Faculty Bibliography

Rationale: Pathophysiology of non-IgE-mediated gastrointestinal food hypersensitivity, including food protein-induced enterocolitis syndrome (FPIES) remains poorly understood. Increased TNF-alpha and IL-8 have been detected in FPIES reactions. We sought to determine the effect of natural plant-derived products E-B-FAHF-2 (ethyl acetate and butanol purified food allergy herbal formula-2) and 7,4'-Dihydroxyflavone (DHF) on TNF-alpha and IL-8 production, respectively using in vitro cell lines.
Method(s): RAW 264.7 mouse macrophage cells that produce TNF-alpha were treated with E-B-FAHF-2 ranging 0-120 mug/mL and stimulated with lipopolysaccharides (LPS,1 mug/mL). Human epithelial cell line, CACO2 that produces IL-8 was treated with DHF (0-40 mug/mL) for 24 hours followed by IL1-beta (10 ng/ml) stimulation for 24 hours. TNF-alpha and IL-8 levels in supernatants were measured by ELISA. Cytotoxic effect was evaluated by trypan blue exclusion or MTT assay. Quality control of compounds was monitored by HPLC.
Result(s): E-B-FAHF-2 treatment significantly reduced TNF-alpha levels in a dose-dependent manner in RAW 264.7 cells (p<0.001 vs vehicle). It essentially eliminated TNF-alpha production at a dose of 120 mug/ml. No cytotoxicity was observed at any tested doses. DHF treatment significantly reduced IL-8 production by CACO2 cells (p<0.001 vs vehicle) without cytotoxicity at any tested doses. These effects were associated with reduction of phosphorylated IkappaBalpha.
Conclusion(s): E-B-FAHF-2 and DHF either alone or in combination may be a potential intervention for non-IgE mediated food hypersensitivity. Studies on inhibitory effects of cross-treatment or combined treatment of E-B-FAHF2 and DHF in RAW 264.7 and CACO2 cells on TNF-alpha and IL-8 are underway.
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Rationale: Clinical trials for food allergy (FA) often end with participants not able to ingest the targeted food(s) ad lib. We describe an approach to transition food-allergic post-study participants from study doses to daily ingestion of real food equivalents.
Method(s): Post-study participants were offered transition to real food equivalents, if possible. Starting dose was determined based on the study dose/eliciting dose during exit OFC and confirmed by observed feeding. The daily amounts could be as low as a teaspoon fraction of undiluted food. Patients were also offered supervised interval dose-escalations. Patients evaluated from January 2016-May 2019 were identified, and charts were reviewed. Families without recent follow-up were contacted by telephone. This study was IRB approved.
Result(s): Thirty-seven patients (65% male; median age 8.8 years, range 4-24 years) from 8 studies (epicutaneous milk and peanut; egg, wheat, and peanut oral immunotherapy (OIT); multi-food OIT+omalizumab) underwent transition to real food equivalents for milk, baked/lightly-cooked egg, wheat, peanut, tree nuts, sesame, and/or shrimp. Eighteen patients dose-escalated over a median 1-year period for milk, wheat, peanut, almond, and shrimp; nineteen attended just one dosing visit. Four patients achieved doses at/near meal-sized servings of milk, wheat, or baked egg; the others consumed low-dose quantities.
Conclusion(s): Thirty-seven post-study participants transitioned to daily ingestion of real food equivalents for a variety of foods, with half continuing low-dose and others dose-escalating to as much as meal-sized amounts. Transitioning to real food equivalents after FA therapeutic clinical trial may be a desirable option for patients/families and can be customized to individual goals.
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Rationale: The Peanut Allergy Burden Study (PABS) assessed the real-world burden of peanut allergy (PA) on patients and caregivers in the United States.
Method(s): Adolescents 13-17-years-old with self-reported, provider-diagnosed PA participated in the PABS online survey. Medical and treatment history and the validated Pediatric Quality of Life Inventory PedsQL (scores 0-100, higher is better) were collected. Between-group analyses were conducted (chi square; t-test).
Result(s): Adolescents with PA (n=102) completed PABS; mean+/-SD age was 14.7+/-1.4 years, 55.9% were male, 62.8% were white. The mean PedsQL Total score was 48.8; mean subscale scores were: Physical (53.6), Emotional (43.0), Social (48.2), School (46.0), and Psychosocial (44.5). These scores were significantly below the scale scores from a general population of 8-16-year-olds (n>5900; range: 78.2-87.0) and exceeded the minimum clinically important difference (4.36-9.12 points). Adolescents experiencing >=1 PA-related reaction in the past year had significantly lower PedsQL Total score (p=0.008), as did those receiving clinician intervention for >=1 PA reaction in the past year (p<0.001), those "not at all" to "somewhat satisfied" with current approaches to PA reaction prevention (p=0.012), those saying PA limited their day-to-day life "somewhat" to "completely" (p=0.013), or who reported a "great" to "100% chance" of not effectively dealing with a reaction (p<0.001).
Conclusion(s): Adolescents with PA have substantially lower PedsQL scores than the general population of similarly aged individuals. PedsQL Total scores were significantly different between subgroups defined by recent allergic reaction/need for clinician intervention, satisfaction with reaction prevention, perceived limitations on day-to-day life, and concern about their ability to deal with a reaction.
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Rationale: Eczema is a chronic inflammatory skin disorder. We sought to evaluate efficacy and safety of TCM in humans and animal model of eczema.
