Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus Disease 2019 (COVID-19), continues to plague the globe. Many approaches involve targeting inflammation to reduce mortality, such as using corticosteroids like dexamethasone and monoclonal antibodies like tocilizumab that target the cytokine IL-6. However, although these therapeutic options reduce mortality among patients, they do not provide 100% protection.

After a surge in the fatality rate (12.6%) by the Delta variant of SARS-CoV-2, lower mortality (7.3%) was recorded with the Omicron variant. Yet, the number of deaths remained high. This was because of the immune evasion ability of this variant of concern (VOC) and reduced vaccine efficacy against the variant.

A role of Interleukin-13 (IL-13) in severe infection outcomes of SARS-CoV-2 infection, including – increased smooth muscle contractility, mucus production, and immune cell recruitment, as well as airway remodeling, has been discovered recently. IL-13 has also been implicated in causing breathing difficulty and wheezing and decreased lung function and capacity in acute infection, explaining the disease’s long-term impact.

A monoclonal antibody, dupilumab, targets the IL-4Ra receptors, blocking the signaling of IL-4 and IL-13.

Study: Dupilumab use is associated with protection from COVID-19 mortality: A retrospective analysis​​​​​​​. Image Credit: Naeblys / Shutterstock

The study

A recent report posted to the medRxiv* preprint server assessed the efficacy of dupilumab in blocking the IL-13 signaling pathway and its efficacy in reducing the COVID-19 associated mortality.

TriNetX and National COVID Cohort Collaborative (N3C) databases were used for this study. Participants were filtered from the N3C database based on the recorded COVID-19 positive test – either by positive SARS-CoV-2 polymerase chain reaction (PCR) test or positive antigen test—the first positive test marking the index date.

Participants were divided into three sub-cohorts – SARS-CoV-2 positive patients with no prior history of dupilumab use within 61 days pre-index date formed the control group; SARS-CoV-2 positive patients with prior history of dupilumab use within 61 days pre-index date formed the Dupilumab (+)ve group; and SARS-CoV-2 negative participants with prior dupilumab use formed the Dupilumab (-)ve group.

The incidence of SARS-CoV-2 positivity in participants who had taken dupilumab was calculated. The outcome ‘Hospitalized’ was defined as a positive SARS-CoV-2 test or diagnosis during hospitalization. ‘Death’ was defined from the record based on the contributing medical record system.

COVID-19 severity was categorized into four groups – the outpatients were marked ‘mild’; hospitalized patients with no extracorporeal membrane oxygenation (ECMO) or intermittent mandatory ventilation (IMV) were marked ‘moderate’; while hospitalized patients with ECMO or IMV were marked ‘severe’ and ‘death’.

Results

Out of the 1,069 patients taking prescribed dupilumab, 220 were diagnosed with SARS-CoV-2 infection within 61 days of taking dupilumab. It was found that Dupilumab (+)ve patients had significantly lower mortality than the control group.

Thereafter, the COVID-19 cases from the TriNetX database were categorized into – patients with recorded dupilumab use (937 and those without (1.7 million) and matched in the ratio of 1:1. It was noted that dupilumab reduced the risk of death compared to controls. Additionally, it was found that Dupilumab (+)ve cohort had lower C-reactive protein (CRP) values – suggesting lower inflammation in this group compared to the control group.

It was inferred that dupilumab usage was associated with higher survival rates compared to the control group. The findings support the causal role of IL-13 in the pathogenesis of COVID-19. It was hypothesized that dupilumab confers protection against SARS-CoV-2 by blocking the IL-13 signaling pathway. The datasets provide analyses supporting this hypothesis.

Conclusion

Dupilumab can be deemed a potent therapeutic option for treating SARS-CoV-2 infection, owing to its lowering effect on the disease severity and fatality rate of COVID-19 patients. The study proves the hypothesis that pharmacological inhibition of the IL-13 signaling pathway may be a therapeutic option against SARS-CoV-2 infection. Large-scale trials of dupilumab are warranted for determining its efficacy against severe outcomes of COVID-19 disease.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.