Opposing actions of (R,R)-isomers and (S,S)-isomers of formoterol on T-cell function.
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Adrenergic beta-Agonists↗
Biomedical subjects
Larry Borish
Publications and source records attributed to Larry Borish.
Proinflammatory effects of IL-4 antagonism.
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Cells, Cultured↗
3. Cytokines and chemokines.
Cytokines and chemokines are secreted proteins with growth, differentiation, and activation functions that regulate the nature of immune responses. Cytokines are involved in nearly every facet of immunity and inflammation, from induction of the innate immune response to the generation of cytotoxic T cells and the development of antibodies by the humoral immune system. The combination of cytokines that are produced in response to an immune insult determines which arm of the immune system will be activated. For this update, recent advances in our understanding of cytokines will be discussed, which includes the IL-10, IL-17, and IL-27 families.
Animals↗
Rhinosinusitis: developing guidance for clinical trials.
The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication "Rhinosinusitis: Establishing definitions for clinical research and patient care" and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.
Chronic Disease↗
Genetics of allergic disease.
Currently, more than 20.3 million Americans report having asthma and an even greater number suffer from allergies. The cost for treatment of these dis-eases in the United States is greater than $8 billion with more than 40% of this total representing drug expenditure [59]. An intense effort has been made to understand the genetic components of asthma and allergies and how the identified genetic differences influence disease progression and response to drugs. In the future, it will be possible in the clinical setting to analyze a patient's genetic repertoire. From this information, the physician will gain in-sight into the genes involved in producing that subject's allergic and asthmatic phenotype; understand the natural history of that patient's disease;and predict responses (positive and negative) to pharmacologic agents. The end result will be the ability to tailor a specific treatment regime for each patient and reduce the overall cost of health care related to allergies and asthma.
Asthma↗
Rhinosinusitis: Developing guidance for clinical trials.
The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication, "Rhinosinusitis: Establishing definitions for clinical research and patient care" and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.
Chronic Disease↗
High prevalence of skin test positivity in severe or difficult-to-treat asthma.
BACKGROUND: Skin tests are considered the gold standard for detecting allergen-specific immunoglobulin E (IgE) in the clinical setting and are an important tool for diagnosing and managing allergic asthma. OBJECTIVE: To assess the prevalence of skin testing in patients > or = 12 years enrolled in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS: Patients were asked whether they had ever been skin tested and, if so, they were asked to provide the test results. Clinical characteristics were used to compare positive (ST+), negative (ST-), and skin test not done (STND) patients. RESULTS: Of 2,985 patients eligible, 85.8% recalled being skin tested. Of those tested, 93.5% were positive (allergist 95.7%, pulmonologist 87.3%). A high proportion of Whites (93.5%) and non-Whites (94.0%) were ST+; however, more non-Whites had never been skin tested (21.7% vs. 12.3%, respectively; p < 0.0001). Total serum IgE was 104.6 IU/mL for ST+ patients, 87.1 IU/mL for STND patients, and 32.4 IU/mL for ST- patients. Age at asthma onset, duration of asthma, and the prevalence of atopic disorders and asthma triggers differentiated the ST+ from the ST- group. Disease severity appeared similar between the two groups. In general, values for STND patients were closer to the ST+ group, suggesting that those not tested would have been ST+ if administered a test. CONCLUSIONS: The prevalence of ST+ patients was high in allergy and pulmonology practices, and in White and non-White patients. These data support the utility of a more complete allergic evaluation in severe asthmatics. Skin testing appears associated with disease pathophysiologies in asthma.
Adult↗
Fungi in chronic hyperplastic eosinophilic sinusitis: reasonable doubt.
Chronic hyperplastic eosinophilic sinusitis (CHES) is a T-helper (Th)2-like, lymphocyteinitiated, eosinophil-rich inflammatory disease. The complex immune interactions required to orchestrate these processes begin with the presentation of antigen by mature dendritic cells to Th lymphocytes that display the appropriate antigen-specific T-cell receptor. The objective of sinus research must be to identify and target that antigen; this will lead to the cure for this condition. This article reviews numerous models that may be responsible for the pathophysiology of this disorder, including putative roles for allergens, bacteria, and bacterial-derived superantigens, as well as recent interest in fungal-derived antigens. Additionally, we speculate that whatever the inciting cause of CHES may be, it is plausible that once initiated, cellular differentiation pathways may lead to the development of an antigen-independent permanent phase. More than one of these may be valid in different subjects and, furthermore, this list almost assuredly does not explain all cases of CHES. The concept that fungal antigens colonizing the sinuses are responsible for CHES represents an intriguing, but unproven, hypothesis. Presently, the case for the fungus remains circumstantial. The case for fungi will be proved only with definitive proof that T-cells within the sinuses are actively responding to fungal antigens present in the sinus and with the further demonstration that removal of those fungal antigens ameliorates the disease.
Antigens, Bacterial↗
Maybe rhinitis, maybe sinusitis, maybe rhinitis and sinusitis, but certainly not rhinosinusitis!
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Humans↗
Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma.
