Relationships between lung function, allergy, and wheezing in urban children.

BACKGROUND: Allergic sensitization and low lung function in early childhood are risk factors for subsequent wheezing and asthma. However, it is unclear how allergic sensitization affects lung function over time. OBJECTIVE: We sought to test whether allergy influences lung function and whether these factors synergistically increase the risk of continued wheezing in childhood. METHODS: We analyzed longitudinal measurements of lung function (spirometry and impulse oscillometry) and allergic sensitization (aeroallergen skin tests and serum allergen-specific IgE) throughout early childhood in the Urban Environmental and Childhood Asthma study, which included high-risk urban children living in disadvantaged neighborhoods. Intraclass correlation coefficients were calculated to assess lung function stability. Cluster analysis identified low, medium, and high allergy trajectories, which were compared with lung function and wheezing episodes in linear regression models. A variable selection model assessed predictors at age 5 years for continued wheezing through age 12 years. RESULTS: Lung function adjusted for growth was stable (intraclass correlation coefficient, 0.5-0.7) from age 5 to 12 years and unrelated to allergy trajectory. Lung function and allergic sensitization were associated with wheezing episodes in an additive fashion. In children with asthma, measuring lung function at age 5 years added little to the medical history for predicting future wheezing episodes through age 12 years. CONCLUSIONS: In high-risk urban children, age-related trajectories of allergic sensitization were not associated with lung function development; however, both indicators were related to continued wheezing. These results underscore the importance of understanding early-life factors that negatively affect lung development and suggest that treating allergic sensitization may not alter lung function development in early to mid-childhood.

A Novel Air Trapping Segment Score Identifies Opposing Effects of Obesity and Eosinophilia on Air Trapping in Asthma.

Rationale: Density thresholds in computed tomography (CT) lung scans quantify air trapping (AT) at the whole-lung level but are not informative for AT in specific bronchopulmonary segments. Objectives: To apply a segment-based measure of AT in asthma to investigate the clinical determinants of AT in asthma. Methods: In each of 19 bronchopulmonary segments in CT lung scans from 199 patients with asthma, AT was categorized as present if lung attenuation was less than -856 Hounsfield units at expiration in ⩾15% of the lung area. The resulting AT segment score (0-19) was related to patient outcomes. Measurements and Main Results: AT varied at the lung segment level and tended to persist at the patient and lung segment levels over 3 years. Patients with widespread AT (⩾10 segments) had more severe asthma (P < 0.05). The mean (±SD) AT segment score in patients with a body mass index ⩾30 kg/m2 was lower than in patients with a body mass index <30 kg/m2 (3.5 ± 4.6 vs. 5.5 ± 6.3; P = 0.008), and the frequency of AT in lower lobe segments in obese patients was less than in upper and middle lobe segments (35% vs. 46%; P = 0.001). The AT segment score in patients with sputum eosinophils ⩾2% was higher than in patients without sputum eosinophilia (7.0 ± 6.1 vs. 3.3 ± 4.9; P < 0.0001). Lung segments with AT more frequently had airway mucus plugging than lung segments without AT (48% vs. 18%; P ⩽ 0.0001). Conclusions: In patients with asthma, air trapping is more severe in those with airway eosinophilia and mucus plugging, whereas those who are obese have less severe trapping because their lower lobe segments are spared.

Comparison of hyperpolarized 3He-MRI, CT based parametric response mapping, and mucus scores in asthmatics.

