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Allergy Asthma Proc ; 42(6): 506-514, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1533595


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.

Angioedema/metabolism , Angioedemas, Hereditary/complications , Bradykinin/metabolism , COVID-19/diagnosis , Complement C1 Inactivator Proteins/genetics , Complement C1 Inhibitor Protein/genetics , Hereditary Angioedema Types I and II/metabolism , Angioedemas, Hereditary/drug therapy , Angioedemas, Hereditary/epidemiology , Angiotensin-Converting Enzyme 2 , Case-Control Studies , Humans , Incidence , Kallikreins , SARS-CoV-2
Curr Med Chem ; 29(3): 467-488, 2022.
Article in English | MEDLINE | ID: covidwho-1344212


Human C1-Inhibitor (C1INH), also known as C1-esterase inhibitor, is an important multifunctional plasma glycoprotein that is uniquely involved in a regulatory network of complement, contact, coagulation, and fibrinolytic systems. C1INH belongs to a superfamily of serine proteinase inhibitors (serpins) and exhibits its inhibitory activities towards several target proteases of plasmatic cascades, operating as a major antiinflammatory protein in the circulation. In addition to its inhibitory activities, C1INH is also involved in non-inhibitory interactions with some endogenous proteins, polyanions, cells and infectious agents. While C1INH is essential for multiple physiological processes, it is better known for its deficiency with regards to Hereditary Angioedema (HAE), a rare autosomal dominant disease clinically manifested by recurrent acute attacks of increased vascular permeability and edema. Since the link was first established between functional C1INH deficiency in plasma and HAE in the 1960s, tremendous progress has been made in the biochemical characterization of C1INH and its therapeutic development for replacement therapies in patients with C1INH-dependent HAE. Various C1INH biological activities, recent advances in the HAE-targeted therapies, and availability of C1INH commercial products have prompted intensive investigation of the C1INH potential for the treatment of clinical conditions other than HAE. This article provides an updated overview of the structural and biological activities of C1INH, its role in HAE pathogenesis, and recent advances in the research and therapeutic development of C1INH; it also considers some trends for using C1INH therapeutic preparations for applications other than angioedema, from sepsis and endotoxin shock to severe thrombotic complications in COVID-19 patients.

Angioedemas, Hereditary , Complement C1 Inhibitor Protein , Angioedemas, Hereditary/drug therapy , COVID-19 , Humans