Aleena Banerji

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group

Angioedema is defined as localized and self‐limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.

Multicenter study of patients with angiotensin- converting enzyme inhibitor-induced angioedema who present to the emergency department

BACKGROUND Recent data are lacking about the number of patients with angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema who present to the emergency department (ED). Current management of the condition and clinical outcomes also are not known. OBJECTIVE To describe the clinical epidemiology of ACEI-induced angioedema in patients who present to the ED. METHODS We performed a medical record review of ACEI-induced angioedema in patients who presented to 5 EDs in the Emergency Medicine Network. A structured data abstraction form was used to collect each patients demographic factors, medical history, and details about the angioedema that prompted the ED visit. The medical record review also focused on treatment provided in the ED and subsequent need for hospitalization. RESULTS We identified a total of 220 patients with ACEI-induced angioedema. The frequency of ACEI-induced angioedema among all patients with angioedema who presented to the ED was 30% (95% confidence interval, 26%-34%). The annual rate of visits for ACEI-induced angioedema was 0.7 per 10,000 ED visits. The most frequent presenting signs were shortness of breath, lip and tongue swelling, and laryngeal edema. Most patients (58%) were sent home directly from the ED, whereas 12% were regular inpatient admissions, 11% were admitted to the intensive care unit, and 18% were admitted under observation status (<24 hours). Pharyngeal swelling and respiratory distress were independent predictors of hospital admission and longer length of stay. CONCLUSION ACEI-induced angioedema accounted for almost one-third of angioedema treated in the ED, although it remains a rare ED presentation. A subgroup of these patients still needs inpatient hospitalization for management of upper airway angioedema.

Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel.

A new form of hereditary angioedema (HAE) with normal C1 inhibitor (C1INH) was first described in 2000. The lack of clear diagnostic criteria, the heterogeneity among affected patients, and the varying names given to this disease have led to substantial confusion among both physicians and patients. This study was designed to bring more clarity to the diagnosis and potential treatment of HAE with normal C1INH. An international symposium of experts was convened to review the field and develop consensus opinions that could help clinicians who evaluate and manage these patients. Criteria were developed for the diagnosis of HAE with normal C1INH in patients with recurrent angioedema in the absence of concurrent urticaria. In addition, potential therapeutic strategies are discussed. The consensus criteria developed during this symposium will allow physicians to better diagnose and treat patients with HAE with normal C1INH.

Multicenter Study of Repeat Epinephrine Treatments for Food-Related Anaphylaxis

OBJECTIVE: We sought to establish the frequency of receiving >1 dose of epinephrine in children who present to the emergency department (ED) with food-related anaphylaxis. PATIENTS AND METHODS: We performed a medical chart review at Boston hospitals of all children presenting to the ED for food-related acute allergic reactions between January 1, 2001, and December 31, 2006. We focused on causative foods, clinical presentations, and emergency treatments. RESULTS: Through random sampling and appropriate weighting, the 605 reviewed cases represented a study cohort of 1255 patients. These patients had a median age of 5.8 years (95% confidence interval [CI]: 5.3–6.3), and the cohort was 62% male. A variety of foods provoked the allergic reactions, including peanuts (23%), tree nuts (18%), and milk (15%). Approximately half (52% [95% CI: 48–57]) of the children met diagnostic criteria for food-related anaphylaxis. Among those with anaphylaxis, 31% received 1 dose and 3% received >1 dose of epinephrine before their arrival to the ED. In the ED, patients with anaphylaxis received antihistamines (59%), corticosteroids (57%), epinephrine (20%). Over the course of their reaction, 44% of patients with food-related anaphylaxis received epinephrine, and among this subset of patients, 12% (95% CI: 9–14) received >1 dose. Risk factors for repeat epinephrine use included older age and transfer from an outside hospital. Most patients (88%) were discharged from the hospital. On ED discharge, 43% were prescribed self-injectable epinephrine, and only 22% were referred to an allergist. CONCLUSIONS: Among children with food-related anaphylaxis who received epinephrine, 12% received a second dose. Results of this study support the recommendation that children at risk for food-related anaphylaxis carry 2 doses of epinephrine.

