Allergic Pathway Research Articles

Neonatal rhinorrhea predicts childhood asthma symptoms and increased heart rate variability

Although the link between rhinorrhea and asthma is thought to occur primarily through an allergic pathway, non-allergic pathways related to parasympathetic nervous system (PNS) signaling may be involved in manifestations of rhinorrhea and asthma. Among children living in New York City, infant rhinorrhea was associated with higher beat-to-beat heart rate variability (HRV) and predicted school age exercise-induced wheeze (EIW), emergency department (ED) visits, and hospitalizations for asthma. We hypothesized that similar associations would be observed in a demographically different cohort of children.

Mucosal penetration and clearance of gluten and milk antigens in eosinophilic oesophagitis.

The Th2 allergic pathway in eosinophilic oesophagitis (EoE) responds to food antigen exposure. To compare the presence and temporal pattern of food antigen penetration in oesophageal mucosa in active and inactive EoE and controls METHODS: Thirty-two patients with EoE (20 active) and 10 controls were asked to eliminate all wheat and/or dairy 12, 24, 48, 72 or 96hours before endoscopy. Immunostaining on endoscopic biopsies was performed for gliadin, casein and whey. Gluten, casein and whey were detected by positive staining in 17/32 (53.1%), 21/32 (65.6%), and 30/32 (92.0%) of patients, respectively. In active vs inactive EoE, 70.0% vs 25.0% (P<0.05), 80.0% vs 41.5%, and 90.0% vs 90.9% patients had detectable gliadin, casein and whey, respectively. Casein and whey (20.0% and 100%, respectively) but not gliadin, were present in controls. The gliadin staining density was greater in active compared to inactive disease at ≤ 24 vs >24hours after exposure (P=0.05) but no differences were detected when comparing active and inactive patients for casein and whey. There was greater staining density for whey than casein for all patients at ≤24hours (mean 2.14±0.91 and 1.07±1.33, P=0.02). In active EoE, IgG4 was present in 14/20 compared to one inactive patient. The oesophageal epithelium is selectively permeable and has relatively long dwell times for food antigens known to trigger EoE. The precise mechanism of antigen-specific mucosal entry and the factors that determine the induction or effector trigger of the Th2 pathway activation merit further study.

The Role of Environmental Controls in Managing Asthma in Lower-Income Urban Communities.

Children living in lower-income urban communities are at much greater risk of developing asthma, going to the emergency department for an asthma attack and being hospitalized for asthma than children living in upper- and middle-income communities. For many asthmatic children living in urban communities, especially those with greater morbidity, the allergic pathway is important in the etiology of the disease. The stages of developing allergic disease can be divided into the onset of allergic sensitization, development of allergic disease and subsequent exacerbations, and it is useful to consider the relevance of interventions at each of these stages. Indoor allergens and environmental exposures are a major contributor to allergic disease, particularly among lower socioeconomic status, urban, minority communities. These exposures include allergens, environmental tobacco smoke, combustion by-products, and mold, all of which can play an important role in asthma progression as well as morbidity. These exposures are often not found in isolation and thus these concomitant exposures need to be considered when conducting environmental interventions. There have been numerous studies looking at both primary and tertiary prevention strategies and the impact on allergic sensitization and asthma with varied results. While the outcomes of these studies have been mixed, what has emerged is the need for tertiary interventions to be targeted to the individual and to reduce all relevant exposures to which an asthmatic child is exposed and sensitized. In addition, effective intervention strategies must also consider other social determinants of asthma morbidity impacting low socioeconomic, urban communities.

Infant rhinitis and watery eyes predict school-age exercise-induced wheeze, emergency department visits and respiratory-related hospitalizations

