Julia Upton

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

Human actin-related protein 2/3 complex (Arp2/3), required for actin filament branching, has two ARPC1 component isoforms, with ARPC1B prominently expressed in blood cells. Here we show in a child with microthrombocytopenia, eosinophilia and inflammatory disease, a homozygous frameshift mutation in ARPC1B (p.Val91Trpfs*30). Platelet lysates reveal no ARPC1B protein and greatly reduced Arp2/3 complex. Missense ARPC1B mutations are identified in an unrelated patient with similar symptoms and ARPC1B deficiency. ARPC1B-deficient platelets are microthrombocytes similar to those seen in Wiskott–Aldrich syndrome that show aberrant spreading consistent with loss of Arp2/3 function. Knockout of ARPC1B in megakaryocytic cells results in decreased proplatelet formation, and as observed in platelets from patients, increased ARPC1A expression. Thus loss of ARPC1B produces a unique set of platelet abnormalities, and is associated with haematopoietic/immune symptoms affecting cell lineages where this isoform predominates. In agreement with recent experimental studies, our findings suggest that ARPC1 isoforms are not functionally interchangeable.

No systemic reactions to influenza vaccination in egg-sensitized tertiary-care pediatric patients

BackgroundThere are numerous, disparate guidelines for influenza vaccination in egg-allergic patients. We aimed to describe the outcome of selectively applied guidelines, based on risk-stratification, to our high risk, egg-allergic, tertiary-care pediatric population.MethodsEgg allergy was confirmed with skin testing. The vaccine administered was an adjuvunated 2009 H1N1 influenza A vaccine with < 0.165 mcg/ml ovalbumin. Patients with mild egg allergy were to receive the vaccination in 1 dose, those with severe egg allergy were to receive 2 split doses, and patients with exquisite egg allergy or significant co-morbidities were to be skin tested with the vaccine (prick full strength, intradermal 1:100 of final concentration without adjuvant) and had 5 step desensitization if the testing was positive, or 1-2 step administration if negative. Patients were observed for 60 minutes after the final dose and anaphylaxis treatment was available. We report the frequency of allergic reactions.ResultsNinety-nine patients were referred and 79 had positive egg testing. Asthma was present in 67% and 30% had prior anaphylaxis to egg. We vaccinated 77 of 79 patients: 71 without performing vaccine skin testing. Two refused vaccination. No patient had a systemic reaction or required treatment. Two patients experienced positive testing to the adjuvanated intradermal vaccine, but were negative without adjuvant.ConclusionsOur results suggest that most egg-allergic tertiary care pediatric patients can be vaccinated with a low ovalbumin content influenza vaccine without prior vaccine testing. Vaccine skin testing, if used at all, can be reserved for special circumstances. The squalene adjuvant may cause an irritant reaction with intradermal testing.

Anaphylaxis to Milk After Elimination Diet for Eosinophilic Gastrointestinal Disease

