Mimics of Allergy and Angioedema: Scombroid, Mast Cell Activation Disorders, and Hereditary Alpha Tryptasemia.

Scombroid poisoning, systemic mastocytosis, and hereditary alpha tryptasemia all present with episodes that resemble allergic reactions. Knowledge regarding systemic mastocytosis and hereditary alpha tryptasemia is quickly evolving. Epidemiology, pathophysiology, and strategies to identify and diagnose are discussed. Evidence-based management in the emergency setting and beyond is also explored and summarized. Key differences are described between these events and allergic reactions.

Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema.

Angioedema is a well-recognized and potentially lethal complication of angiotensin-converting enzyme inhibitor (ACEi) therapy. In ACEi-induced angioedema, bradykinin accumulates due to a decrease in its metabolism by ACE, the enzyme that is primarily responsible for this function. The action of bradykinin at bradykinin type 2 receptors leads to increased vascular permeability and the accumulation of fluid in the subcutaneous and submucosal space. Patients with ACEi-induced angioedema are at risk for airway compromise because of the tendency for the face, lips, tongue, and airway structures to be affected. The emergency physician should focus on airway evaluation and management when treating patients with ACEi-induced angioedema.

gC1qR Antibody Can Modulate Endothelial Cell Permeability in Angioedema.

Angioedema is characterized by swelling of the skin or mucous membranes. Overproduction of the vasodilator bradykinin (BK) is an important contributor to the disease pathology, which causes rapid increase in vascular permeability. BK formation on endothelial cells results from high molecular weight kininogen (HK) interacting with gC1qR, the receptor for the globular heads of C1q, the first component of the classical pathway of complement. Endothelial cells are sensitive to blood-flow-induced shear stress and it has been shown that shear stress can modulate gC1qR expression. This study aimed to determine the following: (1) how BK or angioedema patients' (HAE) plasma affected endothelial cell permeability and gC1qR expression under shear stress, and (2) if monoclonal antibody (mAb) 74.5.2, which recognizes the HK binding site on gC1qR, had an inhibitory effect in HK binding to endothelial cells. Human dermal microvascular endothelial cells (HDMECs) grown on Transwell inserts were exposed to shear stress in the presence of HAE patients' plasma. Endothelial cell permeability was measured using FITC-conjugated bovine serum albumin. gC1qR expression and HK binding to endothelial cell surface was measured using solid-phase ELISA. Cell morphology was quantified using immunofluorescence microscopy. The results demonstrated that BK at 1 µg/mL, but not HAE patients' plasma and/or shear stress, caused significant increases in HDMEC permeability. The mAb 74.5.2 could effectively inhibit HK binding to recombinant gC1qR, and reduce HAE patients' plasma-induced HDMEC permeability change. These results suggested that monoclonal antibody to gC1qR, i.e., 74.5.2, could be potentially used as an effective therapeutic reagent to prevent angioedema.

Angioedema and Fatty Acids.

Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid's function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.

Angioedema: differential diagnosis and acute management.

A clinical vignette illustrates a typical presentation of a patient seeking help for acute angioedema. Despite the risks of SARS-CoV-2 (COVID-19) exposure, it is critical to evaluate patients with acute angioedema in person, because there is always the potential for angioedema to progress to the head, neck, or lungs, which can rapidly compromise the airways and require immediate intervention to avoid potential asphyxiation. There are three mediators of angioedema, histamine, leukotriene, or bradykinin, each requiring different management. This article provides clinicians essential information for differentiating between these types of angioedema, including an overview of the underlying pathogenies of angioedema, and the subjective and objective findings that are useful in differentiating between angioedema types. The article ends with the appropriate management for each type of acute angioedema, including the medications approved by the FDA for on-demand treatment of an HAE attack.

C1 esterase inhibitor for angiotensin-converting enzyme inhibitor-induced angioedema at a community teaching health system: A brief retrospective propensity-matched cohort study.

