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Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

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.

BACKGROUND: Prenatal and early life exposure to maternal stress and depression is linked to development of recurrent wheezing in young children. OBJECTIVE: To determine whether maternal stress and depression in early life is associated with non-atopic wheezing phenotype in urban children. METHODS: The Urban Environment and Childhood Asthma Study examined a birth cohort of children at high risk for asthma in low-income neighborhoods. Prenatal and postnatal (through age three years) maternal stress and depression scores were compared to respiratory phenotypes through age ten years (multinomial regression), self-reported colds (linear regression) and detection of respiratory viruses (Poisson regression). RESULTS: Scores for maternal depression, and, to a lesser extent, maternal perceived stress, were positively related to multiple wheezing phenotypes. In particular, cumulative measures of maternal depression in the first three years were related to the moderate wheeze-low atopy (MW-LA) phenotype (OR=1.13; [1.05, 1.21]; p

BACKGROUND: Black and Hispanic children growing up in disadvantaged urban neighborhoods have the highest rates of asthma and related morbidity in the United States. OBJECTIVE: To identify specific respiratory phenotypes of health and disease in this population, associations with early-life exposures, and molecular patterns of gene expression in nasal epithelial cells that underlie clinical disease. METHODS: The study population consisted of 442 high-risk urban children who had repeated assessments of wheezing, allergen-specific IgE, and lung function through age 10 years. Phenotypes were identified by developing temporal trajectories for these data, and then compared to early life exposures and patterns of nasal epithelial gene expression at age 11. RESULTS: Of the 6 identified respiratory phenotypes, a high-wheeze high-atopy low-lung-function (HW-HA-LF) group had the greatest respiratory morbidity. In early life, this group had low exposure to common allergens and high exposure to ergosterol in house dust. While all high atopy groups were associated with increased expression of a type-2 inflammation gene module in nasal epithelial samples, an epithelium IL-13 response module tracked closely with impaired lung function, and a MUC5AC hypersecretion module was uniquely upregulated in HW-HA-LF. In contrast, a medium-wheeze low-atopy (MW-LA) group showed altered expression of modules of epithelial integrity, epithelial injury, and antioxidant pathways. CONCLUSION: In the first decade of life, high-risk urban children develop distinct phenotypes of respiratory health versus disease that link early-life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of airway gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and non-allergic asthma. CAPSULE SUMMARY: We have demonstrated both distinct respiratory phenotypes – which develop by age 10 and link to asthma development – and related functional gene expression networks in respiratory epithelium.

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. Electronic supplementary material The online version of this article (10.1186/s12890-018-0612-x) contains supplementary material, which is available to authorized users.

Objective: While asthma disproportionately affects minorities, little is known about racial/ethnic differences in asthma care at hospital discharge. Methods: Secondary data analysis of multicenter retrospective study using standardized medical record review. A random sample of patients aged 2–54 years, who were hospitalized for asthma at 25 hospitals from 2012 to 2013 was analyzed. We categorized patients into three race/ethnicity groups: non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic. Multivariable logistic regression using generalized estimating equations was used to examine the relationship between race/ethnicity and the provision of guideline-concordant asthma care at hospital discharge including: the provision of asthma action plans, provision of new prescription of an inhaled corticosteroid, and referral to an asthma specialist. Results: Nine hundred thirteen patients (39% children, 71% minorities) hospitalized for asthma were included. In adjusted models, NHB children were...

Maternal depression and prenatal and early life stress may influence childhood wheezing illnesses, potentially through effects on immune development.To test the hypothesis that maternal stress and/or depression during pregnancy and early life are associated with recurrent wheezing and aeroallergen sensitivity and altered cytokine responses (enhanced type 2 or reduced virus-induced cytokine responses) from stimulated peripheral blood mononuclear cells at age 3 years.URECA (Urban Environment and Childhood Asthma) is a birth cohort at high risk for asthma (n = 560) in four inner cities. Maternal stress, depression, and childhood wheezing episodes were assessed by quarterly questionnaires beginning at birth. Logistic and linear regression techniques were used to examine the relation of maternal stress/depression to recurrent wheezing and peripheral blood mononuclear cell cytokine responses at age 3 years.Overall, 166 (36%) children had recurrent wheeze at age 3 years. Measures of maternal perceived stress at Years 2 and 3 were positively associated with recurrent wheeze (P 0.05). Maternal depression (any year) was significantly associated with recurrent wheezing (P ≤ 0.01). These associations were also significant when considered in a longitudinal analysis of cumulative stress and depression (P ≤ 0.02). Neither stress nor depression was significantly related to aeroallergen sensitization or antiviral responses. Contrary to our original hypothesis, prenatal and Year 1 stress and depression had significant inverse associations with several type 2 cytokine responses.In urban children at high risk for asthma, maternal perceived stress and depression were significantly associated with recurrent wheezing but not increased atopy or reduced antiviral responses.

