Faculty Bibliography

Few patients with food allergy are "highly allergic," meaning they always have severe reactions and always react to very small amounts of allergen. Standard medical approaches for allergy management have focused on the safety and lifestyle modifications this group truly needs, but consequently families with food allergy are typically advised to strictly avoid any exposure to their implicated allergens. Most food-allergic subjects are actually not reactive to very low doses, and many never experience severe reactions. There are also notable conditions where a different care plan is already commonly offered: patients with pollen-related food allergy syndrome, with food-associated exercise-induced anaphylaxis, and with resolving or mild milk or egg allergy might be advised to ingest the allergens in specific circumstances with detailed instructions. Because oral immunotherapy and allergy prevention by early exposure have emphasized alternatives to strict avoidance, there is increasing interest in prospects to forego strict avoidance in those with food allergy. For patients with a high threshold of reactivity (low-dose tolerant, high-dose mildly reactive), there may be options such as allowing the ingestion of products with precautionary allergen labels, allowing dietary indiscretions with small amounts of the allergen, or even encouraging ingestion of subthreshold amounts with therapeutic intent. These practices have not been extensively studied and could be considered controversial. If these approaches are considered, shared decision making is needed in discussing them with patients and families. This review considers the potential approaches to those who are "not highly allergic": the risks, benefits, shared decision making, and research needs.

BACKGROUND/UNASSIGNED:Chronic food protein-induced enterocolitis syndrome (FPIES) is a cell-mediated gastrointestinal food hypersensitivity described almost exclusively in infants fed cow's milk or soy formula. A timely diagnosis is challenging due to a number of factors, including broad differential diagnoses, absence of specific biomarkers, and delayed symptom onset. OBJECTIVE/UNASSIGNED:This report aimed to highlight how the severity of presentation can further impede a timely diagnosis in chronic FPIES. Methods: A case of presumed chronic FPIES to soy with previously unreported complications of intracranial hemorrhage and cerebral venous sinus thrombosis was described. RESULTS/UNASSIGNED:We reported a case of a female infant fed a soy formula who presented during the third week of life with intermittent and progressive emesis, diarrhea, and lethargy, which culminated in severe dehydration, with early hospital course complications of seizures, intracranial hemorrhage, and cerebral venous sinus thrombosis. Although not recognized until weeks into the hospital course, many of the presenting symptoms and laboratory abnormalities were characteristic of chronic FPIES. An ultimate consideration of FPIES led to transition to amino acid-based formula and gradual resolution of gastrointestinal symptoms. Close outpatient follow-up was essential in facilitating subsequent age-appropriate solid food introduction. CONCLUSION/UNASSIGNED:The severity of presentation in FPIES can represent an additional barrier to a timely diagnosis. Early consideration of this entity in the differential diagnosis of patients with typical FPIES features, regardless of the additional presence of atypical and severe complications, may help with more timely recognition and intervention. In addition, there is an increased need for close follow-up as an outpatient in severe FPIES cases.

BACKGROUND:Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy diagnosed via history and/or an oral food challenge (OFC). OBJECTIVE:To determine allergists' approach to FPIES OFCs. METHODS:A web-based survey was e-mailed to 1100 randomly selected American Academy of Allergy, Asthma and Immunology members. RESULTS:A total of 132 individuals responded (12% response rate). A total of 95.5% (n = 105) of respondents perform OFCs in their practice, but only 58.7% (n = 71) perform FPIES OFCs. The median number of FPIES OFCs in children was reported as 3 per year (range, 0-76); all but 1 respondent (2.5%) had not performed any FPIES OFCs in adults. The most common FPIES OFC foods were cow's milk, rice, lightly cooked egg, oat, soy, baked milk, and baked egg. The decision to offer FPIES OFCs was based on the severity of past reactions, the patient and family's desire, and the patient's age. FPIES OFCs were most commonly performed in an outpatient setting, with placement of peripheral intravenous access depending on the severity of past reactions and with a serving appropriate for age divided into 3 equal portions administered over 30 minutes. There was significant variability in the approach to conducting FPIES OFCs. Most respondents (87.4%, n = 127) indicated that specific guidelines for performing FPIES OFCs would be helpful. CONCLUSIONS:Our study highlights the discordance in allergists' practices performing OFCs for IgE-mediated food allergy compared with FPIES. The lack of universal agreement on the optimal way to perform OFCs in FPIES demonstrates the need for future studies to develop a standardized protocol for FPIES OFCs.

