Risk Factors for Asthma-Related Healthcare Use: Longitudinal Analysis Using the NHI Claims Database in a Korean Asthma Cohort

Background

Though insurance claims data are useful for researching asthma, they have important limitations, such as a diagnostic inaccuracy and a lack of clinical information. To overcome these drawbacks, we used the novel method by merging the clinical data from our asthma cohort with the National Health Insurance (NHI) claims data.

Methods and Results

Longitudinal analysis of asthma-related healthcare use from the NHI claims database, merged with data of 736 patients registered in a Korean asthma cohort, was conducted for three consecutive years from registration of the cohort. Asthma-related asthma healthcare referred to outpatient and emergency department visits, hospitalizations, and the use of systemic corticosteroids. Univariate and multivariate logistic regression analysis was used to evaluate risk factors for asthma-related healthcare. Over three years after enrollment, many patients changed from tertiary to primary/secondary hospitals with a lack of maintenance of inhaled corticosteroid-based controllers. An independent risk factor for emergency visits was a previous history of asthma exacerbation. In hospitalizations, old age and Asthma Control Test (ACT) score variability were independent risk factors. An independent risk factor for per person cumulative duration of systemic corticosteroids was the FEV₁ (Forced expiratory volume in one second)%. The use of systemic corticosteroids was independently associated with being female, the FEV₁%, and ACT score variability.

Conclusion

We found that old age, being female, long-standing asthma, a low FEV₁%, asthma brittleness, asthma drug compliance, and a history of asthma exacerbation were independent risk factors for increased asthma-related healthcare use in Korea.     

Longitudinal increase in total IgE levels in patients with adult asthma: an association with poor asthma control

Background

Immunoglobulin (Ig) E is well-known to play a critical role in allergic diseases. We investigated the association between longitudinal change in total IgE level and the asthma control in patients with adult asthma.

Methods

For this retrospective study, 154 patients with asthma aged 21–82 years were recruited from the allergy and pulmonary units of the Showa University Hospital. Data on longitudinal changes in IgE over the preceding 10 years were collected and logarithmically transformed. Associations between longitudinal change in IgE and clinical characteristics including asthma control test (ACT) score, asthma control, pulmonary function test, and antigen specific IgE, were assessed.

Results

Patients with increased IgE tended to have significantly higher mean age, more episodes of acute exacerbation within a year, lower ACT scores, and used oral corticosteroids more frequently than those with decreased or unchanged IgE. The prevalence of uncontrolled asthma was higher in patients with increased IgE than in those with decreased or unchanged IgE. Mean %FEV₁ and FEV_1% were lower in patients with increased IgE than in those with decreased or unchanged IgE. Moreover, the prevalence of Aspergillus-specific IgE was higher in patients with increased IgE than in those with decreased or unchanged IgE.

Conclusions

These data suggest that a longitudinal increase in total IgE is associated with both poor asthma control and Aspergillus-specific IgE in patients with adult asthma.     

Remote Monitoring of Inhaled Bronchodilator Use and Weekly Feedback about Asthma Management: An Open-Group,Short-Term Pilot Study of the Impact on Asthma Control

Objective

Adequate symptom control is a problem for many people with asthma. We asked whether weekly email reports on monitored use of inhaled, short-acting bronchodilators might improve scores on composite asthma-control measures.

Methods

Through an investigational electronic medication sensor attached to each participant''s inhaler, we monitored 4 months'' use of inhaled, short-acting bronchodilators. Participants completed surveys, including the Asthma Control Test^TM (ACT), to assess asthma control at entry and monthly thereafter. After the first month, participants received weekly email reports for 3 months. The reports summarized inhaled bronchodilator use during the preceding week and provided suggestions derived from National Asthma Education and Prevention Program (NAEPP) guidelines. Paired t-tests and random-effects mixed models were implemented to assess changes in primary asthma endpoints.

