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1.
Allergy Asthma Proc ; 43(1): e1-e10, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1605122

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) pandemic has greatly affected health-care provision across the globe. Management of chronic ailments has become challenging because of the strained health-care resources and social distancing measures that prevent on-site clinical visits and treatments. Hereditary angioedema (HAE) is a debilitating, chronic disease characterized by unpredictable swelling attacks in various parts of the body. Controlling HAE symptoms often requires long-term prophylactic medication use and regular medical care; however, limited scientific information has been published about HAE medical care during the COVID-19 pandemic. Objective: To gather patient and health-care professional (HCP) perspectives on the global impact that COVID-19 has had, and the future impact it will have on HAE medical care and to identify differences in perceptions across economic and geographic boundaries. Methods: We conducted two independent but similar online global surveys to capture patient and HCP perspectives on the impact that COVID-19 has had, and the future impact it will have on HAE medical care. Results: Both patients and HCPs globally reported that the pandemic has limited the availability of HAE medical care, and they expect the restrictions to continue far beyond the pandemic. In addition, the results of our study suggested that telehealth use has increased across the globe but has been more successfully implemented in high-income countries. Conclusion: Patients and HCPs expect that HAE-related care will be negatively impacted by the pandemic for many years. Disparities in medical care and technologic infrastructure may exacerbate these challenges in non-high-income countries. Supportive tools and global infrastructure should be established to provide aid to non-high-income countries throughout the pandemic and several years after.


Subject(s)
Angioedemas, Hereditary , COVID-19 , Pandemics , Angioedemas, Hereditary/diagnosis , Angioedemas, Hereditary/epidemiology , Angioedemas, Hereditary/therapy , Humans , Surveys and Questionnaires
3.
Clin Transl Sci ; 15(3): 626-637, 2022 03.
Article in English | MEDLINE | ID: covidwho-1550814

ABSTRACT

Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow-up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty-eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment-emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose-dependent manner. Sustained inhibition of FXIIa-mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose-dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single-dose i.v. and s.c.) was well-tolerated in healthy volunteers. Dose-dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID-19).


Subject(s)
Angioedemas, Hereditary , COVID-19 , Antibodies, Monoclonal/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Factor XIIa , Humans , Male
4.
Allergy Asthma Proc ; 42(6): 506-514, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1533595

ABSTRACT

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.


Subject(s)
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
6.
Allergy Asthma Proc ; 42(5): 403-408, 2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1394715

ABSTRACT

Background: The demonstration that severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) enters the cell via the angiotensin-converting enzyme 2 receptor has raised concerns that, in hereditary angioedema (HAE), a disease characterized by bradykinin-mediated angioedema attacks, coronavirus disease 2019 (COVID-19) may trigger angioedema attacks, increase the frequency and/or severity of attacks, or cause more severe symptoms of COVID-19. Objective: The objective was to evaluate the severity of COVID-19 in patients with HAE, the course of HAE attacks, angioedema activity, and the quality-of-life scores during COVID-19 pandemic. Methods: Patients diagnosed with HAE for at least 6 months were included in the study. The 7-day Angioedema Activity Score and the Angioedema Quality of Life (AE-QoL) Questionnaire were first completed at the onset of the pandemic between March 12 and June 1, 2020, then during SARS-CoV-2 infection, and in the third month after recovering from COVID-19. Results: Ten of 67 patients with HAE (14.9%) were diagnosed with COVID-19. The median (interquartile range) age of the 10 patients diagnosed with COVID-19 was 35.5 years (28.0-55.0 years). Six of the 10 patients (60%) were women. During COVID-19, five of the 10 patients (50%) had no angioedema attack. Two patients with severe HAE experienced a significant increase in angioedema activity during COVID-19 compared with their basal activity scores. The remaining three patients had a similar or lower attack frequency than their basal level. Four (40%) of the 10 patients had a relative increase in their attacks during the convalescence period. There was no statistically significant difference among pre-COVID-19, during COVID-19 and post-COVID-19 periods in function, mood, fear and/or shame, nutrition, and total scores of the AE-QoL Questionnaire although the fear dimension was relatively more affected (p = 0.06). Conclusion: Although the sample size was small, analysis of our data supported that the symptoms of COVID-19 were not more severe in HAE. Also, there was no significant difference in the AE-QoL Questionnaire scores, the frequency, and severity of angioedema attacks during the course of COVID-19 in the patients with HAE.