INTRODUCTION: Angiotensin-converting enzyme inhibitor (ACEi)-induced angioedema is a serious emergency that can cause life-threatening symptoms and death if not treated promptly. Potential treatment options for ACEi-induced angioedema include medications with limited evidence for use in this patient population. The purpose of this study was to evaluate the use, clinical efficacy, and angioedema-related medication costs of C1 esterase inhibitor (C1EI) for ACEi-induced angioedema. METHODS: This was a retrospective, propensity-matched cohort study comparing patients who received C1EI to those who did not receive C1EI for ACEi-induced angioedema. The primary outcome of interest was comparing the proportion of patients who required intubation secondary to ACEi-induced angioedema. Secondary endpoints of interest were also included. RESULTS: After propensity score matching, 22 patients were stratified into both the non-C1EI group and C1EI group, respectively. There was no difference between the groups with respect to the proportion of intubation (13.6% in the C1EI group vs. 9.1% in the non-C1EI group, p > 0.999). Mean cost of angioedema-related medication therapy was higher in the C1EI group compared to the non-C1EI group [$8758.95 (± $2959.30) vs. $15.91 (± $7.32), p < 0.001]. CONCLUSIONS: In this retrospective cohort study, the use of C1EI for ACEi-induced angioedema did not demonstrate improved outcomes with respect to intubation and resulted in increased costs. Larger, multicenter, prospective studies are needed to further validate the results of this study and to provide more clarity on the role of C1EI therapy in ACEi-induced angioedema.

The importance of recognizing and managing a rare form of angioedema: hereditary angioedema due to C1-inhibitor deficiency.

The majority of angioedema cases encountered in clinical practice are histamine-mediated (allergic); however, some cases are bradykinin-related (non-allergic) and do not respond to standard anti-allergy medications. Among bradykinin-related angioedema, hereditary angioedema (HAE) is a rare, but chronic and debilitating condition. The majority of HAE is caused by deficiency (type 1) or abnormal function (type 2) of the naturally occurring protein, C1-inhibitor (C1-INH)-a major inhibitor of proteases in the contact (kallikrein-bradykinin cascade), fibrinolytic pathway, and complement systems. Failure to recognize HAE and initiate appropriate intervention can lead to years of pain, disability, impaired quality of life (QoL) and, in cases of laryngeal involvement, it can be life-threatening. HAE must be considered in the differential diagnosis of non-urticarial angioedema, particularly for patients with a history of recurrent angioedema attacks, family history of HAE, symptom onset in childhood/adolescence, prodromal signs/symptoms before swellings, recurrent/painful abdominal symptoms, and upper airway edema. Management strategies for HAE include on-demand treatment for acute attacks, short-term prophylaxis prior to attack-triggering events/procedures, and long-term or routine prophylaxis for attack prevention. Patients should be evaluated at least annually to assess need for routine prophylaxis. HAE specific medications like plasma-derived and recombinant C1-INH products, kallikrein inhibitors, and bradykinin B2 receptor antagonists, have improved management of HAE. While the introduction of intravenous C1-INH represented a major breakthrough in routine HAE prophylaxis, some patients fail to achieve adequate control and others have psychological barriers or experience complications related to intravenous administration. Subcutaneous (SC) C1-INH, SC monoclonal antibody (mAb)-based therapies, and an oral kallikrein inhibitor offer effective alternatives for HAE attack prevention and may facilitate self-administration. HAE management should be individualized, with QoL improvement being a key goal. This can be achieved with broader availability of existing options for routine prophylaxis, including greater global availability of C1-INH(SC), mAb-based therapy, oral treatments, and multiple on-demand therapies.

Angioedema without wheals: a clinical update.

