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.

Epigenetic alterations on C1-inhibitor expression may influence hereditary angioedema attack frequency and C4 levels: Comment on: Karagianni P, Goules AV, Tzioufas AG. Epigenetic alterations in Sjogren's syndrome patient saliva.

Epigenetic studies reveal how our genes (nature) are influenced by environment (nurture) leading to wide variability in clinical presentations, especially in autoimmune diseases. Patients with C1-inhibitor deficiency, even within the same family, have diverse clinical presentations that may reflect epigenetic control of gene expression by hormones or inflammatory signals.

Recurrent Acute Abdomen as the Main Manifestation of Hereditary Angioedema.

A diagnosis of hereditary angioedema is usually made with recurrent episodes of swelling of the subcutaneous tissue with a family history. We herein report a case in which recurrent acute abdomen was the main manifestation of hereditary angioedema. A 45-year-old womon presented with a 10-year history of recurrent severe abdominal pain. Abdominal computed tomography revealed remarkable submucosal edema of the ileum. A blood examination revealed grossly reduced complement C4 and CH50 with deficiency of C1-inhibitor. Genetic testing revealed a heterozygous nonsense mutation of the SERPING1 gene, and a diagnosis of hereditary angioedema was made. Hereditary angioedema should be listed as a differential diagnosis of recurrent acute abdomen.

[Review of a new subtype of hereditary angio-oedema with normal complement C1-inhibitor].

Hereditary angio-oedema (HAE) is a rare, potentially fatal disease characterized by recurrent swelling of skin and mucosa. Besides HAE with quantitative (type I) or qualitative (type II) deficiency of complement C1-inhibitor (C1-INH), a new subtype of HAE is now described with normal levels of C1-INH. This subtype is possibly underdiagnosed, and a treatment regimen and general knowledge about the condition is still in its infancy. The purpose of this article is to inform Danish doctors about the disease to identify more Danish patients.

An ABC of the Warning Signs of Hereditary Angioedema.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a genetic disorder that clinically manifests with attacks of angioedema in the subcutaneous and submucosal tissues, mainly in the extremities, abdomen, and upper airway. During attacks, vascular permeability is increased due to increased bradykinin (BK). This means that special therapies are needed for attacks that do not respond to traditional antiallergic therapies involving antihistamines, corticosteroids, and epinephrine. The recurring attacks may disable patients and lead to frequent visits to emergency rooms where misdiagnoses are common. HAE attacks may be fatal when upper-airway edema occurs, if proper treatment with a C1 inhibitor concentrate or BK receptor antagonist is not administered or an emergency tracheostomy is not performed. We propose a mnemonic method for the warning signs of HAE for the use as a diagnostic tool, i.e., the so-called "ABC" of the warning signs of HAE. The letters represent the following: A = Angioedema, B = Bradykinin, C = C1 inhibitor, D = Distress factors, E = Epinephrine nonresponsive, F = Family history, and G = Glottis/Gastrointestinal edema. To avoid fatalities, medical staff and patients, including family members, must be aware of HAE. An alphabetical mnemonic method has been developed and we hope it may benefit patients.

Systematic analysis of splicing defects in selected primary immunodeficiencies-related genes.

Both variants affecting splice sites and those in splicing regulatory elements (SREs) can impair pre-mRNA splicing, eventually leading to severe diseases. Despite the availability of many prediction tools, prognosis of splicing affection is not trivial, especially when SREs are involved. Here, we present data on 92 in silico-/55 minigene-analysed variants detected in genes responsible for the primary immunodeficiencies development (namely BTK, CD40LG, IL2RG, SERPING1, STAT3, and WAS). Of 20 splicing-affecting variants, 16 affected splice site while 4 disrupted potential SRE. The presence or absence of splicing defects was confirmed in 30 of 32 blood-derived patients' RNAs. Testing prediction tools performance, splice site disruptions and creations were reliably predicted in contrast to SRE-affecting variants for which just ESRseq, ΔHZEI-scores and EX-SKIP predictions showed promising results. Next, we found an interesting pattern in cryptic splice site predictions. These results might help PID-diagnosticians and geneticists cope with potential splicing-affecting variants.

Hereditary C1 inhibitor deficiency is associated with high spontaneous amidase activity.

