Whole blood transcriptional variations between responders and non-responders in asthma patients receiving omalizumab.

BACKGROUND: Anti-IgE (omalizumab) has been used for the treatment of moderate-to-severe asthma that is not controlled by inhaled steroids. Despite its success, it does not always provide patients with significant clinical benefits. OBJECTIVE: To investigate the transcriptional variations between omalizumab responders and non-responders and to study the mechanisms of action of omalizumab. METHODS: The whole blood transcriptomes of moderate-to-severe adult asthma patients (N = 45:34 responders and 11 non-responders) were analysed over the course of omalizumab treatment. Non-asthmatic healthy controls (N = 17) were used as controls. RESULTS: Transcriptome variations between responders and non-responders were identified using the genes significant (FDR < 0.05) in at least one comparison of each patient response status and time point compared with control subjects. Using gene ontology and network analysis, eight clusters of genes were identified. Longitudinal analyses of individual clusters revealed that responders could maintain changes induced with omalizumab treatment and become more similar to the control subjects, while non-responders tend to remain more similar to their pre-treatment baseline. Further analysis of an inflammatory gene cluster revealed that genes associated with neutrophil/eosinophil activities were up-regulated in non-responders and, more importantly, omalizumab did not significantly alter their expression levels. The application of modular analysis supported our findings and further revealed variations between responders and non-responders. CONCLUSION AND CLINICAL RELEVANCE: This study provides not only transcriptional variations between omalizumab responders and non-responders, but also molecular insights for controlling asthma by omalizumab.

Phenotypic and functional alterations of regulatory B cell subsets in adult allergic asthma patients.

BACKGROUND: IL-10-producing regulatory B cells (Bregs) are widely ascribed immune regulatory functions. However, Breg subsets in human asthma have not been fully investigated. OBJECTIVE: We studied Breg subsets in adult allergic asthma patients by assessing two major parameters, frequency and IL-10 expression. We then investigated factors that affect these two parameters in patients. METHODS: Peripheral blood mononuclear cells (PBMCs) of adult allergic asthma patients (N = 26) and non-asthmatic controls (N = 28) were used to assess the frequency of five subsets of transitional B cells (TBs), three subsets of CD24high CD27+ B cells and B1 cells. In addition to clinical data, IL-10 expression by individual Breg subsets was assessed by flow cytometry. RESULTS: Asthma patients had decreases of CD5+ and CD1d+ CD5+ , but an increase of CD27+ TBs which was significant in patients with moderate asthma (60 < FEV1 < 80). Regardless of asthma severity, there was no significant alteration in the frequencies of 6 other Breg subsets tested. However, we found that oral corticosteroid (OCS) significantly affected the frequency of Bregs in Breg subset-specific manners. OCS decreased CD5+ and CD1d+ CD5+ TBs, but increased CD27+ TBs and CD10+ CD24high CD27+ cells. Furthermore, OCS decreased IL-10 expression by CD27+ TBs, all 3 CD24high CD27+ B cell subsets (CD5+ , CD10+ and CD1d+ ) and B1 cells. OCS-mediated inhibition of IL-10 expression was not observed in the other Breg subsets tested. CONCLUSION & CLINICAL RELEVANCE: Alterations in the frequency of Bregs and their ability to express IL-10 are Breg subset-specific. OCS treatment significantly affects the frequency as well as their ability to express IL-10 in Breg subset-specific manners.

Safety and tolerability of a short ragweed sublingual immunotherapy tablet.

