Does hereditary angioedema make COVID-19 worse?

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.

Evaluation and management of COVID-19-related severity in people with type 2 diabetes

“…Angioedema has been hypothesized to favor COVID-19 progression, and in turn COVID-19 can further exacerbate pre-existing angioedema condition. 35 Therefore, people with T2D who were using ARBs might essentially be at higher risk for developing critical conditions related to COVID-19.…”

Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection

“…As shown in Figure 8, further network-based drug repurposing is calculated and novel and potent drugs targeting SARS-CoV-2 are identified. For instance, danazol (antigonadotropic and anti-estrogen) was discovered in our study and other in silico drug screening studies as a repurposable candidate with demonstrated immunomodulatory properties mediating the attenuation of TNFα-induced IL-8 overexpression [97,98]. Additionally, danazol has been shown to be a candidate agent affecting essential pathways involved in SARS-CoV-2 pathogenesis, including mRNA splicing and ubiquitin-mediated proteolysis pathways [98].…”

“…For instance, danazol (antigonadotropic and anti-estrogen) was discovered in our study and other in silico drug screening studies as a repurposable candidate with demonstrated immunomodulatory properties mediating the attenuation of TNFα-induced IL-8 overexpression [97,98]. Additionally, danazol has been shown to be a candidate agent affecting essential pathways involved in SARS-CoV-2 pathogenesis, including mRNA splicing and ubiquitin-mediated proteolysis pathways [98]. As androgens could be suspected as playing a crucial role in driving both specific SARS-CoV-2 entry receptors' overexpression and anti-viral immune response suppression, therapeutic interventions with danazol must only be administered with great caution and complete consideration [99].…”

Patients With Hereditary Angioedema Do Not Develop More Severe COVID-19 but SARS-CoV-2 Infection May Trigger Attacks: 66 Cases

“…Coagulation and brinolytic pathways are also regulated by C1-INH and it is presumed that the lower C1-INH activity could predispose to more severe SARS-CoV-2 infection 24 . Moreover, C1-INH has been demonstrated to interact with components of the extracellular matrix, leading to the hypothesis that these components concentrate C1-INH at the local site of in ammation in order to regulate complement and contact systems 25 .…”

“…This effect could contribute to attacks in patients with both HAE-C1-INH and HAE-nC1-INH. In addition, the loss of inhibitory activities of C1-INH would be expected to enhance complement activation together with microvascular injury, leading to worse evolution of SARS-CoV-2 infection 25 .…”