Faculty Bibliography

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/CONCLUSIONS: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.

OBJECTIVE:Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare autosomal dominant disease that manifests as sudden unpredictable attacks of subcutaneous or submucosal edema affecting the skin, intestine, and upper airway. Ecallantide is a plasma kallikrein inhibitor indicated for treatment of HAE attacks in patients aged 16 years and older. This analysis examines safety and efficacy of ecallantide for treatment of HAE attacks in patients <18 years of age. METHODS:Data for patients aged 9 to 17 years treated subcutaneously with 30 mg ecallantide or placebo were pooled from 4 clinical studies (2 double-blind, placebo-controlled and 2 open-label). Efficacy end points included 2 HAE-specific patient-reported outcome measures: mean symptom complex severity (MSCS) score and treatment outcome score (TOS). Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated. Treatment-emergent adverse events were examined. RESULTS:Overall, 29 pediatric patients were included; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks. Ecallantide-treated attacks revealed clinically relevant reduction in symptom severity at 4 hours postdosing based on mean change in MSCS score (-1.4 ± 0.9 ecallantide versus -0.9 ± 0.6 placebo) and TOS (73.9 ± 35.50 ecallantide versus 45.0 ± 43.78 placebo). Patients treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes). No serious adverse events related to treatment were observed. CONCLUSIONS:Ecallantide appears effective for HAE attacks in adolescents, with rapid symptom improvement. No unexpected safety issues were identified.

OBJECTIVES/OBJECTIVE:To evaluate the use of Cinryze (nanofiltered C1-esterase inhibitor [C1 INH-nf]) for the acute management and prevention of hereditary angioedema attacks in the subgroup of children and adolescents who participated in 2 placebo-controlled and 2 open-label extension studies. STUDY DESIGN/METHODS:In the acute-attack treatment studies, the efficacy of 1000 U of C1 INH-nf (with an additional 1000 U given 1 hour later if needed) was assessed based on the time to the start of symptomatic relief and the proportion of patients experiencing relief within 4 hours of therapy. In the prophylaxis studies, C1 INH-nf 1000 U was given twice weekly, and efficacy was based on the frequency of attacks. RESULTS:Across 4 studies, 46 children received a total of 2237 C1 INH-nf infusions. The median time to the start of unequivocal relief in the acute-attack treatment study (n = 12) was 30 minutes with C1 INH-nf, compared with 2 hours for placebo. In the open-label extension (n = 22), clinical relief began within 4 hours of therapy in 89% of attacks. In the prophylaxis study (n = 4), the number of attacks was reduced by approximately 2-fold with C1 INH-nf compared with placebo. In the prophylaxis open-label extension (n = 23), the median monthly attack rate decreased from 3.0 before treatment to 0.39 with C1 INH-nf use. CONCLUSION/CONCLUSIONS:In children, C1 INH-nf was well tolerated, provided relief from symptoms of hereditary angioedema attacks, and reduced the rate of attacks.

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare, autosomal-dominant disease. HAE-C1-INH is characterized by recurrent attacks of marked, diffuse, nonpitting and nonpruritic skin swellings, painful abdominal attacks, and laryngeal edema. The extremities and the gastrointestinal tract are most commonly affected. Swelling of the upper respiratory mucosa poses the greatest risk because death from asphyxiation can result from laryngealedema. HAE-C1-INH attacks are variable, unpredictable, and may be induced by a variety of stimuli, including stress or physical trauma. Because the clinical presentation of HAE-C1-INH is similar to other types of angioedema, the condition may be a challenge to diagnose. Accurate identification of HAE-C1-INH is critical in order to avoid asphyxiation by laryngeal edema and to improve the burden of disease. Based on an understanding of the underlying pathophysiology of IHAE-C1-INH, drugs targeted specifically to the disease, such as C1-inhibitor therapy, bradykinin B2-receptor antagonists, and kallikrein-inhibitors, have become available for both treatment and prevention of angioedema attacks. This article reviews the clinical features, differential diagnosis, and current approaches to management of HAE-C1-INH.

BACKGROUND:Although the identification and management of anaphylaxis in an emergency department setting has been well studied, our understanding of the risk factors for admission in a community-based hospital is lacking. OBJECTIVE:To determine the demographics and the predictors of hospitalization, in patients presenting with anaphylaxis to a community-based emergency department (ED). METHODS:We performed a five-year retrospective chart review of all patients seen in the ED of Winthrop University Hospital, a community-based institution, with an International Classification of Diseases, 9(th)Edition code related to anaphylaxis. RESULTS:Fifty-eight visits met inclusion criteria, of which 34% resulted in hospital admission (95% CI: 22-48%). Univariate predictors for admission included (1) the involvement of 2, 3, and 4 organ systems (26%, 55%, and 75%, respectively; P < .02); (2) gastrointestinal symptoms vs no symptoms (59% vs 24%, P < .02); (3) non-sting (ingested and other allergens) vs insect sting allergen (50% vs 12.5%, P < .005); and (4) a history of an ED visit for anaphylaxis vs none (67% vs 30%, P < .05). Multivariate analysis (logistic regression) confirmed non-sting allergens (p < 0.02) and number of organ systems involved (P < .05) as independent predictors of hospitalization. CONCLUSION/CONCLUSIONS:In our study population, the involvement of multiple organ systems, particularly gastrointestinal involvement, a history of ED visits for anaphylaxis, and involvement of ingested or other allergens (non-sting) demonstrated higher admission rates.