BACKGROUND: MK-3641 is a short ragweed sublingual tablet under investigation for immunotherapy of ragweed pollen-induced allergic rhinitis. OBJECTIVE: To characterize the safety and tolerability of a ragweed sublingual tablet (Merck/ALK-Abelló) in ragweed-allergic adults with or without conjunctivitis. METHODS: Data from 4 randomized, double-blinded, placebo-controlled trials of MK-3641 (2 28-day and 2 52-week trials) were evaluated. Pooled analyses examined short-term safety over 28 days from all 4 trials and long-term safety from the 52-week trials. RESULTS: Across all studies, 757, 198, 454, and 1,058 subjects were randomized to placebo or 1.5, 6, or 12 Amb a 1-U of MK-3641, respectively. Treatment-related adverse events were more frequent in the 6- and 12-Amb a 1-U MK-3641 groups than in the placebo group and were primarily local application-site reactions occurring in the first few days of treatment. There was no treatment-associated loss of asthma control or worsening of asthma associated with treatment. No swellings led to airway obstruction or respiratory compromise. No treatment-related anaphylactic shock, life-threatening, or serious treatment-related adverse events were reported for any MK-3641 dose. Of the 1,707 MK-3641-treated subjects, 1 systemic (anaphylactic) reaction was reported (0.06%). The 52-week long-term assessment was generally similar to the safety profile based on the 28-day assessment. CONCLUSION: MK-3641 doses up to and including 12 Amb a 1-U were well tolerated, with no unexpected safety findings. Sublingual immunotherapy risks such as worsening asthma or airway swellings that could cause airway obstruction were not observed. Systemic reactions and use of epinephrine were uncommon. In these studies, after the first dose was administered in a health care setting, self-administration was well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01469182, NCT00783198, NCT00770315, and NCT00978029.

Beclomethasone dipropionate nasal aerosol with an integrated dose counter: functionality and performance.

Consistent medication delivery is critical for disease control including symptom management of allergic rhinitis (AR). Available aqueous intranasal corticosteroid devices lack an accurate dose (actuation) counter, which may lead patients to prematurely discard a unit or use a unit beyond its labeled number of actuations, therefore impacting patient adherence. Beclomethasone dipropionate (BDP) nasal aerosol, a nonaqueous hydrofluoroalkane formulation in a device with a novel integrated dose counter and an established efficacy/safety profile, was approved to treat AR-associated nasal symptoms in adolescent and adult patients. This study was designed to evaluate performance of the BDP nasal aerosol device with an integrated dose counter in perennial AR (PAR) patients. In a 6-week, double-blind, placebo-controlled study in PAR patients (≥12 years), patients were randomized to receive once-daily BDP nasal aerosol at 320 micrograms or placebo. In addition to assessing the primary efficacy end point, patients evaluated the performance of the device and reliability, accuracy, and functionality of the dose counter. Concordance between daily patient-reported actuations and dose counter readings was assessed by classifying discrepancies into four categories: "fire not count," "count not fire," "count unknown fire," and "count up unknown fire." Analysis was performed for the total device completer population (n = 374), which included all randomized patients completing ≥80% of actuations during the last 4 weeks of treatment. Low discrepancy rates were shown for all discrepancy categories. Of 41,891 patient-reported actuations, only 159 discrepancies (diary versus counter) were noted, resulting in an overall discrepancy rate of 0.38 per 100 actuations. The medically important discrepancy rate of "fire not count" was low (0.09 per 100 actuations). Overall, 79.1% of patients reported zero discrepancies, 9.4% reported one discrepancy, and 6.4% reported two discrepancies. These results showed the functionality and reliability of the BDP nasal aerosol device with an integrated dose counter in a clinical setting. (ClinicalTrials.gov identifier: NCT01134705.).

Mometasone furoate nasal spray reduces the ocular symptoms of seasonal allergic rhinitis.

BACKGROUND: Mometasone furoate nasal spray (MFNS), a potent intranasal corticosteroid with proved efficacy in relieving nasal allergic rhinitis symptoms, has demonstrated effectiveness in improving ocular symptoms associated with seasonal allergic rhinitis (SAR) in retrospective analyses. OBJECTIVE: We sought to evaluate prospectively the efficacy of MFNS in reducing total ocular symptom scores (TOSSs) and individual ocular symptoms in subjects with SAR. METHODS: Subjects 12 years or older (n = 429) with moderate-to-severe baseline symptoms were randomized to MFNS, 200 microg once daily, or placebo in this 15-day, double-blind, parallel-group study. Subjects evaluated morning instantaneous TOSSs and daily reflective TOSSs, total nasal symptom scores (TNSSs; both instantaneous TNSSs and reflective TNSSs, respectively), and individual ocular and nasal symptoms. Mean changes from baseline averaged over days 2 to 15 (instantaneous) and days 1 to 15 (reflective) were calculated. Quality of life was assessed by using the Rhinoconjunctivitis Quality of Life Questionnaire. RESULTS: MFNS treatment yielded significant reductions from baseline versus placebo in instantaneous TOSSs (-0.34, P = .026, coprimary end point), instantaneous TNSSs (-0.88, P < .001, coprimary end point), reflective TOSSs (-0.44, P = .005), and reflective TNSSs (-1.06, P < .001). Significant decreases in all individual reflective ocular symptoms and instantaneous eye itching/burning and eye watering/tearing were observed for MFNS versus placebo (P < .05). Numeric improvements in instantaneous eye redness were seen but did not reach statistical significance. Improvements in Rhinoconjunctivitis Quality of Life Questionnaire total scores and individual symptom domains were achieved with MFNS treatment versus placebo (P < .001). MFNS was well tolerated. CONCLUSION: This prospective study demonstrates that MFNS significantly reduces ocular symptoms in subjects with SAR.

