Clinical characterization and outcomes of impulse oscillometry-defined bronchodilator response: an ECOPD cohort-based study.

BACKGROUND: The clinical significance of the impulse oscillometry-defined small airway bronchodilator response (IOS-BDR) is not well-known. Accordingly, this study investigated the clinical characteristics of IOS-BDR and explored the association between lung function decline, acute respiratory exacerbations, and IOS-BDR. METHODS: Participants were recruited from an Early Chronic Obstructive Pulmonary Disease (ECOPD) cohort subset and were followed up for two years with visits at baseline, 12 months, and 24 months. Chronic obstructive pulmonary disease (COPD) was defined as a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio < 0.70. IOS-BDR was defined as meeting any one of the following criteria: an absolute change in respiratory system resistance at 5 Hz ≤ - 0.137 kPa/L/s, an absolute change in respiratory system reactance at 5 Hz ≥ 0.055 kPa/L/s, or an absolute change in reactance area ≤ - 0.390 kPa/L. The association between IOS-BDR and a decline in lung function was explored with linear mixed-effects model. The association between IOS-BDR and the risk of acute respiratory exacerbations at the two-year follow-up was analyzed with the logistic regression model. RESULTS: This study involved 466 participants (92 participants with IOS-BDR and 374 participants without IOS-BDR). Participants with IOS-BDR had higher COPD assessment test and modified Medical Research Council dyspnea scale scores, more severe emphysema, air trapping, and rapid decline in FVC than those without IOS-BDR over 2-year follow-up. IOS-BDR was not associated with the risk of acute respiratory exacerbations at the 2-year follow-up. CONCLUSIONS: The participants with IOS-BDR had more respiratory symptoms, radiographic structural changes, and had an increase in decline in lung function than those without IOS-BDR. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024643. Registered on 19 July, 2019.

A comparative study of bronchodilator response: utilizing pre-bronchodilator versus predicted normal values.

BACKGROUND: A positive bronchodilator response has been defined as a 12% increase in the forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) from their respective pre-bronchodilator values, combined with at least a 0.2 L absolute change. Recent recommendations suggested the use of the percent change in FEV1 and FVC relative to their predicted normal values without having applied them in patients with airflow obstruction. The aim of the current study was to compare the two approaches over a wide range of pre-bronchodilator FEV1 and FVC values. METHODS: A retrospective review of consecutive patients undergoing spirometry and bronchodilator testing was completed. The change in FEV1 and FVC with a bronchodilator was expressed relative to the pre-bronchodilator and predicted normal FEV1 and FVC. RESULTS: In 1,040 patients with a non-paradoxical change in FEV1, 19.0% had a ≥ 12% change in FEV1 using their pre-bronchodilator value compared to 5.7% using their predicted normal value. For FVC, the respective values were 12.7% vs. 5.8%. The difference was retained in patients with a ≥ 0.2 L change in FEV1 or FVC. In unobstructed patients, the upper threshold (two standard deviations above the mean) of the bronchodilator response was 14% for FEV1 and 10% for FVC using predicted normal values. CONCLUSIONS: Expressing the percent change in FEV1 and FVC relative to predicted normal values reduces the over-estimation of the bronchodilator response, especially in patients with a very low pre-bronchodilator FEV1, including in those with a ≥ 0.2 L change in FEV1. Irrespective of pre-bronchodilator values, a ≥ 14% change in FEV1 and ≥ 10% change in FVC relative to the predicted normal values could be considered a positive bronchodilator response.

Peripheral and proximal lung ventilation in asthma: Short-term variation and response to bronchodilator inhalation.