Angioedema without wheals (urticaria) represents a heterogeneous group of clinically indistinguishable diseases of hereditary or acquired etiology. Hereditary angioedema is a rare inherited condition leading to recurrent, sometimes life-threatening angioedema attacks in subcutaneous tissues and gastrointestinal and oropharyngeal mucosa dating back to childhood or adolescence. Most of these patients have mutations in the SERPING1 gene, causing either low C1 inhibitor production (hereditary angioedema with C1 inhibitor deficiency type I) or the production of dysfunctional C1 inhibitor (hereditary angioedema with C1 inhibitor deficiency type II). Hereditary angioedema with normal C1 inhibitor has been defined later. Although C1 inhibitor concentration and function are in the normal range, it leads to typical hereditary angioedema symptoms owing to mutations in FXII, PLG, ANGPT1, KNG1, and MYOF genes. Patients who exhibit none of these genetic mutations despite having a similar clinical presentation are classified as having unknown hereditary angioedema. Fewer than 1 in 10 patients with C1 inhibitor deficiency have acquired angioedema with C1 inhibitor deficiency. The clinical presentation is very similar to that of hereditary angioedema, making it difficult to distinguish these 2 conditions clinically. Unlike hereditary angioedema, there are no genetic mutations, and family history and symptoms tend to appear later in life. Acquired angioedema with C1 inhibitor deficiency is commonly associated with lymphoproliferative and autoimmune diseases. Angioedema attacks might start 1 year before the underlying disease in acquired angioedema with C1 inhibitor deficiency. Approximately half of the patients admitted to the hospital for acute angioedema are patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema typically occurs on the lips, tongue, mouth, pharynx, and subglottic regions. Patients may require hospitalization and intensive care monitoring owing to airway involvement. Idiopathic histaminergic acquired angioedema may be diagnosed only when any possible causes of histaminergic angioedema are excluded (foods, drugs, animal dander, aeroallergens, insect stings, latex, and others), and the symptoms respond well to antihistamine treatment. Idiopathic nonhistaminergic acquired angioedema should be considered when all other types of recurrent angioedema have been ruled out and patients do not respond to high-dose antihistamines. The lack of a standard biochemical laboratory test for patients with idiopathic histaminergic acquired angioedema, idiopathic nonhistaminergic acquired angioedema, angiotensin-converting enzyme inhibitor-induced acquired angioedema, and hereditary angioedema with normal C1 inhibitor makes the diagnosis more challenging. Future efforts should focus on increasing awareness of all the rare types of angioedema among physicians and developing more straightforward and more accessible diagnostic methods.

Assessment of ED triage of anaphylaxis patients based on the Emergency Severity Index.

OBJECTIVES: To describe the emergency department (ED) triage of anaphylaxis patients based on the Emergency Severity Index (ESI), assess the association between ESI triage level and ED epinephrine administration, and determine characteristics associated with lower acuity triage ESI assignment (levels 3 and 4). METHODS: We conducted a cohort study of adult and pediatric anaphylaxis patients between September 2010 and September 2018 at an academic ED. Patient characteristics and management were compared between Emergency Severity Index (ESI) triage level 1 or 2 versus levels 3 or 4 using logistic regression analysis. We adhered to STROBE reporting guidelines. RESULTS: A total of 1090 patient visits were included. There were 26 (2%), 515 (47%), 489 (45%), and 60 (6%) visits that were assigned an ESI triage level of 1, 2, 3, and 4, respectively. Epinephrine was administered in the ED to 53% of patients triaged ESI level 1 or 2 and to 40% of patients triaged ESI level 3 or 4. Patients who were assigned a lower acuity ESI level of 3 or 4 had a longer median time from ED arrival to epinephrine administration compared to those with a higher acuity ESI level of 1 or 2 (28 min compared to 13 min, p < .001). A lower acuity ESI level was more likely to be assigned to visits with a chief concern of hives, rash, or pruritus (OR 2.33 [95% CI, 1.20-4.53]) and less likely to be assigned to visits among adults (OR, 0.43 [0.31-0.60]), patients who received epinephrine from emergency medical services (OR 0.56 [0.38-0.82]), presented with posterior pharyngeal or uvular angioedema (OR, 0.56 [0.38-0.82]), hypoxemia (OR, 0.34 [0.18-0.64]), or increased heart (OR 0.83 [0.73-0.95]) or respiratory (OR 0.70 [0.60-0.82]) rates. CONCLUSION: Patients triaged to lower acuity ESI levels experienced delays in ED epinephrine administration. Adult and pediatric patients with skin-related chief concerns were more likely to be to be assigned lower acuity ESI levels. Further studies are needed to identify interventions that will improve ED anaphylaxis triage.

Urticaria and angioedema as a prodromal cutaneous manifestation of SARS-CoV-2 (COVID-19) infection.

This is a case of a patient who presented with an urticarial rash 48 hours before developing symptoms of fever and a continuous cough. She subsequently developed angioedema of her lips and hands before testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Urticarial rashes occurring 48 hours before other symptoms of COVID-19 infection have been documented. This case demonstrates the importance of heightened awareness that not all urticarial rashes represent spontaneous urticaria and as a consequence, this may result in misdiagnosis and ultimately delayed diagnosis. This is the first reported case in the literature of urticaria with angioedema as a prodromal phenomenon of COVID-19.

Update on bradykinin-mediated angioedema in 2020.