Possible Protective Effect of Omalizumab on Lung Function Decline in Patients Experiencing Asthma Exacerbations.

BACKGROUND: Frequent exacerbations are associated with greater FEV1 decline in patients with asthma. The effect of omalizumab versus placebo on lung function in patients experiencing asthma exacerbations has not been previously examined. OBJECTIVE: To evaluate the relationship between postbaseline (treatment phase) exacerbation status and lung function decline in children, adolescents, and adults treated with omalizumab versus placebo using data from 3 pediatric and adolescent/adult studies. METHODS: Changes in percent predicted FEV1 (ppFEV1) and FEV1 by treatment (omalizumab/placebo) and postbaseline exacerbation status (exacerbators/nonexacerbators) were assessed in patients aged 6 to 11 years (IA05, n = 576) and 12 to 75 years (EXTRA/INNOVATE pooled, n = 1202). Pediatric patients were examined at treatment weeks 12, 24, 28, 40, and 52, and adolescent/adult data at weeks 4, 12, 20, and 28. RESULTS: Omalizumab-treated patients experienced larger increases in ppFEV1 and FEV1 compared with placebo-treated patients in the pediatric and pooled adolescent/adult populations. The response was observed in pediatric exacerbators, with significantly larger increases in ppFEV1 and FEV1 at week 12 (mean difference [95% CI], 4.11% [0.93%-7.30%], P = .011 for ppFEV1; 80 [10-140] mL, P = .017 for FEV1) and week 28 (mean difference [95% CI], 3.65% [0.11%-7.19%], P = .043 for ppFEV1; 100 [30-170] mL, P = .007 for FEV1). In the adolescent/adult population, both exacerbators and nonexacerbators derived similar benefit with omalizumab compared with placebo. CONCLUSIONS: Findings from this post hoc analysis suggest that omalizumab may confer some protection against lung function decline among patients who experienced exacerbations during treatment.

Successful long-term, adjunctive use of guaifenesin in a patient with a complex atopic medical history and primary immune deficiency: A case report.

We report the case of a 45 year old female patient who suffered from recurrent respiratory infections, asthma, allergies and atopic dermatitis since childhood and multiple autoimmune and chronic respiratory conditions as an adult, who has achieved symptoms remission through a combination of immunotherapy and the daily use of over-the-counter high-dose guaifenesin.

National Prevalence of Poor Asthma Control and Associated Outcomes Among School-Aged Children in the United States.

BACKGROUND: The degree of asthma control among school-aged children (SAC) nationally is not well understood. OBJECTIVE: The objective of this study was to characterize poor control among SAC (aged 6-17 years) in the United States. METHODS: This was a retrospective analysis of the 2007-2013 Medical Expenditure Panel Survey. Indicators of poor control included exacerbation in previous year; use of >3 canisters of short-acting ß-agonist (SABA) in 3 months; and asthma-specific (AS) emergency department (ED) or inpatient (IP) visits. Treatment indicators included daily controller medication and peak flow meter use. Negative binomial regression was used for health resource utilization (HRU); generalized linear models with log-link were used for health care expenditures. RESULTS: There were 44,320 SAC, of whom 5,890 had asthma. The prevalence of poor control and treatment among SAC with asthma were as follows: exacerbation (59%), >3 canisters of SABA (4%), ED/IP visit (3%), daily controller (19%), peak flow (12%). In 2013, 3.4 million SAC had an asthma exacerbation and 200,000 had an AS ED/IP visit. SAC with asthma and an exacerbation had 18.9 times more annual AS ED visits (and 43.3 times more AS hospitalizations) than SAC with asthma but no exacerbation. SAC with asthma and an indicator of poor control incurred greater annual all-cause expenditures than SAC without asthma ($US 2015): $1,144 (exacerbation), $1,859 (≥3 canisters of SABA), and $3,063 (ED/IP visit). Use of daily controller medication was low even among SAC with poor control (27% to 61%). CONCLUSION: Renewed and vigilant asthma management and treatment is necessary to mitigate the current and long-term public health effects and expenditures associated with poor asthma control.

