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.).

Immune dysregulation.

The understanding of immune dysregulation in many different diseases continues to grow. There is increasing evidence that altered microbiome and gut barrier dysfunction contribute to systemic inflammation in patients with primary immunodeficiency and in patients with rheumatic disease. Recent research provides insight into the process of induction and maturation of pathogenic age-associated B cells and highlights the role of age-associated B cells in creating tissue inflammation. T follicular regulatory cells are shown to help maintain B-cell tolerance, and therapeutic approaches to increase or promote T follicular regulatory cells may help prevent or decrease immune dysregulation. Meanwhile, novel studies of systemic-onset juvenile idiopathic arthritis reveal a strong HLA association with interstitial lung disease and identify key aspects of the pathogenesis of macrophage activation syndrome. Studies of hyperinflammatory syndromes, including the recently described multisystem inflammatory syndrome of children, characterize similarities and differences in cytokine profiles and T-cell activation. This review focuses on recent advances in the understanding of immune dysregulation and describes potential key factors that may function as biomarkers for disease or targets for therapeutic interventions. Future trials are necessary to address the many remaining questions with regards to pathogenesis, diagnosis, and treatment of autoimmune, inflammatory, and immunodeficiency syndromes.

The role of biologics in pediatric food allergy and eosinophilic gastrointestinal disorders.

Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.

Treatment of food allergy: Oral immunotherapy, biologics, and beyond.

The prevalence of food allergy (FA) has been increasing globally and comes with a heavy burden not just economically, but also on quality of life. Although oral immunotherapy (OIT) is effective at inducing desensitization to food allergens, it has several limitations that weaken its success. Limitations include a long duration of build-up, especially when used for multiple allergens, and a high rate of reported adverse events. Furthermore, OIT may not be effective in all patients. Efforts are underway to identify additional treatment options, either as monotherapy or in combination, to treat FA or enhance the safety and efficacy of OIT. Biologics such as omalizumab and dupilumab, which already have US Food and Drug Administration approval for other atopic conditions have been the most studied, but additional biologics and novel strategies are emerging. In this review, we discuss therapeutic strategies including immunoglobulin E inhibitors, immunoglobulin E disruptors, interleukin-4 and interleukin-13 inhibitors, antialarmins, JAK1 and BTK inhibitors, and nanoparticles, and the data surrounding their application in FA and highlighting their potential.

Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogenous disorders characterized by childhood-onset chronic joint inflammation. It is the most common rheumatologic disease in the pediatric population and an important cause of chronic illness in children. Early recognition and treatment are vital to prevent sequelae of uncontrolled inflammation on the developing skeleton. JIA can have significant complications that general pediatricians should be aware of, especially uveitis, which can be insidious and asymptomatic in very young children, and macrophage activation syndrome, which can be life-threatening if not recognized and appropriately treated. Although advances have been made in the past few decades, the etiology of JIA remains incompletely understood. Efforts are underway to refine the classification of JIA. The currently accepted classification scheme identifies subsets of JIA that are important clinically in terms of prognosis and tailoring treatment approaches. However, it is limited in identifying homogenous groups of children with early childhood onset and antinuclear antibody positivity, which may have different pathogenic mechanisms that could be important in developing more targeted and effective treatment approaches in the future. Treatment strategies for JIA have changed significantly in recent years with the availability of multiple newer targeted therapies, often modeled after medications used in adult-onset forms of arthritis. These treatments, and likely many others to come, have markedly improved symptom control and reduced complications in patients with JIA.

No Evidence for Axions from Chandra Observation of the Magnetic White Dwarf RE J0317-853.

Axions with couplings g_{aγγ}∼few×10^{-11} GeV^{-1} to electromagnetism may resolve a number of astrophysical anomalies, such as unexpected ∼TeV transparency, anomalous stellar cooling, and x-ray excesses from nearby neutron stars. We show, however, that such axions are severely constrained by the nonobservation of x rays from the magnetic white dwarf (MWD) RE J0317-853 using ∼40 ks of data acquired from a dedicated observation with the Chandra X-ray Observatory. Axions may be produced in the core of the MWD through electron bremsstrahlung and then convert to x rays in the magnetosphere. The nonobservation of x rays constrains the axion-photon coupling to g_{aγγ}≲5.5×10^{-13}sqrt[C_{aγγ}/C_{aee}] GeV^{-1} at 95% confidence for axion masses m_{a}≲5×10^{-6} eV, with C_{aee} and C_{aγγ} the dimensionless coupling constants to electrons and photons. Considering that C_{aee} is generated from the renormalization group, our results robustly disfavor g_{aγγ}≳4.4×10^{-11} GeV^{-1} even for models with no ultraviolet contribution to C_{aee}.

