Angiotensin-converting enzyme inhibitor-induced angioedema (ACEI-AE) is mediated by bradykinin. There remains an unmet treatment need because these patients, when presenting to the emergency ...department (ED), do not respond to conventional therapies, such as antihistamines and corticosteroids.
To estimate the treatment effect of ecallantide, a recombinant plasma kallikrein inhibitor, in ED patients with ACEI-AE in whom conventional therapy fails.
This was a triple-blind (patient, physician, and statistician), randomized, controlled, phase 2 study to estimate the magnitude of safety and efficacy signals for designing a definitive phase 3 trial comparing conventional therapy with ecallantide to conventional therapy with placebo. Patients were enrolled from April 1, 2010, through January 31, 2013. The primary efficacy study end point was achieving discharge criteria from the ED within 4 hours after initiating study-related treatment.
Discharge criteria from the ED was met in 4 hours or less for 8 (31%) of 26 patients receiving ecallantide vs 5 of (21%) 24 patients receiving placebo (difference in proportions, 10%; 95% confidence interval, -14% to 34%). Ecallantide was well tolerated in both groups.
The results from this preliminary study reveal that ecallantide is safe to use and may increase the proportion of patients who meet early discharge criteria by approximately10%. A larger phase 3 study is necessary to confirm the efficacy and evaluate the cost-effectiveness of ecallantide use for ACEI-AE in the ED setting.
clinicaltrials.gov Identifier: NCT01036659.
Despite its relatively common occurrence and life‐threatening potential, the management of angioedema in the emergency department (ED) is lacking in terms of a structured approach. It is paramount to ...distinguish the different etiologies of angioedema from one another and more specifically differentiate histaminergic‐mediated angioedema from bradykinin‐mediated angioedema, especially in lieu of the more novel treatments that have recently become available for bradykinin‐mediated angioedema. With this background in mind, this consensus parameter for the evaluation and management of angioedema attempts to provide a working framework for emergency physicians (EPs) in approaching the patient with angioedema in terms of diagnosis and management in the ED. This consensus parameter was developed from a collaborative effort among a group of EPs and leading allergists with expertise in angioedema. After rigorous debate, review of the literature, and expert opinion, the following consensus guideline document was created. The document has been endorsed by the American College of Allergy, Asthma & Immunology (ACAAI) and the Society for Academic Emergency Medicine (SAEM).
Resumen
A pesar de su ocurrencia relativamente común y su potencial riesgo vital, el manejo del paciente con angioedema en el servicio de urgencias está falto de una aproximación estructurada. Es primordial distinguir las diferentes etiologías del angioedema y más específicamente diferenciar el angioedema mediado por histamina del mediado por bradicinina, especialmente en relación con los tratamientos que recientemente están disponibles para el angioedema mediado por bradicinina. Con este escenario en mente, este parámetro consenso para la evaluación y el manejo del angiodema intenta proporcionar un marco de trabajo para los urgenciólogos en la aproximación del paciente con angiodema en términos de diagnóstico y tratamiento en el servicio de urgencias. Este esquema consenso fue desarrollado a través de un esfuerzo de colaboración entre un grupo de urgenciólogos y alergólogos expertos líderes en angiodema. Tras un riguroso debate, una revisión de la literatura y la opinión de los expertos, se creó el siguiente documento de guía clínica de consenso. En reconocimiento a la importancia de este tema, este documento de consenso ha sido respaldado por el American College of Allergy, Asthma, and Immunology (ACAAI) y la Society for Academic Emergency Medicine (SAEM).
Clinical trials of ACEi-induced angioedema have tried to replicate the success of treatments for hereditary angioedema (HAE) based on the widely accepted shared pathophysiology of bradykinin ...accumulation 2. Given the acute nature of angioedema, inclusion of an emergency medicine-trained physician would have benefitted the development of their study design. In this study, C1-INH was dosed at 20 international units per kilogram (IU/kg), rounded up to the next 500 IU vial.