Clinical implications of CD4+ T cell subsets in adult atopic asthma patients.

BACKGROUND: T cells play a central role in chronic inflammation in asthma. However, the roles of individual subsets of T cells in the pathology of asthma in patients remain to be better understood. METHODS: We investigated the potential signatures of T cell subset phenotypes in asthma using fresh whole blood from adult atopic asthma patients (n = 43) and non-asthmatic control subjects (n = 22). We further assessed their potential clinical implications by correlating asthma severity. RESULTS: We report four major features of CD4+ T cells in the blood of atopic asthma patients. First, patients had a profound increase of CCR7+ memory CD4+ T cells, but not CCR7- memory CD4+ T cells. Second, an increase in CCR4+ CD4+ T cells in patients was mainly attributed to the increase of CCR7+ memory CD4+ T cells. Accordingly, the frequency of CCR4+CCR7+ memory CD4+ T cells correlated with asthma severity. Current common asthma therapeutics (including corticosteroids) were not able to affect the frequency of CCR4+CCR7+ memory CD4+ T cell subsets. Third, patients had an increase of Tregs, as assessed by measuring CD25, Foxp3, IL-10 and CTLA-4 expression. However, asthma severity was inversely correlated only with the frequency of CTLA-4+ CD4+ T cells. Lastly, patients and control subjects have similar frequencies of CD4+ T cells that express CCR5, CCR6, CXCR3, CXCR5, CD11a, or α4 integrin. However, the frequency of α4+ CD4+ T cells in patients correlated with asthma severity. CONCLUSIONS: CCR4+CCR7+ memory, but not CCR4+CCR7- memory, α4+, and CTLA4+ CD4+ T cells in patients show significant clinical implications in atopic asthma. Current common therapeutics cannot alter the frequency of such CD4+ T cell subsets in adult atopic asthma patients.

Keys to successful management of patients with allergic rhinitis: focus on patient confidence, compliance, and satisfaction.

OBJECTIVE: The American Academy of Otolaryngic Allergy (AAOA) convened an expert, multidisciplinary Working Group on Allergic Rhinitis to discuss patients' self-treatment behaviors and how health care providers approach and treat the condition. PROCEDURES AND DATA SOURCES: Co-moderators, who were chosen by the AAOA Board of Directors, were responsible for initial agenda development and selection of presenters and participants, based on their expertise in diagnosis and treatment of allergic rhinitis. Each presenter performed a literature search from which a presentation was developed, portions of which were utilized in developing this review article. SUMMARY OF FINDINGS: Allergic rhinitis is a common chronic condition that has a significant negative impact on general health, co-morbid illnesses, productivity, and quality of life. Treatment of allergic rhinitis includes avoidance of allergens, immunotherapy, and/or pharmacotherapy (ie, antihistamines, decongestants, corticosteroids, mast cell stabilizers, anti-leukotriene agents, anticholinergics). Despite abundant treatment options, 60% of all allergic rhinitis patients in an Asthma and Allergy Foundation of America survey responded that they are "very interested" in finding a new medication and 25% are "constantly" trying different medications to find one that "works." Those who were dissatisfied also said their health care provider does not understand their allergy treatment needs and does not take their allergy symptoms seriously. Dissatisfaction leads to decreased compliance and an increased reliance on multiple agents and over-the-counter products. Furthermore, a lack of effective communication between health care provider and patient leads to poor disease control, noncompliance, and unhappiness in a significant portion of patients. CONCLUSIONS: Health care providers must gain a greater understanding of patient expectations to increase medication compliance and patient satisfaction and confidence.

Clinical efficacy of olopatadine vs epinastine ophthalmic solution in the conjunctival allergen challenge model.

