Food insecurity and allergic diseases: A call to collective action.

Food security encompassess the concept of access by all people at all times to enough food for an active, healthy life. Conversely, food insecurity (FI) refers to household-level economic and social conditions of limited or uncertain access to adequate food. FI is a key social determinant of health that can negatively affect nutrition and health outcomes, as it is estimated that 10.2% of the US population meets criteria for FI. Recognizing the impact of FI on our patients and families is critical to promote health equity and optimize health outcomes. This review focuses on FI and allergic disease from the perspective of key multisector stakeholders within the field of allergy and immunology as well as from the larger health care arena, highlighting key resources and initiatives important to patients. Collectively, as specialists in allergy and immunology, and within the medical field more broadly, we must leverage our unique roles as we interface with patients and families and serve as committed advocates for change. Developing innovative strategies to promote health equity can provide a pathway forward for all children, adults, and families to gain access to healthy, nutritious food as part of their routine lifestyle. This is a call to action.

Assessment and management of anxiety and depression in a pediatric high-risk asthma clinic.

OBJECTIVE: The aims of this study were to determine the prevalence of positive mental health (MH) screens in a pediatric high-risk asthma (HRA) clinic population, and to determine the success rate of engagement in MH services before and after adding a clinical psychologist to our multidisciplinary clinic. HYPOTHESIS: We hypothesized that the HRA population would have a higher prevalence of anxiety/depression symptoms than that previously reported for the general pediatric asthma population. We anticipated that the presence of an embedded psychologist in HRA clinic would facilitate successful connection to MH services. METHODS: Pediatric patients in the HRA clinic were prospectively screened for anxiety and depression using validated screening instruments. Positive scores were referred for MH services. Time to MH service engagement was recorded before and after the addition of a clinical psychologist. RESULTS: A total of 186 patients were screened; 60% had a positive MH screen. Female sex was associated with higher median scores on both screening tools and higher likelihood of engagement in MH services. After addition of a clinical psychologist, new engagement in MH services increased (20% vs. 80%, p < 0.0001), and median time to engagement decreased (14.5 vs. 0.0 months, p = 0.003). CONCLUSION: There is a high prevalence of anxiety and depression in this pediatric HRA population. Success of engagement in MH services improved after a clinical psychologist joined our multidisciplinary team, suggesting access to care as a primary barrier to engagement.

Childhood respiratory viral infections and the microbiome.

The human microbiome associated with the respiratory tract is diverse, heterogeneous, and dynamic. The diversity and complexity of the microbiome and the interactions between microorganisms, host cells, and the host immune system are complex and multifactorial. Furthermore, the lymphatics provide a direct highway, the gut-lung axis, for the gut microbiome to affect outcomes related to respiratory disease and the host immune response. Viral infections in the airways can also alter the presence or absence of bacterial species, which might increase the risks for allergies and asthma. Viruses infect the airway epithelium and interact with the host to promote inflammatory responses that can trigger a wheezing illness. This immune response may alter the host's immune response to microbes and allergens, leading to T2 inflammation. However, exposure to specific bacteria may also tailor the host's response long before the virus has infected the airway. The frequency of viral infections, age at infection, sampling season, geographic location, population differences, and preexisting composition of the microbiota have all been linked to changes in microbiota diversity and stability. This review aims to evaluate the current reported evidence for microbiome interactions and the influences that viral infection may have on respiratory and gut microbiota, affecting respiratory outcomes in children.

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.).

Dysbiotic lung microbial communities of neonates from allergic mothers confer neonate responsiveness to suboptimal allergen.

In humans and animals, offspring of allergic mothers have increased responsiveness to allergens. This is blocked in mice by maternal supplementation with α-tocopherol (αT). Also, adults and children with allergic asthma have airway microbiome dysbiosis with increased Proteobacteria and may have decreased Bacteroidota. It is not known whether αT alters neonate development of lung microbiome dysbiosis or whether neonate lung dysbiosis modifies development of allergy. To address this, the bronchoalveolar lavage was analyzed by 16S rRNA gene analysis (bacterial microbiome) from pups of allergic and non-allergic mothers with a basal diet or αT-supplemented diet. Before and after allergen challenge, pups of allergic mothers had dysbiosis in lung microbial composition with increased Proteobacteria and decreased Bacteroidota and this was blocked by αT supplementation. We determined whether intratracheal transfer of pup lung dysbiotic microbial communities modifies the development of allergy in recipient pups early in life. Interestingly, transfer of dysbiotic lung microbial communities from neonates of allergic mothers to neonates of non-allergic mothers was sufficient to confer responsiveness to allergen in the recipient pups. In contrast, neonates of allergic mothers were not protected from development of allergy by transfer of donor lung microbial communities from either neonates of non-allergic mothers or neonates of αT-supplemented allergic mothers. These data suggest that the dysbiotic lung microbiota is dominant and sufficient for enhanced neonate responsiveness to allergen. Importantly, infants within the INHANCE cohort with an anti-inflammatory profile of tocopherol isoforms had an altered microbiome composition compared to infants with a pro-inflammatory profile of tocopherol isoforms. These data may inform design of future studies for approaches in the prevention or intervention in asthma and allergic disease early in life.

The Microbiome as a Gateway to Prevention of Allergic Disease Development.

Allergic diseases exclusively affect tissues that face environmental challenges and harbor endogenous bacterial microbiota. The microbes inhabiting the affected tissues may not be mere bystanders in this process but actively affect the risk of allergic sensitization, disease development, and exacerbation or abatement of symptoms. Experimental evidence provides several plausible means by which the human microbiota could influence the development of allergic diseases including, but not limited to, effects on antigen presentation and induction of tolerance and allergen permeation by endorsing or disrupting epithelial barrier integrity. Epidemiological evidence attests to the significance of age-appropriate, nonpathogenic microbiota development in skin, gastrointestinal tract, and airways for protection against allergic disease development. Thus, there exist potential targets for preventive actions either in the prenatal or postnatal period. These could include maternal dietary interventions, antibiotic stewardship for both the mother and infant, reducing elective cesarean deliveries, and understanding barriers to breastfeeding and timing of food diversification. In here, we will review the current understanding and evidence of allergy-associated human microbiota patterns, their role in the development of allergic diseases, and how we could harness these associations to our benefit against allergies.

A Treatment to Eliminate SARS-CoV-2 Replication in Human Airway Epithelial Cells Is Safe for Inhalation as an Aerosol in Healthy Human Subjects.

BACKGROUND: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS: We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS: Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS: Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.

Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.

Role of the Microbiome in Allergic Disease Development.

PURPOSE OF REVIEW: Evidence suggests that the microbiome of the skin, gastrointestinal tract, and airway contribute to health and disease. As we learn more about the role that the microbiota plays in allergic disease development, we can develop therapeutics to alter this pathway. RECENT FINDINGS: Epidemiologic studies reveal that an association exists between environmental exposures, which alter the microbiota, and developing atopic dermatitis, food allergy, and/or asthma. In fact, samples from the skin, gastrointestinal tract, and respiratory tract reveal distinct microbiotas compared with healthy controls, with microbial changes (dysbiosis) often preceding the development of allergic disease. Mechanistic studies have confirmed that microbes can either promote skin, gut, and airway health by strengthening barrier integrity, or they can alter skin integrity and damage gut and airway epithelium. In this review, we will discuss recent studies that reveal the link between the microbiota and immune development, and we will discuss ways to influence these changes.

Evolving concepts in how viruses impact asthma: A Work Group Report of the Microbes in Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

Over the past decade, there have been substantial advances in our understanding about how viral infections regulate asthma. Important lessons have been learned from birth cohort studies examining viral infections and subsequent asthma and from understanding the relationships between host genetics and viral infections, the contributions of respiratory viral infections to patterns of immune development, the impact of environmental exposure on the severity of viral infections, and how the viral genome influences host immune responses to viral infections. Further, there has been major progress in our knowledge about how bacteria regulate host immune responses in asthma pathogenesis. In this article, we also examine the dynamics of bacterial colonization of the respiratory tract during viral upper respiratory tract infection, in addition to the relationship of the gut and respiratory microbiomes with respiratory viral infections. Finally, we focus on potential interventions that could decrease virus-induced wheezing and asthma. There are emerging therapeutic options to decrease the severity of wheezing exacerbations caused by respiratory viral infections. Primary prevention is a major goal, and a strategy toward this end is considered.

Methods in Lung Microbiome Research.

The lung microbiome is associated with host immune response and health outcomes in experimental models and patient cohorts. Lung microbiome research is increasing in volume and scope; however, there are no established guidelines for study design, conduct, and reporting of lung microbiome studies. Standardized approaches to yield reliable and reproducible data that can be synthesized across studies will ultimately improve the scientific rigor and impact of published work and greatly benefit microbiome research. In this review, we identify and address several key elements of microbiome research: conceptual modeling and hypothesis framing; study design; experimental methodology and pitfalls; data analysis; and reporting considerations. Finally, we explore possible future directions and research opportunities. Our goal is to aid investigators who are interested in this burgeoning research area and hopefully provide the foundation for formulating consensus approaches in lung microbiome research.

Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen.

Allergies are a result of allergen proteins cross-linking allergen-specific IgE (sIgE) on the surface of mast cells and basophils. The diversity and complexity of allergen epitopes, and high-affinity of the sIgE-allergen interaction have impaired the development of allergen-specific inhibitors of allergic responses. This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them. Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis. The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease.

Oral food challenge failures among foods restricted because of atopic dermatitis.

BACKGROUND: Recent studies have suggested that removing foods from the diet to manage atopic dermatitis (AD), based on positive allergy test results, may lead to immediate allergic reactions on reintroduction of that food. OBJECTIVE: To examine the frequency of oral food challenge (OFC) failures among foods removed from the diet as suspected AD triggers, focusing on the 5 major food allergens in the United States. METHODS: OFCs to egg, milk, peanut, soy, and wheat, performed from 2008 to 2014, at a children's hospital's allergy clinics, were reviewed. OFCs were offered based on history and laboratory values. Reasons for food avoidance were classified as food allergy (IgE-mediated reaction occurring within 2 hours); sensitization only (lack of introduction because of positive test results); and removal because of test results during AD evaluation. RESULTS: There were 442 OFCs performed, with 89 failures (20.1%). Reasons for OFCs included a history of food allergy (320 of 442 [72.4%]), food sensitization without any introduction (77 of 442 [17.4%]), and AD (45 of 442 [10.2%]). OFC failures among those who had food allergy (70 of 320 [21.9%]), sensitization only (13 of 77 [16.9%]), and suspected AD trigger (6 of 45 [13.3%]) did not significantly differ (P = .63). Wheat was more likely to be avoided than the other 4 foods for AD concerns (P < .001). CONCLUSION: The frequency of OFC failure among those who removed foods suspected as AD triggers was 13.3%, indicating a loss of tolerance. Restriction of foods to manage AD must be done with caution and close monitoring.