BACKGROUND: Patients with aspirin sensitivity experience hyperplastic sinusitis and nasal polyposis. We speculated that similar mechanisms could be acting in the lower airway and that these individuals would demonstrate more severe asthma and irreversible loss of lung function. OBJECTIVE: We sought to investigate the role of aspirin-exacerbated respiratory disease (AERD) as a risk factor for the development of irreversible airway obstruction. METHODS: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is a multicenter observational study of subjects with severe or difficult-to-treat asthma. Data were compared between subjects who reported asthma exacerbation after aspirin ingestion and those who did not. The primary measure of bronchodilator-resistant obstruction (possible remodeling) was the maximally achieved postbronchodilator spirometry averaged over the 3-year duration of the study. RESULTS: Adult subjects (>/=18 years) with AERD (n = 459) were compared with subjects with non-aspirin-sensitive asthma (n = 2848). Subjects with AERD had significantly lower mean postbronchodilator percent predicted FEV(1) compared with subjects with non-aspirin-sensitive asthma (75.3% vs 79.9%, P < .001). Differences in spirometry between the 2 cohorts persisted after controlling for potential confounding variables. In addition, subjects with AERD were more likely to have severe asthma by means of physician assessment (66% vs 49%, P < .001), to have been intubated (20% vs 11%, P < .001), to have a steroid burst in the previous 3 months (56% vs 46%, P < .001), and to have required high-dose inhaled corticosteroids (34% vs 26%, P < .001). CONCLUSIONS: These data suggest that aspirin sensitivity is associated with increased asthma severity and possible remodeling of both the upper and lower airways.
Adolescent↗
Comparison of test devices for skin prick testing.
BACKGROUND: Allergy skin testing guides developing avoidance plans and writing an immunotherapy prescription. The goal for the allergist is to apply allergen skin testing to the appropriate patient population by using a device that minimizes both false-negative and false-positive findings while minimizing patient discomfort. New skin testing devices continue to be developed with a trend toward production of multiheaded devices. Data on the performance of these devices in a head-to-head prospective fashion are limited. OBJECTIVE: Our goal was to study 8 commonly used devices to compare their performance in a head-to-head fashion. METHODS: In a prospective, double-blind fashion, the performance of 8 skin test devices was evaluated. Devices were tested with histamine and saline on both the arms and back of each subject. Devices were rotated over 4 testing sessions, at least a week apart, so each device was tested in each anatomic testing location. Performance elements examined included wheal, flare, pain, sensitivity, specificity, and intradevice variability. RESULTS: We found significant differences in all areas of device performance among all devices examined. Multiheaded devices also demonstrated significant intradevice variability and were more painful than single devices. Furthermore, multiheaded devices had larger reactions on the back, whereas single devices had larger reactions on the arms. CONCLUSION: Statistically significant differences exist among all devices tested. Providers should consider this data when choosing a device that suits their practice setting and ensure that technicians are sufficiently trained on the correct use of that device.
Adult↗
The diagnosis and management of sinusitis: a practice parameter update.
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Adult↗
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.
Adolescent↗
Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease.
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a disease of intense eosinophilic inflammation that can produce fibrosis, hyperplasia, and remodeling. OBJECTIVE: To investigate the usefulness of quantifying severity of chronic hyperplastic eosinophilic sinusitis in predicting the presence of AERD. METHODS: Data were compared between asthmatic patients who reported exacerbations after aspirin ingestion and those who did not. The primary outcome measure was severity of sinusitis using a validated computed tomography (CT) scan-based scoring system. Indices of lower airway remodeling and other markers of inflammation were also evaluated. RESULTS: Twenty-one patients with AERD were compared with 19 patients with aspirin-tolerant asthma (ATA). Patients were well matched for asthma severity as shown by their similar lung function as measured by postbronchodilator forced expiratory volume in 1 second. Patients with AERD were distinguished by their sinus CT scores (AERD patients: 16.9; 95% confidence interval [CI], 13.4-21.3; ATA patients: 6.2; 95% CI, 4.2-9.1; P < .001), and they were considerably more likely to have nasal polyps (AERD patients: 90%; ATA patients: 26%; P < .001). In addition, AERD patients demonstrated increased total lung capacity (AERD patients: 107.9%; 95% CI, 99.9%-117.6%; ATA patients: 98.0%; 95% CI, 93.7%-102.5%; P = .05), reflecting a trend toward increased air trapping. No significant differences occurred in diffusing capacity, exhaled nitric oxide, eosinophilia, or exhaled breath condensate pH. CONCLUSIONS: AERD can be distinguished from ATA by the extent of hyperplasia on CT scan and the presence of nasal polyps. We hypothesize that AERD represents a remodeling process that affects both the upper and lower airways.
Adult↗
Functional analysis of -571 IL-10 promoter polymorphism reveals a repressor element controlled by sp1.