To the Editor: Eosinophilic gastrointestinal diseases (EGID), which include eosinophilic esophagitis (EoE), eosinophilic gastroenteritis, and eosinophilic colitis, have become increasingly recognized ( 1 ). Cow’s milk has been implicated as being a causative factor in EGID ( 1,2 ) and exclusion diets may be prescribed for all of these conditions ( 2 ). We describe a previously milk-tolerant child who developed anaphylaxis to cow’s milk aft er only a year of avoidance for EGID from age 6 to 7 years old. To the best of our knowledge, the description of anaphylactic allergy aft er avoidance for EGID is novel. Elimination diets for EGID can lead to anaphylactic allergy, even in school-aged children. A 6-year-old male with a history of asthma, atopic dermatitis, and food allergy developed recurrent vomiting. He had a clinical history of allergies to eggs, bananas, fi sh, shellfi sh, peanuts, tree nuts, and peaches confi rmed by positive skin prick tests (SPTs). However, he had always clearly tolerated dairy products and had a negative SPT to milk. He had consistently high eosinophil counts (>3.5×10 9 /l) and very high IgE levels (>8,000 IU). Endoscopy and biopsy showed features of EGID of the esophagus and stomach ( Figure 1 ). Aft er his diagnosis of EGID, an SPT was again negative for milk. He was started on an exclusive elemental formula diet. Foods were gradually reintroduced into his diet with strict milk elimination maintained for 1 year. At the age of 7 years, he consumed cheese and immediately developed urticaria, respiratory diffi culty, and vomiting treated with auto-injectable epinephrine. Aft er this event, SPTs and IgE to milk were strongly positive and corroborated the development of an IgE-mediated allergy to cow’s milk (24×14 mm wheal to milk extract, 30×15 mm wheal to fresh milk, 20×10 mm wheal to boiled milk, and IgE to milk >100 kU/l). At the last visit, he was 14 years old and continued to avoid all forms of milk. Food allergies are strongly associated with EoE as well as other EGID ( 1,2 ). Food elimination diets are helpful in 40–100% of patients ( 1,2 ). To mitigate the risk of reintroduction, the TIGERS consensus ( 2 ) recommends performing SPT and serum IgE CONFLICT OF INTEREST Financial support: None. Potential competing interests: None.

A child with autoimmune polyendocrinopathy candidiasis and ectodermal dysplasia treated with immunosuppression: a case report

IntroductionCommon features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia include candidiasis, hypoparathyroidism and hypoadrenalism. The initial manifestation of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may be autoimmune hepatitis, keratoconjunctivitis, frequent fever with or without a rash, chronic diarrhea, or different combinations of these with or without oral candidiasis.Case presentationWe discuss a profoundly affected 2.9-year-old Caucasian girl of Western European descent with a dramatic response to immunosuppression (initially azathioprine and oral steroids, and then subsequently mycophenolate mofetil monotherapy). At four years of follow-up, her response to mycophenolate mofetil is excellent.ConclusionThe clinical features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may continue for years before some of the more common components appear. In such cases, it may be life-saving to diagnose autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia and commence therapy with immunosuppressive agents. The response of our patient to immunosuppression with mycophenolate mofetil has been dramatic. It is possible that other patients with this condition might also benefit from immunosuppression.

Primum non nocere—first do no harm. And then feed peanut

The Addendum Guidelines for the Prevention of Peanut Allergy in the United States—Report of the NIAID-Sponsored Expert Panel were developed to build on previous food allergy guidelines after several key studies demonstrated the benefit of early introduction of allergenic foods. These landmark studies including the Learning Early about Peanut (LEAP), LEAP-On and Enquiring about Tolerance trials created a paradigm shift in food allergy prevention. The “take home” messages of this guideline include that peanut should be introduced early in the first year of life, and for the majority of infants, peanut can be introduced at home. The only group of infants for which medical assessment is recommended is those with severe eczema, egg allergy or both. Here we summarize the Guideline recommendations, endorsed by the Canadian Society of Allergy and Clinical Immunology, and highlight important aspects relevant to Canadian practitioners.

The Impact of Baked Egg and Baked Milk Diets on IgE- and Non-IgE-Mediated Allergy

Baked milk (BM) and baked egg (BE) diets are increasingly used in the management of milk and egg allergy, rather than avoidance. Children with tolerance versus reactivity to BM and BE may have smaller skin prick test and lower specific IgE, and BM-tolerant children have less basophil reactivity and more peripheral T regulatory cells. However, most milk- and egg-allergic children tolerate BM and BE and an individual’s reactivity is unpredictable. Non-reactivity is due to conformational changes in the allergens. Significant differences in the published advice about methods of introduction exist from graded introduction at home to a medically supervised full dose. These approaches carry different risks and may have different immunological effects. Reactivity to BM is a predictor of a severe milk allergy. Therefore, medical supervision for BM and BE introduction is prudent. The baked diet allows dietary liberation. Most, but not all, BM- and BE-tolerant children continue eating the baked foods. The prognosis of children who can eat BM and BE is favorable with likely resolution of their allergy over the next few years. Murine models of BE diets demonstrate that heated egg can impart clinical protection against anaphylaxis and cause immune changes. Most observational human studies of BM and BE diets demonstrate clinical resolution of allergy and favorable immune changes versus regular care controls. However, the one randomized controlled trial for the BE diet in BE-tolerant children did not support an immune-modifying effect of the BE diet. Another study of BE immunotherapy is expected to be completed in 2018. There is currently no evidence for prevention of allergy with the baked diets. There may be a future role for BM and BE in liberating the diets of individuals with non-IgE-mediated allergy given recent studies that a subset of these patients can consume BM without a clinical reaction.

