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.

Acquired Angioedema in Selected Neoplastic Diseases.

Background and Objectives. Acquired angioedema is a relatively common revelation accompanying some diseases such as autoimmune or cancer. The study aimed to assess the incidence of one subtype of angioedema-C1-INH-AAE (acquired angioedema with C1 inhibitor deficiency). Material and methods. The study was retrospective and based on 1 312 patients with a final diagnosis of breast cancer, colorectal cancer, or lung cancer: 723 women and 589 men with a mean age of 58.2 ± 13.5 years. The cancer diagnosis according to the ICD (International Classification of Diseases)-10 code, medical history including TNM (Tumour, Node, Metastasis) staging, histopathology, and assessment of the occurrence of C1-INH-AAE angioedema were analysed. Results. C1-INH-AAE occurred more often in patients with cancer than in the control group, as follows: 327 (29%) vs. 53 (6%) for p < 0.05. C1-INH-AAEs were observed most often in the group of patients diagnosed with breast cancer compared to colorectal and lung groups: 197 (37%) vs. 108 (26%) vs. 22 (16%) (p < 0.05). A higher incidence of C1-INH-AAE was observed in the early stages of breast cancer. However, there was no relationship between the occurrence of C1-INH-AAE and the BRCA1 (Breast Cancer gene 1)/BRCA2 (Breast Cancer gene 2) mutation or histopathological types of breast cancer. Conclusion. Angioedema type C1-INH-AAE occurs more often in patients with selected neoplastic diseases, especially in the early stages of breast cancer.

Pharmacovigilance study of the association between dipeptidyl peptidase-4 inhibitors and angioedema using the FDA Adverse Event Reporting System (FAERS).

Dipeptidyl peptidase-4 (DPP-4) plays a minor role in degrading vasoactive peptides that cause angioedema when angiotensin-converting enzyme (ACE) is present and fully functional. This study investigated the association between DPP-4 inhibitors (DPP-4Is) and angioedema, including cases where the concomitant use of ACE inhibitors (ACEIs) was absent. We obtained data from the US Food and Drug Administration Adverse Event Reporting System and performed a disproportionality analysis, using the reporting odds ratio (ROR) and information component (IC) for signal detection in patients aged ≥ 40 years, stratified by age group and sex. No signal was detected for DPP-4Is when the entire dataset was analyzed. However, a signal was detected for the entire female subset group, the three stratified female groups aged ≥ 60 years, and males in their 40 s. After excluding the data of concomitant ACEI users, most ROR and IC values were lower and significant only for females in their 60 s and males aged ≥ 80 years. Regarding individual DPP-4Is signals, those detected for saxagliptin and sitagliptin in some age groups disappeared after excluding the data of ACEI users. Notably, linagliptin was the only DPP-4I where signals were detected in most female groups, regardless of age and without concomitant ACEI use. Our findings suggest that some DPP-4Is were associated with a higher reporting of angioedema as per age and sex, even in the absence of concomitant ACEI use.

Risk factors associated with intubation and readmissions in patients with angioedema: A single-center experience al. / Ann Allergy Asthma Immunol 127 (2021) xxx-xxx"?>.

BACKGROUND: Given the heterogeneity of etiologies, pathophysiology, and presentation of angioedema, variations in clinical outcomes, such as intubation and hospital readmissions, need further clarification. OBJECTIVE: To determine the factors associated with intubation and hospital readmissions in patients with angioedema. METHODS: Retrospective study of patients evaluated with a diagnosis of angioedema in a 6-year period. Demographic and clinical data, such as medication use, family history, comorbidities, and symptoms, were recorded. Multivariable logistic regression was used to analyze factors associated with intubation, whereas Cox regression was used to analyze readmissions. RESULTS: Of 636 patients, the most common cause of angioedema was that induced by angiotensin-converting enzyme inhibitor (ACEI) at 58%. The overall mortality was 0.5%. After adjusting for sex, race, comorbidities, and type of angioedema, smoking (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.10-2.93; P = .02), calcium channel blocker therapy (OR, 1.91; 95% CI, 1.18-3.10; P = .009), histaminergic symptoms (OR, 3.21; 95% CI, 1.93-5.33; P < .001), and age (OR, 1.02; 95% CI, 1.00-1.04; P = .02) were independently associated with increased odds of intubation. Involvement of either the pharynx, larynx, or tongue was associated with higher odds of intubation (OR, 20.96; 95% CI, 10.63-41.33; P < .001). A total of 10% of the patients had a readmission for angioedema within 90 days, and 75% occurred within 30 days. After multivariable Cox regression analysis, only chronic obstructive pulmonary disease and asthma (OR, 2.13; 95% CI, 1.12-4.07; P = .02) and ACEI-related angioedema (OR, 2.93; 95% CI, 1.33-6.47; P = .008) were significantly associated with readmissions. CONCLUSION: Smoking, calcium channel blocker use, histaminergic symptoms, age, and upper airway involvement were markedly associated with intubation. The presence of chronic obstructive pulmonary disease, asthma and ACEI-related angioedema were independently associated with increased odds of readmission.

