The Phenotype of the Food-Allergic Patient

Food allergy\u27s increasing prevalence across the globe has initiated research into risk factors associated with the disease and coexistence with other allergic diseases. Longitudinal birth cohorts have identified food allergy phenotypes of patients based on genetic background, racial diversity, and environmental factors. Identifying food sensitization patterns and coexistence of other allergic diseases allows physicians to provide appropriate care for food allergy and personalized anticipatory guidance for the appearance of other allergic diseases. The authors seek to detail key findings of 4 longitudinal allergy birth cohorts that investigate food allergy and other allergic diseases to further characterize food allergy phenotypes

Longitudinal Characterization of Atopic Dermatitis Phenotypes in The Children\u27s Respiratory and Environmental Workgroup (CREW) Birth Cohort Consortium

Rationale: Previously identified longitudinal patterns of atopic dermatitis (AD) may lack generalizability and precision due to small sample size and limited time points. We identify and describe longitudinal AD phenotypes in a large consortium study. Methods: Data from 11 birth cohorts across the United States from the CREW (Children’s Respiratory and Environmental Workgroup) consortium were harmonized to determine physician diagnosis of AD in each year of life from 0-7 years of age (N=7,900). AD phenotypes were identified using Longitudinal Latent Class Analysis, and relationships with demographic variables were determined using multinomial logistic regression with a 3-step procedure to account for uncertainty in class membership. Results: We identified 5 classes of AD expression, selected based on model fit, interpretability, and clinical utility: Persistent AD (15.4%), Early AD with Potential Reoccurrence (2.7%), Late-Onset AD (7.0%), Transient Early AD (3.0%), and Minimal/No AD (72.0%). Males had significantly higher odds of Persistent AD (OR [95% CI]=1.47 [1.22, 1.75]) and Early AD with Potential Reoccurrence (OR [95% CI]=1.89 [1.19, 2.94]). Relative to White children, Black children had higher odds of Persistent AD (OR [95% CI]=2.50 [2.05, 3.05]), Early AD with Potential Reoccurrence (OR [95% CI]=3.07 [1.94, 4.85]), and Transient Early AD (OR [95% CI]=4.12 [2.62, 6.48]). Conclusions: Five AD phenotypes exist in a diverse national sample of children. Black children and males are at increased risk of early and persistent AD. These findings illustrate potential risk factors to target AD prevention

Longitudinal assessment of Allergic Outcomes and Atopic Dermatitis Phenotypes in The Children\u27s Respiratory and Environmental Workgroup (CREW) Birth Cohort Consortium

Rationale: Atopic dermatitis (AD) is a heterogenous inflammatory skin disease often associated with other allergic diseases. We characterized AD phenotypes and associated allergic outcomes longitudinally across a multi-site consortium. Methods: AD expression in 11 U.S. birth cohorts from the CREW (Children’s Respiratory and Environmental Workgroup) consortium was assessed in each year of life from age 0-7 years (N=7,900). Longitudinal Latent Class Analysis was performed to identify AD phenotypes. Five classes of AD were identified: Persistent AD (15.4%), Early AD with Potential Reoccurrence (2.7%), Late-Onset AD (7.0%), Transient Early AD (3.0%), and Minimal/No AD (72.0%). Serum allergen sensitization patterns and allergic clinical disease were associated with AD phenotype using multinomial logistic regression with a 3-step procedure to account for uncertainty in class membership. Results: Children with Persistent AD, Early AD with Potential Reoccurrence, and Transient Early AD were more likely to have food allergy compared to those with Minimal/No AD (OR[95% CI]=2.73[2.15, 3.45], 2.69[1.63, 4.45], 2.54[1.55, 4.16], respectively). These groups had similarly higher odds of food sensitization. Persistent AD (OR[95% CI]=1.81[1.48, 2.21]) and Early AD with Potential Reoccurrence (OR[95% CI]=3.66[1.90, 7.05]) had significantly higher odds of ever asthma relative to Minimal/No AD. At both 2-4 years and 5-7 years, persistent AD (OR[95% CI]=1.35[1.04, 1.74], 1.25[1.01, 1.53]) and Late-Onset AD (OR[95% CI]=1.68[1.13, 2.50], 2.22[1.33, 3.70]) relative to Minimal/No AD had higher odds of allergic rhinitis. Conclusions: Longitudinal AD phenotypes had varying associations with allergic sensitization, food allergy, asthma and allergic rhinitis, demonstrating the heterogeneity of allergic comorbidity risk associated with AD

Epigenetic and Transcriptional Dysregulation in T cells of Patients with Atopic Dermatitis

