Urticária Crônica Espontânea: abordagem clínico-laboratorial e manejo terapêutico

Contexto: Urticária crônica caracteriza-se pela presença de urticas e/ou angioedema, com tempo de evolução superior a 6 semanas. Classifica- se em urticária crônica espontânea (UCE), com causas conhecidas ou não conhecidas e urticária crônica induzida (UCI). Objetivo: Esta revisão de UCE visa abordar os aspectos clínico-laboratoriais e indicações terapêuticas, de acordo com as diretrizes brasileira e internacional. Métodos: para esta revisão de UCE foi realizada pesquisa nas bases de dados PubMed, Embase, Google Acadêmico e Web of Science. Resultados: Foram incluídos artigos em inglês publicados entre 2018 e 2024, de acordo com sua relevância. Discussão: A patogênese da UCE engloba mecanismos imunológicos do tipo I e IIb. O diagnóstico da afecção é clínico, podendo ser realizados exames laboratoriais complementares, incluindo hemograma, VHS, D-dímero, PCR, anticorpos anti-peroxidase tireoidiana e IgE total. O diagnóstico diferencial da UCE apresenta diversas condições clínicas com morfologia semelhante à UCE. O tratamento indicado da UCE envolve medidas como suspensão de eventuais fatores desencadeantes e abordagem farmacológica, com utilização de anti-histamínicos não-sedantes, omalizumabe e uso eventual de ciclosporina. Conclusões: O impacto da UCE para os pacientes e para o sistema de saúde é de extrema relevância e avanços nas pesquisas permitirão um tratamento individualizado, com melhores perspectivas em relação à terapêutica e qualidade de vida dos pacientes.

Nonepisodic angioedema with eosinophilia following a rose-thorn prick injury.

Background: Nonepisodic angioedema with eosinophilia (NEAE) is a condition marked by angioedema and significant eosinophilia and often linked with atopic dermatitis. It predominantly affects young Asian women and occurs more frequently in the autumn and winter. Despite over 100 reported cases, its etiology and pathogenesis remain unclear. Case presentation: A 23-year-old Japanese female florist presented with acute arm swelling following rose-thorn pricks to her hands and fingers in spring. One week later, she developed progressive symmetrical non-pitting edema in her lower legs and a 3 kg weight gain without any rash. She had a history of oral allergy syndrome to apples and pears for which allergen-specific IgE were previously detected. Blood tests showed significant eosinophilia (14,930 cells/µL) and elevated thymus and activation-regulated chemokine (TARC) levels (12,864 pg/mL). Thyroid disease, autoimmune disorders, and hematologic malignancies were ruled out. Normal cardiac markers and a whole-body computed tomography excluded visceral organ involvement. She was diagnosed with NEAE and treated with oral prednisolone, which resolved the edema within 10 days. Prednisolone was tapered gradually on an outpatient basis without recurrence. Conclusion: A review of the literature indicates that NEAE triggered by subcutaneous antigen exposure may not follow the typical age or seasonal patterns. Direct subcutaneous antigen exposure, including rose-thorn pricks, can trigger NEAE. Clinicians should consider NEAE in atypical presentations and thoroughly investigate preceding episodes.

Acute Urticaria: Symptoms, Causes, and Evaluation of Phenotypes Prone to Chronicity.

INTRODUCTION: Urticaria is a condition that is characterized by the development of wheals (hives), angioedema, or both. If symptoms persist for less than 6 weeks, it is classified as acute urticaria (AU), and if they persist for longer than 6 weeks, it is classified as chronic urticaria (CU). Disease activity is evaluated using validated patient-reported outcome measures (PROMs) such as the 7-day urticaria activity score (UAS-7) and urticaria control test (UCT). In this study, we aimed to determine whether there was a difference between patients with chronic and recovered urticaria in terms of age, sex, symptoms, disease severity, disease control, and triggering factors by following patients with AU for 6 months. METHODS: The routine tests were requested at the first admission of the patients. If previously examined, anti-thyroid peroxidase (anti-TPO), anti-nuclear antibody, etc., were recorded. After the first examination, the patients were evaluated again using a visual analog scale (VAS), UCT, UAS-7, and medication scores (MSs) in the 1st, 3rd, and 6th months. RESULTS: One hundred nine (F/M: 80/29) patients were included in the study. Twenty-seven patients had a previous history of AU, 22 of these patients were evaluated as having recurrent AU, and five became chronic during follow-up. Urticaria continued in 22 of 82 patients who presented with first-attack AU in the 3rd month and 17 in the 6th month. We had a chronicity rate of 24.7%. It was determined that having positive anti-TPO increased the risk of CU 1.69 times. A statistically significant improvement was found in the mean VAS, UCT, UAS-7, and MSs evaluated in the 1st, 3rd, and 6th months of patients with CU compared with baseline. CONCLUSION: AU is a common disease and usually heals in a short time without becoming chronic. Studies on the causes of chronicity are limited. Testing anti-TPO in patients presenting with AU may be useful in terms of disease course and risk of chronicity.