BACKGROUND: Angioedema diagnosis classically targets the complement system (via C1 inhibitor (C1Inh) function and antigenic C4 level) and contact phase activation (via amidase activity). Bradykinin is responsible for angioedema attacks and is produced from contact phase activation secondary to failed C1Inh control. OBJECTIVE: We aimed to compare the diagnostic performances of spontaneous amidase activity and antigenic C4 level in C1Inh hereditary angioedema (C1Inh-HAE) patients. METHODS: Samples from 185 C1Inh-HAE patients (81 men, 104 women; confirmed by SERPING1 gene mutations) and from 99 blood donors (50 men, 49 women) were tested for C1Inh function, antigenic C4 level and spontaneous amidase activity. RESULTS: In the C1Inh-HAE group, antigenic C4 level was decreased (n=135) and amidase activity was increased (n=181). Receiver operating characteristic analyses showed higher diagnostic performance values for the spontaneous amidase assay compared to those of antigenic C4. CONCLUSION: The spontaneous amidase activity assay should replace antigenic C4 level testing and should be tested alongside the C1Inh function for both AE screening and follow up of HAE patients.

Recurrent Angioedema: Occurrence, Features, and Concomitant Diseases in an Italian Single-Center Study.

BACKGROUND: Angioedema (AE) is a potentially life-threatening condition with hereditary (HAE), acquired (AAE), or iatrogenic causes. A careful workup allows for the identification of the etiology of attacks and the appropriate management. In this cohort study, based on a clinical practice setting, we aimed at investigating clinical and laboratory findings concerning different features of patients with recurrent AE who were referred to a single, tertiary-level center for HAE. METHODS: Clinical and laboratory data of patients fulfilling the criteria for C1-inhibitor-deficient HAE (C1-INH-HAE), C1-INH-AAE, angiotensin-converting enzyme inhibitor-related AE (ACEI-RA), and idiopathic AAE (I-AAE) were evaluated. Descriptive statistics were analyzed by means of the Mann-Whitney U test. The Fisher exact test was used for group comparisons. RESULTS: Patients were diagnosed with type 1 HAE (n = 14), type 2 HAE (n = 1), C1-INH-AAE (n = 8), ACEI-RA (n = 16), or I-AAE (n = 26). We included only patients with concomitant autoimmune diseases from the I-AAE group (n = 8, aut-I-AAE). Age at disease onset and at diagnosis was younger in type 1 HAE than in all the other groups. The diagnostic delay was longer in type 1 HAE than in ACEI-RA. C4 and C1q levels were lower in C1-INH-AAE than in type 1 HAE, ACEI-RA, and aut-I-AAE. Both HAE and C1-INH-AAE showed lower C1-INH antigen and function compared to the other groups. Peripheral attacks were more frequent in type 1 HAE, while airway, abdominal, and oral attacks were prevalent in C1-INH-AAE. CONCLUSION: Investigating the clinical and laboratory features of recurrent AE without wheals represents a major topic for facilitating early diagnosis and improving treatment strategies for this heterogeneous and misdiagnosed condition.

Mutational spectrum of the SERPING1 gene in Swiss patients with hereditary angioedema.

Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease caused by mutations in the C1 inhibitor gene SERPING1. Phenotype and clinical features of the disease are extremely heterogeneous, varying even within the same family. Compared to HAE cohorts in other countries, the genetic background of the Swiss HAE patients has not yet been elucidated. In the present study we investigated the mutational spectrum of the SERPING1 gene in 19 patients of nine unrelated Swiss families. The families comprise a total of 111 HAE-affected subjects which corresponds to approximately 70% of all HAE-affected patients living in Switzerland. Three of the identified mutations are newly described. Members of family A with a nucleotide duplication as genetic background seem to have a more intense disease manifestation with a higher attack frequency compared to the other families. Newly designed genetic screening tests allow a fast and cost-efficient testing for HAE in other family members.

Identification and characterization of C1 inhibitor in Nile tilapia (Oreochromis niloticus) in response to pathogenic bacteria.

C1 inhibitor (C1INH) is a multi-functional serine protease inhibitor in plasmatic cascades, not only inactivating various proteases, but also regulating both complement and contact system activation. In this study, we described the identification and characterization of a C1INH ortholog from Nile tilapia (Oreochromis niloticus) at molecular, protein and cellular levels. The full-length cDNA of Oreochromis niloticus C1INH (OnC1INH) consisted of 1791 bp of nucleotide sequence encoding polypeptides of 596 amino acids. The deduced protein possessed a serpin domain at the C-terminal domain, and two Ig-like domains in the N-terminal domain with significant homology to teleost. Expression analysis revealed that the OnC1INH was extremely highly expressed in the liver; however, much weakly exhibited in other tissues including spleen, kidney, blood and heart. After the in vivo challenges of the lipopolysaccharide (LPS) and Streptococcus agalactiae, the expression of OnC1INH was significantly up-regulated in liver and spleen at the late phase, which was confirmed at the protein level with immunohistochemical analysis. The up-regulation of OnC1INH expression was also demonstrated in head kidney monocytes/macrophages in vitro stimulated with LPS, Aeromonas hydrophila and Streptococcus agalactiae, which was positively correlated with the protein expression pattern in the culture media. Taken together, the results of this study indicated that OnC1INH might be involved in the immune response of Nile tilapia against to bacterial challenge.

