capacity and 20 function.

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Dupilumab is a human monoclonal antibody which blocks signaling of the closely 22 related cytokines IL-4 and IL-13 by targeting the shared alpha subunit of their receptors, IL-4R [9-11]. IL-4 and IL-13 are both primarily associated with type 2 responses which 1 drive pathogenesis of asthma and atopic dermatitis, for which dupilumab is approved to 2 treat [9-11]. We were interested in whether dupilumab use in patients who were later 3 diagnosed with COVID-19 was associated with protection from mortality due to its ability 4 to block pathogenic IL-13 signaling. Earlier we had performed a randomized double 5 blind placebo controlled clinical trial of dupilumab for the treatment of moderate to 6 severe COVID-19 in a small study of 40 hospitalized adults. Subjects randomized to 7 receive dupilumab had lower mortality, again supporting the potential significance of IL-  Here we report for over two thousand patients that dupilumab usage is 10 associated with reduced mortality compared to matched-control patients. Our findings 11 support the hypothesis that IL-13 signaling during COVID-19 is associated with more 12 severe outcomes, and that pharmacological inhibition of this pathway may be a feasible 13 therapeutic option for treating this disease.    criteria since it is an approved disease for which dupilumab is prescribed and primarily 5 affects respiratory inflammation.  which were generated for each analysis.

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Results: 12 The N3C and TriNetX databases were independently queried. N3C database used allowed for well-defined patient outcomes and temporal windows, 1 however small sampling size may limit the statistical power through this method.
2 Supportive analysis by TriNetX allowed for larger cohort of dupilumab (+) cases, but 3 was limited to lower matching criteria and at a 1:1 ratio. Utilization of both datasets, 4 then, provides two analyses which supported our hypothesis.

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Identification of dupilumab as a being associated with reduction in death due to 6 COVID-19 may implicate this drug as a potential therapeutic option for patients. Future,