Quality of life for parents of children with food allergy in peanut-restricted versus peanut-free schools in the United States and Canada

Peanut allergy policies and management have focused primarily on allergen avoidance and treatment because there is no cure for food allergies. Although there is no evidence of efficacy, schools have implemented peanut exclusion policies in an attempt to increase the safety of children with peanut allergy. Use of a validated Food Allergy Quality of Life Parental Burden (FAQL-PB) questionnaire revealed that social limitations consistently affect the quality of life (QOL) of caregivers of foodallergic children and increased social burden in the school setting. Because of the QOL concerns and increased risk of peanut exposure in peanut-containing schools, various avoidance strategies have been pursued, including separate lunch spaces for food-allergic students (peanut-restricted) and completely peanutfree campuses. The influence of school peanut restriction status on caregiver QOL is unknown. This study sought to explore the QOL of caregivers of peanut-allergic children in peanutrestricted versus peanut-free schools in the United States and Canada. This was a cross-sectional, anonymous online survey (SurveyMonkey) of parent-reported school peanut restriction status with the primary outcome as the FAQL-PB (17 questions) total score. Additional questions identified caregiver and child demographic characteristics as well as school environment (see Figure E1 in this article’s Online Repository at www.jaciinpractice.org). A survey link was distributed to Food Allergy Research & Education and Food Allergy Canada members via emailed newsletters for 6 weeks (August-September 2016). Each question was scored from 0 (not troubled) to 6 (extremely troubled), with lower cumulative score representing a higher QOL. Survey respondents were parent/guardians of a child younger than 18 years with peanut allergy who attended daycare/ school. Subjects with multiple food allergies were excluded. If there were multiple children with peanut allergy in a household, the caregiver chose 1 representative child. Demographic characteristics and FAQL-PB scores were summarized and compared with t test or Fisher exact test. Linear regression assessed the association between FAQL-PB scores and country/peanut restriction status. A multiple linear regression model controlled for potential confounders with and without an interaction term by country and peanut restriction status. Individual questions were analyzed to determine mean scores for country/peanut restriction status. The minimal clinically important difference was defined as 0.5. One thousand two hundred surveys were initiated with 148 excluded because the child was not in school, did not have a peanut allergy, or did not live in the United States/Canada. Nine-hundred sixty-six surveys were completed. Most respondents were from the United States and mothers (Table I). Seventy-seven percent of children attended peanut-restricted schools. Most respondents were white with incomes of