Hereditary Angioedema with Recurrent Abdominal Pain in a Patient with a Novel Mutation.

We describe a patient with hereditary angioedema type I. The patient had experienced recurrent abdominal pain around the time of her menstrual period for 13 years. A laboratory examination showed reduced functional and antigenic levels of C4 and C1 inhibitor (C1-INH). To establish a diagnosis, we carried out a DNA analysis of the patient's C1-INH gene. We determined that the patient was heterozygous for a single base pair transposition of T to C at nucleotide 4429 in exon 4, which had not been reported in the literature. As the patient had no family history of hereditary diseases, it was considered to be a de novo mutation.

Hereditary angioedema: 44 years of diagnostic delay.

We report a 64-year-old man who suffered from recurrent visible swelling attacks since the age of 20 as well as episodes with severe upper airway edema, resulting in 4 emergency tracheotomies. Eventually after 44 years he was diagnosed with hereditary angioedema (HAE) type II. The aims of this report is to emphasize the importance of awareness concerning HAE, which does not respond to traditional anti-allergic therapy, and remind physicians to test for functional C1-INH deficiency.

Frequent life-threatening laryngeal attacks in two Croatian families with hereditary angioedema due to C1 inhibitor deficiency harbouring a novel frameshift mutation in SERPING1.

OBJECTIVE: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease caused by mutations in the SERPING1 gene. It can affect many regions in the body, but potentially life-threatening laryngeal oedemas are of concern. METHODS: Twenty-three subjects from two families were recruited for clinical data evaluation and molecular analysis at General Hospital Sibenik, Croatia. RESULTS: Decreased levels of C1 inhibitor were detected in 12 adult patients and three young asymptomatic persons. The same novel deletion of two nucleotides on exon 3 (c.74_75delAT) was identified in all of them. A history of laryngeal oedema was present in 10 patients (83%), and all patients reported laryngeal attacks at least once a year. The delay in diagnosis decreased noticeably from the first to the last generation. CONCLUSIONS: We identified a novel causative mutation in SERPING1 in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship. Key messages Hereditary angioedema due to C1 inhibitor deficiency is a rare autosomal dominant disease caused by mutations in the SERPING1 gene, and laryngeal oedema is of concern because it can cause death by asphyxiation. A novel causative mutation in SERPING1, a deletion of two nucleotides on exon 3 (c.74_75delAT), was identified in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship because it appears that the mutation type may affect disease severity.

Genetics of Hereditary Angioedema Revisited.

Contemporary genetic research has provided evidences that angioedema represents a diverse family of disorders related to kinin metabolism, with a much greater genetic complexity than was initially considered. Convincing data have also recently been published indicating that the clinical heterogeneity of hereditary angioedema due to C1 inhibitor deficiency (classified as C1-INH-HAE) could be attributed at least in part, either to the type of SERPING1 mutations or to mutations in genes encoding for enzymes involved in the metabolism and function of bradykinin. Alterations detected in at least one more gene (F12) are nowadays considered responsible for 25 % of cases of hereditary angioedema with normal C1-INH (type III hereditary angioedema (HAE), nlC1-INH-HAE). Interesting data derived from genetic approaches of non-hereditary angioedemas indicate that other immune pathways might be implicated in the pathogenesis of HAE. More than 125 years after the recognition of the hereditary nature of HAE by Osler, the heterogeneity of clinical expressions, the genetics of this disorder, and the genotype-phenotype relationships, still presents a challenge that will be discussed in this review. Large scale, in-depth genetic studies are expected not only to answer these emerging questions but also to further elucidate many of the unmet aspects of angioedema pathogenesis. Uncovering genetic biomarkers affecting the severity of the disease and/or the effectiveness of the various treatment modalities might lead to the prevention of attacks and the optimization of C1-INH-HAE management that is expected to provide a valuable benefit to the sufferers of angioedema.