Mast Cell Activation Syndrome: current understanding and research needs.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities which have gained increased attention from patients and medical providers. While several descriptive publications about MCAS exist, there are many gaps in knowledge resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell (MC) activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to MC activation in MCAS patients remain to be elucidated. The purpose of this manuscript is to summarize the known literature, identify gaps in knowledge, and highlight research needs. Several topics are covered: 1) Contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; 2) Mechanistic research; 3) Management of typical and refractory symptoms, and 4) MCAS-specific education for patients and healthcare providers.

Follow-up to Adolescence after Early Peanut Introduction for Allergy Prevention.

BACKGROUND: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption. METHODS: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months. RESULTS: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 µg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 µg/l. Adverse events were uncommon, and the majority were related to the food challenge. CONCLUSIONS: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.).

A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy.

BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Analytical challenges in omics research on asthma and allergy: A National Institute of Allergy and Infectious Diseases workshop.

Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes the major points and conclusions from this NIAID workshop. As a group, the investigators underscored the imperatives for rigorous analytic frameworks, integration of different omics data types, cross-disciplinary interaction, strategies for overcoming current limitations, and the overarching goal to improve scientific understanding and care of asthma and allergic diseases.

Developing a Prediction Model for Determination of Peanut Allergy Status in the Learning Early About Peanut Allergy (LEAP) Studies.

BACKGROUND: The Learning Early About Peanut Allergy (LEAP) study team developed a protocol-specific algorithm using dietary history, peanut-specific IgE, and skin prick test (SPT) to determine peanut allergy status if the oral food challenge (OFC) could not be administered or did not provide a determinant result. OBJECTIVE: To investigate how well the algorithm determined allergy status in LEAP; to develop a new prediction model to determine peanut allergy status when OFC results are not available in LEAP Trio, a follow-up study of LEAP participants and their families; and to compare the new prediction model with the algorithm. METHODS: The algorithm was developed for the LEAP protocol before the analysis of the primary outcome. Subsequently, a prediction model was developed using logistic regression. RESULTS: Using the protocol-specified algorithm, 73% (453/617) of allergy determinations matched the OFC, 0.6% (4/617) were mismatched, and 26% (160/617) participants were nonevaluable. The prediction model included SPT, peanut-specific IgE, Ara h 1, Ara h 2, and Ara h 3. The model inaccurately predicted 1 of 266 participants as allergic who were not allergic by OFC and 8 of 57 participants as not allergic who were allergic by OFC. The overall error rate was 9 of 323 (2.8%) with an area under the curve of 0.99. The prediction model additionally performed well in an external validation cohort. CONCLUSION: The prediction model performed with high sensitivity and accuracy, eliminated the problem of nonevaluable outcomes, and can be used to estimate peanut allergy status in the LEAP Trio study when OFC is not available.

Distinct trajectories distinguish antigen-specific T cells in peanut-allergic individuals undergoing oral immunotherapy.

BACKGROUND: Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions. OBJECTIVE: This study aimed to determine whether inherent qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT). METHODS: We first performed ex vivo T-cell profiling on peanut-reactive CD154+CD137+ T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4+ T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT. RESULTS: Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6-CRTH2+ and CCR6+CRTH2-). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of TH2A pTeff cells. PnOIT induced elimination of TH2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of TH2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation. CONCLUSION: Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies.

Associations between outdoor air pollutants and non-viral asthma exacerbations and airway inflammatory responses in children and adolescents living in urban areas in the USA: a retrospective secondary analysis.

BACKGROUND: Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus. METHODS: We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PM2·5, PM10, O3, NO2, SO2, CO, and Pb from the US Environmental Protection Agency spanning the years of both cohorts, and matched values and concentrations to each illness for each participant. We investigated the associations between regional air pollutant concentrations and respiratory illnesses and asthma exacerbations, pulmonary function, and upper airway transcriptional signatures by use of a combination of generalised additive models, case crossover analyses, and generalised linear mixed-effects models. FINDINGS: Of the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PM2·5 and O3 concentrations, were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection. Moreover, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM2·5 with increased epithelial induction of tissue kallikreins, mucus hypersecretion, and barrier functions and O3 with increased type-2 inflammation. INTERPRETATION: Our findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases.

Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses. OBJECTIVE: We evaluated whether tezepelumab, a human monoclonal anti-TSLP antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis. METHODS: We conducted a double-blind parallel design trial in patients with cat allergy. A total of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study. RESULTS: At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve [AUC0-1h] and as peak score [Peak0-1h] during the first hour after NAC) were significantly reduced in patients receiving tezepelumab/SCIT compared to SCIT alone. At week 104, one year after stopping treatment, the primary end point TNSS AUC0-1h was not significantly different in the tezepelumab/SCIT group compared to SCIT alone, while TNSS Peak0-1h was significantly lower in those receiving combination treatment versus SCIT. Transcriptomic analysis of nasal epithelial samples demonstrated that treatment with the combination of SCIT/tezepelumab, but neither monotherapy, caused persistent downregulation of a gene network related to type 2 inflammation that was associated with improvement in NAC responses. CONCLUSIONS: Inhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196).

Impact of extramural DAIT/NIAID pharmacy programs, research pharmacist scientist oversight on study performance, and lessons learned.

PURPOSE: Over the past two decades, the involvement of a Pharmacist Scientist in clinical settings has improved patient safety, decreased medication errors, and enabled successful conduct of clinical trials and faster product development [1-5]. The impact of an oversight by a Pharmacist Scientist on clinical trial performance and execution in terms of Pharmacy and Investigational Product (IP)-related deviations has not been evaluated by a sponsor. METHODS: This was a retrospective observational study conducted by the Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID). We assessed the association of the number of Pharmacy and Investigational Product (IP)-related deviations with Pharmacist oversight and use of DAIT Pharmacy/ Pharmaceutical services in two groups: Intervention Group (IG) and the Control Group (CG). RESULTS: We evaluated monitoring data from 116 studies conducted between 2006 through 2020. Forty-one eligible clinical trials were included and analyzed: 13 trials were in the IG with Pharmacist oversight and use of Pharmacy Services; 28 trials were in the CG with no Pharmacist oversight and zero to partial use DAIT Pharmacy/ Pharmaceutical Services. The evaluation revealed the expected risk of having a pharmacy and IP-related deviations were 2.94 times higher (95% CI 1.28, 6.67, = 0.01) in trials not having Pharmacist oversight and zero to partial use of Pharmaceutical/ Pharmacy Program services. This significant finding was associated with having Pharmacist oversight when adjusting for study size (# of sites and patients needed), anticipated study duration, design complexity, and whether recruitment was completed or not. CONCLUSION: We found a statistically significant association between Pharmacist Scientist involvement and oversight from protocol development to study execution and a reduction in Pharmacy and IP-related deviations.

The role of epigenetics in multi-generational transmission of asthma: An NIAID workshop report-based narrative review.

There is mounting evidence that environmental exposures can result in effects on health that can be transmitted across generations, without the need for a direct exposure to the original factor, for example, the effect of grandparental smoking on grandchildren. Hence, an individual's health should be investigated with the knowledge of cross-generational influences. Epigenetic factors are molecular factors or processes that regulate genome activity and may impact cross-generational effects. Epigenetic transgenerational inheritance has been demonstrated in plants and animals, but the presence and extent of this process in humans are currently being investigated. Experimental data in animals support transmission of asthma risk across generations from a single exposure to the deleterious factor and suggest that the nature of this transmission is in part due to changes in DNA methylation, the most studied epigenetic process. The association of father's prepuberty exposure with offspring risk of asthma and lung function deficit may also be mediated by epigenetic processes. Multi-generational birth cohorts are ideal to investigate the presence and impact of transfer of disease susceptibility across generations and underlying mechanisms. However, multi-generational studies require recruitment and assessment of participants over several decades. Investigation of adult multi-generation cohorts is less resource intensive but run the risk of recall bias. Statistical analysis is challenging given varying degrees of longitudinal and hierarchical data but path analyses, structural equation modelling and multilevel modelling can be employed, and directed networks addressing longitudinal effects deserve exploration as an effort to study causal pathways.

Peanut-Specific IgG4 and IgA in Saliva Are Modulated by Peanut Oral Immunotherapy.

BACKGROUND: Antigen-specific immunoglobulin responses have yet to be studied at the oral mucosal surface during peanut oral immunotherapy (PnOIT). OBJECTIVE: We aimed to quantify salivary peanut-specific IgG4 (PNsIgG4) and IgA (PNsIgA) and total IgG4 and IgA in participants from the Immune Tolerance Network's IMPACT study, a phase 2 PnOIT trial. METHODS: Peanut-allergic children, aged 12 months to younger than 48 months at screening, were enrolled and randomized to PnOIT or placebo oral immunotherapy (OIT) for 134 weeks. Per-protocol analysis included 69 PnOIT and 23 placebo participants. Double-blind, placebo-controlled food challenges were conducted at weeks 134 and 160 to assess desensitization and remission, respectively. Saliva samples were collected at baseline and 30, 82, 134, and 160 weeks to quantify PNsIgG4, PNsIgA, and total IgG4 and IgA. RESULTS: Participants who received PnOIT experienced significant increases in PNsIgG4 in saliva, whereas participants on placebo did not (P < .01 at all time points). The PNsIgA/total IgA ratio was also significantly increased in participants treated with PnOIT when compared with those receiving placebo at 30 and 82 weeks (P < .05). During PnOIT, desensitized participants had increased PNsIgA that plateaued, whereas the not desensitized/no remission group did not change over time. Interestingly, when the PnOIT group was evaluated by clinical outcome, PNsIgA was higher at baseline in the not desensitized/no remission group than in the desensitized/remission group (P < .05). CONCLUSIONS: PnOIT induces substantial increases in allergen-specific IgG4 and IgA in saliva. These data provide insight into OIT-induced mucosal responses and suggest the utility of these easily obtained samples for biomarker development.

Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations.

BACKGROUND: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. OBJECTIVE: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe-host interactions modify risk of asthma exacerbation in a season-specific manner. METHODS: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. RESULTS: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). CONCLUSIONS: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria-host interactions that significantly increase risk of asthma exacerbation in these children.

Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study.

BACKGROUND: For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. METHODS: We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. FINDINGS: Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8-44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61-80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59-79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755-5005) for peanut oral immunotherapy versus 5 mg (0-105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13-30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10-28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0-2755) for peanut oral immunotherapy and 0 mg (0-55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. INTERPRETATION: In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. FUNDING: National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

Food allergy across the globe.

The prevalence of food allergy (FA) is increasing in some areas of the globe, highlighting the need for better strategies for prevention, diagnosis, and therapy. In the last few decades, we have made great strides in understanding the causes and mechanisms underlying FAs, prompting guideline updates. Earlier guidelines recommended avoidance of common food allergens during pregnancy and lactation and delaying the introduction of allergenic foods in children aged between 1 and 3 years. Recent guidelines for allergy prevention recommend consumption of a healthy and diverse diet without eliminating or increasing the consumption of allergenic foods during pregnancy or breast-feeding. Early introduction of allergenic foods is recommended by most guidelines for allergy prevention after a period of exclusive breast-feedng (6 months [World Health Organization] or 4 months [European Academy of Allergy and Clinical Immunology]). New diagnostics for FA have been developed with varied availability of these tests in different countries. Finally, the first oral immunotherapy drug for FA was approved by the US Food and Drug Administration and European Medicines Agency in 2020. In this review, we will address the global prevalence of FA, our current understanding of the causes of FA, and the latest guidelines for preventing, diagnosing, and treating FA. We will also discuss similarities and differences between FA guidelines.

Heterogeneity of magnitude, allergen immunodominance, and cytokine polarization of cockroach allergen-specific T cell responses in allergic sensitized children.

BACKGROUND: Characterization of allergic responses to cockroach (CR), a common aeroallergen associated with asthma, has focused mainly on IgE reactivity, but little is known about T cell responses, particularly in children. We conducted a functional evaluation of CR allergen-specific T cell reactivity in a cohort of CR allergic children with asthma. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from 71 children, with mild-to-moderate asthma who were enrolled in a CR immunotherapy (IT) clinical trial, prior to treatment initiation. PBMC were stimulated with peptide pools derived from 11 CR allergens, and CD4+ T cell responses assessed by intracellular cytokine staining. RESULTS: Highly heterogeneous responses in T cell reactivity were observed among participants, both in terms of the magnitude of cytokine response and allergen immunodominance. Reactivity against Bla g 9 and Bla g 5 was most frequent. The phenotype of the T cell response was dominated by IL-4 production and a Th2 polarized profile in 54.9% of participants, but IFNγ production and Th1 polarization was observed in 25.3% of the participants. The numbers of regulatory CD4+ T cells were also highly variable and the magnitude of effector responses and Th2 polarization were positively correlated with serum IgE levels specific to a clinical CR extract. CONCLUSIONS: Our results demonstrate that in children with mild-to-moderate asthma, CR-specific T cell responses display a wide range of magnitude, allergen dominance, and polarization. These results will enable examination of whether any of the variables measured are affected by IT and/or are predictive of clinical outcomes.

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.

Understanding the asthmatic response to an experimental rhinovirus infection: Exploring the effects of blocking IgE.

BACKGROUND: Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear. OBJECTIVE: Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection. METHODS: Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection. RESULTS: Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P < .01 for upper respiratory symptom tract scores and P < .001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days. CONCLUSIONS: LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection.

Cockroach allergen component analysis of children with or without asthma and rhinitis in an inner-city birth cohort.

BACKGROUND: Cockroach is one of the most important sources of indoor allergens and can lead to IgE sensitization and development of rhinitis and asthma. OBJECTIVE: We sought to perform a cockroach allergen component analysis to determine the allergens and antibody levels and patterns of sensitization associated with asthma and rhinitis. METHODS: Antibody (IgE, IgG, and IgG4) levels to total cockroach and 8 cockroach allergens were determined in 2 groups of cockroach-sensitized 10-year-old children with (n = 19) or without (n = 28) asthma and rhinitis. Allergen-specific antibody levels were measured in streptavidin ImmunoCAPs loaded with each of the recombinant allergens from groups 1, 2, 4, 5, 6, 7, 9, and 11, and total cockroach-specific IgE levels were measured with the i6 ImmunoCAP. RESULTS: IgE antibody levels to cockroach allergens and extract, but not IgG or IgG4 antibody levels, differed between subjects with and without asthma and rhinitis. Specifically, recognition of more cockroach allergens with higher allergen-specific IgE levels was associated with disease. Variable patterns of sensitization with no immunodominant allergens were found in both groups. There was a good correlation between the sum of allergen-specific IgE and total cockroach IgE levels (r = 0.86, P < .001). CONCLUSIONS: Component analysis of 8 cockroach allergens revealed significant differences in IgE reactivity associated with the presence of asthma and rhinitis. Allergen-specific IgE titers and sensitization profiles were associated with asthma and rhinitis.