Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).

Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Early intervention and prevention of allergic diseases.

Food allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well-developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of (1) an intact epidermal barrier to prevent epicutaneous antigen presentation, (2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and (3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA.

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.

DNA methylation levels associated with race and childhood asthma severity.

OBJECTIVE: Asthma is a common chronic childhood disease worldwide. Socioeconomic status, genetic predisposition and environmental factors contribute to its incidence and severity. A disproportionate number of children with asthma are economically disadvantaged and live in substandard housing with potential indoor environmental exposures such as cockroaches, dust mites, rodents and molds. These exposures may manifest through epigenetic mechanisms that can lead to changes in relevant gene expression. We examined the association of global DNA methylation levels with socioeconomic status, asthma severity and race/ethnicity. METHODS: We measured global DNA methylation in peripheral blood of children with asthma enrolled in the Kansas City Safe and Healthy Homes Program. Inclusion criteria included residing in the same home for a minimum of 4 days per week and total family income of less than 80% of the Kansas City median family income. DNA methylation levels were quantified by an immunoassay that assessed the percentage of 5-methylcytosine. RESULTS: Our results indicate that overall, African American children had higher levels of global DNA methylation than children of other races/ethnicities (p = 0.029). This difference was more pronounced when socioeconomic status and asthma severity were coupled with race/ethnicity (p = 0.042) where low-income, African American children with persistent asthma had significantly elevated methylation levels relative to other races/ethnicities in the same context (p = 0.006, Hedges g = 1.14). CONCLUSION: Our study demonstrates a significant interaction effect among global DNA methylation levels, asthma severity, race/ethnicity, and socioeconomic status.

Indoor tobacco legislation is associated with fewer emergency department visits for asthma exacerbation in children.

BACKGROUND: During the past 3 decades, numerous cities and states have adopted laws that ban smoking in public indoor spaces. The rationale for these policies has been to protect nonsmokers from the adverse health effects of secondhand smoke. OBJECTIVE: To determine whether the implementation of indoor smoking legislation is associated with a decrease in emergency department visits for asthma in children. METHODS: This retrospective analysis used a natural experiment to estimate the impact of clean indoor air legislation on the rate of emergency department admissions for asthma exacerbation in children. Data were obtained from the Pediatric Health Information System. A Poisson regression was used for analyses and controlled for age, sex, race, payer source, seasonality, and secular trends. RESULTS: Asthma emergency department visits were captured from 20 hospitals in 14 different states plus the District of Columbia from July 2000 to January 2014 (n = 335,588). Indoor smoking legislation, pooled across all cities, was associated with a decreased rate of severe asthma exacerbation (adjusted rate ratio 0.83, 95% confidence interval 0.82-0.85, P < .0001). CONCLUSION: Indoor tobacco legislation is associated with a decrease in emergency department visits for asthma exacerbation. Such legislation should be considered in localities that remain without this legislation to protect the respiratory health of their children.

Home dust microbiota is disordered in homes of low-income asthmatic children.

OBJECTIVE: Exposure to microorganisms has repeatedly been found to influence development of atopic diseases, such as asthma. Innovative techniques have been developed that can comprehensively characterize microbial communities. The objective of this study was to characterize the home microbiota of asthmatic children utilizing 16S rRNA-based phylogenetic analysis by microarray. METHODS: In this cross-sectional study, DNA was extracted from home dust and bacterial 16S rRNA genes amplified. Bacterial products were hybridized to the PhyloChip Array and scanned using a GeneArray scanner (Affymetrix, Santa Clara, CA). The Adonis test was used to determine significant differences in the whole microbiome. Welch's t-test was used to determine significant abundance differences and genus-level richness differences. RESULTS: Nineteen homes were included in the analysis (14 asthma and five no asthma). About 1741 operational taxonomic units (OTUs) were found in at least one sample. Bacterial genus richness did not differ in the homes of asthmatics and non-asthmatics (p = 0.09). The microbial profile was significantly different between the two groups (p = 0.025). All the top 12 OTUs with significant abundance differences were increased in homes of asthmatics and belonged to one of the five phyla (p = 0.001 to p = 7.2 × 10(-6)). Nearly half of significant abundance differences belonged to the phylum Cyanobacteria or Proteobacteria. CONCLUSIONS: These results suggest that home dust has a characteristic microbiota which is disturbed in the homes of asthmatics, resulting in a particular abundance of Cyanobacteria and Proteobacteria. Further investigations are needed which utilize high-throughput technology to further clarify how home microbial exposures influence human health and disease.

