Predictive model to differentiate chronic histaminergic angioedema and chronic spontaneous urticaria with angioedema.

Background: Chronic histaminergic angioedema (CHA) may be classified as a separate acquired angioedema (AE) or as an endotype of chronic spontaneous urticaria (CSU). A recent study suggested them to be independent pathologies. Objective: We carried out an exhaustive analysis between CHA and AE-CSU to explore the possible differentiation between them on the bases of a series of predictors. Methods: An observational, retrospective, cross-sectional, and exploratory study was designed. Fifty-six CHA and 40 AE-CSU patients were included. Data were extracted from the year before and year after time of diagnosis. A predictive model was generated by logistic regression, and its discriminatory power was assessed using the area under the receiver operating characteristic curve. Results: The average frequency of AE attacks per year turned out to be higher in the AE-CSU group than in the CHA group, both before (median [interquartile range] 12 [43] vs 8 [16]) and after (24.3 [51.2] vs 2 [4.25]) diagnosis, respectively. The uvula was more frequently affected in CHA. No other differences were found. However, using 7 clinical characteristics of the patients, a multiple logistic regression model was able to predict, with a specificity of 86.4%, a sensitivity of 92.3%, and an area under the curve of 95.1% (P = .024), that CHA and AE-CSU behaved differently. Conclusion: CHA has similar characteristics to AE-CSU, although they slightly differed in the frequency of attacks and their location. Despite its similarities, a multiple logistic regression model that used clinical and evolutionary characteristics allowed the differentiation of both pathologies and supports the idea that these 2 entities are independent.

Gene Mutations Linked to Hereditary Angioedema in Solitary Angioedema Patients With Normal C1 Inhibitor.

BACKGROUND: Chronic recurrent angioedema without wheals (CRA) with normal C1 inhibitor (C1-INH) that is unresponsive to antihistamines may involve patients with recurrent angioedema of unknown cause (ie, so-called non-histaminergic idiopathic angioedema) as well as patients with hereditary angioedema with normal C1-INH (HAEnCI) when HAEnCI occurs in only one family member. OBJECTIVE: To identify patients with one of type of HAEnCI in a group of patients with CRA with normal C1-INH that was unresponsive to antihistamines. METHODS: A total of 132 patients with CRA and normal C1-INH that was unresponsive to antihistamines underwent mutational and clinical analysis. The presence of hereditary angioedema-specific mutations in Factor XII, plasminogen, ANGPT1, KNG1, MYOF, and HS3ST6 genes was tested by Sanger sequencing. When an HAEnCI-causing mutation was identified, available asymptomatic relatives were genetically tested. RESULTS: In 116 of 132 solitary patients with CRA (87.9%), none of the six HAEnCI-linked mutations could be found. Ten patients (7.6%) had the Factor XII mutation c.983C>A (p.T328K) and six (4.5%) the plasminogen mutation c.988A>G (p.K330E). Other mutations linked to HAEnCI were not found in this patient series. In the 16 families with HAEnCI, 11 asymptomatic carriers of one of the HAEnCI-linked mutations were identified. CONCLUSIONS: A search for HAEnCI-linked mutations in patients with solitary CRA may lead to the detection of patients and families with HAEnCI. This is important because family members can be identified who are at risk for developing potentially life-threatening angioedema, although they were previously asymptomatic. Without genetic investigation, the risk for an HAEnCI would have remained undetected in these patients and asymptomatic relatives.

A Comparative Study of Sex Distribution, Autoimmunity, Blood, and Inflammatory Parameters in Chronic Spontaneous Urticaria with Angioedema and Chronic Histaminergic Angioedema.

BACKGROUND: Recurrent idiopathic histaminergic angioedema is currently classified as a subtype of angioedema, as well as a subtype of chronic spontaneous urticaria (CSU), based on the fact that both are mast cell-mediated and respond to the same treatments. OBJECTIVE: In the present work, we sought to verify whether chronic histaminergic angioedema (CHA) is an entity distinct from CSU or represents a CSU subtype that lacks hives. METHODS: We performed a prospective study comparing 68 CHA patients, angioedema without hives, with 63 CSU patients, with hives and angioedema, from whom we collected demographic and clinical data, as well as blood and serum markers. RESULTS: We found key pathogenic features that differentiate CHA from CSU: gender distribution, basophil number, and antibodies against the IgE receptor. The male/female ratio in CHA was 0.78, whereas in CSU it was 0.36 (P = .0466). Basopenia was more often seen in CSU (n = 13 [20%]) than in CHA (n = 5 [7%]). Finally, 31.15% of CSU sera induced basophil activation, whereas no CHA sera were able to activate normal basophils. By contrast, nonspecific inflammation or immune markers, for example, erythrocyte sedimentation rate, C-reactive protein, or IgG antithyroid antibodies, were very similar between both groups. IgE anti-IL-24 could not be assessed because a control population did not differ from CSU. CONCLUSIONS: Inclusion of CHA as part of the spectrum of CSU is an assumption not evidence-based, and when studied separately, important differences were observed. Until there is further evidence, CHA and CSU should not necessarily be considered the same disorder, and it is our opinion that review articles and guidelines should reflect that possibility.