Purpose: The purpose of this study was to anatomically correlate ventilation defects with regions of air trapping by whole lung, lung lobe, and airway segment in the context of airway mucus plugging in asthma. Methods: A total of 34 asthmatics [13M:21F, 13 mild/moderate, median age (range) of 49.5 (36.8-53.3) years and 21 severe, 56.1 (47.1-62.6) years] and 4 healthy subjects [1M:3F, 38.5 (26.6-52.2) years] underwent HP 3He MRI and CT imaging. HP 3He MRI was assessed for ventilation defects using a semi-automated k-means clustering algorithm. Inspiratory and expiratory CTs were analyzed using parametric response mapping (PRM) to quantify markers of emphysema and functional small airways disease (fSAD). Segmental and lobar lung masks were obtained from CT and registered to HP 3He MRI in order to localize ventilation defect percent (VDP), at the lobar and segmental level, to regions of fSAD and mucus plugging. Spearman's correlation was utilized to compare biomarkers on a global and lobar level, and a multivariate analysis was conducted to predict segmental fSAD given segmental VDP (sVDP) and mucus score as variables in order to further understand the functional relationships between regional measures of obstruction. Results: On a global level, fSAD was correlated with whole lung VDP (r = 0.65, p < 0.001), mucus score (r = 0.55, p < 0.01), and moderately correlated (-0.60 ≤ r ≤ -0.56, p < 0.001) to percent predicted (%p) FEV1, FEF25-75 and FEV1/FVC, and more weakly correlated to FVC%p (-0.38 ≤ r ≤ -0.35, p < 0.001) as expected from previous work. On a regional level, lobar VDP, mucus scores, and fSAD were also moderately correlated (r from 0.45-0.66, p < 0.01). For segmental colocalization, the model of best fit was a piecewise quadratic model, which suggests that sVDP may be increasing due to local airway obstruction that does not manifest as fSAD until more extensive disease is present. sVDP was more sensitive to the presence of a mucus plugs overall, but the prediction of fSAD using multivariate regression showed an interaction in the presence of a mucus plugs when sVDP was between 4% and 10% (p < 0.001). Conclusion: This multi-modality study in asthma confirmed that areas of ventilation defects are spatially correlated with air trapping at the level of the airway segment and suggests VDP and fSAD are sensitive to specific sources of airway obstruction in asthma, including mucus plugs.

Chronic intermittent hypoxia increases airway hyperresponsiveness during house dust mites exposures in rats.

INTRODUCTION: Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested effects of Chronic Intermittent Hypoxia (CIH) - a hallmark of OSA - on airway hyperresponsiveness (AHR), in a rat model of chronic allergen-induced inflammation. METHODS: Brown Norway rats were exposed to six weeks of CIH or normoxia (NORM) concurrent with weekly house dust mites (HDM) or saline (SAL) challenges. At endpoint, we assessed responses to seven Methacholine (Mch) doses (0, 4, 8, 16, 32, 64, 128 mg/mL) on a FlexiVent system (Scireq). Maximal (or plateau) responses (reactivity) for total respiratory system Resistance (Rrs) and Elastance (Ers), Newtonian airway resistance (RN, a measure of central airways function) and tissue damping (G, a measure of distal airways function) were plotted. RESULTS: HDM/CIH-treated animals demonstrated the highest reactivity to Mch in Rrs and Ers compared to all other groups (HDM/NORM, SAL/CIH and SAL/NORM p < 0.05 for all comparisons, for doses 5-7 for Rrs, and for doses 4-7 for Ers). The enhanced Rrs response was due to an increase in G (doses 4-7, p < 0.05 for comparisons to all other groups), whereas RN was not affected by CIH. CONCLUSIONS: In rats chronically challenged with HDM, concurrent CIH exposure induces AHR primarily in the distal airways, which affects the respiratory system frequency-dependent elastic properties.

Determinants of lung function across childhood in the Severe Asthma Research Program (SARP) 3.

BACKGROUND: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. OBJECTIVE: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. METHODS: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. RESULTS: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. CONCLUSIONS: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.

Four weeks of repetitive acute hypoxic preconditioning did not alleviate allergen-induced airway dysfunction in rats.

Clinical case series suggest beneficial effects of low-dose intermittent hypoxia in asthma. We tested cardiopulmonary effects of repetitive acute hypoxic preconditioning (RAHP) during allergic inflammation. Brown Norway rats were sensitized to house dust mites (HDM) and exposed to 4-week RAHP or normoxia (SHAM), concurrent with weekly HDM or saline (SAL) challenges. We assessed methacholine responses and lung HIF-1α expression at endpoint, and weekly blood pressure (BP). RAHP relative to SHAM: 1) in HDM-challenged rats, showed no protection against HDM-induced airway dysfunction and did not significantly impact BP (week 4 mean BP difference = 10.51 mmHg, p = 0.09) or HIF-1α expression; 2) in SAL-challenged rats, attenuated airway responses to methacholine, reduced BP (week 4 mean BP average difference = -8.72 mmHg, p = 0.04) and amplified HIF-1α expression (p = 0.0086). Four weeks of RAHP did not mitigate the allergen-induced lower airway dysfunction and may detrimentally affect BP. However, it elicited beneficial cardiopulmonary responses in SAL-challenged rats, concurrent with increased HIF-1α expression.

Mucus Plugs in Asthma at CT Associated with Regional Ventilation Defects at 3He MRI.

Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 (3He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs (P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma.

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline.Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index.Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.

Plasma P-Selectin Is Inversely Associated with Lung Function and Corticosteroid Responsiveness in Asthma.