Results

Thirty individuals participated in the 4-month study; 29 provided complete asthma control information. Mean age was 36.8 years (range: 19–74 years); 52% of respondents were female. Mean ACT scores were 17.6 (Standard Deviation [SD]  = 3.35) at entry and 18.4 (SD = 3.60) at completion of the first month. No significant difference appeared between ACT values at entry and completion of the first month (p = 0.66); however, after participants began receiving email reports and online information about their inhaler use, mean ACT scores increased 1.40 points (95% CI: 0.61, 2.18) for each subsequent study month. Significant decreases occurred in 2-week histories of daytime symptoms (β = −1.35, 95% CI: −2.65, −0.04) and nighttime symptoms (β = −0.84, 95% CI: −1.25, −0.44); no significant change in activity limitation (β = −0.21, 95% CI: −0.69, 0.26) was observed. Participants reported increased awareness and understanding of asthma patterns, level of control, bronchodilator use (timing, location) and triggers, and improved preventive practices.

Conclusions

Weekly email reports and access to online charts summarizing remote monitoring of inhaled bronchodilator frequency and location were associated with improved asthma control and a decline in day-to-day asthma symptoms.     

Restoration of Corticosteroid Sensitivity by p38 Mitogen Activated Protein Kinase Inhibition in Peripheral Blood Mononuclear Cells from Severe Asthma

Background

Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders.

Methodology/Principal Findings

Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-α induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC₅₀ values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r = −0.65; p<0.0005) and with decreased FEV₁ (% predicted) (r = 0.6; p<0.0005). A p38α/β inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV₁ and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s.

Conclusions/Significance

p38MAPKα/β is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/β inhibitor in the future.     

Cluster analysis in severe emphysema subjects using phenotype and genotype data: an exploratory investigation

Background

Numerous studies have demonstrated associations between genetic markers and COPD, but results have been inconsistent. One reason may be heterogeneity in disease definition. Unsupervised learning approaches may assist in understanding disease heterogeneity.

Methods

We selected 31 phenotypic variables and 12 SNPs from five candidate genes in 308 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study cohort. We used factor analysis to select a subset of phenotypic variables, and then used cluster analysis to identify subtypes of severe emphysema. We examined the phenotypic and genotypic characteristics of each cluster.

Results

We identified six factors accounting for 75% of the shared variability among our initial phenotypic variables. We selected four phenotypic variables from these factors for cluster analysis: 1) post-bronchodilator FEV₁ percent predicted, 2) percent bronchodilator responsiveness, and quantitative CT measurements of 3) apical emphysema and 4) airway wall thickness. K-means cluster analysis revealed four clusters, though separation between clusters was modest: 1) emphysema predominant, 2) bronchodilator responsive, with higher FEV₁; 3) discordant, with a lower FEV₁ despite less severe emphysema and lower airway wall thickness, and 4) airway predominant. Of the genotypes examined, membership in cluster 1 (emphysema-predominant) was associated with TGFB1 SNP rs1800470.

Conclusions

Cluster analysis may identify meaningful disease subtypes and/or groups of related phenotypic variables even in a highly selected group of severe emphysema subjects, and may be useful for genetic association studies.     

Serum adiponectin is positively associated with lung function in young adults,independent of obesity: The CARDIA study

Rationale

Adipose tissue produces adiponectin, an anti-inflammatory protein. Adiponectin deficiency in mice is associated with abnormal post-natal alveolar development.

Objective

We hypothesized that lower serum adiponectin concentrations are associated with lower lung function in humans, independent of obesity. We explored mediation of this association by insulin resistance and systemic inflammation.

Methods and Measurements

Spirometry testing was conducted at years 10 and 20 follow-up evaluation visits in 2,056 eligible young adult participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Body mass index, serum adiponectin, serum C-reactive protein (a marker of systemic inflammation), and insulin resistance were assessed at year 15.

Main Results

After controlling for body mass index, years 10 and 20 forced vital capacity (FVC) were 81 ml and 82 ml lower respectively (p = 0.004 and 0.01 respectively) in the lowest vs. highest adiponectin quartiles. Similarly, years 10 and 20 forced expiratory volume in one second (FEV₁) were 50 ml and 38 ml lower (p = 0.01 and 0.09, respectively) in the lowest vs. highest adiponectin quartiles. These associations were no longer significant after adjustment for insulin resistance and C-reactive protein. Serum adiponectin was not associated with FEV₁/FVC or peak FEV₁.