BACKGROUND: The relative involvement of the large and small airways in asthma is not clear. Hyperpolarized gas magnetic resonance imaging (MRI) provides high-resolution 3-dimensional images of ventilation distribution that can be quantified by the ventilated volume percentage (VV%) of the lungs. OBJECTIVE: Our aims were to (1) quantify the baseline reproducibility of VV%, (2) assess the ventilation distribution between the proximal and peripheral lungs, and (3) investigate regional ventilation response to bronchodilator inhalation in a cohort of patients with asthma. METHODS: A total of 33 patients with poorly controlled, moderate-to-severe asthma were scanned with hyperpolarized 3He MRI. Two image data sets were acquired at baseline, and 1 image data set was acquired after bronchodilator inhalation. Images were divided into proximal and peripheral regions for analysis. RESULTS: Bland-Altman analysis showed strong reproducibility of VV% (bias = 0.12%; LOA = -1.86% to 2.10%). VV% variation at baseline was greater in the periphery than in the proximal lung. The proximal lung was better ventilated than the peripheral lung. Ventilation increased significantly in response to bronchodilator inhalation, globally and regionally, and the ventilation increase in response to bronchodilator inhalation was greater in the peripheral lung than in the proximal lung. Hyperpolarized gas MRI was more sensitive to changes in response to bronchodilator inhalation (58%) than spirometry (33%). CONCLUSION: The peripheral lung showed reduced ventilation and a greater response to bronchodilator inhalation than the proximal lung. The high level of baseline reproducibility and sensitivity of hyperpolarized gas MRI to bronchodilator reversibility suggests that it is suitable for low subject number studies of therapy response.

Bronchodilator response after two methods of salbutamol nebulization in asthmatic children.

Introduction: Salbutamol is used in bronchodilator response testing (BDRT), which is an important diagnostic tool in bronchial obstructive diseases. Most available studies compare the bronchodilator response of salbutamol administered with a pressurized metered-dose inhaler and salbutamol in a nebulization solution. Aim: The spirometric evaluation of the bronchodilator response of two methods of salbutamol nebulization in asthmatic children. Material and methods: A randomized, open, comparative study was conducted in which 132 children with partially controlled asthma and current bronchial obstruction determined by spirometry were enrolled. BDRT was conducted using salbutamol solution administered with either a continuous jet nebulizer (CON) or a breath-actuated jet nebulizer (BAN). The BAN group received half the dose of the drug compared to the CON group, i.e. 2.5 mg. Changes in FEV1 and FEF25-75 after drug administration were calculated in relation to the baseline values. Results: The change in FEV1 after salbutamol administration was 16.9 ±9.7% in the BAN group and was statistically significantly higher than in the CON group (12.6 ±8.8%) (p = 0.026). The change in FEF25-75 was 37.7 ±23.2% in the BAN group and 32.7 ±25.5% in the CON group (p = 0.061). There were no statistically significant differences in the frequency of adverse events between the compared groups. Conclusions: Salbutamol inhaled from BAN results in a better bronchodilator response than twice the nominal dose of this drug inhaled from CON, which is due to the absence of drug loss during the expiratory phase and therefore greater pulmonary deposition.

Pharmacogenetics of Bronchodilator Response: Future Directions.

PURPOSE OF REVIEW: Several genome-wide association studies (GWASs) of bronchodilator response (BDR) to albuterol have been published over the past decade. This review describes current knowledge gaps, including pharmacogenetic studies of albuterol response in minority populations, effect modification of pharmacogenetic associations by age, and relevance of BDR phenotype characterization to pharmacogenetic findings. New approaches, such as leveraging additional "omics" data to focus pharmacogenetic interrogation, as well as developing polygenic risk scores in asthma treatment responses, are also discussed. RECENT FINDINGS: Recent pharmacogenetic studies of albuterol response in minority populations have identified genetic polymorphisms in loci (DNAH5, NFKB1, PLCB1, ADAMTS3, COX18, and PRKG1), that are associated with BDR. Additional studies are needed to replicate these findings. Modification of the pharmacogenetic associations for SPATS2L and ASB3 polymorphisms by age has also been published. Evidence from metabolomic and epigenomic studies of BDR may point to new pharmacogenetic targets. Lastly, a polygenic risk score for response to albuterol has been developed but requires validation in additional cohorts. In order to expand our knowledge of pharmacogenetics of BDR, additional studies in minority populations are needed. Consideration of effect modification by age and leverage of other "omics" data beyond genomics may also help uncover novel pharmacogenetic loci for use in precision medicine for asthma treatment.