RATIONALE/BACKGROUND:We recently showed that multicomponent traditional Chinese medicine (TCM) therapy had steroid-sparing effects in moderate-to-severe eczema. We sought to evaluate TCM effects in severe eczema in a 7-year-old male with refractory disease and corticosteroid withdrawal syndrome. METHODS:Prior to referral, the patient had been treated since infancy with increasingly intensive standard of care, including high-dose topical and systemic corticosteroid and antibiotic therapy and was unable to tolerate further steroid treatment. The patient was administered a combination of oral and topical TCM for 17 months following discontinuation of his steroid regimen. His overall medical condition was assessed by SCORAD criteria and laboratory evaluations of serum IgE, absolute eosinophil count, and liver and kidney function tests. RESULTS:The patient showed rapid improvement of clinical measures of disease after starting TCM therapy, with marked improvement of sleep quality within the first week, complete resolution of itching, oozing, and erythema at 2 weeks, and a 79% and 99% decrease in his SCORAD values after one month and 3-6 months of TCM, respectively. Serum total IgE decreased by 75% (from 19,000 to 4630 (kIU/L), and absolute eosinophil counts decreased by 60% (from 1000 to 427 cells/μL) after 12 months of treatment. The patient did not require oral or topical steroids during the 17-month trial of TCM. TCM was tapered without complications. His dermatologic manifestations continued to be well-controlled 3 months after discontinuation. CONCLUSION/CONCLUSIONS:This case study suggests TCM should be further evaluated in controlled clinical studies of patients with severe, refractory eczema and steroid withdrawal syndrome.

Eczema is a complex chronic inflammatory skin disease impacted by environmental factors, infections, immune disorders, and deficiencies in skin barrier function. Shi Zhen Tea (SZT), derived from traditional Chinese medicine Xiao-Feng-San, has shown to be an effective integrative therapy for treating skin lesions, itching, and sleeping loss, and it facilitates reduction of topical steroid and antihistamine use in pediatric and adult patients with severe eczema. Yet, its active compounds and therapeutic mechanisms have not been elucidated. In this study, we sought to investigate the active compounds and molecular mechanisms of SZT in treating eczema using systems pharmacology and in silico docking analysis. SZT is composed of 4 medicinal herbs, Baizhu (Atractylodis macrocephalae rhizome), Jingjie (Schizonepetae herba), Kushen (Sophorae flavescentis radix), and Niubangzi (Arctii fructus). We first identified 51 active compounds from SZT and their 81 potential molecular targets by high-throughput computational analysis, from which we identified 4 major pathways including Th17 cell differentiation, metabolic pathways, pathways in cancer, and the PI3K-Akt signaling pathway. Through network analysis of the compound-target pathway, we identified hub molecular targets within these pathways including carbonic anhydrase II (CA2), peroxisome proliferator activated receptor γ (PPAR γ), retinoid X receptor α (RXRA), and vitamin D receptor (VDR). We further identified top 5 compounds including cynarine, stigmasterin, kushenol, β-sitosterol, and (24S)-24-propylcholesta-5-ene-3β-ol as putative key active compounds on the basis of their molecular docking scores with identified hub target proteins. Our study provides an insight into the therapeutic mechanism underlying multiscale benefits of SZT for eczema and paves the way for developing new and potentially more effective eczema therapies.

BACKGROUND:Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by profuse vomiting within hours of ingestion of the causative food. We have previously reported that FPIES is associated with systemic innate immune activation in the absence of a detectable antigen-specific antibody or T-cell response. The mechanism of specific food recognition by the immune system remains unclear. OBJECTIVE:Our aim was to identify immune mechanisms underlying FPIES reactions by proteomic and flow cytometric analysis of peripheral blood. METHODS:Children with a history of FPIES underwent supervised oral food challenge. Blood samples were taken at baseline, at symptom onset, and 4 hours after symptom onset. We analyzed samples from 23 children (11 reactors and 12 outgrown). A total of 184 protein markers were analyzed by proximity ligation assay and verified by multiplex immunoassay. Analysis of cell subset activation was performed by mass cytometry and spectral cytometry. RESULTS:17 cells. CONCLUSIONS:These results demonstrate a unique IL-17 signature and activation of innate lymphocytes in FPIES.

PURPOSE OF REVIEW/OBJECTIVE:The prevalence of food allergy is increasing on a global scale, and therefore increased attention is being paid to specific food allergy epidemiology and management. There has been a large amount of progress made in the last decade on human trials of wheat oral immunotherapy (WOIT). RECENT FINDINGS/RESULTS:To date, there has been one multicenter, double-blind, randomized controlled trial of WOIT, one randomized, noncontrolled trial of WOIT, and several smaller, nonrandomized clinical trials of WOIT. WOIT trials are generally limited by smaller sample sizes, affecting the demographic skew of evaluated patients. In addition, there is minimal standardization of efficacy and safety outcomes between trial protocols, making head-to-head comparison challenging. However, some common themes emerge. The majority of WOIT regimens result in successful desensitization, and success is more likely with higher maintenance dosing for longer periods of time. Limited studies have looked at sustained unresponsiveness in WOIT. WOIT can induce allergic reactions, including anaphylaxis, but more severe reactions often have an associated augmenting factor, such as exercise. Lower maintenance doses likely are associated with less severe reactions, and food modification and/or adjunct therapeutics may also decrease the risk of reactions. SUMMARY/CONCLUSIONS:WOIT trials are ongoing and will optimize updosing protocols and maintenance doses to improve efficacy and safety.

BACKGROUND:Understanding about patient-reported biphasic food-related allergic reactions currently remains sparse. OBJECTIVE:To characterize patient-reported biphasic food-related allergic reactions among a national food allergy registry. METHODS:We utilized two Patient Registry surveys established by Food Allergy Research & Education (FARE). Variables were described with proportions and 95% confidence intervals; unadjusted results were stratified by respondent type. Multivariable logistic regression evaluated the adjusted odds of reporting a biphasic reaction. RESULTS:The incidence of reported biphasic reactions was 16.4% (CI: 15.3-17.7). 12.8% (CI: 12.5-14.3) of parent/guardian respondents and 21.8% (CI: 19.7-23.8) of self-respondents indicated a biphasic reaction during their most recent food-allergic reaction. Among respondents with a mild initial reaction, 7.4% reported a biphasic reaction compared with 30% with a very severe initial reaction. When the initial reaction was mild, 69.6% of parent/guardian respondents (CI: 47.2 - 85.4) and 52.0% of self-respondents (CI: 38.0 - 35.7) with a biphasic reaction reported a mild secondary reaction. When the initial reaction was very severe, 36.3% of parent/guardian respondents (CI: 26.4 - 47.5) and 42.9% of self-respondents (CI: 31.1 - 55.5) with a biphasic reaction reported a very severe secondary reaction. Female gender, Black/African-American race, reaction age 5-12 and 26-66 years, initial moderate, severe, or very severe reaction, and one or more annual reactions were associated with increased odds of a biphasic reaction. CONCLUSION/CONCLUSIONS:This study characterizes the incidence of patient-reported biphasic reactions and provides valuable information on probable severity of a biphasic food-related allergic reaction. Further research is necessary to understand the epidemiology of food-related biphasic reactions.

Background and aims/UNASSIGNED:The term "Food Allergy" refers to a complex global health problem with a wide spectrum of severity. However, a uniform definition of severe food allergy is currently missing. This systematic review is the preliminary step towards a state-of-the-art synopsis of the current evidence relating to the severity of IgE-mediated food allergy; it will inform attempts to develop a consensus to define food allergy severity by clinicians and other stakeholders. Methods/UNASSIGNED:We undertook a mixed-methods systematic review, which involved searching 11 international biomedical databases for published studies from inception to 31 December 2019. Studies were independently screened against pre-defined eligibility criteria and critically appraised by established instruments. The substantial heterogeneity of included studies precluded meta-analyses and, therefore, narrative synthesis of quantitative and qualitative data was performed. Results/UNASSIGNED:We found 23 studies providing eligible primary data on symptom-specific severity of food allergic reactions, and 31 previously published symptom-severity scoring systems referred to food allergic reactions. There were seven studies which assessed quality-of-life measures in patients (and family members) with different food allergy severity and two studies that investigated the economic burden of food allergy severity. Overall, the quality and the global rating of all included studies were judged as being moderate. Conclusions/UNASSIGNED:There is heterogeneity among severity scoring systems used and even outcomes considered in the context of severity of food allergy. No score has been validated. Our results will be used to inform the development of an international consensus to define the severity of food allergy. Systematic review registration/UNASSIGNED:A protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) database with the registration number CRD42020183103 (https://www.crd.york.ac.uk/prospero/#recordDetails).