Bradykinin-mediated angioedema is a rare disease, due to vasodilation and increased vascular permeability resulting from bradykinin. This kind of angioedema affects abdominal and/or upper airways. It differs clinically from histamine-mediated angioedema by the absence of urticaria or skin rash. Antihistamines and corticosteroids are not effective. Delayed diagnosis can lead to inadequate and potentially fatal management by asphyxiation. Bradykinin-mediated angioedema results from either overproduction of bradykinin or inhibition of its degradation. Etiology can be hereditary or acquired. Deficiency of C1 inhibitor and drug induced are the main causes of bradykinin-mediated angioedema. Its diagnosis is clinical (presentation, family history, seriousness, frequency, etc.) and biological (dosage of C1-INH level, C1-INH activity, and complement protein 4 level). Acute attack treatment is based on C1-inhibitor concentrates and icatibant, a bradykinin receptor antagonist. Long-term prophylaxis can be necessary, especially before surgical and dental procedures. New drugs, including gene therapy, are being tested.

Emergency department evaluation of patients with angiotensin converting enzyme inhibitor associated angioedema.

INTRODUCTION: Angiotensin converting enzyme inhibitor (ACEi) associated angioedema is frequently encountered in the emergency department. Airway management is the primary treatment, but published evidence supporting the decision to intubate patients with this condition is extremely limited. METHOD: We performed a retrospective study of all cases of ACEi associated angioedema encountered in a large, urban, tertiary referral emergency department. We classified demographics, duration of symptoms before presentation, physical exam findings and nasopharyngoscopy findings in patients that did and did not require intubation. RESULTS: We identified a total of 190 separate encounters from 183 unique patients who presented during the 3-year period of the study. Eighteen (9.5%) of these patients required intubation. Patients requiring intubation were more likely to present within 6 h of the onset of angioedema symptoms. Anterior tongue swelling, vocal changes, drooling, and dyspnea were significantly more common in patients requiring intubation. Isolated lip swelling was present in 54% of all patients and was the only finding significantly more common in the group that did not require intubation. CONCLUSIONS: Rapid progression of symptoms within the first 6 h of angioedema onset, anterior tongue swelling, vocal changes, drooling and dyspnea are associated with intubation for ACEi associated angioedema. Isolated lip swelling is significantly more common in patients that do not require intubation. Our data provide risk stratification guidance for providers treating patients with suspected ACEi associated angioedema in the emergency department.

Food-induced anaphylaxis in infancy compared to preschool age: A retrospective analysis.

OBJECTIVE: Little is known regarding food anaphylaxis in infancy. We aimed to describe specificities of food anaphylaxis in infants (≤12 months) as compared to preschool children (1-6 years). METHODS: We conducted a retrospective study of all food anaphylaxis cases recorded by the Allergy Vigilance Network from 2002 to 2018, in preschool children focusing on infants. RESULTS: Of 1951 food anaphylaxis reactions, 61 (3%) occurred in infants and 386 (20%) in preschool children. Two infants had two anaphylaxis reactions; thus, we analyzed data among 59 infants (male: 51%; mean age: 6 months [SD: 2.9]); 31% had a history of atopic dermatitis, 11% of previous food allergy. The main food allergens were cow's milk (59%), hen's egg (20%), wheat (7%) and peanut (3%) in infants as compared with peanut (27%) and cashew (23%) in preschool children. Anaphylaxis occurred in 28/61 (46%) cases at the first cow's milk intake after breastfeeding discontinuation. Clinical manifestations were mainly mucocutaneous (79%), gastrointestinal (49%), respiratory (48%) and cardiovascular (21%); 25% of infants received adrenaline. Hives, hypotension and neurologic symptoms were more likely to be reported in infants than in preschool children (P = .02; P = .004; P = .002, respectively). Antihistamines and corticosteroids were more often prescribed in preschool children than in infants (P = .005; P = .025, respectively). CONCLUSION: Our study found that in infants presenting with their first food allergy, in a setting with a high rate of infant formula use, the most predominant trigger was cow's milk. As compared to older preschool children, hives, hypotonia and hypotension were more likely to be reported in infants. We believe that this represents a distinct food anaphylaxis phenotype that can further support developing the clinical anaphylaxis criteria in infants.