What lessons can we learn? Clinical and epidemiological retrospective analysis of 267 patients with urticaria in a Brazilian tertiary center

Abstract Background: There are few epidemiological studies of urticaria, published in the indexed literature (PubMed/Medline). Objective: The study aimed to evaluate the epidemiological and clinical data among patients with urticaria/angioedema attending a reference clinic in Brazil. Methods: Two hundred sixty-seven patients were evaluated retrospectively considering demographic data, time course of the disease, triggering symptoms, the presence of angioedema, complementary laboratory tests including total blood count, reactive-C protein, erythrocyte sedimentation rate, IgE serum levels, and other, as necessary. Results: The most commonly diagnosed type of urticaria was chronic spontaneous urticaria (56.93%). Angioedema was associated with chronic urticaria in 108 patients (40.08%). Study limitations: Unicentered and retrospective. Conclusion: Some relevant findings in this study are the observation of a female prevalence of cases (4-females: 1-man), a result more elevated than demonstrated in previous studies in Europe and Asia, the median age was 43-years old and the delay of time between the diagnosis of urticaria and the admission for treatment in a specialized center was approximately 2-years. Other multicenter studies can better establish these differences in Brazilian patients.

[Acquired angioedema due to C1-inhibitor deficiency: CREAK recommendations for diagnosis and treatment]. / Angiœdèmes par déficit acquis en C1-inhibiteur : recommandations du CREAK pour le diagnostic et la prise en charge.

Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.

Gleich syndrome: a systematic review.

Characterized chiefly by hypereosinophilia and angioedema, Gleich syndrome is a rare disorder with unclear clinical and therapeutic findings. Other symptoms include increased IgM levels, weight gain, fever, and urticaria. Herein we review Gleich syndrome and assess clinical features, epidemiology, and treatment options. Thirty-two articles including case reports or case series of eosinophilic angioedema and Gleich syndrome were included. Data regarding patient age, gender, and history, clinical and biological manifestations, and treatment protocols were recorded. The most common clinical findings include recurrent or non-recurrent angioedema, fever, urticaria, weight gain, blood eosinophilia, and elevated immunoglobulin levels. Corticosteroid therapy is the mainstay of treatment. Gleich syndrome is a distinctive hypereosinophilic entity with a benign course and good response to systemic corticosteroids. More studies are needed to evaluate the pathophysiology of this syndrome and lead to better therapeutic options.

Angioedemas associated with renin-angiotensin system blocking drugs: Comparative analysis of spontaneous adverse drug reaction reports.

