Andrew J. MacGinnitie

Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13

BACKGROUND Atopic dermatitis (AD) is characterized by local and systemic T(H)2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of T(H)2 cytokines has been suggested as therapy for AD. OBJECTIVES We sought to examine the effect of the absence of IL-4 and IL-13 on the T(H)17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD. METHODS Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined. RESULTS OVA-sensitized DKO mice exhibited impaired T(H)2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4(+) cells. DKO mice mounted exaggerated IL-17A but normal IFN-gamma and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major T(H)2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice. CONCLUSION Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated T(H)17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.

Omalizumab facilitates rapid oral desensitization for peanut allergy

Background: Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti‐IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions. Objective: We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients. Methods: Thirty‐seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1‐day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily. Results: The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab‐treated subjects versus 22.5 mg for placebo‐treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P < .01). Twenty‐three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000‐mg food challenge. Overall reaction rates were not significantly lower in omalizumab‐treated versus placebo‐treated subjects (odds ratio, 0.57; P = .15), although omalizumab‐treated subjects were exposed to much higher peanut doses. Conclusion: Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

Apolipoprotein B messenger Rna editing: insights into the molecular regulation of post-transcriptional cytidine deamination

A site-specific cytidine deamination (cytidine to uridine) in nuclear apolipoprotein B messenger RNA creates a translational stop codon that produces apolipoprotein B48. This process is mediated by an enzyme composed of distinct subunits, including apolipoprotein B messenger RNA editing enzyme catalytic polypeptide-1 and additional complementation factors. The apolipoprotein B messenger RNA editing enzyme catalytic polypeptide-1 is expressed ubiquitously in the rat, but is largely confined to the small intestine in humans and rabbits. By contrast, complementation activity is present in tissues that neither express nor edit apolipoprotein B messenger RNA.

Clinical characteristics of pediatric patients evaluated for primary immunodeficiency

To cite this article: MacGinnitie A, Aloi F, Mishra S. Clinical characteristics of pediatric patients evaluated for primary immunodeficiency. Pediatric Allergy Immunology 2011; 22: 671–675.

Pediatric hereditary angioedema

Hereditary angioedema (HAE) is a lifelong illness characterized by recurrent swelling of the skin, intestinal tract, and, ominously, the upper airway. It is caused by inadequate activity of the protein C1‐inhibitor, with dysfunction in the kallikrein/bradykinin pathway underlying the clinical symptoms. In addition to the physical symptoms, patients experience significant decrements in vocational and school achievement as well as in overall quality of life. Symptoms often begin in childhood and occur by age 20 in most patients, but life‐threatening attacks are uncommon in the pediatric population. The availability of new therapies has transformed the management of HAE.

Use of Ecallantide in Pediatric Hereditary Angioedema

OBJECTIVE: Hereditary angioedema (HAE) due to C1-inhbitor 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.