A comparative analysis of the bronchodilatador response measured by impulse oscillometry and spirometry in asthmatic children living at high altitude.

OBJECTIVE: Although the assessment of a bronchodilator response (BDR) is a routine and important procedure when performing lung function tests, comparisons between spirometric and oscillometric BDRs in asthmatic children living at high altitude have not been previously reported. The aim of the present study was to compare spirometric and oscillometric BDRs in children living at high altitude, and to identify independent predictors of spirometric and oscillometric BDRs. METHODS: Between January and December, 2015, asthmatic children aged between 5 and 17 years old performed impulse oscillometry (IOS) and spirometry during the same visit before and after albuterol administration. The data were analyzed, and children were classified into those positive for oscillometric BDR only, those positive for spirometric BDR only, those positive for both BDRs, and those negative for both BDRs. RESULTS: Ninety-three asthmatic children (56 boys, 37 girls), with a median (IQR) age of 11 (8-13) years, made up the study population. Among the total of 93 participants, 13 (14.0%), 4 (4.3%), 0 (0%), and 76 (81.7%) were positive for spirometric BDR only, positive for oscillometric BDR only, positive for both BDRs, and negative for both BDRs, respectively. Age and baseline lung function were identified as significant predictors of positive spirometric BDR. CONCLUSIONS: The present study shows poor concordance between positive spirometric and oscillometric BDRs, with a greater proportion of patients with a spirometric BDR when compared to those with positive oscillometric BDR. Additionally, age and baseline lung function are useful for predicting spirometric BDR results.

Relationship between age and bronchodilator response at diagnosis in adult-onset asthma.

BACKGROUND: Possible variation in bronchodilator response (BDR) according to age at the diagnosis of adult-onset asthma is unknown. Our aim was to assess if BDR in FEV1 is related to age at diagnosis of adult-onset asthma and how many subjects fulfill the 400 mL criterion of BDR, the suggested cut-off for asthma-like reversibility in asthma-COPD overlap (ACO). METHODS: A total of 1030 patients with adult-onset asthma were included; 245 from SAAS (Seinäjoki Adult Asthma Study, Finland) and 785 from COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) cohorts. BDR in FEV1 at the diagnosis of asthma was assessed. Patients were divided into groups based on age at asthma diagnosis: < 40, 40-59.9, and ≥ 60 years. The cohorts were analyzed separately. RESULTS: BDR % in FEV1 did not differ between the groups of different age at asthma diagnosis and no correlation between BDR and age was found. Of patients aged ≥40 years, only 18% (SAAS-cohort) and 5% (COREA-cohort) reached the 400 mL BDR in FEV1. After exclusion of possible ACO patients, the results remained similar. CONCLUSION: By using two large cohorts of steroid-naive patients with asthma, we have shown that BDR at diagnosis of asthma is constant over large age span range, and the limit of 400 mL in BDR in FEV1 is rarely reached. TRIAL REGISTRATION: Seinäjoki Adult Asthma Study is registered at ClinicalTrials.gov with identifier number NCT02733016 .

Asthma control test reflects not only lung function but also airway inflammation in children with stable asthma.