INTRODUCTION: Angioedema is a subcutaneous swelling typically affecting the face, larynx or pharynx. It is a known adverse drug reaction (ADR) of ACE inhibitors (ACEi), angiotensin-II-receptor blockers (ARBs) and aliskiren (renin inhibitor). Several studies have reported pathophysiological mechanisms and risk factors of ACEi-associated angioedemas, whereas little is known for ARBs and aliskiren. The aim of the study was to analyze comparatively ACEi versus ARBs and aliskiren angioedema reports contained in the European ADR database EudraVigilance with regard to reported risk factors and clinical phenotypes. METHODS: All spontaneous angioedema reports received between 01/2010-06/2017 reporting either an ACEi, ARB, or aliskiren as "suspected/interacting" drug were identified using the Standardized MedDRA Query "angioedema (narrow)". In order to perform a comparative analysis, odds ratios (ORs) were calculated for angioedema reports of ACEi (n = 3.194) versus ARBs (n = 687) and aliskiren (n = 162). RESULTS: More patients with a history of allergy were included in angioedema reports of ARBs (6.8%) and aliskiren (13.6%) versus ACEi (4.3%). "Urticaria" as an ADR was reported more frequently in angioedema reports of ARBs (18.5%) and aliskiren (9.0%) versus ACEi (5.0%). ACEi-associated angioedemas were more often designated as "life-threatening" compared to ARBs (OR 2.2 [1.6-2.9]) and aliskiren-associated angioedemas (OR 14.2 (3.5-57.4). Concomitant therapy with mTOR inhibitors (OR 4.3 [1.0-17.9]) and fibrinolytics (OR 7.8 [1.1-57.2]) was reported more often in ACEi versus ARBs angioedema reports. CONCLUSION: The reported clinical phenotypes differed between ACEi versus ARBs and aliskiren angioedema reports. Differences between the patient populations as observed in our study or differences with regard to underlying pathomechanisms could account for this finding. Due to the methodological limitations of spontaneous reporting systems, we cannot draw a firm conclusion in this regard. Hence, further research is necessary to confirm our observation and elucidate the underyling causes.

Air Pollution and Angioedema.

OBJECTIVE: To identify environmental factors that may precipitate angioedema. STUDY DESIGN: Case series with chart review. SETTING: An urban tertiary care medical center. SUBJECTS AND METHODS: After institutional review board approval was obtained, a chart review of all patients who presented to Temple University Hospital with angioedema from January 2012 to December 2014 was performed. Patient demographics and hospital course were gathered. Environmental data on the dates of presentation, including precipitation, humidity, and air pollution, were obtained from regional Environmental Protection Agency online data banks and used for statistical analysis. RESULTS: In total, 408 patients, representing 450 episodes of angioedema, met the inclusion criteria for the study. Most patients were female (58%), African American (74%), and on an angiotensin-converting enzyme inhibitor (ACE-I) upon presentation (61%). Days with unhealthy levels of air pollution were associated with an increased likelihood of angioedema presentation (odds ratio [OR], 1.82; confidence interval [CI], 1.01-3.30; P = .046). Subgroup analysis revealed that elevated ground-level ozone was the primary air pollutant significantly associated with angioedema presentations (OR, 4.95; CI 1.92-12.76; P = .0009). Higher ground-level ozone was also associated with ACE-I angioedema presentations (P = .017) but not with non-ACE-I angioedema presentations (P = .86). Air quality was not predictive of angioedema severity or need for intubation. CONCLUSION: Angioedema is a complex, multifactorial disease resulting in potentially life-threatening complications. This is the first study to demonstrate that higher levels of air pollution, specifically ground-level ozone, are associated with significantly increased rates of angioedema episodes, although not severity.

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis.

INTRODUCTION: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. METHODS: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. RESULTS: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). DISCUSSION: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.

FACTORS CONTRIBUTING TO CHRONIC URTICARIA/ANGIOEDEMA AND NUMMULAR ECZEMA RESOLUTION - WHICH FINDINGS ARE CRUCIAL?

When working with dermatology patients, the question sometimes arises which diagnostic tests and tools should be used for workup, particularly in cases of chronic urticaria (CU) and discoid nummular eczema, where the treatment of associated systemic diseases and infections may be crucial for patient outcome. The aim was to investigate retrospectively the influence of associated diseases on skin disease outcomes based on medical records of CU and nummular eczema patients in comparison to controls. We included patients admitted to our Dermatology Department over a 6-year period and analyzed their laboratory findings, related factors and outcomes recorded after two years of workup and treatment. Compared to controls, CU patients had a significantly higher prevalence of positive Helicobacter (H.) pylori findings (p=0.020), confirmed allergies (p=0.006), increased IgE (p=0.011) and pathologic thyroid findings (p=0.049), whereas nummular eczema patients only had significantly higher positive H. pylori findings (p=0.046). Meaningful regression of both dermatoses was recorded after treatment of associated diseases, with significant benefit from H. pylori treatment. This indicated that the diagnosis of associated infections (particularly H. pylori and urogenital infections), confirmed allergies, endocrine disorders (particularly of thyroid gland in CU patients) and serum malignancy markers could play a crucial role, as their treatment may improve disease outcomes.