Conclusions

Independent of obesity, lower serum adiponectin concentrations are associated with lower lung function. The attenuation of this association after adjustment for insulin resistance and systemic inflammation suggests that these covariates are on a causal pathway linking adiponectin and lung function.     

Bronchodilator Responsiveness and Reported Respiratory Symptoms in an Adult Population

Background

The relationship between patient-reported symptoms and objective measures of lung function is poorly understood.

Aim

To determine the association between responsiveness to bronchodilator and respiratory symptoms in random population samples.

Methods

4669 people aged 40 years and older from 8 sites in Canada completed interviewer-administered respiratory questionnaires and performed spirometry before and after administration of 200 ug of inhaled salbutamol. The effect of anthropometric variables, smoking exposure and doctor-diagnosed asthma (DDA) on bronchodilator responsiveness in forced expiratory volume in 1 second (FEV₁) and in forced vital capacity (FVC) were evaluated. Multiple logistic regression was used to test for association between quintiles of increasing changes in FEV₁ and in FVC after bronchodilator and several respiratory symptoms.

Results

Determinants of bronchodilator change in FEV₁ and FVC included age, DDA, smoking, respiratory drug use and female gender [p<0.005 to p<0.0001 ]. In subjects without doctor-diagnosed asthma or COPD, bronchodilator response in FEV₁ was associated with wheezing [p for trend<0.0001], while bronchodilator response for FVC was associated with breathlessness. [p for trend <0.0001].

Conclusions

Bronchodilator responsiveness in FEV₁ or FVC are associated with different respiratory symptoms in the community. Both flow and volume bronchodilator responses are useful parameters which together can be predictive of both wheezing and breathlessness in the general population.     

Asthma and COPD in cystic fibrosis intron-8 5T carriers. A population-based study

Background

Carriers of cystic fibrosis intron-8 5T alleles with high exon-9 skipping could have increased annual lung function decline and increased risk for asthma or chronic obstructive pulmonary disease (COPD).

Methods

We genotyped 9131 individuals from the adult Danish population for cystic fibrosis 5T, 7T, 9T, and F508del alleles, and examined associations between 11 different genotype combinations, and annual FEV₁ decline and risk of asthma or COPD.

Results

5T heterozygotes vs. 7T homozygous controls had no increase in annual FEV₁ decline, self-reported asthma, spirometry-defined COPD, or incidence of hospitalization from asthma or COPD. In 5T/7T heterozygotes vs. 7T homozygous controls we had 90% power to detect an increase in FEV₁ decline of 8 ml, an odds ratio for self-reported asthma and spirometry-defined COPD of 1.9 and 1.7, and a hazard ratio for asthma and COPD hospitalization of 1.8 and 1.6, respectively. Both 5T homozygotes identified in the study showed evidence of asthma, while none of four 5T/F508del compound heterozygotes had severe pulmonary disease. 7T/9T individuals had annual decline in FEV₁ of 19 ml compared with 21 ml in 7T homozygous controls (t-test:P = 0.03). 6.7% of 7T homozygotes without an F508del allele in the cystic fibrosis transmembrane conductance regulator gene reported asthma vs. 11% of 7T/9T individuals with an F508del allele (χ²:P = 0.01) and 40% of 7T homozygotes with an F508del allele (P = 0.04). 7T homozygotes with vs. without an F508del allele also had higher incidence of asthma hospitalization (log-rank:P = 0.003); unadjusted and adjusted equivalent hazard ratios for asthma hospitalization were 11 (95%CI:1.5–78) and 6.3 (0.84–47) in 7T homozygotes with vs. without an F508del allele.

Conclusion

Polythymidine 5T heterozygosity is not associated with pulmonary dysfunction or disease in the adult Caucasian population. Furthermore, our results support that F508del heterozygosity is associated with increased asthma risk independently of the 5T allele.     

Respiratory Impairment and Systemic Inflammation in Cedar Asthmatics Removed from Exposure

Background

Prior research has shown that removing occupational asthmatics from exposure does not routinely lead to significant improvements in respiratory impairment. These studies were of limited duration and factors determining recovery remain obscure. Our objective was to evaluate residual respiratory impairment and associated sputum and blood biomarkers in subjects with Western red cedar asthma after exposure cessation.