BACKGROUND: Olopatadine hydrochloride 0.1% ophthalmic solution (Patanol) and epinastine hydrochloride 0.05% ophthalmic solution (Elestat) are two topical antiallergic agents. Olopatadine is indicated for the treatment of the signs and symptoms of allergic conjunctivitis that include itching, redness, tearing, lid swelling, and chemosis. Epinastine is indicated for the prevention of itching associated with allergic conjunctivitis. OBJECTIVE: This study compared the clinical efficacy of olopatadine and epinastine in the prevention of itching and conjunctival redness in the conjunctival allergen challenge (CAC) model. RESEARCH DESIGN AND METHODS: This was a prospective, randomized, double-masked, contralaterally-controlled, single center allergen challenge study. Ninety-six subjects with a history of allergic conjunctivitis were screened, and the 66 who responded to conjunctival allergen challenge at visits 1 and 2 were randomized into 1 of 3 treatment groups at visit 3 to receive one drop of study medication in each eye: (1) olopatadine in one eye and epinastine in the fellow eye, (2) olopatadine in one eye and placebo in the fellow eye, and (3) epinastine in one eye and placebo in the fellow eye. Five minutes after study drop instillation, subjects were bilaterally challenged with the allergen concentration that had elicited a positive conjunctival allergic response at Visits 1 and 2. Subjective itching assessments were given at 3 min, 5 min, and 7 min post challenge. Objective redness and chemosis assessments were made at 10 min, 15 min, and 20 min post challenge. Paired sample two-tailed t-tests were performed on the mean scores at each time point to assess statistical significance in the differences between treatments. MAIN OUTCOME MEASURES; RESULTS: Fifty-three subjects were randomized into the olopatadine/epinastine treatment group, the primary analysis group. Olopatadine treated eyes exhibited significantly lower mean itching and conjunctival redness scores than the contralateral epinastine treated eyes, -0.19 (p = 0.003) and -0.52 (p < 0.001), respectively. Olopatadine treated eyes also exhibited significantly less chemosis -0.24 (p < 0.001), ciliary redness -0.55 (p < 0.001), and episcleral redness -0.58 (p < 0.001) than epinastine treated eyes. CONCLUSION: Olopatadine is significantly more effective than epinastine in controlling itching, redness and chemosis associated with allergic conjunctivitis in the CAC model.

Comparison of olopatadine 0.6% nasal spray versus fluticasone propionate 50 microg in the treatment of seasonal allergic rhinitis.

The efficacy of nasal antihistamines (NAHs) for allergic rhinitis (AR) is comparable with or better than second-generation oral antihistamines, with faster onset of action and greater effect on congestion. Limited data suggest that NAHs may be equivalent to intranasal corticosteroids at reducing the full range of nasal seasonal AR (SAR) symptoms, including congestion. The efficacy of olopatadine 0.6% nasal spray (2 sprays/nostril b.i.d.) for symptoms of SAR was compared with fluticasone 50 microg nasal spray (2 sprays/nostril q.d.) in a double-blind, randomized, parallel-group, 2-week noninferiority trial. A total of 130 symptomatic patients were randomized to treatment and they recorded nasal and ocular allergy symptom scores b.i.d. (morning and evening) in a diary. Both treatments reduced reflective and instantaneous assessments of nasal and ocular symptoms from baseline throughout the 2-week study period (p < 0.05). The reflective total nasal symptom score (the primary efficacy variable) decreased by an average of -45.4% for patients treated with olopatadine 0.6% and by -47.4% for those treated with fluticasone; statistical significance favoring olopatadine was demonstrated at day 1. No significant between-treatment differences were determined for the average 2-week percent changes from baseline for congestion, runny nose, sneezing, itchy nose, and ocular symptoms, although olopatadine had a faster onset of action for reducing all symptoms. Both treatments were safe and well tolerated. Olopatadine and fluticasone nasal sprays both reduced nasal and ocular SAR symptoms with no significant between-treatment differences except for a faster and greater onset of action with olopatadine.

Prevalence and impact of nighttime symptoms in adults and children with asthma: a survey.