Rationale: Atopic dermatitis (AD) is linked to genetic and environmental risk factors. The effect of these factors on molecular and transcriptional events is not well understood. Immunologically, AD involves skin barrier defects and CD4+ T cells that produce inflammatory cytokines and amplify epidermal dysfunction Our objective was to investigate epigenetic mechanisms that may account for genetic susceptibility in CD4+ T cells. Methods: We measured chromatin accessibility (ATAC-seq), NFKB1 binding (ChIP-seq), and gene expression (RNA-seq) in anti-CD3/CD28 stimulated CD4+ T cells from 6 subjects with active moderate-to-severe AD and 6 age-matched non-allergic controls. Results: AD genetic risk loci were enriched for open chromatin regions in stimulated CD4+ T cells. The majority of ATAC-seq peaks were shared between matched AD-control pairs, consistent with those sections of chromatin being equally available. In contrast, NFKB DNA binding motifs were enriched in AD-dependent open chromatin. NFKB1 ChIP-seq identified genomic regions that were more strongly bound in AD cases, more strongly bound in controls, or shared between cases and controls. Chromatin that was strongly accessible and bound by NFKB1 in AD was enriched for AD genetic risk variants. Using whole genome sequencing data, we identified genotype-dependent accessible chromatin at AD risk loci corresponding to 32 genes with genotype-dependent expression in stimulated CD4+ T cells. Conclusions: The response of CD4+ T cells to stimulation is AD-specific and results in differential chromatin accessibility and transcription factor binding. These differences in transcriptional regulation result in epigenetic and transcriptional dysregulation in CD4+ T cells of patients with AD

Epigenetic and transcriptional dysregulation in CD4+ T cells in patients with atopic dermatitis

Atopic dermatitis (AD) is one of the most common skin disorders among children. Disease etiology involves genetic and environmental factors, with 29 independent AD risk loci enriched for risk allele-dependent gene expression in the skin and CD4+ T cell compartments. We investigated the potential epigenetic mechanisms responsible for the genetic susceptibility of CD4+ T cells. To understand the differences in gene regulatory activity in peripheral blood T cells in AD, we measured chromatin accessibility (an assay based on transposase-accessible chromatin sequencing, ATAC-seq), nuclear factor kappa B subunit 1 (NFKB1) binding (chromatin immunoprecipitation with sequencing, ChIP-seq), and gene expression levels (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD, as well as in age-matched non-allergic controls. Open chromatin regions in stimulated CD4+ T cells were highly enriched for AD genetic risk variants, with almost half of the AD risk loci overlapping AD-dependent ATAC-seq peaks. AD-specific open chromatin regions were strongly enriched for NF-κB DNA-binding motifs. ChIP-seq identified hundreds of NFKB1-occupied genomic loci that were AD- or control-specific. As expected, the AD-specific ChIP-seq peaks were strongly enriched for NF-κB DNA-binding motifs. Surprisingly, control-specific NFKB1 ChIP-seq peaks were not enriched for NFKB1 motifs, but instead contained motifs for other classes of human transcription factors, suggesting a mechanism involving altered indirect NFKB1 binding. Using DNA sequencing data, we identified 63 instances of altered genotype-dependent chromatin accessibility at 36 AD risk variant loci (30% of AD risk loci) that might lead to genotype-dependent gene expression. Based on these findings, we propose that CD4+ T cells respond to stimulation in an AD-specific manner, resulting in disease- and genotype-dependent chromatin accessibility alterations involving NFKB1 binding

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Peanut oral immunotherapy in a pediatric allergy clinic: patient factors associated with clinical outcomes

BACKGROUND: Additional information is needed to inform optimal patient selection, expected outcomes, and treatment endpoints for clinical peanut oral immunotherapy (OIT). OBJECTIVE: We analyzed a real-world peanut OIT cohort to provide insight into these questions. METHODS: Records were reviewed for 174 children undergoing peanut OIT at a pediatric allergy clinic. Patient age, peanut skin prick test, peanut-specific IgE (sIgE) results, and inclusion of additional foods in OIT were analyzed for correlations with OIT outcomes. RESULTS: To date, 144 patients have achieved maintenance dosing, 50 of whom transitioned to ad lib twice-weekly peanut ingestion. Thirty discontinued OIT. Fortyseven patients who underwent multi-food OIT had no significant difference in reactions or time to reach maintenance compared to those on peanut OIT alone. Age at initiation inversely correlated with achievement of maintenance: 92% of patients 0.5-\u3c5 \u3eyears, 81% of those 5-\u3c11 \u3eyears, and 70% of those 11-(P=0.013). Baseline peanut-sIgE level positively correlated with number of reactions during updosing (P=0.0004) and maintenance (P=0.0048), though was not significantly different in patients achieving successful maintenance versus those who discontinued OIT (P=0.098). Sixty-six percent of patients experienced ≥1 adverse reaction during OIT. Of those on ad lib peanut ingestion, 2 reported mild reactions after lapses in peanut consumption. CONCLUSION: Clinical peanut OIT has similar outcomes to research protocols. OIT can be successful in older children and those with high peanut-sIgE levels, though these factors impact outcomes. Clinical and laboratory criteria can guide successful transition to intermittent ad lib peanut consumption