Treatment of Life-Threatening ACE-Inhibitor-Induced Angioedema.

Incidence of angioedema associated with angiotensin-converting enzyme inhibitors (ACE-I) has been estimated at 0.1%-2.2% of patients receiving treatment. Despite the potential severity of this disease state, standardized treatment is lacking. Traditional pharmacotherapy options include medications that target inflammatory mediators and the angiotensin pathway. However, because ACE-I-induced angioedema is caused by accumulation of bradykinin, these medications fail to target the underlying pathophysiology. Recently, novel therapies that target the kallikrein-bradykinin pathway have been studied. These include icatibant, ecallantide, C1 esterase inhibitors, and fresh-frozen plasma. Recent randomized controlled trials exhibit contradictory results with the use of icatibant. This is a focused review on traditional and novel treatment strategies for ACE-I-induced angioedema.

Acquired C1 Inhibitor Deficiency.

Acquired angioedema due to C1-INH deficiency (C1-INH-AAE) can occur when there are acquired (not inherited) deficiencies of C1-INH. A quantitative or functional C1-INH deficiency with negative family history and low C1q is diagnostic of C1-INH-AAE. The most common conditions associated with C1-INH-AAE are autoimmunity and B-cell lymphoproliferative disorders. A diagnosis of C1-INH-AAE can precede a diagnosis of lymphoproliferative disease and confers an increased risk for developing non-Hodgkin lymphoma. Treatment focuses on symptom control with therapies that regulate bradykinin activity (C1-INH concentrate, icatibant, ecallantide, tranexamic acid, androgens) and treatment of any underlying conditions.

Incidence of Adverse Contrast Reaction Following Nonintravenous Urinary Tract Imaging.

Adverse reactions (ARs) to intravenous (IV) radiographic contrast range from mild urticaria to life-threatening anaphylaxis. Intraluminal contrast dye is routinely used in the urinary tract with a minimal perceived risk of AR. We used the Healthcare Cost and Utilization Project State Inpatient Databases for California and Florida from 2007 to 2011 to identify patients who received urinary tract contrast dye for retrograde pyelography, percutaneous pyelography, retrograde/other cystogram, and ileal conduitogram. After excluding patients who had received IV contrast for other radiologic studies, ARs to contrast were identified by a composite end point of diagnoses not present on admission including shock, anaphylaxis, iatrogenic hypotension, urticaria, angioedema, laryngospasm, laryngeal edema, and/or a new diagnosis of contrast reaction. Overall, 76 174 patients were included who had undergone non-IV urinary tract imaging, 367 (0.48%) of whom developed an AR. On multivariate analysis, receipt of contrast in the lower urinary tract (odds ratio [OR]: 1.8; p=0.04) or upper urinary tract by retrograde pyelography (OR: 1.6; p=0.04) or antegrade pyelography (OR: 2.0; p=0.007) increased the risk of AR compared with control patients. The use of contrast dye in the urinary tract is associated with a low, but present risk of AR. PATIENT SUMMARY: We looked at patients who underwent a urologic procedure using radiographic contrast media in the urinary tract. Although adverse reactions (ARs) may occur with the use of contrast media in the urinary tract, these reactions are experienced by a minority of patients (approximately 1 in 200). In addition, we found that an allergy to intravenous contrast does not increase a patient's risk of an AR to contrast within the urinary tract.

Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough.

BACKGROUND: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema. OBJECTIVE: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events. METHODS: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons. RESULTS: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10-5, and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10-5. Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10-4) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10-10 and P = 2.6 × 10-4). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups. CONCLUSION: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

Cofactors and comorbidities in patients with aspirin/NSAID hypersensitivity.