Methods

Subjects previously diagnosed with cedar asthma, and removed from exposure to cedar dust for at least one year, were recruited. Subjects completed a questionnaire and spirometry. PC₂₀ (methacholine concentration that produces 20% fall in FEV₁ (forced expiratory volume at 1 second)) sputum cellularity and select T_h1/T_h2 (T helper cells 1 and 2) cytokine concentrations in peripheral blood were determined. The asthma impairment class was determined and multivariate analyses were performed to determine its relationship with sputum cell counts and serum cytokines.

Results

40 non-smoking males (mean age 62) were examined at a mean interval of 25 years from cedar asthma diagnosis and 17 years from last cedar exposure. 40% were in impairment class 2/3. On average, the PC₂₀ had increased by 2.0 mg/ml; the FEV₁ decreased by 1.5 L, with greater decrease in those with greater impairment. Higher impairment was associated with serum interferon-gamma (mean = 1.3 pg/ml in class 2/3 versus 0.62 pg/ml in class 0/1, p = 0.04), mainly due to the FEV₁ component (correlation with interferon-gamma = −0.46, p = 0.005).

Conclusion

Years after exposure cessation, patients with Western red cedar asthma have persistent airflow obstruction and respiratory impairment, associated with systemic inflammation.     

Sputum neutrophils as a biomarker in COPD: findings from the ECLIPSE study

Introduction

The percentage of neutrophils in sputum are increased in COPD patients, and may therefore be a biomarker of airway inflammation. We studied the relationships between sputum neutrophils and FEV₁, health status, exacerbation rates, systemic inflammation and emphysema, and long term variability at 1 year.

Methods

Sputum samples were obtained from 488 COPD patients within the ECLIPSE cohort. 359 samples were obtained at baseline, and 297 after 1 year. 168 subjects provided samples at both visits. Serum interleukin-6 (IL-6), IL-8, surfactant protein D and C-reactive protein levels were measured by immunoassays. Low-dose CT scans evaluated emphysema.

Results

Sputum neutrophil % increased with GOLD stage. There was a weak association between % sputum neutrophils and FEV₁ % predicted (univariate r² = 0.025 and 0.094 at baseline and year 1 respectively, p < 0.05 after multivariate regression). Similar weak but significant associations were observed between neutrophil % and health status measured using the St Georges Respiratory Questionairre. There were no associations between neutrophils and exacerbation rates or emphysema. Associations between sputum neutrophils and systemic biomarkers were non-significant or similarly weak. The mean change over 1 year in neutrophil % was an increase of 3.5%.

Conclusions

Sputum neutrophil measurements in COPD are associated weakly with FEV₁ % predicted and health status. Sputum neutrophil measurements were dissociated from exacerbation rates, emphysema and systemic inflammation.     

Clinical Implications of Having Reduced Mid Forced Expiratory Flow Rates (FEF25-75), Independently of FEV1, in Adult Patients with Asthma

Introduction

FEF_25-75 is one of the standard results provided in spirometry reports; however, in adult asthmatics there is limited information on how this physiological measure relates to clinical or biological outcomes independently of the FEV₁ or the FEV₁/FVC ratio.

Purpose

To determine the association between Hankinson’s percent-predicted FEF_25-75 (FEF_25-75%) levels with changes in healthcare utilization, respiratory symptom frequency, and biomarkers of distal airway inflammation.

Methods

In participants enrolled in the Severe Asthma Research Program 1–2, we compared outcomes across FEF_25-75% quartiles. Multivariable analyses were done to avoid confounding by demographic characteristics, FEV₁, and the FEV₁/FVC ratio. In a sensitivity analysis, we also compared outcomes across participants with FEF_25-75% below the lower limit of normal (LLN) and FEV₁/FVC above LLN.