Outcomes after ecallantide treatment of laryngeal hereditary angioedema attacks

BACKGROUND Hereditary angioedema (HAE) is a rare disorder associated with episodic attacks of well-demarcated angioedema. Attacks that affect the larynx can result in life-threatening airway obstruction. OBJECTIVES To examine efficacy and safety of ecallantide treatment for laryngeal HAE attacks. METHODS Data were combined from 4 clinical studies (EDEMA2, EDEMA3, EDEMA4, and DX-88/19) evaluating 30 mg of subcutaneous ecallantide for treatment of acute HAE attacks. Efficacy was assessed using 2 validated, HAE-specific, patient-reported outcome measures. The change in Mean Symptom Complex Severity (MSCS) score indicates change in symptom severity; a negative score indicates improvement. The calculated minimally important difference (MID) for change in severity is -0.30. The Treatment Outcome Score (TOS) measures treatment response. A positive score indicates improvement; the calculated MID is 30. RESULTS Overall, 98 patients received ecallantide for 220 laryngeal attacks. The mean ± SD change in MSCS score was -1.1 ± 0.73 and -1.6 ± 0.68 at 4 and 24 hours, respectively. The mean ± SD TOS was 73.5 ± 35.8 and 85.5 ± 27.8 at 4 and 24 hours, respectively. Median time to significant improvement was 185 minutes (95% confidence interval, 167-226). One attack required intubation. Four treatment-emergent serious adverse events were reported, including 2 HAE attacks that resulted in hospitalization and 2 anaphylactic reactions. One of these reactions required treatment with epinephrine, but both patients recovered fully. There were no deaths. CONCLUSION In this large attack series, ecallantide was effective for treatment of laryngeal HAE attacks. There is a risk of hypersensitivity, including anaphylaxis, consistent with product labeling. As such, ecallantide should be administered under the supervision of a health care professional. TRIAL REGISTRATION clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before implementation of registration requirements); NCT00262080 for EDEMA3, NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.

Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial

BACKGROUND Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by regulatory agencies. OBJECTIVE We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product. METHODS A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms. RESULTS Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs. CONCLUSIONS In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults.

Indoor allergen sensitization and the risk of asthma and eczema in children in Pittsburgh.

Several studies have shown that sensitization to cockroach and mouse allergens is correlated with presence and severity of asthma, especially among children living in inner cities. This study evaluated the prevalence of positive skin testing to indoor allergens in the Pittsburgh area and the association with asthma and eczema. A retrospective analysis was performed of 540 children from the Pittsburgh area who underwent skin testing to indoor allergens. Presence of asthma and eczema were determined by parent and/or physician report. Asthma and eczema are not significantly more frequent among children who had positive skin testing to cockroaches or mice. However, asthma was more common among children who had positive skin testing to dogs (odds ratio [OR], 1.4; 95% CI, 1.23-1.65), cats (OR, 1.4; 95% CI, 1.21-1.58), and dust mites (OR, 1.2; 95% CI, 1.03-1.37). Eczema was more common in children who had positive skin testing to cats (OR, 1.5; 95% CI, 1.14-2.02). Both asthma (OR, 1.4; 95% CI, 1.18-1.58) and eczema (OR, 1.4; 95% CI, 1.07-1.92) were more prevalent among children with any positive skin test. We did not find that sensitization to cockroaches or mice was correlated with the diagnosis or asthma or eczema in the Pittsburgh area. However, sensitization to any allergen, and to cats and/or dogs specifically, was associated with diagnosis of both asthma and eczema. Our result suggests that allergic sensitization is associated with these diseases, but the implicated allergens may vary.

Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of potentially life-threatening edema. The plasma kallikrein inhibitor ecallantide is approved for treatment of acute HAE attacks. This study evaluates the efficacy and safety of ecallantide for treatment of multiple HAE episodes in the DX-88/19 (continuation) study. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on number of episodes treated. Primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Additional end points included change in MSCS score at 24 hours, treatment outcome score (TOS) at 4 and 24 hours, and time to response. Safety parameters included adverse events. Statistical analyses were conducted on qualifying treatment episodes (those with ≥12 patients). One hundred forty-seven patients received treatment for 625 episodes; analyses were conducted through 13 treatment episodes. Across 13 episodes at 4 hours, mean change in MSCS score ranged from -1.04 to -1.36, and mean TOSs ranged from 56.2 to 79.8. Median time to onset of sustained improvement ranged from 59 to 113 minutes. There was no indication of reduced efficacy with repeated ecallantide use. No new safety signals were detected. Eight patients (5.4%) reported potential hypersensitivity reactions, six of whom met the definition of anaphylaxis based on National Institute of Allergy and Infectious Diseases criteria. Ecallantide is effective for acute recurrent HAE attacks and maintains its efficacy and safety during multiple treatment episodes in patients with HAE. Potential hypersensitivity reactions were consistent with prior reports.