Hereditary angioedema (HAE) results from mutations in the C1-esterase inhibitor (C1 INH) gene that decrease production of C1 INH or render it dysfunctional. HAE is characterized by recurrent, unpredictable, bradykinin-mediated edema of the extremities, face, genitalia, trunk, gastrointestinal tract, or upper airway. Attacks causing laryngeal edema can be fatal. Patients with HAE need medications for acute attacks; some also require prophylaxis. Management requires consideration of the patient's disease burden and effect on the patient's quality of life. This review examines an individualized approach to identifying HAE patients who may benefit from prophylaxis. A literature search was performed for HAE and prophylaxis. HAE guidelines, case reports, safety studies, and randomized, controlled clinical prophylaxis trials were selected. Authors provided cases demonstrating individualized prophylaxis. U.S. Food and Drug Administration-approved options for prophylaxis of HAE include attenuated androgens and nanofiltered C1 INH (C1 INH-nf). In other countries, pasteurized C1 INH and purified C1 INH are also available. Alternative therapies include fresh frozen plasma for preprocedural prophylaxis and antifibrinolytics for long-term prophylaxis. Attenuated androgens reduce attack frequency in many patients. Adverse effects include weight gain, virilization, increased hair growth, hypercholesterolemia, depression, and liver adenomas. C1 INH-nf reduces frequency of attacks and is well tolerated. Each patient with HAE has unique needs, based on the nature and frequency of past attacks, proximity to a medical center, occupation, and the patient's wishes. These factors should be used to create a patient-centered approach to management of HAE.

BACKGROUND:Studies assessing patch testing (PT) in allergy practices are limited. OBJECTIVES/OBJECTIVE:To determine whether PT results using a limited panel of allergens such as in the Thin-Layer Rapid-Use Epicutaneous Test (TT) as compared with an expanded panel, such as the addition of supplemental allergens (North American Contact Dermatitis [NACD] Panel, Dormer Cosmetics, hairdressing series, corticosteroid series, and personal products) will miss a significant number of positive PTs. To compare our PT results with published data from dermatology practices. METHODS:This is a 5-year multicenter retrospective chart review of PT at 3 separate allergy practices. RESULTS:Four hundred twenty-seven patients (mean age, 49.8 years) were patch tested. Eighty-two percent were female; 54% reported an atopic history. Of the standardized allergens, the 5 most common positives were nickel sulfate, fragrance mix I, p-phenylenediamine (PPD), thimerosal, and cobalt chloride. Two hundred eighteen (56.9%; 95% CI = 51.9-61.8%) patients were positive to at least 1 TT allergen. Ninety-eight (25.6%; 95% CI = 21.5-30.2%) patients were positive to both a TT and a supplemental allergen. Forty-eight (12.5%; 95% CI = 9.6-16.2%) patients were negative to a TT allergen but positive to a supplemental allergen. CONCLUSION/CONCLUSIONS:Positive allergens would have been missed in 12.5% of patients when evaluating with TT allergens alone, whereas 25.6% would be partially evaluated. Patch test performance characteristics for these allergy practices appear to parallel that seen for dermatology. The TT remains an adequate screening tool in an allergy practice, but a more comprehensive panel may be needed to fully evaluate contact dermatitis.

Urticaria and angioedema are common disorders that can severely impair the quality of a patient's life and can be extremely difficult to treat. Symptoms can persist for years to decades. The causes of urticaria and angioedema are varied and may be immunologic, nonimmunologic, or idiopathic. This article reviews the literature and provides primary care physicians with up-to-date information of the epidemiology, basic pathophysiology, diagnosis, and management of this common and often debilitating condition. Additionally, clinical manifestations of acute and chronic urticaria, hereditary and acquired angioedema, as well as the physical urticarias will be discussed.

Induction of tolerance protocols have been applied successfully to manage allergic reactions to many medications. Hypersensitivity reactions to natalizumab (TYSABRI®) have been recognized as a growing problem. In circumstances where a hypersensitivity reaction to a medication has occurred, but no suitable alternative exists, drug induction of tolerance protocols may be considered. Drug induction of tolerance protocols were performed in three patients with prior hypersensitivity reactions to natalizumab. All three patients tolerated the protocol without adverse reactions, allowing for the safe reintroduction of natalizumab. To conclude, this case series demonstrates success with an induction of tolerance procedure to a highly effective biological agent for multiple sclerosis, in patients with allergic reactions to natalizumab.