Results

Subjects in the lowest FEF_25-75% quartile had greater rates of healthcare utilization and higher exhaled nitric oxide and sputum eosinophils. In multivariable analysis, being in the lowest FEF_25-75% quartile remained significantly associated with nocturnal symptoms (OR 3.0 [95%CI 1.3–6.9]), persistent symptoms (OR 3.3 [95%CI 1–11], ICU admission for asthma (3.7 [1.3–10.8]) and blood eosinophil % (0.18 [0.07, 0.29]). In the sensitivity analysis, those with FEF_25-75% <LLN had significantly more nocturnal and persistent symptoms, emergency room visits, higher serum eosinophil levels and increased methacholine responsiveness.

Conclusions

After controlling for demographic variables, FEV₁ and FEV₁/FVC, a reduced FEF_25-75% is independently associated with previous ICU admission, persistent symptoms, nocturnal symptoms, blood eosinophilia and bronchial hyperreactivity. This suggests that in some asthmatics, a reduced FEF_25-75% is an independent biomarker for more severe asthma.     

Protective effect of budesonide/formoterol compared with formoterol,salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised,double-blind,cross-over study

Background

The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear.

Methods

The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV₁ 95% of predicted) who previously demonstrated a ≥30% fall in forced expiratory volume in 1 second (FEV₁) after inhaling adenosine 5''-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 μg), formoterol (4.5 μg), salbutamol (2 × 100 μg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day.

Results

In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV₁ within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV₁.

Conclusions

A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.

Trial Registration

ClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT00272753","term_id":"NCT00272753"}}NCT00272753     

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized,placebo-controlled trial

Background

Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.

Methods

Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV₁) 50-80% of predicted normal value and FEV₁ reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV₁ at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV₁.

Results

A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV₁ compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV₁ at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV₁ than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.

Conclusions

FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.

Trial registration

NCT00398645     

Corticosteroid suppression of lipoxin A4 and leukotriene B4from alveolar macrophages in severe asthma

Background

An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B₄ (LTB₄), and lipoxin A₄ (LXA₄) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.

Methods

AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 μg/ml) with or without dexamethasone (10^-6M). LTB₄ and LXA₄ were measured by enzyme immunoassay.

Results

LXA₄ biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA₄ induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB₄ were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB₄ was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB₄ and LXA₄, with lesser suppression of LTB₄ in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA₄ and FEV₁ (% predicted) (r_s = 0.60; p < 0.01).

Conclusions

Decreased LXA₄ and increased LTB₄ generation plus impaired corticosteroid sensitivity of LPS-induced LTB₄ but not of LXA₄ support a role for AMs in establishing a pro-inflammatory balance in severe asthma.     

Passive Smoking Is Associated with Poor Asthma Control during Pregnancy: A Prospective Study of 500 Pregnancies

Background and Aim

Asthma and tobacco exposure is common among pregnant women. We investigated the effect of passive and active smoking on asthma control during pregnancy.

Methods

Prospective observational design. Patients had their asthma control, based on symptoms, use of medication, spirometry, and exhaled nitric oxide [F_ENO], assessed every four weeks during 2^nd and 3^rd trimester of pregnancy; data on tobacco exposure were also collected prospectively. The primary outcome was episodes of uncontrolled and partly controlled asthma during pregnancy (defined according to GINA-guidelines).

Results

A total of 500 pregnant women with asthma (mean age 30.8 years, range 17 to 44) were consecutively included, of whom 32 (6.4%), 115 (23.0%) and 353 (70.6%), respectively, were current smokers, ex-smokers and never smokers [NS]. Sixty-five NS (18.4%) reported passive tobacco exposure. NS with passive tobacco exposure had significantly lower FEV₁% predicted (p<0.02) and F_ENO (p = 0.01) compared to NS without passive tobacco exposure. The relative risk [RR] of an episode of uncontrolled asthma during pregnancy was 4.5 (95% CI 2.7–7.5: p<0.001) in current and ex-smokers compared with never smokers, and 2.9 (95% CI 1.4–5.9; p = 0.004) in NS-women with passive tobacco exposure compared with NS-women not reporting passive tobacco exposure. Treatment with inhaled corticosteroids, most likely as a marker of more severe asthma, was also associated with a higher risk (RR 8.1, 95% CI 5.1–13.0; p<0.001) of an episode of uncontrolled asthma.

