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.).

Alergia al cacahuete en niños: probable ventana de oportunidad para la desensibilización / Peanut allergy in children: probable window of opportunity for desensitization

Conclusiones de los autores del estudio: los niños menores de 4 años de edad alérgicos al cacahuete, que recibieron inmunoterapia oral al alérgeno, presentaron una mayor desensibilización y remisión frente al mismo. Por tanto, parece existir una ventana de oportunidad de desensibilizarse al cacahuete en esta franja etaria.Comentario de los revisores: la inmunoterapia se mostró eficaz para conseguir la desensibilización y remisión en niños alérgicos al cacahuete entre 1 y 4 años. Este efecto fue más evidente en el grupo de menor edad y con niveles más bajos de marcadores inmunológicos. (AU)

Authors’ conclusions: children under 4 years of age allergic to peanuts who received oral allergen immunotherapy exhibited greater desensitization and achieved remission more frequently. Thus, there seems to be a window of opportunity for desensitization to desensitized to peanuts in this age range.Reviewers’ commentary: immunotherapy proved effective in achieving desensitization and remission in children allergic to peanuts aged 1 to 4 years. This effect was more evident in the younger children and in children with lower levels of immunological markers. (AU)

HLA alleles and sustained peanut consumption promote IgG4 responses in subjects protected from peanut allergy.

We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection.

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.

Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells.

Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/ß (TCRα/ß) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into 6 clonally distinct subsets. Four of these subsets demonstrated a convergence of TCR sequences, suggesting antigen-driven T cell fates. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not T follicular helper-like (Tfh-like) clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 cell populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated with both preexisting characteristics of peanut-reactive CD4+ T cells and suppression of a subset of Th2 cells.

High-resolution epitope mapping by AllerScan reveals relationships between IgE and IgG repertoires during peanut oral immunotherapy.

Peanut allergy can result in life-threatening reactions and is a major public health concern. Oral immunotherapy (OIT) induces desensitization to food allergens through administration of increasing amounts of allergen. To dissect peanut-specific immunoglobulin E (IgE) and IgG responses in subjects undergoing OIT, we have developed AllerScan, a method that leverages phage-display and next-generation sequencing to identify the epitope targets of peanut-specific antibodies. We observe a striking diversification and boosting of the peanut-specific IgG repertoire after OIT and a reduction in pre-existing IgE levels against individual epitopes. High-resolution epitope mapping reveals shared recognition of public epitopes in Ara h 1, 2, 3, and 7. In individual subjects, OIT-induced IgG specificities overlap extensively with IgE and exhibit strikingly similar antibody footprints, suggesting related clonal lineages or convergent evolution of peanut-specific IgE and IgG B cells. Individual differences in epitope recognition identified via AllerScan could inform safer and more effective personalized immunotherapy.

Natural Course and Prognostic Factors of Immediate-Type Peanut Allergy in Children.

BACKGROUND: Predicting food allergy resolution is essential to minimize the number of restricted foods in children. However, there have been no studies on the natural history of peanut allergy (PA) in Korea. OBJECTIVE: This study aimed to evaluate the natural course and prognostic factors of immediate-type PA in children till the age of 10 years. METHODS: We retrospectively collected data of 122 children who developed PA before 60 months of age from 3 tertiary hospitals in Korea. Diagnosis and resolution of PA was defined as an oral food challenge test or a convincing history of symptoms within 2 h after peanut ingestion. The prognostic factors for resolution of PA were identified using the Cox proportional hazard model. RESULTS: The median (interquartile range) age at diagnosis was 2.0 (1.3-3.0) years. Among the 122 children, PA resolved in 18 (14.8%) children. The level of peanut-specific IgE (sIgE) at diagnosis in the persistence group was significantly higher than that in the resolution group (p = 0.026). The probabilities of resolution of PA were 10.3% and 32.8% at the ages of 6 and 10 years, respectively. A peanut-sIgE level ≥1 kU/L at diagnosis was significantly associated with persistent PA (hazard ratio, 5.99; 95% confidence interval, 1.89-18.87). CONCLUSIONS: Only 10.3% of our patients had a probability of developing spontaneous resolution of PA by 6 years of age. Peanut-sIgE levels ≥1 kU/L at diagnosis were associated with the persistence of PA.

Allergen extraction: Factors influencing immunogenicity and sensitivity of immunoassays.