Upper Limit on the QCD Axion Mass from Isolated Neutron Star Cooling.

The quantum chromodynamics (QCD) axion may modify the cooling rates of neutron stars (NSs). The axions are produced within the NS cores from nucleon bremsstrahlung and, when the nucleons are in superfluid states, Cooper pair breaking and formation processes. We show that four of the nearby isolated magnificent seven NSs along with PSR J0659 are prime candidates for axion cooling studies because they are coeval, with ages of a few hundred thousand years known from kinematic considerations, and they have well-measured surface luminosities. We compare these data to dedicated NS cooling simulations incorporating axions, profiling over uncertainties related to the equation of state, NS masses, surface compositions, and superfluidity. Our calculations of the axion and neutrino emissivities include high-density suppression factors that also affect SN 1987A and previous NS cooling limits on axions. We find no evidence for axions in the isolated NS data, and within the context of the Kim-Shifman-Vainshtein-Zakharov QCD axion model, we constrain m_{a}≲16 meV at 95% confidence level. An improved understanding of NS cooling and nucleon superfluidity could further improve these limits or lead to the discovery of the axion at weaker couplings.

Food allergy, mechanisms, diagnosis and treatment: Innovation through a multi-targeted approach.

The incidence of food allergy (FA) has continued to rise over the last several decades, posing significant burdens on health and quality of life. Significant strides into the advancement of FA diagnosis, prevention, and treatment have been made in recent years. In an effort to lower reliance on resource-intensive food challenges, the field has continued work toward the development of highly sensitive and specific assays capable of high-throughput analysis to assist in the diagnosis FA. In looking toward early infancy as a critical period in the development of allergy or acquisition of tolerance, evidence has increasingly suggested that early intervention via the early introduction of food allergens and maintenance of skin barrier function may decrease the risk of FA. As such, large-scale investigations are underway evaluating infant feeding and the impact of emollient and steroid use in infants with dry skin for the prevention of allergy. On the other end of the spectrum, the past few years have been witness to an explosive increase in clinical trials of novel and innovative therapeutic strategies aimed at the treatment of FA in those whom the disease has already manifested. A milestone in the field, 2020 marked the approval of the first drug, oral peanut allergen, for the indication of peanut allergy. With a foundation of promising data supporting the safety and efficacy of single- and multi-allergen oral immunotherapy, current efforts have turned toward the use of probiotics, biologic agents, and modified allergens to optimize and improve upon existing paradigms. Through these advancements, the field hopes to gain footing in the ongoing battle against FA.

Phase 2, randomized multi oral immunotherapy with omalizumab 'real life' study.

BACKGROUND: Oral immunotherapy (OIT) is frequently discontinued due to adverse events (AEs) and current data suggests that lowering OIT doses can minimize severity and frequency of AEs. However, the minimum daily dose that can enable desensitization and induce immune responses in multi-food OIT (mOIT) is unknown. METHODS: Participants aged 2-25 years with multi-food allergies were pretreated with fixed-dose omalizumab (150 mg, 3 doses, every 4 weeks), and randomized 1:1 to receive mOIT to a total maintenance dose of either 300 or 1200 mg total protein, (total dose includes at least two and up to a max of five allergens) and then transitioned to real-food protein equivalents after 18 weeks of treatment. The primary endpoint was the proportion of subjects with increases in IgG4/IgE ratio of at least 2 allergens by ≥25% from baseline after 18 weeks of therapy. The primary efficacy and safety analyses were done in the intention-to-treat population. RESULTS: Sixty participants were enrolled across two sites. Seventy percent of participants in both arms showed changes in sIgG4/sIgE ratio in at least 2 allergens with no difference between the treatment groups (OR [95% CI] = 1.00 [0.29, 3.49]). Overall, there were no differences in AEs between the 300 and 1200 mg groups (19% vs. 17%, p = .69), respectively. CONCLUSIONS: Our data suggest that plasma marker changes are induced early, even at a total protein dose of 300 mg inclusive of multiple allergens when mOIT is combined with fixed-dose omalizumab. Identification of optimal mOIT dosing with adjunct omalizumab is needed for the long-term success of OIT. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03181009).