Conclusion

Passive tobacco exposure in never smokers is associated with an increased risk of episodes of uncontrolled asthma during pregnancy, which is likely to have adverse effects on pregnancy outcome.     

Application of the Asthma Phenotype Algorithm from the Severe Asthma Research Program to an Urban Population

Rationale

Identification and characterization of asthma phenotypes are challenging due to disease complexity and heterogeneity. The Severe Asthma Research Program (SARP) used unsupervised cluster analysis to define 5 phenotypically distinct asthma clusters that they replicated using 3 variables in a simplified algorithm. We evaluated whether this simplified SARP algorithm could be used in a separate and diverse urban asthma population to recreate these 5 phenotypic clusters.

Methods

The SARP simplified algorithm was applied to adults with asthma recruited to the New York University/Bellevue Asthma Registry (NYUBAR) to classify patients into five groups. The clinical phenotypes were summarized and compared.

Results

Asthma subjects in NYUBAR (n = 471) were predominantly women (70%) and Hispanic (57%), which were demographically different from the SARP population. The clinical phenotypes of the five groups generated by the simplified SARP algorithm were distinct across groups and distributed similarly to those described for the SARP population. Groups 1 and 2 (6 and 63%, respectively) had predominantly childhood onset atopic asthma. Groups 4 and 5 (20%) were older, with the longest duration of asthma, increased symptoms and exacerbations. Group 4 subjects were the most atopic and had the highest peripheral eosinophils. Group 3 (10%) had the least atopy, but included older obese women with adult-onset asthma, and increased exacerbations.

Conclusions

Application of the simplified SARP algorithm to the NYUBAR yielded groups that were phenotypically distinct and useful to characterize disease heterogeneity. Differences across NYUBAR groups support phenotypic variation and support the use of the simplified SARP algorithm for classification of asthma phenotypes in future prospective studies to investigate treatment and outcome differences between these distinct groups.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00212537","term_id":"NCT00212537"}}NCT00212537     

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma

Background

Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.

Methods

509 people (6–50 yr) were enrolled, 78% were atopic, median FEV₁ 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV₁ on at least one of two tests, to methacholine a PC₂₀ ≤ 16 mg/ml and to mannitol a 15% fall in FEV₁ at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.

Results

Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV₁ in subjects positive to exercise was 19%, (SD 9.2), mannitol PD₁₅ 158 (CI:129,193) mg, and methacholine PC₂₀ 2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.

Conclusion

In this group with normal FEV₁, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.

Trial registration

This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).     

Effect of Lifestyle on Asthma Control in Japanese Patients: Importance of Periodical Exercise and Raw Vegetable Diet

Background

The avoidance of inhaled allergens or tobacco smoke has been known to have favorable effects on asthma control. However, it remains unclear whether other lifestyle-related factors are also related to asthma control. Therefore, a comprehensive study to examine the associations between various lifestyle factors and asthma control was conducted in Japanese asthmatic patients.

Methods

The study subjects included 437 stable asthmatic patients recruited from our outpatient clinic over a one-year period. A written, informed consent was obtained from each participant. Asthma control was assessed using the asthma control test (ACT), and a structured questionnaire was administered to obtain information regarding lifestyle factors, including tobacco smoking, alcohol drinking, physical exercise, and diet. Both bivariate and multivariate analyses were conducted.

Results

The proportions of total control (ACT = 25), well controlled (ACT = 20-24), and poorly controlled (ACT < 20) were 27.5%, 48.1%, and 24.5%, respectively. The proportions of patients in the asthma treatment steps as measured by Global Initiative for Asthma 2007 in step 1, step 2, step 3, step 4, and step 5 were 5.5%, 17.4%, 7.6%, 60.2%, and 9.4%, respectively. Body mass index, direct tobacco smoking status and alcohol drinking were not associated with asthma control. On the other hand, younger age (< 65 years old), passive smoking, periodical exercise (> 3 metabolic equivalents-h/week), and raw vegetable intake (> 5 units/week) were significantly associated with good asthma control by bivariate analysis. Younger age, periodical exercise, and raw vegetable intake were significantly associated with good asthma control by multiple linear regression analysis.

Conclusions

Periodical exercise and raw vegetable intake are associated with good asthma control in Japanese patients.