BACKGROUND: Severe asthma has multiple phenotypes for which biomarkers are still being defined. Plasma P-selectin reports endothelial and/or platelet activation. OBJECTIVE: To determine if P-selectin is associated with features of asthma in a longitudinal study. METHODS: Plasmas from 70 adult patients enrolled in the Severe Asthma Research Program (SARP) III at the University of Wisconsin-Madison were analyzed for concentration of P-selectin at several points over the course of 3 years, namely, at baseline (BPS), after intramuscular triamcinolone acetonide (TA) injection, and at 36 months after baseline. Thirty-four participants also came in during acute exacerbation and 6 weeks after exacerbation. RESULTS: BPS correlated inversely with forced expiratory volume in 1 s (FEV1) and with residual volume/total lung capacity, an indicator of air trapping. BPS was inversely associated with FEV1 change after TA, by regression analysis. FEV1 did not change significantly after TA if BPS was above the median, whereas patients with BPS below the median had significantly increased FEV1 after TA. BPS was higher in and predicted assignment to SARP phenotype cluster 5 ("severe fixed-airflow asthma"). P-selectin was modestly but significantly increased at exacerbation but returned to baseline within 3 years. CONCLUSIONS: High BPS is associated with airway obstruction, air trapping, the "severe fixed-airflow" cluster, and lack of FEV1 improvement in response to TA injection. P-selectin concentration, which is a stable trait with only modest elevation during exacerbation, may be a useful biomarker for a severe asthma pheno- or endotype characterized by low pulmonary function and lack of corticosteroid responsiveness.

Ventilation defects on hyperpolarized helium-3 MRI in asthma are predictive of 2-year exacerbation frequency.

BACKGROUND: There is an unmet need for an objective biomarker to predict asthma exacerbations. OBJECTIVE: Our aim was to assess the ventilation defect percent (VDP) on hyperpolarized helium-3 magnetic resonance imaging as a predictor of exacerbation frequency following imaging. METHODS: Subjects underwent hyperpolarized helium-3 and conventional clinical measurements, including pulmonary function tests, during a period of disease stability, and exacerbations were recorded prospectively over the following 2 years. We used a Poisson regression tree model to estimate an optimal VDP threshold for classifying subjects into high- versus low-exacerbation groups and then used statistical regression to compare this VDP threshold against conventional clinical measures as predictors of exacerbations. RESULTS: A total of 67 individuals with asthma (27 males and 40 females, 28 with mild-to-moderate asthma and 39 with severe asthma) had a median VDP of 3.75% (1.2% [first quartile]-7.9% [third quartile]). An optimal VDP threshold of 4.28% was selected on the basis of the maximum likelihood estimation of the regression tree model. Subjects with a VDP greater than 4.28% (n = 32) had a median of 1.5 exacerbations versus 0.0 for subjects with a VDP less than 4.28% (n = 35). In a stepwise multivariate regression model, a VDP greater than 4.28% was associated with an exacerbation incidence rate ratio of 2.5 (95% CI = 1.3-4.7) versus a VDP less than or equal to 4.28%. However, once individual medical history was included in the model, VDP was no longer significant. Nonetheless, VDP may provide an objective and complementary quantitative marker of individual exacerbation risk that is useful for monitoring individual change in disease status, selecting patients for therapy, and assessing treatment response. CONCLUSION: VDP measured with magnetic resonance imaging shows promise as a biomarker of prospective asthma exacerbations.

Safety of repeated hyperpolarized helium 3 magnetic resonance imaging in pediatric asthma patients.

BACKGROUND: Hyperpolarized helium 3 magnetic resonance imaging (3He MRI) is useful for investigating pulmonary physiology of pediatric asthma, but a detailed assessment of the safety profile of this agent has not been performed in children. OBJECTIVE: To evaluate the safety of 3He MRI in children and adolescents with asthma. MATERIALS AND METHODS: This was a retrospective observational study. 3He MRI was performed in 66 pediatric patients (mean age 12.9 years, range 8-18 years, 38 male, 28 female) between 2007 and 2017. Fifty-five patients received a single repeated examination and five received two repeated examinations. We assessed a total of 127 3He MRI exams. Heart rate, respiratory rate and pulse oximetry measured oxygen saturation (SpO2) were recorded before, during (2 min and 5 min after gas inhalation) and 1 h after MRI. Blood pressure was obtained before and after MRI. Any subjective symptoms were also noted. Changes in vital signs were tested for significance during the exam and divided into three subject age groups (8-12 years, 13-15 years, 16-18 years) using linear mixed-effects models. RESULTS: There were no serious adverse events, but three minor adverse events (2.3%; headache, dizziness and mild hypoxia) were reported. We found statistically significant increases in heart rate and SpO2 after 3He MRI. The youngest age group (8-12 years) had an increased heart rate and a decreased respiratory rate at 2 min and 5 min after 3H inhalation, and an increased SpO2 post MRI. CONCLUSION: The use of 3He MRI is safe in children and adolescents with asthma.