Objective: Various numerical asthma control tools have been developed to distinguish different levels of symptom control. We aimed to examine whether the asthma control test (ACT) is reflective of objective findings such as lung function, fractional exhaled nitric oxide (FeNO) and laboratory data in patients with stable asthma.Methods: We included patients who were enrolled in the Korean Childhood Asthma Study. ACT, spirometry, blood tests and FeNO were performed in patients after stabilization of their asthma. We examined differences among spirometry parameters, blood tests and FeNO according to control status as determined by ACT and investigated for any significant correlations.Results: The study population consisted of 441 subjects. Spirometry showed that forced expiratory volume in one second (FEV1), forced expiratory flow between 25% and 75% of forced vital capacity and FEV1/forced vital capacity were all significantly higher in the controlled asthma group. Likewise, FeNO and percent-change in FEV1 were both significantly lower in the controlled asthma group. In blood tests, the eosinophil fraction was significantly lower in the controlled asthma group while white blood cell count was significantly higher in the controlled asthma group. Lastly, among the various factors analyzed, only provocative concentration of methacholine causing a 20% fall in FEV1 significantly correlated with ACT score.Conclusion: ACT is useful as part of the routine evaluation of asthmatic children and should be used as a complement to existing tools such as spirometry and FeNO measurement.

Area Under the Expiratory Flow-Volume Curve (AEX): Assessing Bronchodilator Responsiveness.

BACKGROUND: Area under expiratory flow-volume curve (AEX) is a useful spirometric tool in stratifying respiratory impairment. The AEX approximations based on isovolumic flows can be used with reasonable accuracy when AEX is unavailable. We assessed here pre- to post-bronchodilator (BD) variability of AEX4 as a functional assessment tool for lung disorders. METHODS: The BD response was assessed in 4330 subjects by changes in FEV1, FVC, and AEX4, which were derived from FVC, peak expiratory flow, and forced expiratory flow at 25%, 50%, and 75% FVC. Newly proposed BD response categories (negative, minimal, mild, moderate and marked) have been investigated in addition to standard criteria. RESULTS: Using standard BD criteria, 24% of subjects had a positive response. Using the new BD response categories, only 23% of subjects had a negative response; 45% minimal, 18% mild, 9% moderate, and 5% had a marked BD response. Mean percent change of the square root AEX4 was 0.3% and 14.3% in the standard BD-negative and BD-positive response groups, respectively. In the new BD response categories of negative, minimal, mild, moderate, and marked, mean percent change of square root AEX4 was - 8.2%, 2.9%, 9.2%, 15.0%, and 24.8%, respectively. CONCLUSIONS: Mean pre- to post-BD variability of AEX4 was < 6% and stratified well between newly proposed categories of BD response (negative, minimal, mild, moderate and marked). We suggest that AEX4 (AEX) could become a useful measurement for stratifying dysfunction in obstructive lung disease and invite further investigation into indications for using bronchodilator agents or disease-modifying, anti-inflammatory therapies.

Depressive symptom-associated IL-1ß and TNF-α release correlates with impaired bronchodilator response and neutrophilic airway inflammation in asthma.

BACKGROUND: Depressive symptoms worsen asthma outcomes; however, the mechanism remains largely unexplored. OBJECTIVE: This study aimed to determine whether depressive symptom-associated immune inflammation correlates with impaired bronchodilator response (BDR) and airway inflammatory phenotypes. METHODS: Eligible adults with asthma (n = 198) underwent clinical assessment, sputum induction and blood sampling. Depressive symptoms were defined by scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Pre- and post-bronchodilator spirometry was performed for BDR. Airway inflammatory phenotypes were defined by sputum cell counts. CRP, IL-1ß, IL-5, IL-6, IL-8, TNF-α, IFN-γ, CCL17 and CCL22 in serum and sputum were detected. RESULTS: Compared with the non-depressive group (n = 174), the depressive group (n = 24) exhibited impaired BDR (P = 0.032) and increased sputum neutrophils (P = 0.023), which correlated with the HADS-D scores (P = 0.027 and P = 0.029). Levels of IL-1ß, TNF-α and IFN-γ in the serum and those of IL-1ß and IFN-γ in the sputum were elevated in the depressive group compared to those in the non-depressive group (all P < 0.05). Multiple regression models indicated that TNF-α in the sputum and IL-1ß, IL-6 and IFN-γ in both the serum and sputum were inversely associated with BDR; TNF-α in the sputum and IL-1ß in both the serum and sputum were positively correlated with sputum neutrophils. Mediation analyses revealed that IL-1ß and TNF-α in the sputum and IL-1ß in both the serum and sputum mediate the correlations of the HADS-D scores with BDR and sputum neutrophils, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Asthma patients with depressive symptoms present worse asthma control, which is most likely explained by impaired BDR and neutrophilic airway inflammation. IL-1ß and TNF-α, which are two key pro-inflammatory cytokines that mediate the correlation of depressive symptoms with impaired BDR and neutrophilic airway inflammation, may serve as targeted biomarkers in the neuropsychological phenotype of asthma; however, this result needs to be further validated.

