Urticária Crônica Espontânea: abordagem clínico-laboratorial e manejo terapêutico / Chronic Spontaneous Urticaria: clinical-laboratory approach and therapeutic management

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.

Hereditary angioedema presented as isolated ascending and transverse colon swelling mimicking acute abdomen.

Hereditary angioedema (HAE) is a rare autosomal dominant condition characterized by C1-INH gene mutations, leading to recurrent angioedema episodes affecting various body parts, including the gastrointestinal tract. This case report describes a 24-year-old female presenting with symptoms mimicking an acute abdomen, characterized by severe abdominal cramps, anorexia, and diarrhea, with a significant past medical history of angioedema flares and emergency intubation for asphyxiation at age 11. Despite initial treatment with antihistamines showing no improvement, her symptoms spontaneously resolved. Further investigation revealed low complement C4 levels and reduced C1-INH function, confirming HAE with an unusual isolated involvement of the ascending and transverse colon. This case underscores the importance of considering HAE in patients presenting with acute abdominal symptoms, especially with a history suggestive of angioedema. It highlights the need for emergency physicians and gastroenterologists to be aware of HAE's clinical manifestations to avoid misdiagnosis and unnecessary interventions. Moreover, the case emphasizes the significance of patient education on recognizing symptoms and seeking timely medical attention to prevent severe complications. This report adds to the existing literature by detailing an uncommon presentation of HAE, aiming to enhance early diagnosis and management of this potentially life-threatening condition.

Drug-Induced Angioedema Without Urticaria: A Case Report.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for various conditions but are associated with numerous adverse drug reactions (ADRs). Understanding these ADRs is necessary to reduce morbidity and mortality. NSAID-induced angioedema, although rare, can be life-threatening and is often due to increased leukotriene production from COX pathway inhibition. Mast cells and basophil degranulation play vital roles in its pathogenesis. Prompt recognition and immediate cessation of the culprit drug, along with the administration of corticosteroids and antihistamines, are essential. Here, we report a case of angioedema caused by diclofenac administration, which needs prompt vigilance and a rapid therapeutic response.

Acute Abdominal Pain as the Initial Presentation of an Acquired C1 Inhibitor Deficiency.

Introduction: Acquired angioedema (AAE), a rare cause of adult-onset non-urticarial mucocutaneous angioedema, can present as acute abdomen, a frequent complaint in the emergency room (ER), often leading to unnecessary and potentially harmful procedures. Case Presentation: We report a 47-year-old hypertense male, controlled with an angiotensin converting enzyme inhibitor (ACEI), who presented in the ER with progressively worsening abdominal pain, nausea, and vomiting, and a radiologic workup revealing small intestine thickening, initially diagnosed with ACEI-induced angioedema. However, further investigation revealed low serum levels of C4, C1q, and C1 inhibitors, with an abnormal function of the latter, favoring the diagnosis of AAE instead. The frequent association of this condition with lymphoproliferative disorders encouraged further studies, which unveiled a monoclonal gammopathy IgM/Kappa, representing an increased risk of Waldenström macroglobulinemia, non-Hodgkin lymphoma, and multiple myeloma. Discussion: AAE should be regarded as an important differential diagnosis in patients presenting with acute abdomen in the ER, especially when more common causes are excluded. A correct and early diagnosis may represent a chance for a better prognosis of underlying diseases.

Introdução: O angioedema adquirido (AA), causa rara de angioedema mucocutâneo não urticariforme de início tardio, pode ter como apresentação inicial abdómen agudo, motivo frequente de admissão no serviço de urgência (SU), promovendo frequentemente procedimentos desnecessários e potencialmente prejudiciais. Apresentação do caso: Um homem de 47 anos, hipertenso e controlado com um inibidor da enzima conversora de angiotensina (IECA), recorreu ao SU por um quadro de dor abdominal com agravamento progressivo, náuseas e vómitos. A investigação radiológica inicial revelou espessamento do intestino delgado, culminando num diagnóstico preliminar de angioedema induzido por IECA. No entanto, uma investigação mais aprofundada em regime ambulatório revelou níveis séricos reduzidos de C4, C1q e de inibidor de C1, com função anormal deste último, favorecendo o diagnóstico de AA. A associação frequente desta condição com distúrbios linfoproliferativos incentivou investigação adicional, que revelou uma gamopatia monoclonal IgM/Kappa, representando um risco aumentado de macroglobulinemia de Waldenström, linfoma não-Hodgkin e mieloma múltiplo. Discussão: O AA deve ser considerado um diagnóstico diferencial de abdómen agudo, principalmente após exclusão de causas mais frequentes. Um diagnóstico precoce pode contribuir para um melhor prognóstico da patologia subjacente.