Hereditary Angioedema: A Gynecology and Obstetrics Perspective.

Hereditary angioedema is an autosomal dominant genetic disease that causes tissue edema mediated by bradykinin. The angioedema attacks have several triggers including stress, trauma, infection, and increased estrogens levels. This explains the greater incidence and clinical severity in women, which are usually asymptomatic until puberty, when the attacks begin to occur. It may involve multiple locations on the body, leading to complications, such as surgical intervention prompt by severe acute abdominal pain, and laryngeal edema that can culminate in death from asphyxia. This is of particular concern as this angioedema does not respond to life-saving medications commonly used in its treatment, namely, high doses of second-generation antihistamines, corticosteroids, and epinephrine. Hereditary angioedema attacks are treated with specific medication that includes icatibant, ecallantide, and C1 inhibitor, the latter being also used in short-term and long-term prophylaxis. There are other pharmacological strategies for long-term prophylaxis like lanadelumab, danazol, stanozolol, aminocaproic acid, and tranexamic acid. During pregnancy and lactation, the preferred treatment and prophylaxis is C1 inhibitor. We report a case of hereditary angioedema describing its chronological evolution over a period of a woman's life, and highlighting some of the specificities of this pathology that intersect with the specialty of Obstetrics and Gynecology. Our aim is to draw attention to these particularities, namely the triggering factors of crisis, the need for high suspicion of the diagnosis, and the treatment and prophylaxis options for pregnant and non-pregnant women that can make the difference between life and death. To achieve a favorable outcome, the multidisciplinary teamwork between the specialties of Immunoallergology and Obstetrics and Gynecology was crucial.

Recurrent angioedema in childhood: hereditary angioedema or histaminergic angioedema?

BACKGROUND: Recurrent angioedema is a rare entity during childhood. This study aimed to clarify differences between hereditary angioedema (HAE) and histaminergic angioedema (HA) in children. METHODS: Fifty-seven children with HAE (male 36.8%, 8.9 years [5.4-12.5]) and 42 children with recurrent HA (male 42.9%, 11.5 years [8.1-16.8]) were analyzed. RESULTS: The median age at symptom onset (6 [3-10]; 7.8 [4.5-13] years), frequency of angioedema episodes within last year (3 [2-5]; 5 [2-10]), and duration of symptoms (48 [24-48]; 24 [12-48] hours) were similar in the HAE and HA group, respectively. Recurrent urticaria was observed in 7.3% (n = 3) of patients in the HAE group and in 45.2% (n = 19) of the HA group (P < .001). While angioedema episodes involving the lips (n = 30; 71.4%; P = .035) and eyelids (n = 28; 66.7%; P = .012) were observed more frequently in the HA group, gastrointestinal involvement/abdominal pain (n = 15; 36.6%) was more common in HAE (P < .001). Itching as a prodromal symptom was detected in 47.6% (n = 20) of HA patients versus 14.6% (n = 6) of those with HAE (P = .002). In the logistic regression analysis for the diagnosis of HAE, a family history of angioedema (OR = 58.289 [95% CI 10.656-318.853], P < 001) and trauma (OR = 35.208 [95% CI [4.368-283.794]], P = .001) as a triggering factor were determined to be independent variables. CONCLUSION: A family history of angioedema, trauma as a triggering factor, and abdominal pain should suggest the diagnosis of HAE and the need for further investigation.

H1R mediates local anesthetic-induced vascular permeability in angioedema.