Impulse oscillometry and spirometry exhibit different features of lung function in bronchodilation.

OBJECTIVE: Bronchodilator responses (BDRs) from impulse oscillometry (IOS) are not interchangeable with those from spirometry. We aimed to identify the characteristics of children with small airway hyperresponsiveness and to determine whether BDR from IOS provides an important supplement to BDR from spirometry. METHODS: The records of 592 children with asthma or suspected asthma who underwent spirometric and oscillometric BDRs were retrospectively reviewed. Oscillometric BDR was defined as positive when relative or absolute changes of Rrs5 or Xrs5 were beyond two standard deviations and spirometric BDR as positive when absolute change of forced expiratory volume in one second (FEV1) was ≥12%. Subjects were classified as positive for spirometric BDR only, positive for oscillometric BDR only, positive for both BDRs, or negative for both BDRs. RESULTS: The results indicated that 101 (17.6%) subjects were positive for spirometric BDR only, 49 (8.5%) positive for oscillometric BDR only, 48 (8.3%) positive for both BDRs, and 377 (65.6%) negative for both BDRs. The agreement between spirometric and oscillometric BDRs was poor. Baseline FEV1, Rrs5, and Xrs5 values strongly influenced the BDRs. Subjects positive for oscillometric BDR only were found to be younger than those positive for spirometric BDR only (P < 0.001). Subjects positive for both BDRs were more likely to have asthma, atopic dermatitis, wheezing apart from cold, or decreased baseline lung function relative to those positive in either test (P < 0.001). CONCLUSIONS: There was a low concordance between spirometric and oscillometric BDRs. Use of IOS to detect small airway hyperresponsiveness may add more information about a clinical profile of subjects with asthma.

Early Changes in eDiary COPD Symptoms Predict Clinically Relevant Treatment Response at 12 Weeks: Analysis from the CRYSTAL Study.

Early detection of treatment response is important in the long-term treatment and management of patients with chronic obstructive pulmonary disease (COPD). This analysis evaluated whether early improvement in symptoms, recorded in the first 7 or 14 days via an electronic diary (eDiary) compared with baseline, can predict clinically meaningful treatment responders at 12 weeks. CRYSTAL was a 12-week, randomized, open-label study that demonstrated the increased effectiveness of indacaterol/glycopyrronium (IND/GLY) or glycopyrronium (GLY), after a direct switch from on-going baseline therapies, in patients with symptomatic COPD and moderate airflow obstruction. The co-primary endpoints were trough forced expiratory volume in 1 second (FEV1) and transition dyspnea index (TDI) at Week 12. Patients' symptom status was recorded daily in an eDiary. Of 4,389 patients randomized, 3,936 and 3,855 reported symptoms on Days 7 and 14, respectively. Patients who reported an early decrease in symptoms on Day 7 or 14 were more likely to achieve the minimal clinically important difference of ≥100 mL in trough FEV1 or ≥ 1 point in TDI at Week 12. Using stepwise multivariate regression models we identified as best predictors of FEV1 responders the decrease in wheeze on Day 7, and nighttime symptoms and wheeze on Day 14; best predictors of TDI responders were decrease in nighttime symptoms and wheeze on Day 7, and nighttime symptoms, sputum and wheeze on Day 14. Early symptom improvement at Day 7 or 14, especially wheeze and nighttime symptoms, may identify patients with clinically important improvement in lung function and dyspnea at Week 12.