Validation and correlations of the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT) in Chinese patients with angioedema.

Background: The impact of recurrent angioedema can be severely debilitating and remains difficult to quantify. Several standardized patient-reported outcome measures (PROMs), including the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT), have been developed and translated into different languages. However, these PROMs have yet to be validated in Chinese individuals, and their correlations in the Chinese population remain unknown. Objective: Our aim was to validate the Chinese versions of the AAS, AE-QoL questionnaire, and AECT and assess their intercorrelations. Methods: A prospective cohort of 118 Chinese patients with recurrent angioedema at the Angioedema and Urticaria Centre of Reference and Excellence in Hong Kong completed the traditional Chinese versions of the AAS, AE-QoL questionnaire, and AECT. We analyzed the reliability and validity of these PROMs and their correlations with each other as well as with generic PROMs. Results: The Chinese AAS, AE-QoL questionnaire, and AECT demonstrated excellent internal consistency (Cronbach α = 0.920, 0.976, and 0.832, respectively; McDonald ω = 0.972, 0.977, and 0.901, respectively). Confirmatory factor analysis for the AE-QoL questionnaire showed an acceptable fit with the 4-dimensional model (comparative fit index = 0.869; Tucker-Lewis index = 0.842). The AECT showed significant correlations with both the AAS and AE-QoL questionnaire (ρ = -0.750 and -0.456 respectively [both P < .05]). The AE-QoL questionnaire was moderately correlated with certain domains of generic PROMs such as the Work Productivity and Activity Impairment Questionnaire: General Health, version 2.0, and the Short Form 12-Item Health Survey, version 2 (all ρ < 0.60). Conclusion: The Chinese AE-QoL questionnaire, AAS, and AECT are valid and reliable tools for use with Chinese patients. More validated tools should be made available to improve patient care and research for all patients with angioedema globally.

CD4+CCR5+ T cells and CCL3+ mast cells are increased in the skin of patients with chronic spontaneous urticaria.

Background: The proximity of activated T cells and mast cells in the lesional skin of patients with chronic spontaneous urticaria (CSU) is held to contribute to the development of wheals and angioedema. In a previous study, we demonstrated that increased IL-17 expression in T cells and mast cells in skin lesions of patients with CSU is associated with T/mast cell proximity, but the mechanisms that drive T cell/mast cell co-localization remain unknown. Objectives: To assess if chemokines expressed in lesional CSU skin contribute to T cell/mast cell proximity. Patients and methods: Biopsies from lesional CSU skin were compared to biopsies from healthy skin for expression of CCR5 and its ligand CCL3 by CD4+ T cells and mast cells, respectively. Results: Numbers of CCR5-positive CD4+ T cells in lesional CSU skin were significantly increased as compared to healthy normal skin (p < 0.0001). The number of mast cells expressing CCL3 (ligand for CCR5) in CSU skin was also increased (p < 0.0002) and significant association with T-cell close proximity (p < 0.0001) is noticed. Conclusions: The close proximity of T cells and mast cells in the skin of severe CSU may be driven, at least in part by increased CCR5 and CCL3 expression. Therapies that target CCL3 interaction with CCR5 should be assessed for their effects in CSU.

Navigating Aspirin Hypersensitivity in Patients Undergoing Percutaneous Coronary Intervention.

Aspirin hypersensitivity continues to be a major clinical challenge in patients with coronary artery disease (CAD), particularly in those requiring percutaneous coronary intervention (PCI) in the absence of a validated alternative antiplatelet regimen. Although true aspirin allergies are uncommon, they can manifest with severe reactions such as angioedema or anaphylaxis, highlighting the critical role of diagnostic challenge tests and tolerance induction strategies. Here, a 61-year-old female with end-stage renal disease (ESRD) on hemodialysis presented with new-onset heart failure and elevated troponins in the setting of a hypertensive emergency. A subsequent left heart catheterization revealed severe multivessel disease, but PCI was deferred due to her history suggestive of aspirin-induced angioedema and the absence of a known optimal approach in this scenario. Given the feasibility of completing a desensitization protocol, aspirin desensitization was pursued, facilitating the successful placement of a drug-eluting stent. This case highlights the need for validated protocols to manage aspirin hypersensitivity, as the current treatment paradigm necessitates a highly individualized approach by the treating clinician.