Transcriptional dysregulation of the IL-10 gene may contribute to the development and severity of autoimmune, infectious, neoplastic, and allergic diseases. A C to A base substitution has been identified at -571 bp in the IL-10 promoter and has been linked to immune diseases. The role of this polymorphism in IL-10 promoter function was assessed using luciferase reporter constructs. The presence of an A at -571 (A allele) increases promoter activity compared with that of a promoter with a C at this position (C allele). Binding of nuclear extract proteins from IL-10-producing human cell lines to DNA sequences including this base exchange and flanking sequences was demonstrated using EMSAs. Specific binding of the transcription factors Sp1 and Sp3 was demonstrated to a region immediately upstream of the polymorphism. No differences in the binding affinity of recombinant Sp1 were observed between the two forms of the promoter. Reconstitution of Sp1 expression decreased IL-10 promoter function in an Sp1-deficient cell line, demonstrating that this element functions as a repressor. The C to A base exchange relieves the repression mediated by Sp1. Individuals carrying the A allele of the IL-10 promoter may display increased synthesis of IL-10, resulting in suppressed immune responses and a modulation of their susceptibility to autoimmune, infectious, neoplastic, or atopic disease.
B-Lymphocytes↗
Leukotriene receptors in rhinitis and sinusitis.
Cysteinyl leukotrienes (CysLTs) mediate their biologic activities through interactions with the CysLT1 and CysLT2 receptors. CysLT1 receptors are prominently expressed on smooth muscle cells and lung fibroblasts, whereas CysLT2 receptors are expressed on heart Purkinje fiber cells, adrenal chromaffin cells, and endothelial cells. Both receptors are expressed on eosinophils and mast cells, but CysLT1 receptors alone are on neutrophils. Antigen-presenting cells more prominently express the type 2 receptor. CysLT1 receptors are uniquely important for bronchospasm, whereas CysLT2 receptors can stimulate endothelial cell adherence, myofibroblast proliferation, and chemokine production by mast cells. Comprehensive inhibition of the proinflammatory activities of CysLTs might require either combination CysLT1 and CysLT2 receptor antagonists or inhibitors of the CysLT synthesis pathway.
Chronic Disease↗
Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.
BACKGROUND: Fatal reactions associated with skin testing and injection immunotherapy have not been surveyed in North America since 1989. OBJECTIVE: A survey of fatal reactions related to skin testing and immunotherapy and of near-fatal immunotherapy reactions that transpired from 1990 through 2001 was conducted among member practices of the American Academy of Allergy, Asthma and Immunology. METHODS: A short survey of fatal reactions was sent to all American Academy of Allergy, Asthma and Immunology physicians, and an 87-item follow-up detailed questionnaire was sent to those reporting fatal reactions. RESULTS: Of 2404 members, 646 (25%) responded to the short survey. There were 20 fatal immunotherapy reactions that were directly reported and 21 indirectly reported cases by local physicians. There were 273 (42% of the responding sample) reports of near-fatal reactions. It was estimated that fatal reactions occurred every 1 per 2.5 million injections, with an average of 3.4 deaths per year. One fatality was confirmed after skin prick testing with multiple food allergens. Of 17 fatal deaths described in long questionnaires, 15 were in asthmatic patients, the majority of whose symptoms were not optimally controlled. Three reactions occurred in a medically unsupervised setting. None were receiving beta-blockers, and one was taking an angiotensin-converting enzyme inhibitor. Most fatal reactions (59%) occurred with maintenance allergen doses. The onset of 3 reactions began more than 30 minutes after injections, with a significant delay in starting epinephrine. Epinephrine was not administered in 3 other fatal reactors. CONCLUSIONS: Fatal reactions to immunotherapy injections occurred at similar rates reported in previous surveys. Certain clinical practices have improved (ie, exclusion of beta-blockers), and dosing errors were infrequent. Fatal reactions to immunotherapy often occur in settings inappropriate for optimal treatment of anaphylaxis. Strict adherence to practice guidelines might prevent or minimize future fatal reactions.
Asthma↗
Identification of an Sp factor-dependent promoter in GCET, a gene expressed at high levels in germinal center B cells.
Antigen-stimulated B lymphocytes undergo genetic and phenotypic changes in germinal centers (GCs), including affinity maturation of immunoglobulin (Ig) genes and Ig heavy chain isotype switching. Expression of the Germinal Center Expressed Transcript (GCET) gene is up-regulated in murine GC B cells. The human homolog of GCET, HGAL/GCET2, is an important prognostic marker for staging lymphomas derived from GCs. To identify mechanisms that control cell type-specific transcription of GCET, we localized promoter sequences using S1 nuclease protection and functional assays. Sequences comprising a TATA-less promoter were localized to a short region upstream of multiple mRNA start sites. In functional assays, the promoter is active in cells irrespectively of endogenous GCET gene expression. In vitro binding assays identified a non-consensus binding site for Sp factors near sites of transcriptional initiation. The site binds Spl and Sp3 in nuclear extracts and recombinant Spl in vitro, and is required for full promoter function in transient promoter assays. Activation of the promoter by Spl or Sp3 in Spl/3-deficient cells was largely dependent on the Sp site. Together, these data provide the first analysis of regulatory modules necessary for GCET expression, a model for GC B cell-specific transcription.
Animals↗