Utility of next generation sequencing in clinical primary immunodeficiencies.

Primary immunodeficiencies (PIDs) are a group of genetically heterogeneous disorders that present with very similar symptoms, complicating definitive diagnosis. More than 240 genes have hitherto been associated with PIDs, of which more than 30 have been identified in the last 3 years. Next generation sequencing (NGS) of genomes or exomes of informative families has played a central role in the discovery of novel PID genes. Furthermore, NGS has the potential to transform clinical molecular testing for established PIDs, allowing all PID differential diagnoses to be tested at once, leading to increased diagnostic yield, while decreasing both the time and cost of obtaining a molecular diagnosis. Given that treatment of PID varies by disease gene, early achievement of a molecular diagnosis is likely to enhance treatment decisions and improve patient outcomes.

Secondhand tobacco smoke exposure in low-income children and its association with asthma.

Secondhand tobacco smoke (SHS) is a common indoor environmental exposure that is particularly prevalent in low-income families. It has been found to be associated with asthma in some studies; however, across all relevant studies, results have been conflicting. This study aimed to determine the prevalence of SHS exposure in the home environment in a low-income, minority population and to determine the association of exposure with childhood asthma, wheeze, and oral corticosteroids use. This retrospective study analyzed self-reported data collected as part of the Kansas City Safe and Healthy Homes Partnership to determine prevalence of SHS exposure. A logistic regression model was then used to assess the association between exposure and asthma, oral steroid use, and wheeze. Overall, 40% of children lived with at least one smoker and 15% of children lived with at least one smoker who smoked inside the house. No significant association was found between asthma or oral corticosteroid use and SHS exposure. Children who lived with a smoker had a 1.54 increased odds of wheeze in the past year. A large percentage of low-income children in the Kansas City area continue to suffer the adverse effects of SHS. These data support the need for innovative public policy to protect children from such exposure in their home environment.

Homes of low-income minority families with asthmatic children have increased condition issues.

The home is increasingly associated with asthma. It acts both as a reservoir of asthma triggers and as a refuge from seasonal outdoor allergen exposure. Racial/ethnic minority families with low incomes tend to reside in neighborhoods with low housing quality. These families also have higher rates of asthma. This study explores the hypothesis that black and Latino urban households with asthmatic children experienced more home mechanical, structural condition-related areas of concern than white households with asthmatic children. Participant families (n = 140) took part in the Kansas City Safe and Healthy Homes Program, had at least one asthmatic child, and met income qualifications of no more than 80% of local median income; many were below 50%. Families self-identified their race. Homes were assessed by environmental health professionals using a standard set of criteria and a specific set of on-site and laboratory sampling and analyses. Homes were given a score for areas of concern between 0 (best) and 53 (worst). The study population self-identified as black (46%), non-Latino white (26%), Latino (14.3%), and other (12.9%). Mean number of areas of concern were 18.7 in Latino homes, 17.8 in black homes, 13.3 in other homes, and 13.2 in white homes. Latino and black homes had significantly more areas of concern. White families were also more likely to be in the upper portion of the income. In this set of 140 low-income homes with an asthmatic child, households of minority individuals had more areas of condition concerns and generally lower income than other families.

A comparison of subject room dust with home vacuum dust for evaluation of dust-borne aeroallergens.

