COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications

Allergy Asthma Proc. 2021 Nov 1;42(6):506-514. doi: 10.2500/aap.2021.42.210083.


Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

MeSH terms

  • Angioedema / metabolism*
  • Angioedemas, Hereditary / complications*
  • Angioedemas, Hereditary / drug therapy
  • Angioedemas, Hereditary / epidemiology
  • Angiotensin-Converting Enzyme 2
  • Bradykinin / metabolism*
  • COVID-19 / diagnosis*
  • Case-Control Studies
  • Complement C1 Inactivator Proteins / genetics*
  • Complement C1 Inhibitor Protein / genetics*
  • Hereditary Angioedema Types I and II / metabolism*
  • Humans
  • Incidence
  • Kallikreins
  • SARS-CoV-2


  • Complement C1 Inactivator Proteins
  • Complement C1 Inhibitor Protein
  • Angiotensin-Converting Enzyme 2
  • Kallikreins
  • Bradykinin