Disparate diagnostic accuracy of lung function tests as predictors of poor asthma control in children.

Rationale: In practice, asthma control is assessed according to symptom burden and office spirometry. However, spirometry poorly tests peripheral lung function, which may be abnormal in asthma. Impluse oscillometry (IOS) and multiple-breath washout (MBW) are novel methods which measure reactance (X5) and ventilation heterogeneity (VH) in the peripheral lung, but how well these tests reflect asthma control is poorly understood. Objective: To compare the diagnostic accuracy of tests of large airways caliber (FEV1, FEV1/FVC, R20), peripheral zone properties (X5, VH), and airways inflammation (FeNO) as predictors of poor control in asthmatic children (44 poorly controlled/10 controlled). Methods: 54 children enriched in severe asthma completed a symptom-based control scale (ACT/cACT) and lung function tests after overnight bronchodilator withhold. The accuracy of each variable to predict poor control was ranked by area under the receiver operating characteristic (ROC) curve, sensitivity and specificity. Results: Among measures of large airways caliber, the FEV1% had the highest ROC curve area, with low sensitivity but perfect specificity. Among measures of peripheral lung function, X5 and VH in the conducting zone had fair curve areas with higher sensitivity but lower specificity compared to the FEV1%. VH in the acinar zone and FeNO both had poor accuracy. Conclusion: Tests of large airway and peripheral zone lung function performed disparately as predictors of poor control in a sample of children enriched in severe asthma. Further studies in a larger sample with more diverse phenotypic features are necessary to validate this preliminary conclusion.

Development and initial validation of the Asthma Severity Scoring System (ASSESS).

BACKGROUND: Tools for quantification of asthma severity are limited. OBJECTIVE: We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. METHODS: Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. RESULTS: ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. CONCLUSIONS: The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

Compressive air trapping in asthma: effects of age, sex, and severity.

Air trapping due to airway closure has been associated with unstable asthma. In addition to airway closure that occurs at lower lung volumes during slow expiration, there may be further closure during a forced expiration because of airway compression. The purpose of this study was to define a reference range from a nonasthmatic population and investigate the characteristics of compressive air trapping in asthma. Spirometry and plethysmography were performed in 117 nonasthmatic subjects (ages 18-87 yr) and 153 asthma subjects (ages 12-72 yr). Air trapping was assessed as residual lung volume and the ratio of forced expiratory vital capacity (FVC) to slow inspiratory vital capacity (iVC) (FVC/iVC). There were no significant age or sex effects on the FVC/iVC ratio in the nonasthmatic subjects, and a fifth percentile lower limit of normal (LLN) of 0.93 was computed. An FVC/iVC ratio less than LLN defined compressive air trapping. Asthma subjects exhibited an age-related decline in the FVC/iVC ratio of 0.0027 per year (P < 0.0001) in a mixed effects model, with additional decreases associated with severe asthma and male sex. FVC/iVC ratios< LLN were infrequent in subjects <30 yr but evident in most asthma subjects >50 yr. Lung residual volumes followed similar patterns of greater elevations in subjects with severe asthma, older age, and male sex. Compressive air trapping occurs frequently in older asthmatics, appearing to be a feature of the natural history of asthma that is greater in severe asthma and men. This component of premature airway closure affects spirometric assessment of airway function and may contribute to asthma symptoms during physical exertion. NEW & NOTEWORTHY Premature airway closure during exhalation is a component of airway obstruction that is associated with asthma severity and instability. Compressive air trapping is airway closure that is more extensive during a forced exhalation than with a slow, passive exhalation. We report that compressive air trapping occurs in most people > 50 yr with asthma, affects men more than women, and persists after bronchodilator treatment. This component of obstruction appears to be part of the natural history of asthma.

Multiview Cluster Analysis Identifies Variable Corticosteroid Response Phenotypes in Severe Asthma.