Hypersensitivity reactions to aspirin and other NSAIDs occur in individuals genetically predisposed and exhibit different clinical manifestations, especially respiratory, cutaneous, and generalised. Five different phenotypes define distinct clinical pictures: aspirin-exacerbated respiratory disease, aspirin/NSAID cutaneous disease, NSAID-induced urticaria, angio-oedema and anaphylaxis, single NSAID reactions, and delayed reactions. They are observed more frequently in middle-aged women, and in atopic individuals. While ASA/NSAID hypersensitivity shares comorbidities with asthma, chronic rhinosinusitis, nasal polyposis, chronic urticaria and angio-oedema, ASA and other NSAIDs can also be cofactors for other clinically relevant conditions, especially food-dependent exercise-induced anaphylaxis, angio-oedema induced by angiotensin-converting enzyme inhibitors, and oral mite anaphylaxis. Awareness on these relationships is required for the correct diagnosis, classification, and treatment of affected patients.

Epidemiology of angioedema without wheals in an allergy and immunology center

We describe the diagnostic epidemiology, the clinical course, the family history and the response to treatment of patients with angioedema without wheals (AWW) at an Allergy and Immunology Clinical Center. We reviewed the case records of all patients at our office from January 1997 to April 2013. We recorded sex, age, age at onset of symptoms, family history of angioedema, number of visits to the office, type of angioedema, and response to treatment from those patients with angioedema without wheals. We classified angioedema according to its pathophysiology. We also describe those patients with angioedema mimics. From a total of 17 823 new patients, 303 had a presumptive diagnosis of angioedema without wheals. Twenty-three patients had an angioedema mimic. Forty percent were male and 60% were female. Average age at first visit was 40.6. Average number of visits was 2.4. Fifty-seven patients referred a family history. We attributed idiopathic angioedema to 55.7% of patients, 24.3% were drug related, 15.7% were due to C1 inhibitor deficiency, 2.1% were drug related + idiopathic angioedema, 1.4% were type III and 0.7% had exercise-induced angioedema. Ninety six percent of 53 evaluable idiopathic angioedema patients referred a benefit with anti-histamine therapy. AWW was a rare cause of consultation. Most of our patients had anti H1 responsive idiopathic angioedema and none had allergic angioedema. Women cases prevailed over men´s. Family history and average age of onset of symptoms were different among the different types of angioedema.

Describimos la epidemiología, historia clínica, antecedentes familiares y respuesta al tratamiento de los pacientes consultando por angioedema sin urticaria en nuestra clínica especializada en Alergia e Inmunología. Revisamos retrospectivamente todas las historias clínicas de nuestro consultorio entre enero de 1997 y abril de 2013. Seleccionamos aquellos pacientes que habían consultado por angioedema sin urticaria y registramos el sexo, edad, edad de comienzo de síntomas, antecedentes familiares de angioedema, número de consultas, tipo de angioedema y respuesta al tratamiento. Clasificamos el angioedema de acuerdo a su fisiopatología. Describimos también los diagnósticos diferenciales que encontramos. De un total de 17 823 pacientes, 303 consultaron por angioedema sin ronchas. Veintitrés presentaban un diagnóstico alternativo. El 40% eran hombres y el 60% mujeres. La edad promedio de la primera visita fue 40.6 años. El promedio de consultas fue 2.4. Cincuenta y siete refirieron antecedentes familiares. El 55.7% fue clasificado como angioedema idiopático, el 24.3% secundario a drogas, el 15.7% secundario a deficiencia del inhibidor C1, 2.1% por drogas + idiopático, 1.4% angioedema tipo III y 0.71% asociado al ejercicio. Noventa y seis por ciento de 53 pacientes evaluables con angioedema idiopático se beneficiaron con antihistamínicos. El angioedema sin urticaria fue una causa rara de consultas. Las mujeres prevalecieron sobre los hombres. Los antecedentes familiares y la edad de comienzo de síntomas variaron de acuerdo al tipo de angioedema.

[Acquired angioedema]. / Angiœdèmes bradykiniques acquis non médicamenteux.

Acquired angioedema are rare. They are associated with monoclonal gammapathies of uncertain significance (MGUS) or lymphomas. They give the same symptoms as the hereditary form and the same laryngeal risk. They are characterized by a low level of C4, C1Inh and C1q. They are linked to the consumption of C1Inh by the lymphoid cells or to the presence of anti-C1Inh autoantibodies. They must be treated by symptomatic treatment when attack occur (C1Inh concentrate and icatibant). The use of rituximab needs to prove its efficiency.