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Human allergic asthma is a chronic inflammatory disease of the airways thought to be driven by allergen-specific Th2 cells, which are recruited into the lung in response to inhaled allergen. To identify chemoattractant receptors that control this homing pattern, we used endobronchial segmental allergen challenge in human atopic asthmatics to define the pattern of chemoattractant receptor expression on recruited T cells as well as the numbers of recruited CD1d-restricted NKT cells and levels of chemokines in the bronchoalveolar (BAL) fluid. CD1d-restricted NKT cells comprised only a small minority of BAL T cells before or after Ag challenge. BAL T cells were enriched in their expression of specific chemoattractant receptors compared with peripheral blood T cells prechallenge, including CCR5, CCR6, CXCR3, CXCR4, and BLT1. Surprisingly, following segmental allergen challenge, no chemoattractant receptor was specifically increased. However, CCR6 and CXCR3, which were expressed on virtually all CD4+ BAL T cells prechallenge, were markedly decreased on all recruited BAL T cells following Ag challenge, suggesting that these receptors were internalized following encounter with ligand in the airway. Our data therefore suggests a role for CCR6 and CXCR3, in conjunction with other chemoattractant receptors, in the recruitment of inflammatory T cells into the BAL during the allergic asthmatic response.

US Hereditary Angioedema Association Medical Advisory Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor Deficiency

BACKGROUND The treatment of hereditary angioedema (HAE) has undergone dramatic changes as newer medicines have become available in recent years. Optimal care of these patients requires a comprehensive management plan. Although several consensus papers have been published concerning the diagnosis and treatment of HAE, guidelines for a comprehensive management plan have not been developed. OBJECTIVE To develop state-of-the-art recommendations for the treatment and management of HAE due to C1 inhibitor (C1INH) deficiency in the United States. METHODS Members of the US Hereditary Angioedema Association Medical Advisory Board began by reviewing the literature concerning treatment of HAE. Preliminary recommendations were developed based on the literature review, discussions in a face-to-face meeting, and refinements in a series of drafts. Final recommendations reflect the unanimous consensus of the medical advisory board and the US Hereditary Angioedema Association leadership. RESULTS Recommendations are provided regarding a comprehensive care plan for HAE, including the following: development of an overall management plan, treatment of angioedema attacks, prophylactic treatment, and patient monitoring. CONCLUSION A comprehensive individualized management plan developed between an expert HAE physician and the patient, in collaboration with local medical providers and emergency departments, can provide patients with the best opportunity to lead a normal life.

