Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:First described in the mid 20th century, it was just in the last decade that diagnostic and treatment guidelines for food protein-induced enterocolitis syndrome (FPIES) were established. Awareness of the diagnosis is improving, and epidemiologic data are emerging. RECENT FINDINGS/RESULTS:Recent studies suggest that FPIES may affect as many as 0.5% of children worldwide. FPIES in adults is usually triggered by seafood and may be more common than previously thought. Many patients with FPIES have other allergic disorders. SUMMARY/CONCLUSIONS:With refined diagnostic criteria and improved awareness, FPIES is now diagnosed with increasing frequency, and epidemiologic data are emerging. FPIES appears to be increasing in prevalence, and the frequent association with other allergic disorders suggests a shared predisposition or immune mechanism that remains to be elucidated.

Rationale: Gut microbiota play an important role in food allergy. We previously showed that the natural compound berberine (BBR) reduces IgE and others have reported that BBR alters gut microbiota implying a potential role for microbiota changes in BBR function. We evaluated an orally available BBR-containing natural medicine (BCNM) for efficacy as food allergy treatment and explored whether treatment-induced changes in gut microbiota correlated with therapeutic outcomes Methods: C3H/HeJ mice were orally sensitized with peanut and cholera toxin. Allergic mice were orally treated with BCNM or its individual components. Allergic mice given no treatment and naive mice were controls. Mice received periodic post-therapy peanut exposures. Anaphylaxis was assessed by symptom visualization and measurement of body temperature. Histamine and serum peanut-specific IgE were measured by ELISA. IgE+B cells in spleen were assessed by flow cytometry. Fecal pellets were used for sequencing bacterial 16S rDNA by Illumina MISeq. Microbiota data were analyzed using microbiomeanalyst.ca.
Result(s): BCNM-treatment regimen induced long-term tolerance to peanut accompanied by profound and sustained reduction of IgE. Symptom scores, plasma histamine, body temperatures, IgE levels and number of IgE+ B cells (P<0.05-P<0.001 vs Sham). Significant differences were observed for Firmicutes/Bacteroidetes ratio across treatment groups (P<0.05-0.01). Bacterial genera positively correlated with post-challenge histamine and PN-IgE included Lachnospiraceae, Ruminococcaceae and Hydrogenanaerobacterium (R²= 0.82 to 0.36, P<0.05-0.0001) while Verrucromicrobiacea. Caproiciproducens, Enterobacteriaceae and Bacteroidales, were negatively correlated (R²= -0.73 to -0.43, P<0.05-0.0001)
Conclusion(s): BCNM is effective as food allergy treatment and its benefits are associated with a distinct microbiota signature.
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Rationale: Following completion of clinical trials for food allergy (FA) therapies, many patients/families wish to maintain desensitization. We describe the results of follow-up of participants transitioned to real food equivalents following epicutaneous (EPIT) and oral immunotherapy (OIT) clinical trials.
Method(s): Post-study participants were offered the option to transition to daily ingestion of real food equivalents based upon their OFC outcomes upon study completion. Charts of those who transitioned to ingestion of daily doses of real food equivalents from January 2016-May 2019 were reviewed. Participants 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 (milk and peanut EPIT; egg, wheat, and peanut OIT; multi-food OIT+omalizumab) underwent transition to ingestion of daily doses of real food equivalents for milk, baked/lightly-cooked egg, wheat, peanut, tree nuts, sesame, and/or shrimp; 35 patients had follow-up. Thirty-one patients continued dosing for at least one year or were confirmed to be actively dosing if transitioned in the past year, with 22 patients contacted in the prior 4 months confirmed to be actively dosing (median of 2.6 years). Five patients discontinued dosing after a median of 0.2 years, with reasons including dosing-related side effects (gastrointestinal, hives, wheezing; n=3), eosinophilic esophagitis (n=1), or unknown (n=1).
Conclusion(s): Most post-study participants (88.6%) who transitioned to real food equivalents continued dosing long-term. This suggests that transitioning to real food equivalents may be a desirable and sustainable option for patients/families wishing to maintain desensitization achieved during FA therapeutic studies.
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Rationale: Oral food challenges (OFC) are recommended for introducing peanut to infants at high risk of developing peanut allergy. We examined peanut-OFC safety, utility of pre-challenge risk assessment and rates of peanut tolerance at follow-up.
Method(s): his is a single-center, retrospective review of infant peanut-OFC per LEAP protocol performed between 01/2015-01/2019. Pre-challenge skin prick test (SPT) wheal size, serum whole and component peanut-sIgE were analyzed via area under the ROC curve (MedCalc Statistical Software).
Result(s): We analyzed 87 peanut-OFCs; 55.8% were male infants, median age at OFC 8 months (IQR 7-10). Indications for OFC were: eczema, egg allergy or both (n=71); sibling with food allergy (n=7); adverse reaction to peanut-containing food (n=6) or adverse reaction to other food (n=3). OFC outcome was negative in 70 (80.5%), positive in 17 (19.5%). Of those who reacted, 16 (94.1%) received oral antihistamine therapy alone; one (5.9%) received epinephrine. Post-OFC follow up was available in 45 who passed peanut-OFC. Of those, 35 (77.7%) consumed peanut regularly, whereas 10 (22.3%) avoided peanut, including 6 (13.3%) who reported allergic symptoms attributed to peanut. Arah2-sIgE testing outperformed whole peanut-sIgE and SPT in predicting positive challenge outcome by ROC analysis (cutoff >0.56 kU/L, AUC 0.78; p=0.003 vs. sIgE AUC 0.63; p=0.23 and SPT AUC 0.69; p=0.007).
Conclusion(s): Infant peanut-OFC and early introduction are safe in select patients. The majority of infants passing peanut-OFC continue to consume peanut, however a subset avoids peanuts due to potential mild allergic reactions at home. Arah2-sIgE testing has superior diagnostic capacity in our cohort.
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Rationale: Peanut OIT induces desensitization in peanut-allergic participants after 1-3 years of treatment; tolerance induction has not been evaluated in young children.
Method(s): A multi-center study was conducted in peanut-allergic children (ages 1-3 years), reactive to <500mg peanut protein during baseline double-blind, placebo-controlled food challenge (

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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