Canning B.J.,Johns Hopkins Asthma and Allergy Center
Pulmonary Pharmacology and Therapeutics | Year: 2011
At least 2 airway vagal afferent nerve subtypes can directly initiate coughing upon activation. The capsaicin-insensitive, acid-sensitive mechanoreceptors innervating the larynx, trachea and large bronchi regulate coughing in both conscious and anesthetized animals. Activation of capsaicin-sensitive C-fibers innervating these airways will also produce coughing, but C-fiber dependent cough is prevented entirely by anesthesia. The different stimuli activating these afferent nerve subtypes and their differential sensitivity to anesthesia implies the existence of 2 parallel pathways for cough, and by extension, 2 types of cough, one essential and homeostatic, the second nonessential and pathophysiologic. The basic properties of the afferent nerves regulating cough, their interactions both centrally and peripherally and their responsiveness to tussive stimuli are briefly reviewed. Also reviewed is evidence against the notion of 2 completely separate types of cough regulated by parallel afferent pathways, asserting instead that multiple afferent nerve subtypes contribute to all types of cough. © 2011.
Saini S.S.,Johns Hopkins Asthma and Allergy Center
Journal of Investigative Dermatology | Year: 2014
ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H1 antihistamine treatment at licensed doses. Patients aged 12-75 years with CIU/CSU who remained symptomatic despite treatment with approved doses of H1 antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of follow-up. The primary end point was change from baseline in weekly itch severity score (ISS) at week 12. Among randomized patients (N=319: placebo n=80, omalizumab 75 mg n=78, 150 mg n=80, 300 mg n=81), 262 (82.1%) completed the study. Compared with placebo (n=80), mean weekly ISS was reduced from baseline to week 12 by an additional 2.96 points (95% confidence interval (CI): -4.71 to -1.21; P=0.0010), 2.95 points (95% CI: -4.72 to -1.18; P=0.0012), and 5.80 points (95% CI: -7.49 to -4.10; P<0.0001) in the omalizumab 75-mg (n=77), 150-mg (n=80), and 300-mg groups (n=81), respectively. The omalizumab 300-mg group met all nine secondary end points, including a significant decrease in the duration of time to reach minimally important difference response (≥5-point decrease) in weekly ISS (P<0.0001) and higher percentages of patients with well-controlled symptoms (urticaria activity score over 7 days (UAS7) ≤6: 51.9% vs. 11.3%; P<0.0001) and complete response (UAS7=0: 35.8% vs. 8.8%; P<0.0001) versus placebo. During the 24-week treatment period, 2 (2.9%), 3 (3.4%), 0, and 4 (5.0%) patients in the omalizumab 75-mg, 150-mg, 300-mg, and placebo groups, respectively, experienced a serious adverse event. Omalizumab 300 mg administered subcutaneously every 4 weeks reduced weekly ISS and other symptom scores versus placebo in CIU/CSU patients who remained symptomatic despite treatment with approved doses of H1 antihistamines.Journal of Investigative Dermatology advance online publication, 21 August 2014; doi:10.1038/jid.2014.306.
Hamilton R.G.,Johns Hopkins Asthma and Allergy Center
Archives of Pathology and Laboratory Medicine | Year: 2010
Context.-The diagnostic algorithm for human allergic disease involves confirmation of sensitization by detection of allergen-specific immunoglobulin E (IgE) antibody in individuals suspected of having allergic disease because of a history of allergic symptoms after known allergen exposure. Previous studies showed wide disparity among clinically reported allergen-specific IgE levels from different serologic assays. Objective.-To validate the relative analytic performance (sensitivity, interassay reproducibility, linearity/parallelism, intermethod agreement) of clinically used total and allergen-specific IgE assays by using College of American Pathologists' Diagnostic Allergy "SE" Proficiency Survey data. Design.-Data from 2 SE survey cycles were used to assess relative analytic performance of the ImmunoCAP (Phadia), Immulite (Siemens Healthcare-Diagnostics), and HYTEC 288 (HYCOR-Agilent Technologies) total and allergen-specific IgE assays. In each cycle, 2 recalcified plasma pools from atopic donors were diluted twice with IgE-negative serum and evaluated in approximately 200 federally certified clinical laboratories for total IgE and IgE antibody to 5 allergen specificities. Statistical analysis evaluated analytic sensitivity, linearity, reproducibility, and intermethod agreement. Results.-Interlaboratory intramethod, intermethod, and interdilution agreement of all 6 clinically used total serum IgE assays were excellent, with coefficients of variation (CVs) below 15%. Interlaboratory intramethod, and interdilution agreement of 3 clinically used allergenspecific IgE assays were also excellent with CVs below 15%. However, intermethod CVs identified between-assay disagreement greater than 20% in 80% of allergen-specific IgE measurements. Allergen reagents and patients' immune response heterogeneity are suggested probable causes. Conclusions.-Clinical total and allergen-specific IgE assays display excellent analytic sensitivity, precision, reproducibility, and linearity. Marked variability in quantitative estimates of allergen-specific IgE from clinically used automated immunoassays is a concern that may be ameliorated with component allergen use.