Subject(s)
Angioedemas, Hereditary/complications , COVID-19/complications , Disease Progression , Quality of Life , Severity of Illness Index , Acute Disease , Adult , Aged , Aged, 80 and over , Angioedemas, Hereditary/diagnosis , Angioedemas, Hereditary/physiopathology , Angioedemas, Hereditary/psychology , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/psychology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Quality of Life/psychology
7.
Curr Med Chem ; 29(3): 467-488, 2022.
Article in English | MEDLINE | ID: covidwho-1344212

ABSTRACT

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.


Subject(s)
Angioedemas, Hereditary , Complement C1 Inhibitor Protein , Angioedemas, Hereditary/drug therapy , COVID-19 , Humans
10.
Clin Exp Allergy ; 51(7): 947-950, 2021 07.
Article in English | MEDLINE | ID: covidwho-1153430

ABSTRACT

Acute attacks could occur during the convalescent phase of COVID-19 illness, more commonly in patients with a history of frequent attacks. However it is unclear whether the acute attacks during the convalescent phase are specifically triggered by COVID-19 or not.


Subject(s)
Angioedemas, Hereditary , COVID-19/metabolism , Registries , Adult , Aged , Aged, 80 and over , Angioedemas, Hereditary/blood , Angioedemas, Hereditary/epidemiology , Angioedemas, Hereditary/therapy , COVID-19/blood , COVID-19/epidemiology , COVID-19/therapy , Female , Humans , Male , Middle Aged , SARS-CoV-2
11.
Allergy ; 76(8): 2535-2543, 2021 08.
Article in English | MEDLINE | ID: covidwho-1112196

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) attacks can be provoked with psychological factors. The aim of this study was to assess the effects of anxiety, depression and stress related to COVID-19 pandemic on disease activity of HAE patients during the quarantine period (QP) and the return to normal period (RTNP). METHODS: This study was conducted between March 2020 and September 2020 in four allergy centres. Demographic, clinical features and mental health status were evaluated in QP (from March to the beginning of June) and RTNP (from June to the beginning of September) applied by the government. The 10-point visual analogue scale (VAS10) was used to define the severity of HAE attacks. Depression, Anxiety and Stress Scales-21 (DASS-21) and Fear of COVID-19 (FC-19) scale were performed to assess mental health status. RESULTS: 139 HAE patients were included in the study. In QP, median attack numbers and median VAS10 scores were 5 (min-max: 0-45) and 6 (min-max: 0-10), respectively. HAE attack numbers, DASS-21 stress, anxiety, depression and total DASS-21 scores, and FC-19 scores were higher in QP than RTNP (p = 0.001, p < 0.001, p = 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). However, there was no difference in attack severity scores between the two periods (p > 0.05). CONCLUSIONS: This study revealed that the restriction measures during COVID-19 outbreak cause an increase in the number of HAE attacks in relation to anxiety, depression, stress and fear of COVID-19 pandemic. Therefore, it is important to provide psychological support to HAE patients during the pandemic.


Subject(s)
Angioedemas, Hereditary , COVID-19 , Angioedemas, Hereditary/diagnosis , Angioedemas, Hereditary/epidemiology , Anxiety/epidemiology , Anxiety/etiology , Complement C1 Inhibitor Protein , Depression/epidemiology , Depression/etiology , Humans , Pandemics , SARS-CoV-2
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