Trends in pediatric emergency department visits for food-induced anaphylaxis

with no allergen declared. More research needs to be done to better define thresholds, and more attention is needed to determine risks and how best to label foods. Based on our data, it is clear that some products pose risks for consumers, and we advocate avoidance of products with advisory statements. Although our data also suggest that many contaminated products are close to and likely below ‘‘threshold’’ levels, we must emphasize that we analyzed only 1 sample per product and thus cannot exclude the possibility that other samples of the same product might have contained higher levels. However, if these low amounts are representative, it implies that changes in manufacturing procedures and more widespread testing might allow production of many more safe products that would not require advisory labeling. Our study has several limitations. Because we sampled products from certain categories, our results are not applicable across all manufactured foods. At 10.2%, the frequency of milk contamination among advisory-labeled products in our sample was lower than the 42% (34/81) recently found by Crotty and Taylor, but their study included products from different categories, including more high-risk chocolate products, and tested 2 samples of each product. Similarly, the study by Hefle et al detected peanut protein in 7.3% (13/179) of products bearing advisory statements compared with our rate of 4.5% (5/112) but also tested 2 lots of each food. The differences between these studies and our findings might be attributable to differences in product and food category selections. Nonetheless, the prior studies also represent convenience samples, and our study provides an important snapshot of the risks among foods with the highest rates of advisory labeling and uniquely includes evaluation of multiple foods and testing of products without advisory labeling. For consumers with food allergy, effective avoidance is confusing and requires enormous lifestyle upheaval. For industry, prevention of allergen contamination is costly and currently lacks scientific and government guidance. Our study underscores the need for allergic consumers to avoid advisory-labeled products, which present a small but real risk, and to have some concern for products without advisory labeling, particularly from small companies, especially within categories of higher-risk products. Additionally, our observation that most contamination is lowlevel provides an opportunity for industry and government to work together to further reduce contamination and begin formulating evidence-based guidelines on appropriate labeling to inform of risks. Lara S. Ford, MD, MPH Steve L. Taylor, PhD Robert Pacenza, BA Lynn M. Niemann Debra M. Lambrecht, BS Scott H. Sicherer, MD From the Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and Immunology, Department of Pediatrics, Mount Sinai School of Medicine, New York, NY; the Food Allergy Research and Resource Program, Department of Food Science and Technology, University of Nebraska, Lincoln, Neb; and the Food Allergy Initiative, New York, NY. E-mail: lara.ford@mssm.edu. Funding for this project was provided by the Food Allergy Initiative (FAI). Disclosure of potential conflict of interest: S. L. Taylor has received research support from the Food Allergy Research & Resource Program, a consortium of more than 50 food companies. R. Pacenza was, at the time of the study, Executive Director of the Food Allergy Initiative. S. H. Sicherer is a consultant for the Food Allergy Initiative and has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, the Food Allergy Initiative, and the Food Allergy & Anaphylaxis Network. The rest of the authors have declared that they have no conflict of interest.

Season of birth and food allergy in children

BACKGROUND The prevalence of food allergy is rising, and etiologic factors remain uncertain. Evidence implicates a role for vitamin D in the development of atopic diseases. Based on seasonal patterns of UV-B exposure (and consequent vitamin D status), we hypothesized that patients with food allergy are more often born in fall or winter. OBJECTIVE To investigate whether season of birth is associated with food allergy. METHODS We performed a multicenter medical record review of all patients presenting to 3 Boston emergency departments (EDs) for food-related acute allergic reactions between January 1, 2001, and December 31, 2006. Months of birth in patients with food allergy were compared with that of patients visiting the ED for reasons other than food allergy. RESULTS We studied 1002 patients with food allergy. Of younger children with food allergy (age < 5 years), but not older children or adults, 41% were born in spring or summer compared with 59% in fall or winter (P = .002). This approximately 40:60 ratio differed from birth season in children treated in the ED for non-food allergy reasons (P = .002). Children younger than 5 years born in fall or winter had a 53% higher odds of food allergy compared with controls. This finding was independent of the suspected triggering food and allergic comorbidities. CONCLUSIONS Food allergy is more common in Boston children born in the fall and winter seasons. We propose that these findings are mediated by seasonal differences in UV-B exposure. These results add support to the hypothesis that seasonal fluctuations in sunlight and perhaps vitamin D may be involved in the pathogenesis of food allergy.

Risk stratification for desensitization of patients with carboplatin hypersensitivity: Clinical presentation and management

BACKGROUND Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for desensitization is uncertain. OBJECTIVES To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin desensitization. METHODS Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 desensitizations to carboplatin. RESULTS Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR (<3 months), 20 of 24 (83%) tested positive, whereas 5 of 14 (36%) with remote HSR (>9 months) tested positive (P < .01). Nineteen carboplatin ST+ and 11 ST- patients underwent desensitization to carboplatin. Seven ST+ patients (37%) had mild HSR during desensitization but completed the desensitization with additional treatment or protocol modification. ST- patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST- with repeated testing. Six of 8 ST- patients (75%) with remote HSR reacted during desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST+ before the second desensitization. Carboplatin desensitization was successfully completed in 105 of 106 (99%) treatment courses. CONCLUSIONS The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent desensitization. Initial ST- patients with a remote history of HSR are at high risk for conversion to ST+ and can develop more severe HSR.