Method(s): We retrospectively analyzed data of 28 patients with moderate-to-severe eczema who received TCM for at least 3 months in three cohorts based on eczema phenotype/endotype. Cohort #1 (n=10), ages 6 to 48 months, used topical steroids for at least 3 months prior to TCM with inadequate response. Cohort #2 (n=8), ages 2-40 years, had worsening eczema associated with sudden topical steroid withdrawal (TSW, n=8) at least 3 months prior to TCM. Cohort #3 had a very high total IgE (>5,000 kIU/L, n=10), ages 1-13 years. The TCM regimen included external herbal bath, cream, and oral tea. We also tested the TCM effects in a mouse model of eczema treated daily for 9 days.
Result(s): Following TCM treatment, cohort #1 showed reduced SCORAD and steroid use as early as one month (p<0.001) and close to zero by 6 months. Cohort #2 showed improved SCORAD (73.6%, p<0.001), and markedly decreased sleep disturbance (80%, p<0.001) as early as one month. Cohort #3 had markedly reduced total IgE from median 12,328 to 3,994 kIU/L after 6-24 months. TCM significantly reduced elevated blood eosinophils (p<0.05). No liver or kidney function abnormality was observed. Animal model of eczema showed distinctly reduced SCORAD, scratching scores, and skin eosinophil counts. TCM tea also showed dose dependent reduction of IgE, TNF-alpha and exotoxin production in vitro.
Conclusion(s): TCM is efficacious and safe in children and adults with steroid dependent-eczema.
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Rationale: With peanut allergy therapies under development, peanut-allergic children are completing clinical trials wishing to maintain desensitization. We describe our experience transitioning children to real food equivalents of peanut following trial completion.
Method(s): Children who completed peanut clinical trials with interest in continuing (post-oral immunotherapy [OIT]) or starting (post-epicutaneous immunotherapy [EPIT]) daily peanut ingestion were offered an oral food challenge (OFC) for the starting dose, which was determined based on study dose/eliciting dose during exit OFC. Dose-escalation to 2000 mg peanut protein was offered. The charts of post-study participants transitioned to daily peanut ingestion from May 2016-May 2019 were reviewed. Families without recent follow-up were contacted by telephone. This study was IRB approved.
Result(s): Twenty children (80% male; median age 7.6 years, range 4-15 years; n=5 post-EPIT, n=15 post-OIT) were transitioned to daily peanut ingestion. The median starting dose was 300 mg (post-EPIT: 100 mg [range 30-300 mg]; post-OIT: 400 mg [range 30-2000 mg]). Four participants started at 2000 mg; 11/16 dose-escalated. Thirteen participants reached a daily dose >1000 mg. Median follow-up was 1.7 years. Seventeen participants (85%) continued dosing for at least one year or were confirmed to currently actively dose if transitioned in the past year. Two participants discontinued due to side effects (gastrointestinal, hives, wheezing); one was lost to follow-up.
Conclusion(s): Most post-study children transitioned to daily peanut reached a maintenance dose of >1000 mg and continued dosing long-term with real food equivalents. This suggests that families are motivated to follow-through with daily peanut to maintain desensitization after study completion.
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It is well-established that food proteins, such as egg, soya, cow's milk and wheat, are detectable in breastmilk for many hours or days after ingestion. Exposure to these proteins is important to the process of developing tolerance but can also sometimes elicit IgE-mediated and non-IgE-mediated allergic symptoms in breastfed infants. Non-IgE-mediated allergy, outside of food protein-induced allergic proctocolitis and eosinophilic oesophagitis, is not well understood, leading to variations in the diagnosis and management thereof. A primary objective of the European Academy for Allergy and Clinical Immunology is to support breastfeeding in all infants, including those with food allergies. A Task Force was established, to explore the clinical spectrum of non-IgE-mediated allergies, and part of its objectives was to establish diagnosis and management of non-IgE-mediated allergies in breastfed infants. Eight questions were formulated using the Patient, Intervention, Comparison, Outcome (PICO) system and Scottish Intercollegiate Guideline Network (SIGN) criteria for data inclusion, and consensus was achieved on practice points through the Delphi method. This publication aims to provide a comprehensive overview on this topic with practice points for healthcare professionals.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that manifests with projectile, repetitive emesis that can be followed by diarrhea and may be accompanied by lethargy, hypotonia, hypothermia, hypotension, and metabolic derangements. FPIES usually starts in infancy although onset at older ages is being increasingly recognized. FPIES is not rare, with the cumulative incidence of FPIES in infants estimated to be 0.015% to 0.7%, whereas the population prevalence in the US infants was 0.51%. FPIES diagnosis is challenging and might be missed because of later (1-4 hours) onset of symptoms after food ingestion, lack of typical allergic skin and respiratory symptoms, and food triggers that are perceived to be hypoallergenic. Diagnosis is based on the recognition of symptoms because there are no biomarkers of FPIES. The pathophysiology remains obscure although activation of the innate immune compartment has been detected. Management relies of avoidance of food triggers, treatment of accidental exposures, and periodic re-evaluations with supervised oral food challenges to monitor for resolution. There are no strategies to accelerate development of tolerance in FPIES. Here we review the most important current concepts in epidemiology, pathophysiology, diagnosis, and management of FPIES.

Oral food challenges are an integral part of an allergist's practice and are used to evaluate the presence or absence of allergic reactivity to foods. A work group within the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology was formed to update a previously published oral food challenge report. The intention of this document was to supplement the previous publication with additional focus on safety, treatment of IgE-mediated allergic reactions, guidance for challenges in infants and adults, psychosocial considerations for children and families participating in an oral food challenge, specific guidance for baked milk or baked egg challenges, masking agents and validated blinding recipes for common food allergens, and recommendations for conducting and interpreting challenges in patients with suspected food protein-induced enterocolitis syndrome. Tables and figures within the report and an extensive online appendix detail age-specific portion sizes, appropriate timing for antihistamine discontinuation, serum and skin test result interpretation, written consents, and instructional handouts that may be used in clinical practice.