Canning B.J.,Johns Hopkins Asthma and Allergy Center
Otolaryngologic Clinics of North America | Year: 2010
Bronchopulmonary C fibers and acid-sensitive, capsaicin-insensitive mechanoreceptors innervating the larynx, trachea, and large bronchi regulate the cough reflex. These vagal afferent nerves may interact centrally with sensory input arising from afferent nerves innervating the intrapulmonary airways or even extrapulmonary afferents such as those innervating the nasal mucosa and esophagus to produce chronic cough or enhanced cough responsiveness. The mechanisms of cough initiation in health and in disease are briefly described. © 2010 Elsevier Inc. All rights reserved.
Macglashan Jr. D.W.,Johns Hopkins Asthma and Allergy Center
Journal of Allergy and Clinical Immunology | Year: 2013
Both the treatment of patients with allergic diseases and the study of allergic disease mechanisms depend on a wide variety of assays that in various ways assess the presence and function of IgE antibody. The study of allergic diseases could benefit from the study of its 2 principle cellular participants, mast cells and basophils, but the basophil is more accessible than mast cells for ex vivo studies. Its functionality is tested by using 2 predominant methodologies: the secretion of mediators of allergic inflammation and the expression of proteins on the plasma membrane after stimulation. Each approach has benefits. There are also many operational details to consider regardless of which general approach is taken, and proper interpretation of the methods requires a good understanding of the reagents used and the receptors expressed on basophils and a detailed understanding of the factors regulating aggregation of cell-surface IgE. © 2013 American Academy of Allergy, Asthma and Immunology.
MacGlashan Jr. D.,Johns Hopkins Asthma and Allergy Center
Clinical and Experimental Allergy | Year: 2010
Background Activation of human basophils results in the release of many different mediators and the expression of new cell surface proteins. The markers CD63 and CD203c have been used in recent years to assess basophil activation but there have been many studies that demonstrate that expression of these markers can be dissociated from histamine release. Objective To determine the signal transduction requirements for CD203c and CD63 expression. Methods The current study began by exploring the dependency of CD203c and CD63 expression on protein kinase C (PKC) using known selective inhibitors of PKC. Results Between 30 and 300 nm, Ro-31-8220 and bisindoylmaleimide II (Bis II) had no effect on formyl-met-leu-phe- or anti-IgE-induced CD63 or CD203c but enhanced IgE-mediated expression of CD63 by an average of 15-fold at concentrations >1 μm. These results led to the suggestion that these inhibitors altered the normal pathways of degranulation (by a non-PKC dependent mechanism), shifting the normal presence of piecemeal degranulation to the process termed anaphylactic degranulation (AND). Morphological studies demonstrated that concentrations of Ro-31-8220 and Bis II>1 μm dramatically increased the presence of degranulation sacs, a morphological feature of AND. Conclusion It is proposed that CD63 expression results from only the AND form of histamine release. © 2010 Blackwell Publishing Ltd.
Barnes K.C.,Johns Hopkins Asthma and Allergy Center
Journal of Allergy and Clinical Immunology | Year: 2010
A genetic basis for atopic dermatitis (AD) has long been recognized. Historic documents allude to family history of disease as a risk factor. Before characterization of the human genome, heritability studies combined with family-based linkage studies supported the definition of AD as a complex trait in that interactions between genes and environmental factors and the interplay between multiple genes contribute to disease manifestation. A summary of more than 100 published reports on genetic association studies through mid-2009 implicates 81 genes, in 46 of which at least 1 positive association with AD has been demonstrated. Of these, the gene encoding filaggrin (FLG) has been most consistently replicated. Most candidate gene studies to date have focused on adaptive and innate immune response genes, but there is increasing interest in skin barrier dysfunction genes. This review examines the methods that have been used to identify susceptibility genes for AD and how the underlying pathology of this disease has been used to select candidate genes. Current challenges and the potential effect of new technologies are discussed. © 2010 American Academy of Allergy, Asthma & Immunology.