Gravitino Swampland Conjecture.

We extend the swampland from effective field theories (EFTs) inconsistent with quantum gravity to EFTs inconsistent with quantum supergravity. This enlarges the swampland to include EFTs that become inconsistent when the gravitino is quantized. We propose the "gravitino swampland conjecture": the gravitino sound speed must be nonvanishing in all EFTs that are low-energy limits of quantum supergravity. This seemingly simple statement has important consequences for both theories and observations. The conjecture is consistent with and supported by the Kachru-Kallosh-Linde-Trivedi and large volume scenarios for moduli stabilization in string theory.

Identification of Pru du 6 as a potential marker allergen for almond allergy.

BACKGROUND: Oral food challenges have demonstrated that diagnosis of almond allergy based on extract-sIgE tests displays low specificity. Molecular allergy diagnosis is expected to improve accuracy, but its value in diagnosing almond allergy remains unknown. The aim of this study was to identify relevant almond allergens and examine their ability to improve almond allergy diagnosis. METHODS: IgE-reactive proteins were purified from almond kernels. IgE binding to almond extract and the allergens was analyzed by quantitative ELISA using sera from 18 subjects with a proven almond allergy. The control group consisted of sera from 18 subjects allergic to peanut and/or tree nuts but tolerant to almond. RESULTS: Three IgE-binding proteins were identified: legumin (Pru du 6), alpha-hairpinin (Pru du 8), and mandelonitrile lyase (Pru du 10). Positive IgE (≥0.35 kU/L) to almond extract showed 94% sensitivity but only 33% specificity. IgE to Pru du 6 maintained high sensitivity (83%) and provided superior specificity (78%). Sera from almond-allergic subjects had significantly higher IgE levels to almond extract (P < .0001) and Pru du 6 (P < .0001) than sera from tolerant donors. Sensitization to Pru du 6 was highly specific for almond allergy, while frequencies of sensitization to legumins from peanut, walnut, hazelnut, and cashew were similar in both groups. IgE to Pru du 8 and Pru du 10 was less sensitive (41% and 67%), but showed specificities of 100% and 61%. CONCLUSION: The use of almond allergens markedly increases the diagnostic specificity compared to the extract. Pru du 6 is a potential new molecular marker for almond allergy.

Artificial intelligence enabled applications in kidney disease.

Artificial intelligence (AI) is considered as the next natural progression of traditional statistical techniques. Advances in analytical methods and infrastructure enable AI to be applied in health care. While AI applications are relatively common in fields like ophthalmology and cardiology, its use is scarcely reported in nephrology. We present the current status of AI in research toward kidney disease and discuss future pathways for AI. The clinical applications of AI in progression to end-stage kidney disease and dialysis can be broadly subdivided into three main topics: (a) predicting events in the future such as mortality and hospitalization; (b) providing treatment and decision aids such as automating drug prescription; and (c) identifying patterns such as phenotypical clusters and arteriovenous fistula aneurysm. At present, the use of prediction models in treating patients with kidney disease is still in its infancy and further evidence is needed to identify its relative value. Policies and regulations need to be addressed before implementing AI solutions at the point of care in clinics. AI is not anticipated to replace the nephrologists' medical decision-making, but instead assist them in providing optimal personalized care for their patients.

H2-antagonist in IgE-mediated type I hypersensitivity reactions: what literature says so far?

Histamine is a monoamine synthesized from the amino acid histidine that is well-known for its role in IgE-mediated anaphylaxis but has shown pleiotropic effects on the immune system, especially in order to promote inflammatory responses. H1-receptor antagonist are common drugs used in mild/moderate allergic reactions whereas H2-receptor antagonist are commonly administered in gastric ulcer but showed some properties in allergy too. The EAACI guidelines for diagnosis and treatment of anaphylactic reactions recommend their use as third-line therapy in adjunct to H1-antagonists. The purpose of this article is to produce a complete summary of findings and evidence known so far about the usefulness of H2-receptor antagonist in allergic reactons.

Diversity of Viruses Infecting Eukaryotic Algae.

