COVID-19 and Hereditary Angioedema (HAE): Incidence, Outcomes and Mechanistic Implications

Background: HAE patients have been postulated to be at increased risk for COVID-19 infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data has been available to explore this hypothesis. The aim of this study was to assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity and mortality were surveyed using an online questionnaire. Subjects included HAE with C1 inhibitor deficiency (HAE-C1INH), normal C1 inhibitor (HAE-nl-C1INH and household controls. The impact of HAE medications was examined. Results: 1445 participants completed the survey, including: 695 HAE-C1INH, 175 HAE-nl-C1INH, and 292 controls. The incidence of reported COVID-19 was not significantly different between controls (9%) and HAE-C1INH (11%) but was greater in HAE-nl-C1INH (19%, p=0.006). Obesity was positively correlated with COVID-19 across the overall population (16% vs 10%, p=0.012), with a similar but non-significant trend in HAE-C1INH (14% vs 9%). Co-morbid autoimmune disease was a risk factor for COVID-19 in HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all groups. Reported COVID-19 was reduced in HAE-C1INH subjects receiving prophylactic subcutaneous C1INH (5.6%, p=0.0371) or on-demand icatibant (7.8%, p=0.0016). HAE-C1INH subjects not on any HAE medications had an increased risk of COVID-19 compared to normal controls (24.5%, p=0.006). Conclusions: HAE-C1INH subjects not taking HAE medications had an enhanced risk for COVID-19 infection. Subcutaneous C1INH and icatibant significantly reduced this risk. The results implicate roles for the complement cascade as well as non-contact system related kinin generating pathways in the pathogenesis of COVID-19 in HAE-C1INH.