BackgroundRhinitis and conjunctivitis are often linked to asthma development through an allergic pathway. However, runny nose and watery eyes can result from nonallergic mechanisms. These mechanisms can also underlie exercise-induced wheeze (EIW), which has been associated with urgent medical visits for asthma, independent of other indicators of asthma severity or control. ObjectiveTo test the hypothesis that rhinitis or watery eyes without cold symptoms (RWWC) in infancy predict development of EIW and urgent respiratory-related medical visits at school age, independent of seroatopy. MethodsWithin a prospective birth cohort of low-income, urban children (n = 332), RWWC was queried during the first year of life. Relative risks (RRs) for EIW, emergency department (ED) visits, and hospitalizations for asthma and other breathing difficulties at 5 to 7 years of age were estimated with multivariable models. Seroatopy was determined at 7 years of age. ResultsInfant RWWC was common (49% of children) and predicted school-age EIW (RR, 2.8; P < .001), ED visits (RR, 1.8; P = .001), and hospitalizations (RR, 9.8; P = .002). These associations were independent of infant wheeze. They were also independent of birth order, an indicator of increased risk of exposure to viruses in infancy, and infant ear infections, an indicator of sequelae of upper airway infections. The association between infant RWWC and ED visits at 5 to 7 years of age was attenuated (RR, 1.2; P = .23) when EIW at 5 to 7 years of age was included in the model, suggesting EIW mediates the association. Adjustment for seroatopy did not diminish the magnitudes of any of these associations. ConclusionThese findings suggest a nonallergic connection between infant nonwheeze symptoms and important consequences of urban respiratory health by school age through EIW.

Eosinophilic Esophagitis: Leaky Gullet or Leaky Gut?

Eosinophilic esophagitis (EoE) is a food allergen disorder driven by antigen recognition in the gastrointestinal tract. The study by Warners et al., strongly supports the esophageal epithelium as the area of disturbed permeability and primary target for initiation of the TH2-induced allergic pathway. In contrast, small bowel assessment reveals a lack of clear change in aspects of permeability compared to controls. It is not clear, however, if the available testing used for this purpose accurately assesses the mechanisms by which antigen recognition may occur in this organ. As a result, the role of the small bowel in EoE remains unclear.

Advance and prospect in studies on anaphylactoid reaction of traditional Chinese medicine injections

Because of the rapid action and high bioavailability, traditional Chinese medicine injections (TCMIs) had been widely used in clinical critical field. In recent years, with the increasing reports of clinical adverse reaction, more and more attention was paid to them, and acute allergic reaction was the main adverse reaction. Acute allergic reaction included type-I anaphylaxis reaction and anaphylactoid reaction, the latter had been found in a variety of TCMIs and accounted for 77% of adverse reaction. But the mechanism of anaphylactoid reaction was not completely understood, the standard animal model for TCMIs was not established, and the technical guidance for anaphylactoid reaction was not formulated. Thus the three aspects included mechanism, evaluation index and evaluation methods of TCMIs for anaphylactoid were reviewed. Five ways including direct stimulating pathway, complement pathway, coagulation pathway, kallikrein-kinin pathway and acute allergic pathway were the main mechanism of anaphylactoid reaction; whole animal model and cell model were the main evaluation methods; the occurrence index and effect index were reviewed for the evaluation index analysis.

An overview of the effects of anti-IgE therapies.

Omalizumab, a humanized mAb that binds to the CH3 domain near the binding site for the high-affinity type-I IgE Fc receptors of human IgE, can neutralize free IgE and inhibit the IgE allergic pathway without sensitizing mast cells and basophils. We found that omalizumab in patients with severe persistent asthma (SPA) was an effective therapy for asthma and the following co-morbid conditions: chronic urticaria (CU), bee venom allergy, latex allergy, atopic dermatitis, food allergy and Samter’s syndrome. Information on the use of omalizumab in treatment of asthma and other allergic diseases has improved our understanding that treatment acts on many levels, including regulating levels of inflammatory proteins, including cytokines (copper-containing alpha- 2-glycoprotein, total antioxidant capacity, MDA, NO, H2O2, CXCL8, IL-10, TGF-β, GMCSF, IL-17, IL-1β), MPV, Hs-CRP, eosinophil cationic peptide, vitamin-D (25(OH)D), homocysteine (Hcy), OX-2, d- dimer, albumin, and sApo-2L. The decrease in Hcy concentrations and increase in 25(OH)D also support the existence of a vascular endothelial protection mechanism. Mediators and cells classically involved in pro-coagulant and anticoagulant pathways together play a role in SPA and CU pathophysiology and omalizumab effect.The mechanism of action of omalizumab in the treatment of asthma is believed to be multifactorial, and includes effects mediated through altered production of redox metabolites, extrinsic coagulation pathway, oxidative markers-related mi RNA, TRAIL-related mi RNA, and regulation of production of known inflammatory proteins