Food allergy prevalence is increasing worldwide, therefore there is a high demand for reliable tests to correctly diagnose this disease. Knowledge of proteins allergenicity and how they react both in the body and in diagnostic tests is necessary to adequately assess the potential immunogenicity of both natural foods and those produced through biotechnological processes. Thus, our aim was to analyze the factors that influence the protein extraction of foods in terms of, immunogenicity and immunoassays sensitivity. Peanut proteins were extracted using four distinct extraction buffers with different pH values (physiological saline, tris buffer, borate buffer with and without ß-mercaptoethanol), the protein concentration was determined by the Lowry method and polyacrylamide electrophoresis (SDS-PAGE) was used to compare the protein profile of each extract. The immunogenicity of each extract was verified by sensitizing two mouse strains (Balb/c and C57Bl/6) with a solution containing 100 µg of the extracted proteins and was determined by ELISA. Results show that extraction with the distinct buffers resulted in protein solutions with different yields and profiles. The immunogenicity of the different extracts also demonstrated distinct patterns that varied depending on the extraction methods, mouse strain and in vitro test. Immunoreactivity varied in accordance with the protein extract used to coat the microtitration plates. In conclusion, the protein profile in the extracts is critically influenced by the salt composition and pH of the extraction buffers, this in turn influences both in vivo immunogenicity and in vitro immunoreactivity.

Memory and naïve gamma delta regulatory T-cell gene expression in the first 24-weeks of peanut oral immunotherapy.

BACKGROUND: Peanut oral immunotherapy (POIT) has provided desensitization to peanut allergic individuals. Limited immunological evaluation exists during the first 24-weeks of POIT. OBJECTIVE: Regulatory T-cells (Tregs) are antigen induced immunosuppressive T-cells important in establishing tolerance. Delineation of early immunologic changes contributing to the development of peanut desensitization would help clarify the mechanism of action in POIT. We performed single-cell RNA sequencing (scRNAseq) on Tregs in pediatric subjects undergoing POIT during the first 24-weeks of therapy to evaluate early immunological changes induced by POIT. METHODS: PBMC samples from peanut allergic subjects between 5 and 12 years of age enrolled in a Phase 1/2a POIT study were collected and analyzed at 0, 6, and 24-weeks after POIT initiation and samples were compared to healthy non-peanut allergic controls. Tregs were enriched from PBMCs and scRNAseq analysis performed. Cell Ranger 3.1.0 (10× Genomics) was utilized to identify cell clusters and differentially expressed genes, and results were analyzed with Seurat suite version 3.0.0. RESULTS: Gene analysis revealed 10 major clusters corresponding to different cell types observed to change during POIT when compared to the healthy, non-peanut-allergic state. scRNAseq analysis of Tregs revealed strong CD3G expression correlating with gdTregs. scRNAseq analysis of gdTregs revealed dynamic changes occurring within the first 6-weeks of treatment and cell frequencies of naïve and memory gdTregs at 24-weeks of treatment reducing to levels similar to healthy controls. Analysis of transcriptomic cell identity analysis using SingleR showed gene expression in gdTregs similar to healthy control after 24-weeks of POIT treatment. scRNAseq analysis revealed alterations in gene expression for memory and naïve gdTregs during this timeframe. Specifically, expression of OX40R (TNFRSF4), GITR (TNFRSF18), TGFB1, CTLA4, ISG20, CD69 were upregulated in memory gdTregs compared to naive gdTregs by 24-weeks of POIT, while IL7R and SELL were downregulated in memory gdTregs compared to naïve gdTregs. CONCLUSIONS: There are specific expression profiles of peripheral naïve and mature gdTreg cells in peanut allergic patients undergoing POIT in the first 24-weeks of treatment implicating pathways involved in maintenance of immune homeostasis. gdTreg cells may contribute to the tolerogenic effect of POIT within the first 24-weeks of POIT treatment. These findings suggest that gdTregs cells may be an early marker of desensitization in subjects undergoing POIT.

Early Introduction of Food Allergens and Risk of Developing Food Allergy.

There is increasing evidence that early introduction of allergenic foods may decrease the risk of developing IgE-mediated food allergy. Patterns of food introduction before the 2015 publication of the Learning Early about Peanut Allergy (LEAP) trial are not well-studied, but are important as a baseline for evaluating subsequent changes in infant feeding practices and potentially food allergy. We performed a retrospective longitudinal study using data from a multicenter cohort of infants hospitalized with bronchiolitis between 2011-2014. The primary outcomes were IgE-mediated egg or peanut allergy by age 3 years. Of 770 participants included in the analysis, 635 (82%) introduced egg, and 221 (27%) introduced peanut by age 12 months per parent report. Four participants had likely egg allergy, and eight participants had likely peanut allergy by age 3 years. Regular infant egg consumption was associated with less egg allergy. The association was suggestive for infant peanut consumption with zero peanut allergy cases. Overall, our results suggest that early introduction of peanut was uncommon before 2015. Although limited by the small number of allergy cases, our results suggest that early introduction of egg and peanut are associated with a decreased risk of developing food allergy, and support recent changes in practice guidelines.

Diagnostic accuracy of Ara h 2 for detecting peanut allergy in children.