Late-Onset Angioedema With Olanzapine in a Tertiary Hospital.

A medical condition known as angioedema is characterized by sudden swelling of the mucosa, subcutaneous tissue, dermis, and submucosal tissues. If airway obstruction results in respiratory distress, this condition may be fatal. Histamine, bradykinin, and leukotrienes are just a few of the complex chemotactic mediators that play a role in the pathophysiology of angioedema and can lead to fluid buildup in deeper skin layers. Many things, such as medication side effects, genetic disorders, and allergic reactions, can cause angioedema. Olanzapine, an atypical antipsychotic mainly used to treat a few mental disorders, is one notable drug linked to angioedema. Angioedema is a documented side effect of olanzapine, albeit rare. Although the exact mechanism by which olanzapine causes angioedema is unknown, immunological-mediated or idiosyncratic reactions are thought to be involved. This study aims to review the current literature on the association between olanzapine and angioedema, including potential mechanisms of action and implications for clinical management. The possible risk factors, presentation, diagnosis, and treatment options for olanzapine-induced angioedema will also be discussed.

Implications of Family-Oriented Psychotherapy for Hereditary Angioedema Management: A Case Series.

The role of psychotherapy in the management of chronic conditions has been widely explored and supported. The current approach to the utilization of family-oriented psychotherapy in treatment plans is individualized to the patient and focused on the development of personal coping skills alongside identifying and changing negative thoughts, emotions, and behaviors. Alleviation of symptom burden, improvement in psychiatric co-morbidities like anxiety and depression, and enhancement of quality of life have all been found to be associated with incorporating family-oriented psychotherapy in the management of chronic conditions. In contrast, heritable conditions, such as hereditary angioedema (HAE), have not been the center of extensive research. Heritable conditions introduce a new category of stressors that require management like the anxiety of a parent, a sibling, a child, or another family member decompensating at the same time as oneself. Family-centered psychotherapy focuses on discussing the stressors of the family unit and the development of coping strategies to prevent the time course of one family member's condition from exacerbating another family member's condition. This model has been utilized for families with separate chronic conditions, but its role and effectiveness in managing inherited conditions have room for investigation. This paper presents a case series on a family engaging in family-centered psychotherapy for HAE.

Does angioedema in patients with chronic spontaneous urticaria impact response to omalizumab?

The presence of angioedema, or deep skin swelling, in addition to hives (wheals) in patients with chronic spontaneous urticaria (CSU) can complicate disease management. There is evidence that omalizumab is effective for patients with CSU with angioedema, but the time to a clinically meaningful response has not been assessed. This post hoc analysis examined data from the phase 3, randomized, double-blind ASTERIA I and ASTERIA II studies: patients with CSU with hives were grouped by presence (n = 216) or absence of angioedema (n = 265) at baseline. The time to minimally important difference (MID, change from baseline of ≥11 points) in weekly Urticaria Activity Score (UAS7) was analyzed using Kaplan-Meier analyses. Median time to MID for omalizumab 300 mg was similar in patients with and without angioedema. Median time to MID for omalizumab 150 mg was similar to 300 mg for patients without angioedema, and was longer for patients with angioedema. Therefore, the response to omalizumab for patients with CSU with angioedema was dose dependent. We recommend that the best approach for clinicians, in line with guidelines, would be initial administration of omalizumab 300 mg every 4 weeks for all patients. Clinical trials registration: Clinicaltrials.gov NCT01287117 (registered 27 January 2011) and NCT01292473 (registered 7 February 2011).

Patient-Reported Outcome Measures in Chronic Spontaneous Urticaria, Angioedema, and Atopic Dermatitis.