Angioedema may occur during local anesthetic (LA) injection in the perioperative period. Histaminergic angioedema is the most common form of angioedema. It has been reported that LA is a potential exogenous ligand for histamine receptor 1 (H1R). Whether H1R participates in LA-induced angioedema is still controversial. By using a constructed H1R high-expressed cell model, siRNA transfection, pharmacologic means, and genetically modified animal models, here we showed that H1R mediated LA-induced hyperpermeability. LA with uncycled N-methyl scaffold in the side chain (procaine, tetracaine and lidocaine) had a better strength of drug-H1R affinity than that for LA with cycled N atom (bupivacaine and ropivacaine) by the molecular docking assay and equilibrium dissociation constant (KD values) obtained from the cell membrane chromatography (CMC) relative standard method. Procaine, tetracaine, and lidocaine triggered big calcium mobilization in H1R-HEK293 cells and human umbilical vein endothelial cells (HUVECs) but much weaker in NC-HEK293 cells or H1R knockdown HUVECs. Besides, the results of transendothelial resistance measurement, paracellular flux assay and immunofluorescence showed that procaine induced H1R-dependent hyperpermeability, which involved in PLCγ/IP3R/PKC, ERK1/2, Akt signaling pathways, downstream vascular endothelial cadherin (VE-cad) destabilization. Furthermore, H1R gene knockout prevented paw swelling and vascular leakage caused by procaine, tetracaine, and lidocaine in vivo. This study supported a key role of H1R in LA-induced angioedema, and suggested that in the design of LA structure, the ring formation of the N-methyl scaffold on the side chain can properly avoid the angioedema.

Isolated angioedema: An overview of clinical features and etiology.

Angioedema can occur in isolation, accompanied by urticaria, or as a feature of anaphylaxis in mast cell-mediated disorders, bradykinin-mediated disorders, as well as in others with unknown mechanisms, such as infections, rare disorders, or idiopathic angioedema. In mast cell-mediated angioedema, other signs and symptoms of mast cell-mediator release are frequently seen. However, clear evidence of mast cell degranulation may be absent in histaminergic angioedema. Bradykinin-induced angioedema is not associated with urticaria or other symptoms of type I hypersensitivity reactions. For many of the known triggers of angioedema, the mechanism is unclear. While mast cell and bradykinin-mediated angioedema are relatively well defined in terms of diagnostic and therapeutic approach, angioedema with unknown mechanisms represents a challenge for patients and clinicians alike. Elucidating the clinical pattern and the possible causes of isolated angioedema is the key to a correct diagnosis. This review summarizes the causes, and clinical features of angioedema, with a focus on isolated angioedema.

Threshold-stimulated kallikrein activity distinguishes bradykinin- from histamine-mediated angioedema.

BACKGROUND: The lack of specific biomarkers makes the diagnosis of hereditary angioedema (HAE) with normal levels of C1-inhibitor (C1INH) protein (HAE-nl-C1INH) and idiopathic non-histaminergic angioedema (INHA) difficult. Confirming or excluding these diagnoses is a significant challenge for clinicians evaluating patients with angioedema. OBJECTIVE: To develop a reliable biomarker that would aid the diagnosis of HAE-nl-C1INH and INHA. METHODS: A total of 154 consecutive patients referred for angioedema at a single centre were enrolled and evaluated. Subjects were clinically phenotyped based on clinical history and response to treatment by clinicians blinded to laboratory assay results. Plasma kallikrein activity was measured by the cleavage of the fluorometric substrate Z-Phe-Arg-AMC-HCL in plasma samples stimulated ex vivo with submaximal doses of dextran sulphate. RESULTS: Stimulated plasma kallikrein activity (mean relative fluorescence units/min ± SD) was significantly increased in both HAE-nl-C1INH (1804 ± 600) and INHA (1579 ± 371) subjects compared to non-swelling controls (171 ± 46) and histaminergic angioedema (133 ± 30) subjects. Using a threshold cut-off based on the normal controls, HAE-nl-C1INH and INHA subjects could be differentiated from histaminergic angioedema subjects with high sensitivity (negative predictive value 86%-89%) and specificity (positive predictive value 80%-100%). CONCLUSION AND CLINICAL RELEVANCE: The stimulated kallikrein activity assay allows differentiation of bradykinin- from histamine-mediated angioedema. The assay could feasibly be considered as a potential clinical tool for the diagnosis of bradykinin-mediated angioedema.

Idiopathic Non-histaminergic Angioedema: Successful Treatment with Omalizumab in Five Patients.

Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease characterized by AE resistant to antihistamines and a chronic course. We report five new cases of InH-AAE (two women and three men) with a rapid and dramatic response to the anti-immunoglobulin-E antibody omalizumab. In our literature review, we found 13 other relevant cases with a good response to this treatment. Overall, in 6 out of 18 patients, the doses of omalizumab required to prevent recurrences of attacks were higher than the licensed dose for chronic urticaria. No significant adverse effects have been reported.