BACKGROUND: Specific IgE to Ara h 2 is a diagnostic test for peanut allergy which may reduce the need for double-blind placebo-controlled food challenges (DBPCFC); however, guidance for using Ara h 2 in place of DBPCFCs has not been validated. OBJECTIVE: To prospectively evaluate 1) diagnostic accuracy of previously published Ara h 2 cut-off levels to diagnose peanut allergy in children and 2) costs. METHODS: A consecutive series of 150 children age 3.5 to 18 years was evaluated in secondary and tertiary settings in the Netherlands. sIgE to Ara h 2 was the index test, and oral peanut ingestion was the reference test. Oral peanut ingestion was home or supervised introduction for Ara h 2 ≤ 0.1, DBPCFC for 0.1-5.0 and open food challenge for ≥5.0. Costs were calculated using financial healthcare data. RESULTS: A conclusive reference test was performed in 113 children (75%). Sixty-four children (57%) had peanut allergy, as confirmed by a DBPCFC (27/47) or an open challenge (37/50). Forty-nine children (43%) were considered peanut-tolerant after peanut introduction (19/19), a DBPCFC (20/47) or an open challenge (10/50). Area under the curve for Ara h 2 was 0.94 (95% CI 0.90-0.98). The diagnostic flow chart correctly classified 26/26 (100%; 84-100) of children with Ara h 2 ≤ 0.1 as peanut-tolerant and 34/35 (97%; 83-100) of children with Ara h 2 ≥ 5.0 as peanut-allergic. At a cut-off of ≤0.1 and ≥5.0, a sensitivity of respectively 100% (93-100) and 53% (38-67) was observed and a specificity of 53% (38-67) and 98% (87-100). Mean annual costs of the flow chart were estimated as €320-€636 per patient lower than following national allergy guidelines. CONCLUSIONS: In this diagnostic accuracy study, which did not take into account pretest probability, we have validated previously published Ara h 2 cut-off levels which are associated with peanut tolerance and allergy.

The airway as a route of sensitization to peanut: An update to the dual allergen exposure hypothesis.

Food allergies have increased at an alarming rate over the past 2 decades, indicating that environmental factors are driving disease progression. It has been postulated that sensitization to foods, in particular, peanut, occurs through impaired skin. Peanut allergens have been quantified in household dust and may be the culprit source. Indeed, TH2 cell-skewing innate cytokines can be driven by application of food antigens on both intact and impaired skin of mice, resulting in antigen-specific IgE production and anaphylaxis following allergen exposure. However, allergy induction through the skin can be prevented by induction of oral tolerance before skin exposure. These observations led to the dual allergen exposure hypothesis, according to which oral exposure to food antigens leads to tolerance and antigen exposure on impaired skin leads to allergy. Here, we propose the airway as an alternative route of sensitization in the dual allergen exposure hypothesis that leads to food allergy. Specifically, we will provide evidence from mouse models and human cell-based studies that together implicate the airway as a plausible route of sensitization.

Human monocyte-derived type 1 and 2 macrophages recognize Ara h 1, a major peanut allergen, by different mechanisms.

Evidence has suggested that major peanut allergen Ara h 1 activates dendritic cells (DCs) via interaction with DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), a C-type lectin receptor, and contributes to development of peanut allergy. Since macrophages, as well as DCs, play a crucial role in innate immunity, we investigated whether natural Ara h 1 (nAra h 1) activates two different subsets of macrophages, human monocyte derived macrophage type 1 (hMDM1: pro-inflammatory model) and type 2 (hMDM2: anti-inflammatory model). hMDM1 and hMDM2 predominantly produced pro-inflammatory cytokines (IL-6 and TNF-α) and an anti-inflammatory cytokine (IL-10) in response to nAra h 1, respectively. hMDM2 took up nAra h 1 and expressed DC-SIGN at higher levels than hMDM1. However, small interfering RNA knockdown of DC-SIGN did not suppress nAra h 1 uptake and nAra h 1-mediated cytokine production in hMDM2. Inhibitors of scavenger receptor class A type I (SR-AI) suppressed the response of hMDM2, but not of hMDM1, suggesting that SR-AI is a major receptor in hMDM2 for nAra h 1 recognition and internalization. nAra h 1 appears to exert stimulatory capacity on DC and macrophages via different receptors. This study advances our understanding how a major peanut allergen interacts with innate immunity.

Identification of antigen-specific TCR sequences based on biological and statistical enrichment in unselected individuals.