Small airway bronchodilator response to different doses of salbutamol in 7-year-old children.

The Global Initiative for Asthma (GINA) guidelines do not specify a bronchodilator range for bronchodilator response (BDR) testing and simply recommend a salbutamol dose of 200 to 400 µg. We determined the oscillometric BDR results of children given low-dose (2 puffs, 200 µg) and standard-dose (4 puffs, 400 µg) salbutamol to compare the small airway responses of healthy controls (defined using criteria based on the guidelines developed at the American Thoracic Society) and exclusion subjects (defined as any child that did not meet the inclusion criteria for healthy controls). The oscillometric reactance of small airways is significantly associated with the dose of salbutamol used for BDR testing in exclusion children. We suggest use of the standard-dose of salbutamol for oscillometric BDR testing.

Combined use of fractional exhaled nitric oxide and bronchodilator response in predicting future loss of asthma control among children with atopic asthma.

BACKGROUND AND OBJECTIVE: Recognition of patients at risk of asthma exacerbation is important for future asthma care and improved outcome. The aim of the present study was to see whether measurements of bronchodilator response (BDR) and fractional exhaled nitric oxide (FeNO) in combination provide prognostic information superior to either measurement alone in children with atopic asthma. METHODS: A total of 201 atopic children aged 8-16 years with intermittent or mild persistent asthma were included. Pulmonary function tests including BDR and FeNO were serially monitored 10 times or more over 2 years when subjects were not receiving controller medications. After completion of monitoring, 1-year observation for a loss of asthma control was performed. RESULTS: During the monitoring period, positive BDRs (≥12% in forced expiratory volume in 1 s (FEV1 ) from pre-bronchodilator value) and FeNO higher than 35 parts per billion (ppb) were observed at least once in 59% and 77% of participants. When analysed as continuous variables, both BDR (hazard ratio (HR): 1.21; 95% CI: 1.04-1.41; P = 0.014) and FeNO (HR: 1.27; 95% CI: 1.09-1.49; P = 0.003) were associated with increased risks for a control loss. Compared with patients showing either positive BDRs (HR: 3.19; 95% CI: 1.05-9.64) or FeNO higher than 35 ppb (HR: 4.70; 95% CI: 1.68-13.11), patients with both findings (HR: 7.08; 95% CI: 2.57-19.49) had greater risks for a control loss. CONCLUSION: These data support that combined use of BDR and FeNO measurements can modify predictive risk obtained from either measurement alone.

Post-traumatic Stress Disorder, Bronchodilator Response, and Incident Asthma in World Trade Center Rescue and Recovery Workers.

RATIONALE: Post-traumatic stress disorder (PTSD) has been associated with asthma in cross-sectional studies. Whether PTSD leads to clinically significant bronchodilator response (BDR) or new-onset asthma is unknown. OBJECTIVES: We sought to determine the relationship between probable PTSD and both BDR and incident asthma in a high-risk cohort of World Trade Center workers in New York (NY). METHODS: This study was conducted on data from a high-risk cohort of 11,481 World Trade Center workers in New York, including 6,133 never smokers without a previous diagnosis of asthma. Of the 6,133 never smokers without asthma, 3,757 (61.3%) completed a follow-up visit several years later (mean = 4.95 yr, interquartile range = 3.74-5.90 yr). At the baseline visit, probable PTSD was defined as a score 44 points or greater in the PTSD Checklist questionnaire, and BDR was defined as both a change of 12% or greater and an increment of 200 ml or greater in FEV1 after bronchodilator administration. Incident asthma was defined as a self-report of new physician-diagnosed asthma after the baseline visit. Multivariable logistic regression was used for the analysis of probable PTSD and baseline BDR or incident asthma. Measurements and Main and Results: At baseline, probable PTSD was associated with BDR among all participants (adjusted odds ratio = 1.43; 95% confidence interval = 1.19-1.72), with similar results among never smokers without asthma. Among 3,757 never smokers, probable PTSD at baseline was associated with incident asthma, even after adjustment for baseline BDR (odds ratio = 2.41; 95% confidence interval = 1.85-3.13). This association remained significant in a confirmatory analysis after excluding 195 subjects with baseline BDR. CONCLUSIONS: In a cohort of adult workers exposed to a severe traumatic event, probable PTSD is significantly associated with BDR at baseline and predicts incident asthma.