Angiotensin-converting enzyme inhibitor-associated angioedema: from bed to bench

BACKGROUND: Angiotensin-converting enzyme inhibitor-associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood. OBJECTIVE: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE. METHODS: The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients. RESULTS: A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed. CONCLUSIONS: Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE

ANTECEDENTES: El angioedema asociado al consumo de inhibidores de la enzima convertidora de angiotensina (IECA-AAE) ocurre en el 0,1%-0,7% de los pacientes tratados con IECA. Aunque se sugiere que los ataques de angioedema son el resultado de una mayor permeabilidad vascular, la patogénesis de este proceso no está plenamente esclarecida. OBJETIVO: En este trabajo se estudiaron los parámetros clínicos, genéticos y de laboratorio de pacientes con IECA-AAE, así como el papel de los factores de crecimiento endotelial vascular A y C (VEGF-A y VEGF-C), las angiopoyetinas 1 y 2 (Ang1/Ang2) y la fosfolipasa secretora A2 (sPLA2). MÉTODOS: Se recogieron datos clínicos y de laboratorio de pacientes con IECA-AAE procedentes de dos centros de referencia en angioedema. Se utilizaron pacientes control, que incluyeron a voluntarios sanos y a pacientes tratados con IECA sin angioedema, para comparar las concentraciones de los parámetros de laboratorio. Finalmente, se realizó un análisis genético en un subconjunto de pacientes para detectar mutaciones en los genes SERPING1, ANGPT1, PLG y F12. RESULTADOS: Se diagnosticaron a 51 pacientes (57% hombres) con IECA-AAE. El tiempo promedio para el inicio de los síntomas desde el comienzo del tratamiento con IECA fue de 3 años (rango de 30 días a 20 años). Los lugares más comúnmente afectados fueron: labios (74,5%), lengua (51,9%) y cara (41,2%). El cambio de IECA a ARA-II no se asoció con un mayor riesgo de angioedema en pacientes con antecedentes de IECA-AAE. Los niveles plasmáticos de VEGF-A, VEGF-C y sPLA2 fueron más altos en pacientes con IECA-AAE que en los controles. No se detectaron cambios en las concentraciones de Ang1/Ang2, ni se detectaron mutaciones en los genes analizados. CONCLUSIONES: Nuestros datos sugieren que los ARA-II pueden ser una alternativa terapéutica segura en pacientes con IECA-AAE. El aumento de las concentraciones de VEGF-A, VEGF-C y sPLA2 en pacientes con ACEI-AAE sugiere un posible papel de estos mediadores en la patogénesis de esta enfermedad

[Hereditary angioedema]. / Hereditäres Angioödem.

Hereditary angioedema (HAE) encompasses a heterogeneous group of diseases with similar phenotypes but different underlying genotypes. Specific clinical signs may point to HAE as opposed to histaminergic angioedema: the typical prolonged development of angioedema over time, positive family history, a lack of response to antihistamines and steroids and response to bradykinin antagonists are typical signs of HAE. The different types of HAE may be associated with a severe clinical course. They are life-long conditions and are still potentially life-threatening. The quality of life of patients with HAE may be considerably impaired. Management plans should be individualized, which is facilitated by the variety of specific medicastions available.

Acute Management, Diagnosis, and Follow-Up of Suspected Perioperative Hypersensitivity Reactions in Flanders 2001-2018.

BACKGROUND: Despite numerous efforts to describe the clinical manifestations and the epidemiology of perioperative hypersensitivity (POH), there remains room to increase awareness among anesthetists and immunologists/allergists. OBJECTIVE: To report the findings of a 17-year survey of suspected POH in Antwerp, Belgium. METHODS: We analyzed clinical and diagnostic data from 715 patients referred because of a suspected POH reaction, between January 1, 2001, and May 31, 2018. A total of 456 patients demonstrating a POH could be queried about subsequent anesthesia. RESULTS: A total of 608 cases formed the final dataset; 208 had a non-life-threatening reaction and 400 a life-threatening reaction. In life-threatening reactions, hypotension was predominating. In the non-life-threatening reactions, 83.9% of the patients displayed cutaneous manifestations. In life-threatening reactions, intravenous adrenaline and fluids were administered in 75.7% and 31%, respectively, and 41.3% had their intervention abandoned. Mast cell activation (MCA) was mainly, but not exclusively, observed in severe grades but did not predict the mechanistic process nor the culprit. A cause was identified in 77.8% of severe and 48.6% of milder cases. Main culprits were neuromuscular blocking agents, latex, cefazolin, and dyes. A total of 156 cases had uneventful anesthesia, except 1 patient who was inadvertently re-exposed to hidden chlorhexidine. CONCLUSIONS: This study highlights that there is room for an improved acute management and an optimized diagnostic workup that should not be restricted to patients with severe reactions and/or showing MCA.