Recent advances in high-throughput T cell receptor (TCR) sequencing have allowed for new insights into the human TCR repertoire. However, methods for capturing antigen-specific repertoires remain an area of development. Here, we describe a potentially novel approach that utilizes both a biological and statistical enrichment to define putatively antigen-specific complementarity-determining region 3 (CDR3) repertoires in unselected individuals. The biological enrichment entailed FACS of in vitro antigen-activated memory CD4+ T cells, followed by TCRß sequencing. The resulting TCRß sequences were then filtered by selecting those that are statistically enriched when compared with their frequency in the autologous resting T cell compartment. Applying this method to define putatively peanut protein-specific repertoires in 27 peanut-allergic individuals resulted in a library of 7345 unique CDR3ß amino acid sequences that had similar characteristics to other validated antigen-specific repertoires in terms of homology and diversity. In-depth analysis of these CDR3ßs revealed 36 public sequences that demonstrated high levels of convergent recombination. In a network analysis, the public CDR3ßs were shown to be core sequences with more edges than their private counterparts. This method has the potential to be applied to a wide range of T cell-mediated disorders and to yield new biomarkers and biological insights.

A positive feedback loop reinforces the allergic immune response in human peanut allergy.

Food allergies are a leading cause of anaphylaxis, and cellular mechanisms involving antigen presentation likely play key roles in their pathogenesis. However, little is known about the response of specific antigen-presenting cell (APC) subsets to food allergens in the setting of food allergies. Here, we show that in peanut-allergic humans, peanut allergen drives the differentiation of CD209+ monocyte-derived dendritic cells (DCs) and CD23+ (FcєRII) myeloid dendritic cells through the action of allergen-specific CD4+ T cells. CD209+ DCs act reciprocally on the same peanut-specific CD4+ T cell population to reinforce Th2 cytokine expression in a positive feedback loop, which may explain the persistence of established food allergy. In support of this novel model, we show clinically that the initiation of oral immunotherapy (OIT) in peanut-allergic patients is associated with a decrease in CD209+ DCs, suggesting that breaking the cycle of positive feedback is associated with therapeutic effect.

Regulatory Requirements for the Quality of Allergen Products for Allergen Immunotherapy of Food Allergy.

PURPOSE OF REVIEW: Medicinal products for allergen immunotherapy (AIT) of food allergies have gained enormous momentum in recent years. With this new class of products entering marketing authorization procedures, compliance to regulatory requirements becomes a critical element. Here, an overview is provided on specific requirements and aspects concerning the quality control and manufacturing of these products. RECENT FINDINGS: Recent developments in the field of AIT for food allergies are divers, including products for oral, epicutaneous, and subcutaneous application, most notably targeting egg, milk, and peanut allergy. As the source materials for food AIT product are typically produced for food consumption and not for medicinal purposes, unique challenges arise in the manufacturing processes and controls of these medicinal products. Individual approaches are needed to assure acceptable quality, including control of relevant quantitative and qualitative characteristics. Major characteristics for quality verification include determination of protein content, total allergenic activity, and major allergen content. The applied manufacturing processes need to be established such that relevant process parameters are kept within justified limits and consistency of produced batches is assured. Allergen products for food AIT present specific challenges with respect to quality aspects that differentiate them from other commonly available AIT products. While established regulation is available and provides clear guidance for most aspects, other issues require consideration of new and individual settings relevant here. Consequently, as experience grows, respective amendments to currently available guidance may be needed.

Increased risk of asthma at age 10 years for children sensitized to multiple allergens.

BACKGROUND: Childhood sensitization patterns have been previously found to be related to variable risk of early life allergic disease in several birth cohorts. OBJECTIVE: To determine whether these risks persist into later childhood. METHODS: In the birth cohort of the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study, previous latent class analysis based on sensitization to 10 allergens found the following 4 early life sensitization patterns at age 2 years: "highly sensitized," "milk/egg dominated," "peanut and inhalant(s)," and "low to no sensitization." At an age 10 study-specific visit, children were evaluated by an allergist for current asthma and atopic dermatitis through a physical examination and interviews with the child and parent or guardian. Total and specific immunoglobulin E (IgE), spirometry, and methacholine challenge were also completed. RESULTS: Compared with children sensitized to none or 1 allergen, children sensitized to 4 or more food and inhalant allergens at age 2 had the highest risk of current asthma (relative risk [RR], 4.42; 95% confidence interval [CI], 2.58-7.59; P < .001) and bronchial hyperresponsiveness (RR, 1.77; 95% CI, 1.29-2.42; P < .001). In addition, they had the highest levels of total IgE (geometric mean, 800 IU/mL; 95% CI, 416-1536) among the 4 groups. Risk of current atopic dermatitis did not depend on pattern of sensitization but remained increased for children with any sensitization (RR, 2.23; 95% CI, 1.40-3.55; P < .001). No differences in spirometry (forced expiratory volume in 1 second, forced expiratory flow between 25% and 75%, and forced expiratory volume in 1 second/forced vital capacity) were identified. CONCLUSION: The previously reported importance of a specific pattern of sensitization in early life (sensitization to ≥4 inhalant and food allergens) continues to be associated with an increased risk of asthma, bronchial hyperresponsiveness, and high total IgE at age 10 years.