In chronic spontaneous urticaria, increased Galectin-9 expression on basophils and eosinophils is linked to high disease activity, endotype-specific markers, and response to omalizumab treatment.

BACKGROUND: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. OBJECTIVES: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU. METHODS: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils. RESULTS: Our CSU patients had markedly increased rates of circulating Gal-9+ eosinophils and basophils and high numbers of lesional Gal-9+ cells. High rates of blood Gal-9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9+ eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9+ eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9+ eosinophils/basophils in responders. Gal-9+ eosinophils/basophils were negatively correlated with TIM-3+TH17 cells. CONCLUSION: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance.

Unmasking Carcinoid Syndrome in a Chronic Obstructive Pulmonary Disease (COPD) Patient: A Rare Presentation with Wheezing and Angioedema.

Carcinoid syndrome is a rare condition resulting from neuroendocrine tumors (NETs) that secrete vasoactive substances like serotonin. This report describes the case of a 61-year-old man with a history of chronic obstructive pulmonary disease (COPD) and hypertension who presented with new-onset angioedema, loss of consciousness, and a fall. He had been treated for COPD exacerbations during ER visits without improvement and was unaware of a prior mesenteric carcinoid tumor diagnosis from 2012. The next emergency evaluation revealed significant airway and facial edema necessitating intubation. Imaging and biopsy identified a well-differentiated grade 1 NET with extensive liver metastases. Laboratory tests showed elevated levels of serum serotonin, chromogranin A, and 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA). Post-discharge, a PET scan confirmed metastatic lesions primarily in the liver and small bowel, with an unresectable mesenteric mass. The patient was treated with lanreotide and became symptom-free. This case underscores the need to consider carcinoid syndrome in patients with COPD presenting with unexplained respiratory symptoms, as timely diagnosis and treatment can significantly enhance patient outcomes.

The Burden of Hereditary Angioedema in a Large Family in Brazil.

INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disease characterized by submucosal and subcutaneous edema with high morbidity and possibility of mortality. This study presents the sociodemographic characteristics of a large Brazilian family with HAE. METHODS: Descriptive cross-sectional study with patients from two family branches coming from the same city and HAE diagnosis was carried out. Clinical, laboratory, and treatment data of patients have been collected. Genetic testing was performed on some individuals. Correlation tests and comparisons between variables were applied using IBM SPSS Statistics® 2.0 program. RESULTS: We provide a detailed characterization of two families affected by HAE due to C1-INH deficiency, residing in a small town in southern Brazil. These families harbor an identified mutation in the SERPING1 gene (c.1104del, p.Asp369ThrfsTer2). The mean age at HAE diagnosis was 16.7 (±14.0) years, with the mean onset of symptoms at 6.0 (±6.1) years of age. A correlation was observed between patients' current age and age at HAE diagnosis, with older patients being diagnosed later than younger individuals (p < 0.0001). On average, there were 16.8 emergency visits in the past year (±24.8), and 53.5% of patients reported at least one lifetime hospitalization. Notably, treatment modalities often diverged from consensus recommendations regarding optimal prophylaxis and management of HAE attacks. CONCLUSIONS: This study describes one of the largest known families with HAE in Brazil and highlights the significant impact of unfavorable social conditions on disease control.

Systemic inflammation biomarkers during angioedema attacks in hereditary angioedema.

Background: Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks. Methods: Patients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients F12 gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured. Results: Seventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6-88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 vs. baseline) and D-dimer in 71% (p=0.001 vs. baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p<0. 0001), ESR (p<0.0001) and D-dimer (p= 0.004). No significant differences were observed in CRP (p=0.7), ACE (p=0.67) and WCC (p=0.54). These findings remained consistent regardless of HAE type, disease activity or location of angioedema. Conclusion: The systemic increase in APR observed during HAE attacks suggests that inflammation extends beyond the localized edematous area. This finding underscores the potential involvement of inflammatory pathways in HAE and highlights the need for further investigation into their role in the pathophysiology of HAE.