BACKGROUND: Assessment of indoor allergen is valuable in exposure research and evaluation of allergic individuals. Collection methods range from grab vacuum samples to filtration devices located in the breathing range of an individual. For practical purposes, many research studies use analysis of collected house dust to evaluate allergen reservoirs. OBJECTIVE: To test the hypothesis that house dust collected from the family vacuum is equivalent to house dust collected by a technician following standard protocol. METHODS: Homes from a healthy homes demonstration project (n = 41) were sampled using a specific Department of Housing and Urban Development-suggested protocol in the bedroom of the child with asthma and a simple grab procedure from the family vacuum. Samples were evaluated for the presence of 5 allergens, Bla g2, Can f1, Der f1, and Der p1 combined as total mite, Fel d1, and Mus m1. Samples were also evaluated for total antigenic protein from 4 fungal taxa, including Alternaria, Aspergillus, Cladosporium, and Penicillium. RESULTS: All of the allergens and antigens tested showed good correlation between the 2 collection methods. Fungal antigens ranged up to 92,651 nanograms per gram of dust for Aspergillus, and allergens ranged up to 17,928 nanograms per gram of dust for Can f1. The best correlation was for Cladosporium (r = 0.91), and the weakest was for dust mite (r = 0.34). CONCLUSION: Allergens and antigens tested from samples collected by protocol and by grab sampling from the home vacuum were highly positively correlated. Grab samples taken from the family vacuum may be a good surrogate for evaluating home allergen exposure.

Association of tobacco smoke exposure and atopic sensitization.

BACKGROUND: Forty million children are regularly exposed to environmental tobacco smoke (ETS) each year, increasing their risk for premature death and middle ear and acute respiratory infections. Early life exposure to ETS also is clearly associated with wheezing. However, there is no clear understanding of the influence of ETS on the development of allergic sensitization. OBJECTIVE: To determine the association of combined exposure to ETS and indoor allergens on IgE sensitization to aeroallergens in children. METHODS: This case-control study enrolled 116 cases and 121 controls from low-income families from Kansas City, Missouri. The adjusted odds ratio was calculated using a logistic model to assess the association between ETS and allergic sensitization using dust allergen levels as a covariate. RESULTS: Thirty-six percent of atopic children and 39% of controls were exposed to ETS (P < .05). Unadjusted analyses showed no significant influence of ETS on IgE sensitization to indoor allergens. Logistic regression analyses also showed no significant influence of ETS on sensitization when adjusted for levels of allergens in the home dust and family history of allergic rhinitis. CONCLUSION: These data suggest that ETS exposure was not associated with IgE sensitization to indoor allergens, even when home allergen levels were taken into consideration. Further understanding of how components of tobacco smoke influence the immune response is necessary to interpret the disparate findings across studies.

Effects of tobacco smoke exposure in childhood on atopic diseases.

Although the smoking prevalence in the United States continues to decline since the Surgeon General's first report in 1964, certain vulnerable populations continue to be disproportionately affected by the adverse consequences of tobacco smoke exposure. Children are particularly vulnerable to exposure and are likely to suffer from both short- and long-term adverse consequences after early life tobacco smoke exposure. An overwhelming amount of evidence supports an association between asthma development and tobacco smoke exposure, and evidence is mounting that tobacco smoke exposure may also increase risk of IgE sensitization. This manuscript will review the effects of tobacco smoke exposure in childhood on the development of asthma and allergic sensitization, and will review practical strategies to assist motivated parents with smoking cessation.

Higher Environmental Relative Moldiness Index (ERMI) values measured in homes of asthmatic children in Boston, Kansas City, and San Diego.