Algae are photosynthetic organisms that drive aquatic ecosystems, e.g. fuelling food webs or forming harmful blooms. The discovery of viruses that infect eukaryotic algae has raised many questions about their influence on aquatic primary production and their role in algal ecology and evolution. Although the full extent of algal virus diversity is still being discovered, this review summarizes current knowledge of this topic. Where possible, formal taxonomic classifications are referenced from the International Committee on Taxonomy of Viruses (ICTV); since the pace of virus discovery has far surpassed the rate of formal classification, however, numerous unclassified viruses are discussed along with their classified relatives. In total, we recognized 61 distinct algal virus taxa with highly variable morphologies that include dsDNA, ssDNA, dsRNA, and ssRNA genomes ranging from approximately 4.4 to 560 kb, with virion sizes from approximately 20 to 210nm in diameter. These viruses infect a broad range of algae and, although there are a few exceptions, they are generally lytic and highly species or strain specific. Dedicated research efforts have led to the appreciation of algal viruses as diverse, dynamic, and ecologically important members of the biosphere, and future investigations will continue to reveal the full extent of their diversity and impact.

Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Dietary avoidance is recommended for peanut allergies. We evaluated the sustained effects of peanut allergy oral immunotherapy (OIT) in a randomised long-term study in adults and children. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we enrolled participants at the Sean N Parker Center for Allergy and Asthma Research at Stanford University (Stanford, CA, USA) with peanut allergy aged 7-55 years with a positive result from a double-blind, placebo-controlled, food challenge (DBPCFC; ≤500 mg of peanut protein), a positive skin-prick test (SPT) result (≥5 mm wheal diameter above the negative control), and peanut-specific immunoglobulin (Ig)E concentration of more than 4 kU/L. Participants were randomly assigned (2·4:1·4:1) in a two-by-two block design via a computerised system to be built up and maintained on 4000 mg peanut protein through to week 104 then discontinued on peanut (peanut-0 group), to be built up and maintained on 4000 mg peanut protein through to week 104 then to ingest 300 mg peanut protein daily (peanut-300 group) for 52 weeks, or to receive oat flour (placebo group). DBPCFCs to 4000 mg peanut protein were done at baseline and weeks 104, 117, 130, 143, and 156. The pharmacist assigned treatment on the basis of a randomised computer list. Peanut or placebo (oat) flour was administered orally and participants and the study team were masked throughout by use of oat flour that was similar in look and feel to the peanut flour and nose clips, as tolerated, to mask taste. The statistician was also masked. The primary endpoint was the proportion of participants who passed DBPCFCs to a cumulative dose of 4000 mg at both 104 and 117 weeks. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02103270. FINDINGS: Between April 15, 2014, and March 2, 2016, of 152 individuals assessed, we enrolled 120 participants, who were randomly assigned to the peanut-0 (n=60), peanut-300 (n=35), and placebo groups (n=25). 21 (35%) of peanut-0 group participants and one (4%) placebo group participant passed the 4000 mg challenge at both 104 and 117 weeks (odds ratio [OR] 12·7, 95% CI 1·8-554·8; p=0·0024). Over the entire study, the most common adverse events were mild gastrointestinal symptoms, which were seen in 90 of 120 patients (50/60 in the peanut-0 group, 29/35 in the peanut-300 group, and 11/25 in the placebo group) and skin disorders, which were seen in 50/120 patients (26/60 in the peanut-0 group, 15/35 in the peanut-300 group, and 9/25 in the placebo group). Adverse events decreased over time in all groups. Two participants in the peanut groups had serious adverse events during the 3-year study. In the peanut-0 group, in which eight (13%) of 60 participants passed DBPCFCs at week 156, higher baseline peanut-specific IgG4 to IgE ratio and lower Ara h 2 IgE and basophil activation responses were associated with sustained unresponsiveness. No treatment-related deaths occurred. INTERPRETATION: Our study suggests that peanut OIT could desensitise individuals with peanut allergy to 4000 mg peanut protein but discontinuation, or even reduction to 300 mg daily, could increase the likelihood of regaining clinical reactivity to peanut. Since baseline blood tests correlated with week 117 treatment outcomes, this study might aid in optimal patient selection for this therapy. FUNDING: National Institute of Allergy and Infectious Diseases.

STAT3 phosphorylation mediates the stimulatory effects of interferon alpha on B cell differentiation and activation in SLE.

OBJECTIVE: Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. METHODS: Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. RESULTS: Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. CONCLUSION: IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.

Filtered Dark Matter at a First Order Phase Transition.

We describe a new mechanism of dark matter production. If dark matter particles acquire mass during a first order phase transition, it is energetically unfavorable for them to enter the expanding bubbles. Instead, most of them are reflected and quickly annihilate away. The bubbles eventually merge as the phase transition completes and only the dark matter particles that have entered the bubbles survive to constitute the observed dark matter today. This mechanism can produce dark matter with masses from the TeV scale to above the PeV scale, surpassing the Griest-Kamionkowski bound.