There Might be a Risk of Anaphylaxis Due to Omalizumab (Anti-IgE) Therapy

Omalizumab, a humanized mAb that binds to the CH3 domain, near the binding site for the high-affinity type-I IgE Fc receptors of human IgE, can neutralize free IgE and inhibit the IgE allergic pathway without sensitizing mast cell and basophils. The clinical experience during the patient follow-up of an omalizumab treated severe persistent allergic asthma patient with complicated viral infection is introduced. A female patient (aged 58) with severe persistent allergic asthma, on omalizumab therapy had laryngeal oedema during a complicated common cold infection with bacterial sinusitis after omalizumab injection. Systemic steroids, ketotifen fumarate, antibiotic and antihistamines (desloratadine) were given. We did not stop omalizumab therapy. To our knowledge, this is the first time an association between omalizumab use and laryngeal oedema has been documented. In fact we do not know the exact mechanism behind this relationship. In conclusion we do not suggest Omalizumab during the first five days of complicated viral infections such as common cold and bacterial sinus infections.

Biologic therapy for atopic asthma and beyond

Most asthma patients are easily managed with a standard combination of therapies consisting of inhaled controller and reliever drugs, but there remains a large unmet need at the severe end of the disease spectrum. For these patients, development of safer and more effective therapies for asthmatic patients with severe refractory disease remains a top priority. Here, drugs in development for the severe asthma sufferers and their specific mechanism-based pharmacological rationale will be reviewed with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Here, the authors will review the existing efficacy and safety data from clinical trials of some of the new biologic therapies that are in development for severe asthma. Despite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics have been largely disappointing. However, there is scope for their specific role in distinctively targeted subpopulations of severe asthmatic patients. It is clear that more efforts should be devoted towards establishing new and more efficient key targets. A closer interaction between industry, academia and health workers will be required to achieve this goal effectively.

Stratified approaches to the treatment of asthma

While asthma is a chronic inflammatory disorder that is managed with inhaled controller and reliever drugs, there remains a large unmet need at the severe end of the disease spectrum. Here, a novel stratified approach to its treatment is reviewed, based upon identification of causal pathways, with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Despite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics in moderate to severe asthma as a group have been disappointing. However, subgroup analyses based upon pathway-specific biomarkers suggest specific endotypes that are responsive. Application of hypothesis-free analytical approaches (the 'omics') to well-defined phenotypes is leading to the stratification of asthma along causal pathways. Refinement of this approach is likely to be the future for diagnosing and treating this group of diseases, as well as helping to define new causal pathways. The identification of responders and nonresponders to targeted asthma treatments provides a new way of looking at asthma diagnosis and management, especially with biologics that are costly. The identification of novel biomarkers linked to well-phenotyped patients provides a stratified approach to disease management beyond simple disease severity and involving causal pathways. In order to achieve this effectively, a closer interaction will be required between industry (therapeutic and diagnostic), academia and health workers.

Use of animal models to investigate major allergens associated with food allergy.

Food allergy is an emerging epidemic that affects all age groups, with the highest prevalence rates being reported amongst Western countries such as the United States (US), United Kingdom (UK), and Australia. The development of animal models to test various food allergies has been beneficial in allowing more rapid and extensive investigations into the mechanisms involved in the allergic pathway, such as predicting possible triggers as well as the testing of novel treatments for food allergy. Traditionally, small animal models have been used to characterise immunological pathways, providing the foundation for the development of numerous allergy models. Larger animals also merit consideration as models for food allergy as they are thought to more closely reflect the human allergic state due to their physiology and outbred nature. This paper will discuss the use of animal models for the investigation of the major food allergens; cow's milk, hen's egg, and peanut/other tree nuts, highlight the distinguishing features of each of these models, and provide an overview of how the results from these trials have improved our understanding of these specific allergens and food allergy in general.

Beneficial Effect of Anti-Interleukin-33 on the Murine Model of Allergic Inflammation of the Lower Airway