OBJECTIVE: Mold in water-damaged homes has been linked to asthma. Our objective was to test a new metric to quantify mold exposures in asthmatic children's homes in three widely dispersed cities in the United States. METHODS: The Environmental Relative Moldiness Index (ERMI) metric was created by the US Environmental Protection Agency, with assistance by the Department of Housing and Urban Development (HUD), to quantify mold contamination in US homes. The ERMI values in homes of asthmatic children were determined for the three widely dispersed cities of Boston, Kansas City, and San Diego. RESULTS: Asthmatic children in Boston (n = 76), Kansas City (n = 60), and San Diego (n = 93) were found to be living in homes with significantly higher ERMI values than were found in homes randomly selected during the 2006 HUD American Healthy Homes Survey (AHHS) from the same geographic areas (n = 34, 22, and 28, respectively). Taken together, the average ERMI value in the homes with an asthmatic child was 8.73 compared to 3.87 for the AHHS homes. In addition, Kansas City homes of children with "Mild, Moderate, or Severe Persistent Asthma" had average ERMI value of 12.4 compared to 7.9 for homes of children with only "Mild Intermittent Asthma." Aspergillus niger was the only mold of the 36 tested which was measured in significantly greater concentration in the homes of asthmatic children in all three cities. CONCLUSION: High ERMI values were associated with homes of asthmatic children in three widely dispersed cities in the United States.

Accelerating Food Allergy Research: Need for a Data Commons.

Food allergy is a significant health problem affecting approximately 8% of children and 11% of adults in the United States. It exhibits all the characteristics of a "complex" genetic trait; therefore, it is necessary to look at very large numbers of patients, far more than exist at any single organization, to eliminate gaps in the current understanding of this complex chronic disorder. Advances may be achieved by bringing together food allergy data from large numbers of patients into a Data Commons, a secure and efficient platform for researchers, comprising standardized data, available in a common interface for download and/or analysis, in accordance with the FAIR (Findable, Accessible, Interoperable, and Reusable) principles. Prior data commons initiatives indicate that research community consensus and support, formal food allergy ontology, data standards, an accepted platform and data management tools, an agreed upon infrastructure, and trusted governance are the foundation of any successful data commons. In this article, we will present the justification for the creation of a food allergy data commons and describe the core principles that can make it successful and sustainable.

A new model for environmental assessment and exposure reduction.

Environmental assessment and exposure reduction are a set of diagnostic and treatment techniques that work in tandem with the traditional medical approach by reducing a patient's exposure to adverse environmental conditions as part of medical care. Assessment involves identifying the specific exposures to which a patient is sensitive and locating the corresponding contaminants in the patient's environment. This provides a more complete diagnostic evaluation of a patient's problem than could be obtained merely by examining the patient alone. Exposure reduction involves reducing the identified triggers to levels that are below thresholds that are associated with increased risk of sensitization and disease morbidity. Assessment of an environment for contaminants focuses on a chain of factors that include contaminant sources such as cockroaches, rodents, dust mites and fungi that excrete contaminants into an environment, facilitative factors such as moisture, food, water and shelter that help sources to thrive, and reservoirs where contaminants can accumulate prior to subsequent transport to occupants. By using this model to guide environmental assessments and their corresponding interventions, the root cause of health problems can be addressed, leading to improved quality of life for patients and reduced need for chronic medications.

Diagnostic Testing Procedures and Challenges for Primary Immunodeficiencies.

Primary immunodeficiencies are rare but are often on the differential diagnosis list when patients present with recurrent or atypical infections. Patients with primary immunodeficiencies can present with a variety of symptoms and can present providers with diagnostic challenges given this variability, and the severe implications of immunodeficiencies can sometimes lead providers to pursue broad workups that may not be necessary. However, there are certain symptom patterns providers can look out for and diagnostic steps that can be taken to triage these presentations. We have used the practice modeled in the "Five Fingers of the Immune Workup" to outline common laboratory tests for clinicians to order when they are concerned for immunodeficiencies while remembering that these diagnoses are often rare, and true concern for this pathology would warrant referral to a specialist. [Pediatr Ann. 2022;51(12):e480-e484.].