BACKGROUND: The frequency of nighttime asthma symptoms is an important measure of asthma severity. This study was designed to determine the prevalence of daytime and nighttime symptoms in adults and children with asthma and to evaluate the impact of nighttime symptoms on sleep and daytime activities. METHODS: An online survey was conducted among adults (> 18 years) and mothers of children aged 2 to 17 years with asthma. The survey included questions on daytime and nighttime asthma symptoms and asthma controller medication. Invitations to complete the survey were sent to 6349 members of a global opinion panel who were identified as having asthma. Data collection was from April to May 2005. RESULTS: A total of 1600 invited panelists responded to the survey. Overall, 61% of participants reported nighttime asthma symptoms and 74% reported daytime asthma symptoms. Asthma-related sleep difficulties occurred approximately 4 times per week in adults and approximately 3 times per week in children. A significantly greater proportion of adults than children reported bothersome symptoms in the morning on awakening. Wheezing and difficulty breathing were reported in a greater proportion of adults, whereas coughing was reported in a greater proportion of children. A greater proportion of adults than children reported feelings of tiredness and impaired activity on days after experiencing nighttime symptoms. Absenteeism and lateness were more commonly reported by mothers of children with asthma than by other adults. CONCLUSIONS: The prevalence of reported asthma symptoms, particularly nighttime symptoms, and the effects of nighttime symptoms on sleep and daytime activities indicates that survey participants had poorly controlled asthma.

State of world allergy report 2008: allergy and chronic respiratory diseases.

It is widely recognized that the incidence of allergies and allergic diseases is on the rise globally. As an international umbrella organization for regional and national allergy and clinical immunology societies, the World Allergy Organization is at the forefront of a combined united effort across nations and organizations to address this global concern by promoting the science of allergy and clinical immunology, and advancing exchange of information.The World Allergy Organization's State of World Allergy Reports will provide a biennial review of allergic diseases worldwide, consider their medical and socioeconomic contexts, and propose effective approaches to addressing these problems.In this first State of World Allergy Report 2008, experts from different regions of the world have attempted to define the extent of the global allergy problem, examine recent trends, and provide a framework for the collaboration among world medicine, science, and government agencies that is needed to address the rapidly developing issues associated with allergy and allergic diseases.

Pathophysiology and progression of nasal septal perforation.

OBJECTIVE: To review the prevalence, causes, and treatments of nasal septal perforation (NSP). DATA SOURCES: A literature search was conducted in MEDLINE to identify peer-reviewed articles related to NSP using the keywords nasal septal perforation and septal perforation for articles published between January 1, 1969, and December 31, 2006, and references cited therein. STUDY SELECTION: Articles were selected based on their direct applicability to the subject matter. RESULTS: Causes of NSPs include piercings, exposure to industrial chemicals, illicit drug use, intranasal steroid use, surgical trauma, bilateral cautery, and possibly improper use of nasal applicators. Prevalence is poorly reported. Mechanisms of substance-induced NSP formation are not understood. Progression from epistaxis to ulceration to NSP could not be substantiated by the literature. CONCLUSION: Depending on the patient, NSP may be viewed as desirable (nose rings), problematic (whistling, congestion), or inconsequential. Understanding the pathogenesis of NSP is important for the practicing physician required to make decisions about whether to recommend surgical correction or medical treatment. Although the etiology of NSP is overwhelmingly iatrogenic, there is an association with a number of medical diseases in addition to use of illicit drugs and/or prescription nasal sprays.

Newer aspects in the treatment of pediatric and adult asthma: monoclonal anti-IgE.

OBJECTIVE: To review the results of the first anti-IgE agent to undergo clinical evaluation in the treatment of allergic asthma and allergic rhinitis. DATA SOURCES: Treatment protocols conducted in Europe and the United States in moderate to severe allergic asthmatic patients who continued to show symptoms despite treatment with inhaled corticosteroids with the addition of monoclonal humanized anti-IgE treatment. STUDY SELECTION: Double-blind, placebo-controlled studies, published and in press, are reviewed. RESULTS: Treatment with anti-IgE allowed a decrease in inhaled corticosteroid and rescue medication use and significantly reduced the incidence and frequency of asthma exacerbations among these patients over a 28-week time period and a 6-month extension period. CONCLUSIONS: Anti-IgE shows great promise as an adjunctive therapy in moderate to severe asthmatic patients.