Objective. Interleukin (IL)-33, which mediates the Th2 allergic pathway, may play a key role in allergic airway inflammation. This study was conducted to evaluate the therapeutic potential of anti-IL-33 antibody for treatment of allergic inflammation of the lower airway in a murine model. Methods. Twenty-four BALB/c mice were used in this study. Saline was used for sensitization and challenge of mice in Group A (control group, n = 6). Mice in Group B (ovalbumin (OVA) group, n = 6) received intraperitoneal (ip) and intranasal OVA challenge. In Group C (control IgG group, n = 6), mice received ip injection with control IgG prior to OVA challenge. Mice in Group D (anti-IL-33 group, n = 6) received an ip injection of anti-IL-33 prior to challenge. Measurements of serum total and OVA-specific IgE and the number of eosinophils, neutrophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid were performed. We performed histopathologic examination to evaluate the degree of eosinophilic infiltration in lung tissue. Airway hyperreactivity was measured according to change of enhanced pause (Penh). Results. A significant decrease in serum total and OVA-specific IgE and the number of eosinophils and neutrophils in BAL fluid was observed in Group D, compared with Group B or Group C (p < .05). In Group D, treatment with anti-IL-33 resulted in a significant decrease in eosinophilic infiltration in lung tissue, compared with Group B and Group C (p < .05). Degree of airway hyperreactivity, measured by Penh, showed a significant decrease in the anti-IL-33 treatment group, compared with the OVA group or the control IgG treatment group (p < .01, at 50 mg/mL of methacholine). Conclusions: Anti-IL-33 has therapeutic potential for treatment of allergic inflammation of the lower airway.

Eosinophilic Esophagitis: Allergic Contribution, Testing, and Management

Both basic science and clinical data indicate a strong role for allergy as a cause of eosinophilic esophagitis. As a result, one of the desired goals of therapy is identification and elimination of food antigens that trigger the allergic inflammatory pathway. Traditional methods for identification of causative food antigens include induction of symptoms with exposure to the antigen, demonstration of serum IgE antibodies against antigens and induction of immediate (IgE) or delayed (Th2) reactions against dermal instillation of antigens. Although some data support the use of these tests in patients with eosinophilic esophagitis, they are limited in this disease. This limitation results from an inability to provoke recognizable symptoms and a lack of concordance between allergies identified in the skin and the blood with the antigens that trigger esophageal disease. As a result, allergy therapy in eosinophilic esophagitis consists of global elimination of food antigens with an elemental diet or exclusion of the most common antigens. As compliance is difficult with these strategies, the mainstay of allergy therapy in eosinophilic esophagitis has become the use of medications that blunt the allergic pathway such as steroids with a future aimed toward more specific inhibitors of this pathway in eosinophilic esophagitis specifically.

Asthma symptoms in early childhood – what happens then?

To study the outcome in early adulthood for children with early asthma symptoms and to analyse the factors associated with current asthma. In a prospective study, we have re-investigated 89/101 children who were hospitalized before the age of two years due to wheezing. The children were investigated using a questionnaire and allergy and bronchial hyper-responsiveness tests at the age of 17-20 years and compared with age-matched controls. In the cohort, 43% had had asthma symptoms in the preceding 12 months compared with 15% in the control group. The strongest risk factors for asthma were current allergy, bronchial hyper-responsiveness and female gender. Female gender and passive smoking in infancy were independent infantile risk factors. In addition to female gender, two pathways led to current asthma: an allergic pathway from family atopy via the development of allergy and another pathway from early passive smoking via hyper-responsiveness and active smoking. In children with early wheezing disorder, current allergy, bronchial hyper-responsiveness and female gender were the strongest risk factors for asthma in early adulthood, while female gender and passive smoking in infancy were independent infantile risk factors. The effects of early passive smoking persist longer than previously reported.

Asthma symptoms in early childhood – what happens then?

Abstract Aim: To study the outcome in early adulthood for children with early asthma symptoms and to analyse the factors associated with current asthma. Methods: In a prospective study, we have re‐investigated 89/101 children who were hospitalized before the age of two years due to wheezing. The children were investigated using a questionnaire and allergy and bronchial hyper‐responsiveness tests at the age of 17–20 years and compared with age‐matched controls. Results: In the cohort, 43% had had asthma symptoms in the preceding 12 months compared with 15% in the control group. The strongest risk factors for asthma were current allergy, bronchial hyper‐responsiveness and female gender. Female gender and passive smoking in infancy were independent infantile risk factors. In addition to female gender, two pathways led to current asthma: an allergic pathway from family atopy via the development of allergy and another pathway from early passive smoking via hyper‐responsiveness and active smoking. Conclusion: In children with early wheezing disorder, current allergy, bronchial hyper‐responsiveness and female gender were the strongest risk factors for asthma in early adulthood, while female gender and passive smoking in infancy were independent infantile risk factors. The effects of early passive smoking persist longer than previously reported.

The Editors’ Choice

The Editors’ Choice