Acute urticaria is a frequent presentation in emergency departments (EDs), urgent care centers, and other clinical arenas. Treatment options are limited if diphenhydramine is the only intravenous ...antihistamine offered because of its short duration of action and well-known adverse effects. We evaluate cetirizine injection, the first second-generation injectable antihistamine, for acute urticaria in this multicenter, randomized, noninferiority, phase 3 clinical trial.
Adult patients presenting to EDs and urgent care centers with acute urticaria requiring an intravenous antihistamine were randomized to either intravenous cetirizine 10 mg or intravenous diphenhydramine 50 mg. The primary endpoint was the 2-hour pruritus score change from baseline, with time spent in treatment center and rate of return to treatment centers as key secondary endpoints. Frequency of sedation and anticholinergic adverse effects were also recorded.
Among 262 enrolled patients, the 2-hour pruritus score change from baseline for intravenous cetirizine was statistically noninferior to that for intravenous diphenhydramine (–1.6 versus –1.5; 95% confidence interval –0.1 to 0.3), and in favor of cetirizine. Treatment differences also favored cetirizine for mean time spent in treatment center (1.7 versus 2.1 hours; P=.005), return to treatment center (5.5% versus 14.1%; P=.02), lower change from baseline sedation score at 2 hours (0.1 versus 0.5; P=.03), and adverse event rate (3.9% versus 13.3%).
Intravenous cetirizine is an effective alternative to intravenous diphenhydramine for treating acute urticaria, with benefits of less sedation, fewer adverse events, shorter time spent in treatment center, and lower rates of revisit to treatment center.
Study objective Patient-reported penicillin allergies are often unreliable and can result in unnecessary changes in antibiotic therapy. Although penicillin allergy skin testing is commonly performed ...in allergy clinics, it has not been used in emergency departments (EDs) to verify self-reported allergies. We hypothesize that ED-based testing is possible and that the false-positive rate of patients with self-reported penicillin allergy are greater than 90%. Methods This prospective observational cohort study enrolled a convenience sample of ED patients with a self-reported penicillin allergy. Patients were enrolled by one of 2 emergency physicians who performed skin prick and intracutaneous tests with penicillin major and minor determinants. The total testing time was 30 minutes. The proportion of false-positive self-reported allergies was computed with 95% confidence intervals (CIs) by using the score method. Results A total of 150 patients (mean age 42 years; SD 16 years; 46% men; 47% black) were enrolled. The false-positive rate for self-reported penicillin allergy was 137 of 150 (91.3%; 95% CI 85.3% to 95.1%). There were no adverse reactions associated with penicillin skin testing. Compared with patients with a false-positive penicillin allergy result (confirmed by negative penicillin skin testing result), patients reporting a true penicillin allergy confirmed by positive penicillin skin test results tended to be more frequently men (61.5% versus 44.5%; Δ 17.0%; 95% CI −13.5% to 42%), black (69.2% versus 44.5%; Δ 24.7%; 95% CI −6.9% to 46.8%), and have no family history of drug allergy (7.7% versus 17.5%; Δ9.8%; 95% CI −20.9% to 20.4%), but self-reported other drug allergies more frequently (61.5% versus 38.7%; Δ 22.9%; 95% CI −7.7% to 47.5%). Conclusion Penicillin skin testing is feasible in the ED setting. A substantial number of patients who self-report a penicillin allergy do not exhibit immunoglobulin E-mediated sensitization to penicillin major and minor determinants. Penicillin testing in the ED may allow the use of more appropriate antibiotics for patients presenting with a history of penicillin allergy.
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.
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.
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.
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.
Abstract Background Hereditary angioedema (HAE) is a rare and often debilitating condition associated with substantial morbidity and mortality in the absence of appropriate intervention. An ...underlying deficiency in functional C1-inhibitor (C1-INH) protein induces a vulnerability to unchecked activation of the complement, contact, and coagulation/fibrinolytic systems. The clinical consequence is a pattern of recurring attacks of non-pitting, non-pruritic edema, the urgency of which varies by the affected site. Laryngeal edema can escalate rapidly to asphyxiation, and severe cases of abdominal swelling can lead to hypovolemic shock. Objectives This report reviews the emergency diagnosis and treatment of hereditary angioedema and the impact of recently introduced treatments on treatment in the United States. Discussion Until recently, emergency physicians in the United States were hindered by the lack of rapidly effective treatment options for HAE attacks. In this article, general clinical and laboratory diagnostic procedures are reviewed against the backdrop of two case studies: one patient presenting with a known history of HAE and one with previously undiagnosed HAE. In many countries outside the United States, plasma-derived C1-INH concentrate has for decades been the first-line treatment for acute attacks. The end of 2009 ushered in a new era in the pharmacologic management of HAE attacks in the United States with the approval of two new treatment options for acute treatment: a plasma-derived C1-INH concentrate and a kallikrein inhibitor. Conclusion With access to targeted and effective treatments, emergency physicians are now better equipped for successful and rapid intervention in urgent HAE cases.
Hereditary angioedema (HAE) is a rare disorder generally caused by a deficit in the activity of C1-esterase inhibitor (C1-INH). Symptoms manifest as recurrent episodes of nonallergic, nonpruritic, ...and nonpitting edema. Attacks commonly occur on the extremities, trunk, genitalia, abdomen, or head and neck-the latter 2 locations are associated with the greatest morbidity and mortality. In the United States, there has been a considerable void in effective HAE treatments and emergency management guidelines. Clinical outcomes using agents such as fresh-frozen plasma, attenuated androgens (danazol), or plasmin inhibitors (aminocaproic acid) have not been ideal. Recent years have seen progress with US Food and Drug Administration (FDA) approval of several products for acute HAE treatment. Plasma concentrate of C1-INH has long been the treatment of choice in many parts of the world, and a pasteurized formula received FDA approval in October 2009 for treating attacks. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a bradykinin receptor antagonist, were approved in December 2009 and August 2011, respectively, for treatment of acute attacks. A recombinant C1-INH product is in late development stages for treating acute attacks. These new treatments provide symptom relief within hours, dramatically shorten attack duration, and decrease mortality from airway compromise. For the first time, US physicians have rapid-acting and highly effective treatments for managing acute HAE attacks.
Objective
Clinical triage in coronavirus disease 2019 (COVID-19) places a heavy burden on senior clinicians during a pandemic situation. However, risk stratification based on serum biomarker ...bioprofiling could be implemented by a larger, nonspecialist workforce.
Method
Measures of Complement Activation and inflammation in patientS with CoronAvirus DisEase 2019 (CASCADE) patients (
n
= 72), (clinicaltrials.gov: NCT04453527), classified as mild, moderate, or severe (by support needed to maintain SpO
2
> 93%), and healthy controls (HC,
n
= 20), were bioprofiled using 76 immunological biomarkers and compared using ANOVA. Spearman correlation analysis on biomarker pairs was visualised
via
heatmaps. Linear Discriminant Analysis (LDA) models were generated to identify patients likely to deteriorate. An X-Gradient-boost (XGB) model trained on CASCADE data to triage patients as mild, moderate, and severe was retrospectively employed to classify COROnavirus Nomacopan Emergency Treatment for covid 19 infected patients with early signs of respiratory distress (CORONET) patients (
n
= 7) treated with nomacopan.
Results
The LDA models distinctly discriminated between deteriorators, nondeteriorators, and HC, with IL-27, IP-10, MDC, ferritin, C5, and sC5b-9 among the key predictor variables during deterioration. C3a and C5 were elevated in all severity classes vs. HC (
p
< 0.05). sC5b-9 was elevated in the “moderate” and “severe” categories vs. HC (
p
< 0.001). Heatmap analysis shows a pairwise increase of negatively correlated pairs with IL-27. The XGB model indicated sC5b-9, IL-8, MCP1, and prothrombin F1 and F2 were key discriminators in nomacopan-treated patients (CORONET study).
Conclusion
Distinct immunological fingerprints from serum biomarkers exist within different severity classes of COVID-19, and harnessing them using machine learning enabled the development of clinically useful triage and prognostic tools. Complement-mediated lung injury plays a key role in COVID-19 pneumonia, and preliminary results hint at the usefulness of a C5 inhibitor in COVID-19 recovery.
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