New Developments in Non-allergen-specific Therapy for the Treatment of Food Allergy.

PURPOSE OF REVIEW: The prevalence of food allergy is increasing. At the current time, there are no approved treatments for food allergy. Major limitations of immunotherapy are long treatment periods (months or years), frequent clinic visits, high costs, increased risk of adverse events during treatment, and lack of durability of desensitization. Additionally, it is allergen-specific, and in those allergic to multiple allergens, the length and cost of treatment are further increased. In this review, we summarize recent developments in novel non-allergen-specific treatments for food allergy. RECENT FINDINGS: A number of monoclonal antibodies that block IgE or specific pro-allergenic cytokines or their receptors have shown promise in clinical trials for food allergy. The insight we have gained through the use of one drug for the treatment of an atopic disease is quickly being translated to other atopic diseases, including food allergy. The future for food allergy treatment with biologics looks bright.

Randomized controlled trial to improve primary care follow-up among emergency department patients.

STUDY OBJECTIVE: Primary care (PC) follow-up for discharged emergency department (ED) patients provides patients with further medical attention. We conducted a pilot randomized controlled trial to determine whether using a freely-available physician appointment-booking website results in higher self-reported PC follow-up. METHODS: We randomized discharged patients whom treating physicians determined PC follow-up was important and who possessed health insurance but had no PC provider to one of three groups: (1) a PC appointment booked through the booking website prior to ED discharge; (2) written information on how to use the booking website; or (3) usual care (i.e. standard follow-up instructions). We phoned subjects two weeks after the ED visit to determine whether they had completed a PC follow-up visit. We also asked subjects about their satisfaction with obtaining a PC appointment, satisfaction with the ED visit, symptom resolution and subsequent ED visits. The self-reported PCP follow-up rate was compared among the study groups by estimating the risk difference (RD) and 95% CI between usual care and each intervention group. RESULTS: 272 subjects were enrolled and randomized and 68% completed the two-week telephone follow-up interview. The self-reported PCP follow-up rate was higher (52%) among subjects whose appointment was booked on the website before ED discharge (RD = 16%; 95% CI -1%, 34%) and lower (25%) for subjects who received booking website information (RD = 13%; 95% CI -32%, 7%) compared to subjects (36%) in the usual care group. A higher percentage of subjects in the booking group were more likely to report being extremely or very satisfied with obtaining a PC appointment (78%) compared to those who received booking website information (54%) or usual care (40%). CONCLUSION: Among ED patients that providers judged PC follow-up is important, using a booking website to schedule an appointment before ED discharge resulted in a higher but not statistically significant self-reported PC follow-up rate. This intervention warrants further investigation in a study with a larger sample size and objective follow-up visit data.

Epigenetics and the Environment in Airway Disease: Asthma and Allergic Rhinitis.

Asthma and rhinitis are complex, heterogeneous diseases characterized by chronic inflammation of the upper and lower airways. While genome-wide association studies (GWAS) have identified a number of susceptible loci and candidate genes associated with the pathogenesis of asthma and allergic rhinitis (AR), the risk-associated alleles account for only a very small percent of the genetic risk. In allergic airway and other complex diseases, it is thought that epigenetic modifications, including DNA methylation, histone modifications, and non-coding microRNAs, caused by complex interactions between the underlying genome and the environment may account for some of this "missing heritability" and may explain the high degree of plasticity in immune responses. In this chapter, we will focus on the current knowledge of classical epigenetic modifications, DNA methylation and histone modifications, and their potential role in asthma and AR. In particular, we will review epigenetic variations associated with maternal airway disease, demographics, environment, and non-specific associations. The role of specific genetic haplotypes in environmentally induced epigenetic changes are also discussed. A major limitation of many of the current studies of asthma epigenetics is that they evaluate epigenetic modifications in both allergic and non-allergic asthma, making it difficult to distinguish those epigenetic modifications that mediate allergic asthma from those that mediate non-allergic asthma. Additionally, most DNA methylation studies in asthma use peripheral or cord blood due to poor accessibility of airway cells or tissue. Unlike DNA sequences, epigenetic alterations are quite cell- and tissue-specific, and epigenetic changes found in airway tissue or cells may be discordant from that of circulating blood. These two confounding factors should be considered when reviewing epigenetic studies in allergic airway disease.