Early introduction without screening is a good deal, if caregivers will buy it

50,000 or more. Approximately 40% of children in peanut-free schools were in prekindergarten or kindergarten. Canadian students ate lunch in the classroom (68%) and US students in the cafeteria (43%) (P < .001). Supervision in the lunchroom/cafeteria was more often performed by school staff in the United States (78%) versus Canada (52%), where volunteers and other nonstaff personnel supervised (P < .001). Most children in both countries ate snacks in the classroom (64%) and were supervised by teachers (54%), but US children had snacks in the classroom/ lunchroom more often than Canadian children (P < .001). QOL was lower among US and Canadian caregivers with children in peanut-free compared with peanut-restricted schools (P 1⁄4 .037) with a 3.6 point higher total FAQL-PB score, corresponding to lower QOL. There was significant effect modification between country and peanut status (P 1⁄4 .029). The total survey score was 4.4 points higher among Canadian compared with US caregivers (P 1⁄4 .015) (Table I). Among those with children in peanut-free schools, the score was 8.14 points lower in the United States compared with Canada (P 1⁄4 .01), corresponding to better QOL. The score was 8.5 points higher among Canadian caregivers with children in peanut-free compared with peanut-restricted schools (P 1⁄4 .026), but no difference was seen in the United States (Figure 1, A). After adjusting for education (P < .0001), grade (P < .001), and race/ethnicity (P 1⁄4 .192), the interaction between country and peanut restriction maintained statistical significance (P 1⁄4 .016). Among those in peanutfree schools, the score was 7.03 points lower among US caregivers compared with Canadian caregivers (P 1⁄4 .035). Among Americans, the score was 5.6 points lower (P 1⁄4 .057) for caregivers in peanut-free schools compared with peanut-restricted schools (Figure 1, B). In Canada, scores for questions related to anxiety/sadness (P 1⁄4 .017 and .015, respectively) and burden regarding extra time spent in preparation of meals and precautions before leaving the home (P 1⁄4 .012), and troubled feelings when leaving the child in the care of others were higher among caregivers with children in peanut-free compared with peanut-restricted schools (P 1⁄4 .004). Peanut-free schools trended toward improved caregiver QOL in the United States (P 1⁄4 .057) and reduced QOL in Canada (P 1⁄4 .026). In both the adjusted and unadjusted results, the direction of the effect was opposite in Canada and the United

Potential Therapeutic Strategies for Severe Anaphylaxis Targeting Platelet-Activating Factor and PAF Acetylhydrolase

More than three years after the LEAP trial,1 the best way to implement early introduction (EI) of foods to infants at high-risk of food allergy (FA) is still a matter of debate. Given the cost of screening and limited healthcare resources, the perfect balance between fair resources allocation and optimal patient care can be elusive. Currently in Allergy, two cost-effectiveness studies comparing different approaches to promote EI of peanut2 or egg3 in infants at high risk of FA are published. The authors have considered a variety of clinical scenarios including no testing, testing with a reflex food challenge as well as delayed introduction due to positive testing and they have performed extensive sensitivity analyses considering realistic prevalence and cost ranges. Both studies provide compelling evidence that EI at home without prior screening is the most cost-effective approach to prevention. This article is protected by copyright. All rights reserved.

Primary immunodeficiencies associated with eosinophilia

Opinion statementCharacterization of mediators and mechanisms of anaphylaxis will allow for more specific and effective treatment with fewer side effects. Recent studies have shown that platelet-activating factor (PAF) is a pivotal mediator of the life-threatening manifestations of anaphylaxis. The putative role of PAF in human anaphylaxis is based on a large body of evidence in experimental and human anaphylaxis. In animal models of anaphylaxis, intravenous administration of PAF reproduces the severe physiologic derangements of anaphylaxis. PAF receptor knock-out mice are resistant to experimental anaphylaxis. Data from human anaphylaxis show that levels of PAF increase proportionately with the severity of anaphylaxis, whereas a deficiency in the enzyme that inactivates PAF predisposes to severe or fatal anaphylaxis. Many of the biologic effects of PAF appear to be transduced by nitric oxide production. PAF receptor antagonists protect against the lethal effects of exogenous PAF, but, importantly, also protect against experimental anaphylaxis following allergen challenge. Mice treated with an enzyme that inactivates PAF are similarly resistant to anaphylaxis. Some clinically available medications for anaphylaxis act at different points of the PAF pathway. Epinephrine, the first-line treatment for anaphylaxis, appears to act in part by phosphorylation and inactivation of the PAF receptor, whereas methylene blue, which reduces the actions of nitric oxide, can reverse severe anaphylaxis that is refractory to conventional treatment. Taken together, these studies have shown that therapies targeting the PAF pathway might hold the potential for more specific and effective treatments for this potentially life-threatening condition.