Respiratory reactance in children aged three to five years with postinfectious bronchiolitis obliterans is higher than in those with asthma.

AIM: We investigated airway function in preschoolers with postinfectious bronchiolitis obliterans (PIBO) using impulse oscillometry (IOS). METHODS: This study enrolled 182 children aged three to five years: 12 with PIBO, 135 with asthma and 35 nonatopic controls. Respiratory resistance and reactance were assessed using IOS. RESULTS: The percentage predicted (% predicted) of prebronchodilator respiratory resistance at 5 Hz was significantly higher in children with PIBO (177.9 ± 118.4%) than the asthma (126.1 ± 30.5%, p = 0.013) or control (121.1 ± 21.8%, p = 0.014) groups. After bronchodilator use, children with PIBO did not reach the values of Rrs5% predicted in the asthma and control groups. Respiratory reactance (Xrs5% predicted) in children with PIBO (337.1 ± 478.5%) was significantly higher than both asthma (130.0 ± 80.0%, p = 0.004) and control (105.1 ± 30.8%, p < 0.001) groups before bronchodilator use and significantly higher than the two groups after bronchodilator use (p = 0.010 and p = 0.004, respectively). The changes in Rrs5 and Xrs5 were not significantly different between the children with PIBO and asthma. CONCLUSION: Measuring Rrs5 and Xrs5 before and after bronchodilator use may help to discriminate PIBO from asthma in children aged three to five years with chronic or recurrent respiratory symptoms.

A literature review of the evidence that a 12% improvement in FEV1 is an appropriate cut-off for children.

INTRODUCTION: A well-performed spirometry, using a change in forced expiratory volume in one second (FEV(1)) after albuterol, is commonly used to support the likelihood of an asthma diagnosis. The current standard, accepted by the 2007 National Heart Lung and Blood Institute Asthma Expert Panel Report-3 (EPR-3) guidelines, is a 12% improvement in the FEV(1) after a bronchodilator. OBJECTIVE: We sought to determine whether existing studies support or refute using a 12% improvement as a significant change in FEV(1) in children and adolescents. DATA SOURCES: We reviewed the literature of children and adolescents using Medline searches to discover pertinent population studies and comparative studies that included FEV(1) measurements. RESULT: The majority of the discovered studies suggest a less stringent improvement in FEV(1) in children might be applicable. CONCLUSION: Supported by the published literature, we suggest an alternative interpretive strategy of expressing the results of a spirometry measurement when a diagnosis of asthma in a child is being considered using a bronchodilator response.

Stress and Bronchodilator Response in Children with Asthma.

RATIONALE: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). OBJECTIVES: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma. METHODS: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. MEASUREMENTS AND MAIN RESULTS: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the ß2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). CONCLUSIONS: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.

Inhaled corticosteroid treatment modulates ZNF432 gene variant's effect on bronchodilator response in asthmatics.

BACKGROUND: Single nucleotide polymorphisms (SNPs) influence a patient's response to inhaled corticosteroids and ß2-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of ß2-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with a bronchodilator response. OBJECTIVE: To assess whether, among subjects with asthma, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids versus those on placebo. METHODS: A genome-wide association analysis was conducted by using 581 white subjects from the Childhood Asthma Management Program. By using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial. RESULTS: The combined P value for the Childhood Asthma Management Program and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial populations was 4.8 × 10(-8) for rs3752120, which is located in the zinc finger protein gene ZNF432 and has an unknown function. CONCLUSIONS: Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma.