Social disparities in early childhood prevention and management of food allergy.

Food allergy (FA) affects 8% of US children. Navigating and managing FA permeates across multiple facets of childhood. In this article, we review research on social disparities in feeding practices, managing meals, and selecting childcare and schools. Key highlights include the following: (1) although preference for breast-feeding or formula feeding does not reduce FA risk, there are disparities in access to formula that may affect children with FA; (2) disparities likely exist in the early introduction to allergenic foods, though additional research is needed to identify barriers to following the most recent consensus guidelines on early introduction; (3) families with limited income face challenges in providing safe meals for their children; (4) disparities exist in early childcare options for preschool-age children, though there is a lack of research on FA practices in these settings; and (5) there is evidence that schools with different student demographics implement different types of FA policies. Further research is needed to better understand and characterize social disparities in FA prevention and management in early childhood and to develop evidence-based strategies to reduce them.

HEPA filtration intervention in classrooms may improve some students' asthma.

OBJECTIVE: The School Inner-City Asthma Intervention Study 2 (SICAS 2) tested interventions to reduce exposures in classrooms of students with asthma. The objective of this post-hoc analysis was limited to evaluating the effect of high-efficiency particulate (HEPA) filtration interventions on mold levels as quantified using the Environmental Relative Moldiness Index (ERMI) and the possible improvement in the students' asthma, as quantified by spirometry testing. METHODS: Pre-intervention dust samples were collected at the beginning of the school year from classrooms and corresponding homes of students with asthma (n = 150). Follow-up dust samples were collected in the classrooms at the end of the HEPA or Sham intervention. For each dust sample, ERMI values and the Group 1 and Group 2 mold levels (components of the ERMI metric) were quantified. In addition, each student's lung function was evaluated by spirometry testing, specifically the percentage predicted forced expiratory volume at 1 sec (FEV1%), before and at the end of the intervention. RESULTS: For those students with a higher Group 1 mold level in their pre-intervention classroom than home (n = 94), the FEV1% results for those students was significantly (p < 0.05) inversely correlated with the Group 1 level in their classrooms. After the HEPA intervention, the average Group 1 and ERMI values were significantly lowered, and the average FEV1% test results significantly increased by an average of 4.22% for students in HEPA compared to Sham classrooms. CONCLUSIONS: HEPA intervention in classrooms reduced Group 1 and ERMI values, which corresponded to improvements in the students' FEV1% test results.

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis.

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

Food Allergies in Inner-City Schools: Addressing Disparities and Improving Management.

OBJECTIVE: Food allergy (FA) affects approximately 8% of children in the United States. Management comprises both preventing and treating allergic reactions, which poses unique challenges in the inner-city school setting. In this article, we review the epidemiology of FA in school-aged children and management challenges and opportunities specific to the inner-city population. DATA SOURCES: A literature search of the PubMed database was performed to identify published literature on FA epidemiology, FA management, school policies, disparities, inner-city, race, ethnicity, and socioeconomic status. STUDY SELECTIONS: Relevant articles on FA management best practices and challenges in schools, with a particular emphasis on inner-city schools and populations and socioeconomic, racial, and ethnic disparities, were reviewed in detail. RESULTS: Disparities in FA prevalence, management, and treatment exist. Additional research is needed to better characterize these disparities and elucidate the mechanisms leading to them. There is a lack of evidence-based interventions for the prevention and treatment of food allergic reactions in schools and specifically in inner-city schools, in which a greater proportion of students may rely on school food. CONCLUSION: There are opportunities for partnership among health care providers, schools, and communities to address unmet needs in FA management and disparities in the inner-city school setting.

The evolution of food protein-induced enterocolitis syndrome: From a diagnosis that did not exist to a condition in need of answers.

OBJECTIVE: Although food protein-induced enterocolitis syndrome (FPIES) was first described approximately 50 years ago and research is increasing, there are still considerable unmet needs in FPIES. This article catalogs the areas of progress and areas for further research. DATA SOURCES: Through our personal experiences in caring for patients with FPIES, our personal research, and a review of the existing FPIES literature as indexed in PubMed, we explored what is known and what is needed in FPIES. STUDY SELECTIONS: The studies that have improved the knowledge of FPIES, defined phenotypes, allowed for better-informed management of FPIES, and laid the groundwork for further research. RESULTS: Further research is needed in the areas of prevalence, natural history, trigger foods, threshold doses, how and when to perform oral food challenges, and immunopathogenesis of this disorder. Development of a biomarker and determination of the best method to treat reactions is also needed. Furthermore, FPIES has a substantial psychosocial and economic impact on families, and more research is needed in developing and implementing ameliorating strategies. CONCLUSION: By partnering together, health care providers, advocacy organizations, and families can continue to advance our understanding and improve the care of patients and families living with FPIES.

Effect of School Integrated Pest Management or Classroom Air Filter Purifiers on Asthma Symptoms in Students With Active Asthma: A Randomized Clinical Trial.

Importance: School and classroom allergens and particles are associated with asthma morbidity, but the benefit of environmental remediation is not known. Objective: To determine whether use of a school-wide integrated pest management (IPM) program or high-efficiency particulate air (HEPA) filter purifiers in the classrooms improve asthma symptoms in students with active asthma. Design, Setting, and Participants: Factorial randomized clinical trial of a school-wide IPM program and HEPA filter purifiers in the classrooms was conducted from 2015 to 2020 (School Inner-City Asthma Intervention Study). There were 236 students with active asthma attending 41 participating urban elementary schools located in the Northeastern US who were randomized to IPM by school and HEPA filter purifiers by classroom. The date of final follow-up was June 20, 2020. Interventions: The school-wide IPM program consisted of application of rodenticide, sealing entry points, trap placement, targeted cleaning, and brief educational handouts for school staff. Infestation was assessed every 3 months, with additional treatments as needed. Control schools received no IPM, cleaning, or education. Classroom portable HEPA filter purifiers were deployed and the filters were changed every 3 months. Control classrooms received sham HEPA filters that looked and sounded like active HEPA filter purifiers. Randomization was done independently (split-plot design), with matching by the number of enrolled students to ensure a nearly exact 1:1 student ratio for each intervention with 118 students randomized to each group. Participants, investigators, and those assessing outcomes were blinded to the interventions. Main Outcomes and Measures: The primary outcome was the number of symptom-days with asthma during a 2-week period. Symptom-days were assessed every 2 months during the 10 months after randomization. Results: Among the 236 students who were randomized (mean age, 8.1 [SD, 2.0] years; 113 [48%] female), all completed the trial. At baseline, the 2-week mean was 2.2 (SD, 3.9) symptom-days with asthma and 98% of the classrooms had detectable levels of mouse allergen. The results were pooled because there was no statistically significant difference between the 2 interventions (P = .18 for interaction). During a 2-week period, the mean was 1.5 symptom-days with asthma after use of the school-wide IPM program vs 1.9 symptom-days after no IPM across the school year (incidence rate ratio, 0.71 [95% CI, 0.38-1.33]), which was not statistically significantly different. During a 2-week period, the mean was 1.6 symptom-days with asthma after use of HEPA filter purifiers in the classrooms vs 1.8 symptom-days after use of sham HEPA filter purifiers across the school year (incidence rate ratio, 1.47 [95% CI, 0.79-2.75]), which was not statistically significantly different. There were no intervention-related adverse events. Conclusions and Relevance: Among children with active asthma, use of a school-wide IPM program or classroom HEPA filter purifiers did not significantly reduce symptom-days with asthma. However, interpretation of the study findings may need to consider allergen levels, particle exposures, and asthma symptoms at baseline. Trial Registration: ClinicalTrials.gov Identifier: NCT02291302.

Impact of school peanut-free policies on epinephrine administration.

BACKGROUND: Children with food allergies spend a large proportion of time in school but characteristics of allergic reactions in schools are not well studied. Some schools self-designate as peanut-free or have peanut-free areas, but the impact of policies on clinical outcomes has not been evaluated. OBJECTIVE: We sought to determine the effect of peanut-free policies on rates of epinephrine administration for allergic reactions in Massachusetts public schools. METHODS: In this retrospective study, we analyzed (1) rates of epinephrine administration in all Massachusetts public schools and (2) Massachusetts public school nurse survey reports of school peanut-free policies from 2006 to 2011 and whether schools self-designated as "peanut-free" based on policies. Rates of epinephrine administration were compared for schools with or without peanut-restrictive policies. RESULTS: The percentage of schools with peanut-restrictive policies did not change significantly in the study time frame. There was variability in policies used by schools self-designated as peanut-free. No policy was associated with complete absence of allergic reactions. Both self-designated peanut-free schools and schools banning peanuts from being served in school or brought from home reported allergic reactions to nuts. Policies restricting peanuts from home, served in schools, or having peanut-free classrooms did not affect epinephrine administration rates. Schools with peanut-free tables, compared to without, had lower rates of epinephrine administration (incidence rate per 10,000 students 0.2 and 0.6, respectively, P = .009). CONCLUSIONS: These data provide a basis for evidence-based school policies for children with food allergies. Further studies are required before decisions can be made regarding peanut-free policies in schools.

Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis.

BACKGROUND: Sensitization to food antigen can occur through cutaneous exposure. OBJECTIVE: We sought to test the hypothesis that epicutaneous sensitization with food antigen predisposes to IgE-mediated anaphylaxis on oral allergen challenge. METHODS: BALB/c mice were epicutaneously sensitized by repeated application of ovalbumin (OVA) to tape-stripped skin over 7 weeks or orally immunized with OVA and cholera toxin (CT) weekly for 8 weeks and then orally challenged with OVA. Body temperature was monitored, and serum mouse mast cell protease 1 levels were determined after challenge. Tissue mast cell (MC) counts were examined by using chloroacetate esterase staining. Levels of serum OVA-specific IgE and IgG(1) antibodies and cytokines in supernatants of OVA-stimulated splenocytes were measured by means of ELISA. Serum IL-4 levels were measured by using an in vivo cytokine capture assay. RESULTS: Epicutaneously sensitized mice exhibited expansion of connective tissue MCs in the jejunum, increased serum IL-4 levels, and systemic anaphylaxis after oral challenge, as evidenced by decreased body temperature and increased serum mouse mast cell protease 1 levels. Intestinal MC expansion and anaphylaxis were IgE dependent because they did not occur in epicutaneously sensitized IgE(-/-) mice. Mice orally immunized with OVA plus CT did not have increased serum IL-4 levels, expanded intestinal MCs, or anaphylaxis after oral challenge, despite OVA-specific IgE levels and splenocyte cytokine production in response to OVA stimulation, which were comparable with those of epicutaneously sensitized mice. CONCLUSION: Epicutaneously sensitized mice, but not mice orally immunized with antigen plus CT, have expansion of intestinal MCs and IgE-mediated anaphylaxis after single oral antigen challenge. IgE is necessary but not sufficient for food anaphylaxis, and MC expansion in the gut can play an important role in the development of anaphylaxis.

The Coronavirus Disease 2019 Pandemic and Mental Health-Related School-Nurse Visits in United States Schools.

OBJECTIVE: No studies have examined school-nurse visits related to mental health (MH) during the coronavirus disease 2019 (COVID-19) pandemic. We examined changes in the rate of MH-related school-nurse visits before and during the COVID-19 pandemic. METHODS: We analyzed school-nurse visit data (n = 3,445,240) for subjects Grade K-12 in US public schools using electronic health record software (SchoolCare, Ramsey, NJ). Data between January 1 and December 31 in 2019 (pre-COVID-19 pandemic) versus January 1 to December 31 in 2020 (during COVID-19 pandemic) were compared. For each year, total visits to a school-nurse were calculated for general MH, anxiety, and self-harm. The exposure was number of school-nurse visits in each time period (2019 vs 2020). The main outcome was change in the rate of general MH, anxiety, and self-harm visits in 2019 versus 2020. RESULTS: There were 2,302,239 total school-nurse visits in 2019 versus 1,143,001 in 2020. During the COVID-19 pandemic, the rate of visits for general MH increased by 30% (4.7-6.1 per 10,000 visits, 95% confidence interval [CI] {18%, 43%}; P < .001), and visits for anxiety increased by 25% (24.8-31 per 10,000 visits, 95% CI [20%,30%]; P < .001). There was no significant difference in self-harm visits across all ages during the COVID-19 pandemic. CONCLUSIONS: Our study found a significant increase in the rate of school-nurse visits for MH and anxiety during the COVID-19 pandemic, suggesting the pediatric population is at-risk for increased negative MH-effects associated with the pandemic and highlights a critical role of school-nurses in identifying youth with potential MH-needs.

Rethinking Immunological Risk: A Retrospective Cohort Study of Severe SARS-Cov-2 Infections in Individuals With Congenital Immunodeficiencies.

BACKGROUND: Debates on the allocation of medical resources during the coronavirus disease 2019 (COVID-19) pandemic revealed the need for a better understanding of immunological risk. Studies highlighted variable clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. OBJECTIVE: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. METHODS: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged 2 months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020, through March 31, 2022. Risks of hospitalization were assessed using a multivariable logistic regression analysis. RESULTS: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 4.50; 95% confidence interval [95% CI] 1.57-13.4), a diagnosis of any genetically defined immunodeficiency (OR 3.32; 95% CI 1.24-9.43), obesity (OR 4.24; 95% CI 1.38-13.3), and neurological disease (OR 4.47; 95% CI 1.44-14.3). The COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; 95% CI 0.31-0.81). Defects in T cell and innate immune function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. CONCLUSIONS: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunological risk factors for individuals with inborn errors of immunity.

Rethinking immunologic risk: a retrospective cohort study of severe SARS-CoV-2 infections in individuals with congenital immunodeficiencies.

Background: Debates on the allocation of medical resources during the COVID-19 pandemic revealed the need for a better understanding of immunologic risk. Studies highlighted variable clinical outcomes of SARS-CoV-2 infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. Objective: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. Methods: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged two months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020 through March 31, 2022. Risks of hospitalization was assessed using a multivariable logistic regression analysis. Results: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 5.29; confidence interval [CI], 1.76-17.0), a diagnosis of any genetically-defined immunodeficiency (OR 4.62; CI, 1.60-14.8), use of B cell depleting therapy within one year of infection (OR 6.1; CI, 1.05-38.5), obesity (OR 3.74; CI, 1.17-12.5), and neurologic disease (OR 5.38; CI, 1.61-17.8). COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; CI, 0.31-0.81). Defective T cell function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. Conclusions: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunologic risk factors for individuals with inborn errors of immunity. Highlights: What is already known about this topic? Outcomes of SARS-CoV-2 infections in individuals with inborn errors of immunity (IEI) are highly variable. Prior studies of patients with IEI have not controlled for race or social vulnerability. What does this article add to our knowledge ? For individuals with IEI, hospitalizations for SARS-CoV-2 were associated with race, ethnicity, obesity, and neurologic disease. Specific types of immunodeficiency, organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization. How does this study impact current management guidelines? Current guidelines for the management of IEIs focus on risk conferred by genetic and cellular mechanisms. This study highlights the importance of considering variables linked with social determinants of health and common comorbidities as immunologic risk factors.

Human inherited complete STAT2 deficiency underlies inflammatory viral diseases.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

Predicting food challenge outcomes for baked milk: role of specific IgE and skin prick testing.

BACKGROUND: Cow's milk allergy is the most common food allergy in childhood. Many children with IgE-mediated cow's milk allergy may tolerate baked milk products, but few data exist on predictors of outcomes of baked milk challenges. OBJECTIVE: To determine the relation of milk protein allergen specific IgE (sIgE) levels and skin prick test (SPT) wheal size with baked milk challenge outcomes. METHODS: A retrospective medical record review was conducted of 35 baked milk challenges. SPT results, sIgE levels, demographic characteristics, and food challenge results were analyzed. RESULTS: Thirty-five children underwent open challenges to baked milk and 29 (83%) passed. Of those who failed, 3 (50%) passed the initial clinic challenge but developed symptoms to ongoing exposure at home, days to months later. One child who ultimately failed at home required epinephrine. Compared with those who passed, children who failed were younger (median age, 8.9 and 3.7 years, respectively; P = .02). Children with a milk SPT wheal less than 12 mm were more than 90% likely to pass a baked milk challenge, and no child with a milk SPT wheal less than 7 mm failed a baked milk challenge. We were also able to establish more than 90% predictive values for passing baked milk challenges with a casein SPT wheal of 9 mm, a milk sIgE level of 1.0 kU/L, and a casein sIgE level of 0.9 kU/L. CONCLUSION: Most children allergic to cow's milk tolerated baked milk. Milk protein SPT wheal may be more reliable than sIgE level in predicting outcomes of baked milk challenges. It is important to be aware of the possibility of late reactions to ongoing baked milk exposure.

Atopic Dermatitis Mediates the Association Between an IL4RA Variant and Food Allergy in School-Aged Children.

BACKGROUND: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests. OBJECTIVE: To test the hypothesis that AD mediates the relationship between an IL-4 receptor alpha chain gene (IL4RA) variant, the human IL-4 receptor alpha chain protein-R576 polymorphism, and FA. METHODS: A total of 433 children with asthma enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA576 allele. Surveys were administered to determine FA, AD, and associated allergic responses. Mediation analysis was performed adjusting for race and ethnicity, age, sex, and household income. Multivariate models were used to determine the association between genotype and FA severity. RESULTS: AD was reported in 193 (45%) and FA in 80 children (19%). Each risk allele increased odds of AD 1.39-fold ([1.03-1.87], P = .03), and AD increased odds of FA 3.67-fold ([2.05- 6.57], P < .01). There was an indirect effect of genotype, mediated by AD, predicting FA; each risk allele increased the odds of FA by 1.13 (odds ratio [95% CI], Q/R = 1.13 [1.02-1.24], R/R = 1.28 [1.04-1.51]; P < .01). Each risk allele increased the odds of severe FA symptoms 2.68-fold ([1.26-5.71], P = .01). CONCLUSIONS: In a cohort of children with asthma, AD is part of the causal pathway between an IL4RA variant and FA. This variant is associated with increased risk of severe FA reactions. Addressing AD in children with an IL4RA polymorphism may modulate the risk of FA.