Rationale: Corticosteroids (CSs) are the most effective asthma therapy, but responses are heterogeneous and systemic CSs lead to long-term side effects. Therefore, an improved understanding of the contributing factors in CS responses could enhance precision management. Although several factors have been associated with CS responsiveness, no integrated/cluster approach has yet been undertaken to identify differential CS responses. Objectives: To identify asthma subphenotypes with differential responses to CS treatment using an unsupervised multiview learning approach. Methods: Multiple-kernel k-means clustering was applied to 100 clinical, physiological, inflammatory, and demographic variables from 346 adult participants with asthma in the Severe Asthma Research Program with paired (before and 2-3 weeks after triamcinolone administration) sputum data. Machine-learning techniques were used to select the top baseline variables that predicted cluster assignment for a new patient. Measurements and Main Results: Multiple-kernel clustering revealed four clusters of individuals with asthma and different CS responses. Clusters 1 and 2 consisted of young, modestly CS-responsive individuals with allergic asthma and relatively normal lung function, separated by contrasting sputum neutrophil and macrophage percentages after CS treatment. The subjects in cluster 3 had late-onset asthma and low lung function, high baseline eosinophilia, and the greatest CS responsiveness. Cluster 4 consisted primarily of young, obese females with severe airflow limitation, little eosinophilic inflammation, and the least CS responsiveness. The top 12 baseline variables were identified, and the clusters were validated using an independent Severe Asthma Research Program test set. Conclusions: Our machine learning-based approaches provide new insights into the mechanisms of CS responsiveness in asthma, with the potential to improve disease treatment.

Racial disparities in asthma-related health care use in the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.

BACKGROUND: Despite advances in asthma care, disparities persist. Black patients are disproportionally affected by asthma and also have poorer outcomes compared with white patients. OBJECTIVE: We sought to determine associations between black and white patients and asthma-related health care use, accounting for complex relationships. METHODS: This study was completed as part of the National Heart, Lung, and Blood Institute's Severe Asthma Research Program, a prospective observational cohort. Between November 2012 and February 2015, it enrolled 579 participants 6 years and older with 1 year of observation time and complete data. Inverse probability of treatment weighting was used to balance racial groups with respect to community and family socioeconomic variables and environmental exposure variables. The primary outcome was emergency department (ED) use for asthma. Secondary outcomes included inhaled corticosteroid use, outpatient physician's office visits for asthma, and asthma-related hospitalization. RESULTS: Black patients had greater odds of ED use over 1 year (odds ratio, 2.19; 95% CI, 1.43-3.35) but also differed in the majority (>50%) of baseline variables measured. After statistical balancing of the racial groups, the difference between black and white patients with respect to ED use no longer reached the level of significance. Instead, in secondary analyses black patients were less likely to see an outpatient physician for asthma management (adjusted odds ratio, 0.57; 95% CI, 0.38-0.85). CONCLUSIONS: The disparity in ED use was eliminated after consideration of multiple variables. Social and environmental policies and interventions tailored to black populations with a high burden of asthma are critical to reduction (or elimination) of these disparities.

Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma.

BACKGROUND: Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. METHODS: To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6-18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. RESULTS: From pre-/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. CONCLUSIONS: These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01748175 .

Spirometry and Impulse Oscillometry in Preschool Children: Acceptability and Relationship to Maternal Smoking in Pregnancy.

BACKGROUND: Comparisons of the technical acceptability of spirometry and impulse oscillometry (IOS) and clinical correlations of the measurements have not been well studied in young children. There are no large studies focused on African American and Hispanic children. OBJECTIVES: We sought to (1) compare the acceptability of spirometry and IOS in 3- to 5-year-old children and (2) examine the relationship of maternal smoking during pregnancy to later lung function. METHODS: Spirometry and IOS were attempted at 4 sites from the Urban Environmental and Childhood Asthma Study birth cohort at ages 3, 4, and 5 years (472, 471, and 479 children, respectively). We measured forced expiratory flow in 0.5 s (forced expiratory volume in 0.5 seconds [FEV0.5]) with spirometry and area of reactance (AX), resistance and reactance at 5 Hz (R5 and X5, respectively) using IOS. RESULTS: Children were more likely to achieve acceptable maneuvers with spirometry than with IOS at age 3 (60% vs 46%, P < .001) and 5 years (89% vs 84%, P = .02). Performance was consistent among the 4 study sites. In children without recurrent wheeze, there were strong trends for higher FEV0.5 and lower R5 and AX over time. Maternal smoking during pregnancy was associated with higher AX at ages 4 and 5 years (P < .01 for both years). There was no significant difference in FEV0.5 between children with and without in utero exposure to smoking. CONCLUSION: There is a higher rate of acceptable maneuvers with spirometry compared with IOS, but IOS may be a better indicator of peripheral airway function in preschool children.

Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age.

BACKGROUND: The effect of age on asthma severity is poorly understood. OBJECTIVES: The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. METHODS: SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. RESULTS: Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. CONCLUSIONS: The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.