Golden D.B.K.,Johns Hopkins Asthma and Allergy Center
Current Opinion in Allergy and Clinical Immunology | Year: 2010
Purpose of Review: There have been a limited number of studies examining the outcome after discontinuing venom immunotherapy (VIT), all of which showed continued protection in the great majority of patients. Several different criteria have been proposed to select patients to stop treatment based on immunologic and clinical factors. Specific high-risk factors have been reported from these published reports. There have been very few reports of the outcome more than 5 years after stopping VIT and virtually none on patients who had discontinued treatment for more than 10 years. This review will summarize the published evidence for current guidelines and recommendations, with emphasis on long-term outcomes. Recent findings: There has been a paucity of studies of VIT in recent years, particularly regarding long-term outcomes. These studies have raised questions about whether the long-term outcome is different with less than 3 years than with more than 3 years of treatment. Recent studies have confirmed the roughly 15% chance of systemic reaction to a sting after stopping VIT and the low risk (<3%) of a severe reaction. New and meaningful observations have been made in several reports regarding the increased risk of relapse, and even death, in patients with mastocytosis or elevated baseline serum tryptase, who had discontinued VIT. Summary: This review incorporates old and new observations that provide the basis for the guidelines and practice parameters on discontinuing VIT. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Barnes K.C.,Johns Hopkins Asthma and Allergy Center
Proceedings of the American Thoracic Society | Year: 2011
Asthma is a heterogeneous Disease for which a strong genetic basis is firmly established. Although the generally accepted definition includes three domains of symptoms (variable airway obstruction, airway hyper-responsiveness, and airway inflammation), there is general agreement that, rather than being a single disease entity, asthma consists of related, overlapping syndromes. A considerable proportion of asthma is IgE-mediated, but the observation that not all individuals with asthma are atopic adds to the heterogeneity. Although a genetic basis for asthma is undeniable, elucidation of polymorphisms that are "e;causal"e; is greatly hampered by variability in the clinical phenotype, which is likely due to the multiple molecular mechanisms underlying the complex pathological processes involved in disease development and progression. One objective of this review is toconsider progress that has been made to date ingene discovery in the field of asthma, with a focus on the evolution ofmolecular genetic methods that have led to the discoveries thus far, and with a particular focus on the major advances owed to the published genome-wide association studies(GWAS)on asthma to date. A second objective is to consider a Darwinian approach toward understanding the genetic underpinnings of asthma, including evidence supporting a modified Hygiene Hypothesis, which suggests that there are co-associations between asthma risk polymorphisms and polymorphisms associated with another IgE-mediated disease, schistosomiasis. The overall conclusion is that the huge research efforts and expense committed to asthma genetics have changed the perception about disease etiology in general and the functional relevance of the asthma genes identified thus far in particular.
Macglashan D.,Johns Hopkins Asthma and Allergy Center
International Archives of Allergy and Immunology | Year: 2012
Many techniques are being used to examine the status of circulating human basophils including the enhanced expression of a variety of cell surface proteins. There is accumulating evidence that there are at least two compartments containing these activation marker proteins but there are only some indications for the signaling requirements for each of the compartments. This study began with published reports by other investigators who potentially dissociated CD63 expression from anaphylactic degranulation with the p38 inhibitor, SB203580, a possible falsification of a previously proposed hypothesis regarding CD63 expression. To explore the signaling requirements for CD63, a variety of pharmacological agents were used to inhibit or enhance 4 endpoints of basophil activation. First, it was found that inhibition of both histamine release and CD63 expression with SB203580 was concordant. But it was also found that this agent had no effect on increased expression of CD203c and CD11b. Actin polymerization inhibitors caused marked enhancement of CD63 expression (concordant with their effects on degranulation) with no effect on expression of CD203c and CD11b. The third generation syk inhibitor, NVP-QAB205, showed a 5-fold lower potency for inhibiting expression of CD203c and CD11b than for CD63. Finally, while desensitization of CD11b and CD203c expression occurs, it is slower than desensitization of the CD63 response. Taken together, these various observations demonstrate a marked difference in the early signaling requirements for the CD11b/CD203c compartment and CD63 degranulation and provide support for the hypothesis that CD11b and CD203c reside in a similar compartment. Copyright © 2012 S. Karger AG, Basel.