Case Report: Early presentation of hereditary angioedema symptoms in a 2-year-old boy.

Hereditary angioedema (HAE) is a rare autosomal-dominant disease that is caused by a deficiency (type I) or dysfunction (type II) of the C1 inhibitor (C1-INH) due to a mutation in the SERPING1 gene, which codes for C1-INH. HAE with quantitatively and qualitatively normal C1-INH (type III) is often caused by a mutation in the F12 gene and no mutations in the SERPING1 gene and is a group of very rare diseases. The C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases vascular permeability and allows the flow of fluids into the extracellular space, resulting in angioedema. HAE clinically manifests with intermittent attacks of swelling of the subcutaneous tissue or submucosal layers of the respiratory and gastrointestinal tract. Young children are typically asymptomatic, and those affected by HAE usually present with symptoms in their early 20s. This article describes the case of very early onset of hereditary angioedema caused by C1-INH deficiency in a 2-year-old boy who experienced recurrent episodes of hand and abdominal angioedema not associated with urticaria or pruritus. His father suffered from severe HAE due to a de novo mutation of the SERPING1 gene. The same mutation of the SERPING1 gene was detected in his son at the age of 9-months prior to the occurrence of angioedema symptoms, during genetic family counseling. This paper advances the understanding of HAE and highlights the importance of genetic counseling of families with HAE to avoid late or inaccurate diagnosis and to initiate treatment on time.

Epidemiology, economic, and humanistic burden of hereditary angioedema: a systematic review.

BACKGROUND: This systematic study aims to assess the global epidemiologic, economic, and humanistic burden of illness associated with all types of hereditary angioedema. METHODS: A systematic search for articles reporting the epidemiologic, economic, and humanistic burden associated with patients with HAE was conducted using English and Chinese literature databases from the inception to May 23, 2022. The selected studies were assessed for their quality and risk of bias. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022352377). RESULTS: In total, 65 articles that met the search inclusion criteria reported 10,310 patients with HAE, of whom 5861 were female patients. Altogether, 4312 patients (81%) and 479 patients (9%) had type 1 and type 2 HAE, respectively, whereas 422 patients (8%) had HAE-normal C1-INH. The overall prevalence of all types of HAE was between 0.13 and 1.6 cases per 100,000. The mean or median delay from the first onset of a symptom of HAE to confirmed diagnosis ranged from 3.9 to 26 years. The estimated risk of death from asphyxiation was 8.6% for patients with HAE. Hospitalization, medication, unnecessary surgeries, doctor visits, specialist services, and nursing costs are direct expenses that contribute to the growing economic burden. The indirect cost accounted mostly due to missing work ($3402/year) and loss of productivity ($5750/year). Furthermore, impairment of QoL as reported by patient-reported outcomes was observed. QoL measures identified depression, anxiety, and stress to be the most common symptoms for adult patients and children. CONCLUSION: This study highlights the importance of early diagnosis and the need for improving awareness among health care professionals to reduce the burden of HAE on patients and society.

Androgen transition and management of hereditary angioedema long-term prophylaxis in real life: a single-center case series.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that manifests clinically as recurrent episodes of swelling affecting multiple anatomical locations. Long-term prophylaxis (LTP) aims to control the disease by preventing HAE attacks. Previously, treatments such as attenuated androgens have been used for LTP, but they have an unfavorable adverse effect profile. Today, these limitations may be overcome by patients transitioning to newer, targeted therapies including oral berotralstat and subcutaneous lanadelumab. This case series reports the transition process between different prophylactic therapies in a family with HAE in a real-world setting. RESULTS: Four adult patient cases from the same family who underwent transitions in HAE prophylaxis are presented. Three were female and one male. Two patients who transitioned to berotralstat were initially prescribed attenuated androgens. Two patients were not taking LTP at the time of initiating targeted treatment but had previously been prescribed tranexamic acid. The length of transition varied between the patients, with the longest time taken to stabilize on new therapy being 26 months. All patients received regular follow-up in person or by telephone and all four required an adjustment from their initial treatment plan. CONCLUSIONS: Transitioning between LTP in HAE may help improve control of attacks, avoid unwanted adverse effects, or better cater to individual patient preferences. Newer targeted therapies have been shown to be effective and should be discussed with patients. Shared decision-making is a tool that can aid these discussions. The transition journey between LTP therapies in HAE may not be straightforward and is specific to each patient. Physicians should consider complicating factors such as patient anxieties around changing treatment, adverse effects, preferred routes of administration, and speed of transition. Following patients closely during the transition period helps identify any issues, including difficulties with treatment adherence, and may allow the transition plan to be adapted when necessary.

