Larry Borish

Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose

BACKGROUND Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions. OBJECTIVE We sought to determine whether IgE antibodies to alpha-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb. METHODS Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens. RESULTS Twenty-four patients with IgE antibodies to alpha-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cows milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for alpha-gal. CONCLUSION We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope alpha-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.

Design and baseline characteristics of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma

BACKGROUND Patients with severe and difficult-to-treat asthma represent a small percentage of asthma patients, yet they account for much of the morbidity, mortality, and cost of disease. The goal of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is to better understand the natural history of asthma in these patients. OBJECTIVE To describe the methods and baseline characteristics of the TENOR study cohort. METHODS The TENOR study is a 3-year, multicenter, observational study of patients with severe or difficult-to-treat asthma. From January through October 2001, more than 400 US pulmonologists and allergists enrolled patients. Patients 6 years or older who were considered to have severe or difficult-to-treat asthma by their physicians were eligible. Patients have been receiving care for 1 year or more, have a smoking history of 30 pack-years or less, and have current high medication or health care utilization in the past year. Data are collected semiannually. RESULTS A total of 4,756 patients enrolled and completed a baseline visit. Overall, 73% of the TENOR study patients are adults, 10% are adolescents, and 16% are children. According to physician evaluation, 48% of patients have severe asthma, 48% have moderate asthma, 3% have mild asthma, and 96% have difficult-to-treat asthma. Severe asthmatic patients have the highest health care utilization in the past 3 months (P < .001). CONCLUSIONS The TENOR study is the largest cohort of patients with severe or difficult-to-treat asthma. Although patients are equally divided into moderate or severe asthma categories, most are considered difficult-to-treat. The TENOR study highlights the lack of control in moderate-to-severe asthma and provides a unique opportunity to examine factors related to health outcomes in this understudied population.

Th2 cytokines and asthma — Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists

Interleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma is a complex genetic disorder that has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. We report the results of initial clinical trials, which demonstrate clinical efficacy of this naturally occurring IL-4 antagonist as a therapeutic agent in asthma.

Immunologic messenger molecules: Cytokines, interferons, and chemokines

Cytokines and chemokines are secreted proteins involved in numerous aspects of cell growth, differentiation, and activation. A prominent feature of these molecules is their effect on the immune system with regard to cell trafficking and development of immune tissue and organs. The nature of an immune response determines which cytokines are produced and ultimately whether the response is cytotoxic, humoral, cell mediated, or allergic. For this chapter, cytokines are grouped according to those that are predominantly antigen-presenting cell or T lymphocyte derived; that mediate cytotoxic, humoral, cell mediated, and allergic immunity; or that are immunosuppressive. A discussion of chemokine function and their role in cell trafficking and disease follows.

The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29.

Cytokines are involved in virtually every aspect of immunity and inflammation. A cascade of responses evolves after cytokine activation, although optimal function might ultimately involve several complementary cytokines. Understanding the function of individual cytokines is complicated because their role can vary depending on the cellular source, target, and phase of the immune response. In fact, numerous cytokines have both proinflammatory and anti-inflammatory potential, with the contrasting outcome observed being determined by the immune cells present and their state of responsiveness to the cytokine. These issues make the study of cytokine biology daunting, particularly so for IL-10 and IL-10-related genes. The IL-10 superfamily is highly pleiotropic. These genes are linked together through genetic similarity and intron-exon gene structure. Significant commonality exists not only through shared receptors but also through conserved signaling cascades. However, its members mediate diverse activities, including immune suppression, enhanced antibacterial and antiviral immunity, antitumor activity, and promotion of self-tolerance in autoimmune diseases.

Update on cytokines

Summary Cytokines that are important in the pathophysiology of allergic disorders are summarized on Table V. The IgE isotype switch results from the activities of IL-4 and IL-13 and is inhibited by IFN-ggg and TGF-β. IL-2, IL-5, and IL-6 synergize with IL-4 and IL-13 to enhance IgE secretion. IL-4 is responsible for the differentiation of IL-4-producing lymphocytes, whereas IL-12 inhibits the differentiation of IL-4-producing T cells. IL-5 is the most important eosinophilopoietin, and together with GM-CSF and IL-3, prolongs the survival of and activates mature eosinophils. These three cytokines are responsible for the generation of the hypodense eosinophils which characterize the asthmatic state. Eosinophilia may also result from selective recruitment by the eosinophil chemotactic factors RANTES, MIP-1α, and eotaxin. Mast cell proliferation results from the activities of IL-3, IL-9, IL-10, nerve growth factor, and stem cell factor. Finally, several cytokines contribute to the inflammatory state of allergic disorders. IL-1, TNF, and IFN-γ increase expression of endothelial cell adhesion molecules and support the egress of mononuclear cells, neutrophils, and eosinophils into the lungs. Induction of vascular cell adhesion molecule-1 by IL-4 may promote the selective recruitment of eosinophils, basophils, and lymphocytes. Many cytokines may then contribute to the activation of these leukocytes once they have reached the airways.

Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study

BACKGROUND Identification of patients at risk for asthma exacerbations can assist physicians in addressing disease management and improve asthma-related health outcomes. OBJECTIVE We sought to evaluate whether level of impairment, as defined by the 2007 asthma guidelines, predicts risk for future asthma exacerbations. METHODS The study included children aged 6 to 11 years (n = 82) and adolescent/adult patients aged 12 years and older (n = 725) from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study with data representing all components of the impairment domain of the asthma guidelines at baseline, month 12, and month 24. Patients were categorized into 2 cohorts: (1) consistently very poorly controlled (VPC) asthma from baseline through 2 years of follow-up and (2) improved from VPC asthma at baseline (including patients who improved to not well-controlled or well-controlled asthma), with improvement maintained through 2 years of follow-up. Odds ratios (ORs) and 95% CIs for risk of asthma exacerbations at month 30 were generated by using multivariable logistic regression by age group. RESULTS After adjustment, children with consistently VPC asthma over the 2-year period demonstrated a 6-fold increased risk of hospitalization, emergency department visit, or corticosteroid burst (OR, 6.4; 95% CI, 1.2-34.5) compared with the improved group. Adolescent/adult patients with consistently VPC asthma were more likely to have a corticosteroid burst (OR, 2.8; 95% CI, 1.7-4.8) or have a hospitalization, emergency department visit, or corticosteroid burst (OR, 3.2; 95% CI, 1.9-5.3). CONCLUSIONS Consistently VPC asthma, as defined by the impairment domain of the 2007 asthma guidelines, is strongly predictive of future asthma exacerbations.

Total serum IgE levels in a large cohort of patients with severe or difficult-to-treat asthma

BACKGROUND Limited data are available on levels of IgE in large cohorts of patients with severe or difficult-to-treat asthma. OBJECTIVE To examine IgE levels and disease in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS From January 2001 to October 2001, 4,923 patients were screened for inclusion in the study. Of these, 4,756 patients 6 years or older with severe or difficult-to-treat asthma were enrolled and completed a baseline study visit. Total serum IgE levels were measured at the baseline visit and are summarized by geometric means. RESULTS The mean total IgE level of the population is 106.6 IU/mL (95% confidence interval, 101.5-112.0 IU/mL). Children (6-12 years old) and adolescents (13-17 years old) have higher mean IgE levels than adults (> or =18 years old) (P < .001). Males have a higher mean IgE level than females (P < .001). IgE levels are higher among nonwhite patients than white patients (P < .001). Current smokers have higher IgE levels than past smokers or never smokers (P < .001). Among children, patients with severe asthma have a higher mean IgE level (280.2 IU/mL) than patients with moderate (145.8 IU/mL) or mild (137.8 IU/mL) asthma (P < .001). Among adults, patients with childhood-onset asthma have higher IgE levels (124.3 IU/mL [n = 1,348]) than patients with adult-onset asthma (65.7 IU/mL [n = 1,956]) (P < .001). CONCLUSION In patients with severe or difficult-to-treat asthma from the TENOR study, higher total IgE levels were observed in males, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset disease. In addition, IgE levels are associated with asthma severity among younger patients.

Molecular and cellular staging for the severity of chronic rhinosinusitis

Objectives: To correlate objective and subjective clinical parameters with molecular, cellular, and histologic markers and to acknowledge the importance of these basic science parameters in a severity classification system for chronic rhinosinusitis (CRS).

Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis.

Background Cysteinyl leukotrienes (CysLTs) are bioactive lipids that have been shown to contribute to allergic and inflammatory diseases. Eosinophils and mast cells have the capacity to produce large amounts of CysLTs after allergic or non‐allergic stimulation. Molecular identification of both the synthetic and signalling proteins in the CysLT pathway allows the investigation of expression of the CysLT enzymes and receptors in active allergic rhinitis.