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

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.

C1-Inhibitor: Structure, Functional Diversity and Therapeutic Development

: 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 inhibitor (serpins) and exhibits its inhibitory activities towards several target proteases of plasmatic cascades, operating as a major anti-inflammatory 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 treatment of clinical conditions other than HAE. This article provides an updated overview of the structure 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.

Pathophysiology of Hereditary Angioedema

Background Laryngeal angioedema may be associated with significant morbidity and even mortality. Because of the potential severity of attacks, both allergists and otolaryngologists must be knowledgeable about the recognition and treatment of laryngeal angioedema. This study describes the clinical characteristics and pathophysiology of bradykinin-mediated angioedema. Methods A literature review was conducted concerning the clinical characteristics and pathophysiology of types I and II hereditary angioedema (HAE), type III HAE, acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor–associated angioedema. Results The diagnosis of type I/II HAE is relatively straightforward as long as the clinician maintains a high index of suspicion. Mutations in the SERPING1 gene result in decreased secretion of functional C1INH and episodic activation of plasma kallikrein and Hageman factor (FXII) of the plasma contact system with cleavage of high molecular weight kininogen and generation of bradykinin. In contrast, there are no unequivocal criteria for making a diagnosis of type III HAE, although a minority of these patients may have a mutation in the factor XII gene. Angioedema attacks and mediator of swelling in acquired C1INH deficiency are similar to those in type I or II HAE; however, it occurs on a sporadic basis because of excessive consumption of C1INH in patients who are middle aged or older. ACE inhibitor–associated angioedema should always be considered in any patient taking an ACE inhibitor who experiences angioedema. ACE is a kininase, which when inhibited is thought to result in increased bradykinin levels. Bradykinin acts on vascular endothelial cells to enhance vascular permeability. Conclusion Laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema. Novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and from histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders.

Waldenstrom's Microglobulinemia Presenting with Recurrent Angioedema Secondary to C1q Esterase Inhibitor (C1 INH) Deficiency

Abstract 5009 Description: A 57 year-old Bangladeshi man presented to the emergency room with a 4-day history of shortness of breath, productive cough and sensation of choking. He had a history of recurrent dyspnea, chest pain and chronic bilateral pedal edema. He had recent admissions for similar complaints at different hospitals where he was diagnosed with low grade non-Hodgkin lymphoma not requiring treatment and was discharged with bronchodilators and anti-tussives. He was symptom-free between episodes. There was no fever, night sweats or weight loss and there was no history of asthma. Physical exam revealed moderate dyspnea with some stridor, cervical lymphadenopathy with many firm and mobile small lymph nodes. There was no hepato-splenomegaly, urticaria or rashes. Results of routine blood tests including CBC and C-reactive protein were normal. Chest X-ray showed mild pulmonary congestion and CT images of the chest and abdomen showed multiple lymph nodes of about 1–1.5 cm in size. X-rays of the hands showed multiple small lytic lesions. Laryngoscopy showed laryngeal edema. Bone marrow biopsy showed a few paratrabecular areas with increased numbers of small lymphocytes and a lymph node biopsy revealed low grade B-cell lymphoma with plasmacytic differentiation, which was positive for CD19, 20, 22, 38, and CD44. Serum viscosity was 1.6. Immunological studies showed a low C4 at 4 mg/dl (normal range 10–40 mg/dl), low C1q at <3.6 (normal range 5–8.6), C1 esterase inhibitor low-normal at 16 (normal range 11–26). Serum immunoglobulins showed IgM gammopathy with low IgA and normal IgG levels. Beta-2 microglubulin was also elevated at 4.93 mg/dl (normal range < 2.51). Serum protein electrophoresis showed a monoclonal IgM spike measuring 1.5 g/dl with immunofixation positive for a IgM kappa band. Total protein, alpha2- and beta-globulins were elevated and urine electrophoresis was positive for kappa light chains. A diagnosis of Waldenström's macroglobulinemia with angioneurotic edema was made. He was treated with 4 cycles of bortezomib (Velcade®), dexamethasone and rituximab. The patient's angioedema and respiratory symptoms improved dramatically. Follow-up serum electrophoresis showed a very good response to treatment, with a major decrease in total protein and the M-spike. Complement levels returned to normal. Discussion: C1 is the first protein of the classical and kinin pathways which is an arm of the innate immune system. Triggering factors activate the complement cascade and lead to activation of C1 which in turn cleaves C2, the product of which is an inflammatory mediator responsible for angioedema by causing increased capillary permeability and extravasations. In C1INH deficiency, this process occurs uninhibited, triggered by minimal stimulation. C1q esterase inhibitor deficiency is a rare manifestation of Waldenström's macroglobulinemia with very few reported cases in literature. Symptoms are non-allergic, non-pruritic and clinical presentation depends on parts of the anatomy affected and may be as mild as inconvenient skin blotching up to life-threatening laryngeal edema or shock. They vary widely, often self limiting and recurrent. Angioedema, acquired or inherited, is complement mediated, characterized by low levels of complement proteins during attacks. C1INH deficiency can be acquired due to increased consumption or/and inactivation by circulating autoantibodies or secondary to lymphoproliferative diseases that lead to increased catabolism. These are often associated with B-cell disorders but may be associated with other disease patterns. Symptomatology is variable and periods of remission and recurrence lead to easy misdiagnosis and incomplete treatment. Proper diagnosis is dependent on awareness and knowledge of the various clinical presentations, adequate and focused use of laboratory analyses and immunopathology studies. The key to treatment is first therapy of the acute stage (in our patient with the use of intravenous steroids) and then more specific treatment of the underlying disease entity (in our patient with bortezomib, dexamethasone and rituximab). Conclusion: Waldenstrom's macroglobulinemia presenting with angioedema is rare, often misdiagnosed and acquired C1 esterase inhibitor deficiency should be at least ruled out, as presentation is varied and could be potentially life-threatening. Disclosures: No relevant conflicts of interest to declare.