Substance Use Disorder as Risk Factor for Intubation in Angioedema: A Nationwide Cohort Study.

OBJECTIVES: Individuals with angioedema (AE) are at high risk for airway compromise and often require endotracheal intubation. Patient factors predisposing one to airway compromise are not well described. The objective of this study is to examine whether substance use disorder (SUD) in patients with AE is associated with need for airway intervention. METHODS: This population-based retrospective cohort study compared AE patients with SUD versus propensity-matched control groups. Outcomes were hospitalization, intubation, and tracheotomy. Using the TriNetX National Database, this study included 28,931 patients with SUD and 117,509 patients without SUD who presented with AE. RESULTS: Among patients with AE, those with each subtype of SUD (alcohol, cannabis, cocaine, tobacco, and opioids) were found to have higher risk of severe AE compared to propensity-matched non-SUD cohorts. Rate of hospitalization after cohort matching ranged from 20.4% for tobacco use disorder to 30.4% for cocaine use disorder, all significantly higher than the 8.0% in a population without SUD. Each SUD subtype was associated with a higher rate of intubation compared with matched non-SUD groups, with cannabis use disorder having the highest relative risk (RR) of 3.67 (95% CI: 2.69-5.02). Tobacco (RR = 2.45, 95% CI: 1.79-3.34) and alcohol (RR = 2.82, 95% CI: 1.73-4.58) use disorders were both associated with significantly higher risk of tracheotomy. CONCLUSION: These data suggest that patients with SUD, regardless of subtype, and after propensity matching for demographics and comorbidities are at higher risk for adverse outcomes when presenting with AE. This study highlights clinically relevant predictors of airway compromise. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2024.

[Clinical development of anti-FXII therapeutics as a target in thrombo-inflammation]. / Développement clinique des thérapeutiques anti-facteur XII ciblant la thrombo-inflammation.

The history of anticoagulation has evolved considerably, from non-specific drugs to molecules that directly target specific coagulation factors, such as direct oral anticoagulants (DOACs). Since last decade, DOACs are widely used in clinical practice because of their ease to use with favorable pharmacological profile and not requiring monitoring. New therapeutics targeting the contact phase of coagulation are currently under development, and could make it possible to prevent thrombotic risk without altering hemostasis, thereby reducing the risk of bleeding. Factor XII, being at the crossroads between hemostasis and inflammation, appears to be an interesting target that could limit thrombo-inflammation without increasing bleeding risk. The aim of this article is to summarize the main information concerning FXII inhibitors and to review the results of various clinical trials available to date, focusing on applications beyond hemostasis, such as in the management of hereditary angioedema.

DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.

BACKGROUND: In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified. OBJECTIVES: To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied. METHODS: Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant. RESULTS: A missense variant (p.D239N) in DAB2IP was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding. CONCLUSIONS: The study identified a novel missense variant (p.D239N) in DAB2IP in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.

Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration.

Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in relatively heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE.

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.

Chronic Spontaneous Urticaria: Quality of Life and Economic Impacts.

This study focuses on quality of life (QoL) assessment in chronic urticaria, delving into tools, disease-specific measures, and its profound impact. With expanding therapeutic options, understanding QoL becomes crucial. QoL measures often involve comparisons of patient-reported outcomes in addition to quantitative measures of disease control. Emerging tools include the Urticaria Activity and Impact Measure, which may provide a balanced evaluation. In addition to discussions of the various QoL measures, the psychological impact of chronic urticaria are highlighted, covering emotional burden, stress, and psychiatric comorbidities. Finally, the economic impacts reveal escalating health care costs and cost-effectiveness considerations of therapies like omalizumab.

Classification, Diagnosis, and Pathology of Angioedema Without Hives.

A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach involves several key steps. Foremost is the recognizing of the clinical clues which allow for the differentiation of mast cell-mediated disorders from bradykinin-mediated angioedema. Enhanced vascular permeability related to bradykinin is of critical importance to identify given the implications for disease morbidity and risk of mortality. The ability to efficiently categorize and diagnose all forms of angioedema results in improved patient outcomes.