Reducing the burden of disease for patients and families requires being able to measure health status changes related to disease severity, control, and response to treatment over time. Patient-reported outcomes are patient perceptions of their health status. Such perceptions are critical to decision making. Some patient-reported outcome measures (PROMs) are extensive and often intended to be used only for detailed research assessments. Many PROMs, however, form critical components of valid, reliable, and responsive assessments in clinical research and routine clinical practice. The smallest score change in a PROM that would lead to different decision making by patients is called the minimally important difference. Using PROMs may also offer advantages over general questions or unvalidated tools. With the innovation of technology, the ability to chronicle disease symptoms using communication technology (mobile phone applications) has become increasingly available. Collection of real-world data in this capacity will be very useful for identifying more precise phenotypes/endotypes necessary for investigation of tailored therapies for chronic spontaneous and inducible urticaria, angioedema, and atopic dermatitis. Here, we provide an overview of PROMs that have been developed for the assessment of disease severity, control, and quality of life and that have been validated for the use of adults and children with these skin disorders.

A human centred innovative approach based on persona in hereditary angioedema.

BACKGROUND: Hereditary Angioedema (HAE) due to C1-inhibitor deficiency (C1INH) is a rare condition, clinically characterised by recurrent swelling. The unpredictability of attacks affects the patients' quality of life (QoL). HAE patients and their families have vast unmet physical, psychological, and social needs. A human-centred design (HCD) approach to describing the needs of different user types is to utilise personas, a data-driven narrative tool for communicating user archetypes that capture the individuals' attitudes, goals, and behaviours. The aim of this study was to create and analyse personas based on HAE patients' and their caregivers' interviews. Semi-structured interviews were conducted through anthropological conversations with patients, patient-caregivers (double role of patient and caregiver), and non-affected caregivers. Qualitative and quantitative insights from analyses formed the basis to create personas. RESULTS: We enrolled 17 subjects: 15 patients (6 of them were patient-caregivers) and 2 non-affected caregivers. The mean age of participants was 50.3 ± 14.4 years. Eight patients were on treatment with prophylactic therapy. The mean percentage score of Angioedema Quality of Life (AE-QoL) for HAE patients was 19.8 ± 12.0. Six personas were identified describing the participants' personal history, disease management, and needs: four personas referred to patients, one to patient-caregivers, and one non-affected caregiver personas were identified. Across patient personas, the most expressed needs were psychological support and better awareness amongst healthcare professionals. Caregivers, on their side, desired better information about the disease, including the latest therapies, and higher awareness within the community. CONCLUSION: A Human Centred Innovative Approach Based on Persona extends beyond the physical symptoms to encompass the psychological and social aspects of the individual's well-being also including the family in the evaluation.

Tramadol-Induced Fatal Angioedema: A Rare Case.

Angioedema is a non-pitting edema that involves the subcutaneous and submucosal layers of the face, lips, neck, oral cavity, larynx, and gut. It may become life-threatening when it involves tissues of the larynx. Angioedema can be triggered by exposure to drugs such as angiotensin-converting enzyme inhibitors (ACE inhibitors), opioid drugs, and nonsteroidal anti-inflammatory drugs (NSAIDs). Tramadol is an opioid analgesic medication that may also induce angioedema, but the incidence of tramadol-induced angioedema is very rare in literature to date. It has been postulated that tramadol may cause fatal angioedema in the presence of underlying diseases such as systemic lupus erythematosus (SLE) or concomitant drugs such as NSAIDs. We describe the case of a patient with SLE who experienced fatal angioedema following tramadol intake.

A pharmacovigilance study assessing risk of angioedema with angiotensin receptor blockers using the US FDA Adverse Event Reporting System.

BACKGROUND: Angiotensin receptor blockers (ARBs) are widely used for treating hypertension and heart failure. Angioedema has been reported as a controversial adverse effect of ARBs and the evidence on individual ARB risks is limited. This study aimed to assess signals of angioedema with different ARBs using the US FDA Adverse Event Reporting System (AERS) database. RESEARCH DESIGN AND METHODS: Reports of angioedema from 2004 to 2024 in AERS with an ARB as the primary suspect were extracted using Medical Dictionary for Regulatory Activities queries. Disproportionality analyses including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network and multi-item gamma Poisson shrinker were conducted to identify safety signals for individual ARBs. RESULTS: A total of 3,683 unique reports met the selection criteria. Irbesartan and losartan generated signals in all statistical measures, followed by telmisartan and candesartan in some measures. Valsartan had the highest report count. Most reports reported hospitalization, prolonged hospitalization or life-threatening outcomes consequent to angioedema. CONCLUSION: This pharmacovigilance study using AERS highlights potential higher risks of angioedema with losartan and irbesartan compared to other ARBs, warranting validation through prospective epidemiological studies to characterize individual ARB safety profiles.

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.

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.