Background Our objective was to determine those characteristics associated with reversibility of airflow obstruction and response to maximal bronchodilation in children with severe asthma through the Severe Asthma Research Program (SARP). Methods We performed a cross-sectional analysis evaluating children ages 6 to 17 years with nonsevere asthma (NSA) and severe asthma (SA). Participants underwent spirometry before and after 180 µg of albuterol to determine reversibility (≥12% increase in FEV1 ). Participants were then given escalating doses up to 720 µg of albuterol to determine their maximum reversibility. Results We evaluated 230 children (n = 129 SA, n = 101 NSA) from five centers across the United States in the SARP I and II cohorts. SA (odds ratio [OR], 2.08, 95% confidence interval [CI], 1.05-4.13), second-hand smoke exposure (OR, 2.81, 95%CI, 1.23-6.43), and fractional exhaled nitric oxide (FeNO; OR, 1.97, 95%CI, 1.35-2.87) were associated with increased odds of airway reversibility after maximal bronchodilation, while higher prebronchodilator (BD) FEV1 % predicted (OR, 0.91, 95%CI, 0.88-0.94) was associated with decreased odds. In an analysis using the SARP III cohort (n = 186), blood neutrophils, immunoglobulin E (IgE), and FEV1 % predicted were significantly associated with BD reversibility. In addition, children with BD response have greater healthcare utilization. BD reversibility was associated with reduced lung function at enrollment and 1-year follow-up though less decline in lung function over 1 year compared to those without reversibility. Conclusions Lung function, that is FEV1 % predicted, is a predictor of BD response in children with asthma. Additionally, smoke exposure, higher FeNO or IgE level, and low peripheral blood neutrophils are associated with a greater likelihood of BD reversibility. BD response can identify a phenotype of pediatric asthma associated with low lung function and poor asthma control.

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.

Although community violence may influence asthma morbidity by increasing stress, no study has assessed exposure to gun violence and childhood asthma. We examined whether exposure to gun violence is associated with asthma in children, particularly in those reporting fear of leaving their home.Case-control study of 466 children aged 9-14 years with (n = 234) and without (n = 232) asthma in San Juan, Puerto Rico. Lifetime exposure to gun violence was defined as hearing a gunshot more than once. We also assessed whether the child was afraid to leave his/her home because of violence. Asthma was defined as physician-diagnosed asthma and wheeze in the prior year. We used logistic regression for the statistical analysis. All multivariate models were adjusted for age, gender, household income, parental asthma, environmental tobacco smoke, prematurity and residential distance from a major road.Cases were more likely to have heard a gunshot more than once than control subjects (n = 156 or 67.2% vs. n = 122 or 52.1%, P 0.01). In a multivariate analysis, hearing a gunshot more than once was associated with asthma (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.1-1.7, P = 0.01). Compared with children who had heard a gunshot not more than once and were not afraid to leave their home because of violence, those who had heard a gunshot more than once and were afraid to leave their home due to violence had 3.2 times greater odds of asthma (95% CI for OR = 2.2-4.4, P 0.01).Exposure to gun violence is associated with asthma in Puerto Rican children, particularly in those afraid to leave their home. Stress from such violence may contribute to the high burden of asthma in Puerto Ricans.

RationaleStress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).ObjectivesTo examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma.MethodsThis 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 resultsHigh 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 β2-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).ConclusionsHigh 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.

Background Puerto Ricans share a disproportionate burden of childhood asthma in the United States. Little is known about the impact of low parental numeracy (a health literacy skill) on asthma morbidity in Puerto Rican children. Our objective was to examine whether low parental numeracy is associated with increased asthma morbidity in Puerto Rican children. Methods This was a cross-sectional study of 351 children with asthma, aged 6 to 14 years, living in San Juan, Puerto Rico. Parents of study participants completed a modified version of the Asthma Numeracy Questionnaire. Multivariate linear or logistic regression was used to examine the relation between low parental numeracy (defined as no correct answers in the modified Asthma Numeracy Questionnaire) and indicators of asthma morbidity (severe asthma exacerbations, core measures of asthma exacerbations, and lung function measures). All multivariate models were adjusted for age, sex, household income, reported use of inhaled corticosteroids in the previous 6 months, and exposure to secondhand tobacco smoke. Results Low parental numeracy was associated with increased odds of visits to the ED or urgent care for asthma (adjusted OR [aOR] = 1.7, 95% CI=1.03-2.7, P = .04). The association between low parental numeracy and hospitalizations for asthma was significant only among children not using inhaled corticosteroids (aOR = 2.8, 95% CI=1.4-5.6, P = .004). There was no association between low parental numeracy and use of systemic steroids or lung function measures. Conclusions Low parental numeracy is associated with increased asthma morbidity in Puerto Rican children.

Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined.To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA.Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP-1 + 2 cohort.Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index units, and 1.2 [1.1-1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4-2.1] and 1.6 [1.3-2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP-1 + 2 multivariable model.EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Background Despite the significant burden of childhood asthma, little is known about prevention-oriented management before and after hospitalizations for asthma exacerbation. Objective To investigate the proportion and characteristics of children admitted to the intensive care unit (ICU) for asthma exacerbation and the frequency of guideline-recommended outpatient management before and after the hospitalization. Methods A 14-center medical record review study of children aged 2 to 17 years hospitalized for asthma exacerbation during 2012-2013. Primary outcome was admission to the ICU; secondary outcomes were 2 preventive factors: inhaled corticosteroid (ICS) use and evaluation by asthma specialists in the pre- and posthospitalization periods. Results Among 385 children hospitalized for asthma, 130 (34%) were admitted to the ICU. Risk factors for ICU admission were female sex, having public insurance, a marker of chronic asthma severity (ICS use), and no prior evaluation by an asthma specialist. Among children with ICU admission, guideline-recommended outpatient management was suboptimal (eg, 65% were taking ICSs at the time of index hospitalization, and 19% had evidence of a prior evaluation by specialist). At hospital discharge, among children with ICU admission who had not previously used controller medications, 85% were prescribed ICSs. Furthermore, 62% of all children with ICU admission were referred to an asthma specialist during the 3-month posthospitalization period. Conclusion In this multicenter study of US children hospitalized with asthma exacerbation, one-third of children were admitted to the ICU. In this high-risk group, we observed suboptimal pre- and posthospitalization asthma care. These findings underscore the importance of continued efforts to improve prevention-oriented asthma care at all clinical encounters.

© 2015 American Academy of Allergy, Asthma & Immunology. Background: Earlier studies reported that many patients were frequently hospitalized for asthma exacerbation. However, there have been no recent multicenter studies to characterize this patient population with high morbidity and health care utilization. Objective: To examine the proportion and characteristics of children and adults with frequent hospitalizations for asthma exacerbation. Methods: A multicenter chart review study of patients aged 2 to 54 years who were hospitalized for asthma exacerbation at 1 of 25 hospitals across 18 US states during the period 2012 to 2013 was carried out. The primary outcome was frequency of hospitalizations for asthma exacerbation in the past year (including the index hospitalization). Results: The cohort included 369 children (aged 2-17 years) and 555 adults (aged 18-54 years) hospitalized for asthma exacerbation. Over the 12-month period, 36% of the children and 42% of the adults had 2 or more (frequent) hospitalizations for asthma exacerbation. Among patients with frequent hospitalizations, guideline-recommended outpatient management was suboptimal. For example, among adults, 32% were not on inhaled corticosteroids at the time of index hospitalization and 75% had no evidence of a previous evaluation by an asthma specialist. At hospital discharge, among adults with frequent hospitalizations who had used no controller medications previously, 37% were not prescribed inhaled corticosteroids. Likewise, during a 3-month postdischarge period, 64% of the adults with frequent hospitalizations were not referred to an asthma specialist. Although the proportion of patients who did not receive these guideline-recommended outpatient care appeared higher in adults, these preventive measures were still underutilized in children; for example, 38% of the children with frequent hospitalizations were not referred to asthma specialist after the index hospitalization. Conclusions: This multicenter study of US patients hospitalized with asthma exacerbation demonstrated a disturbingly high proportion of patients with frequent hospitalizations and ongoing evidence of suboptimal longitudinal asthma care.

Background Puerto Rican children share a disproportionate burden of prematurity and asthma in the United States. Little is known about prematurity and childhood asthma in Puerto Rican subjects. Objective We sought to examine whether prematurity is associated with asthma in Puerto Rican children. Methods We performed a case-control study of 678 children aged 6 to 14 years with (n = 351) and without (n = 327) asthma living in San Juan, Puerto Rico. Prematurity was defined by parental report for our primary analysis. In a secondary analysis, we only included children whose parents reported prematurity that required admission to the neonatal intensive care unit. Asthma was defined as physician-diagnosed asthma and wheeze in the prior year. We used logistic regression for analysis. All multivariate models were adjusted for age, sex, household income, atopy (≥1 positive IgE level to common allergens), maternal history of asthma, and early-life exposure to environmental tobacco smoke. Results In a multivariate analysis there was a significant interaction between prematurity and atopy on asthma ( P = .006). In an analysis stratified by atopy, prematurity was associated with a nearly 5-fold increased odds of asthma in atopic children (adjusted odds ratio, 4.7; 95% CI, 1.5-14.3; P = .007). In contrast, there was no significant association between prematurity and asthma in nonatopic children. Similar results were obtained in our analysis of prematurity requiring admission to the neonatal intensive care unit and asthma. Conclusions Our results suggest that atopy modifies the estimated effect of prematurity on asthma in Puerto Rican children. Prematurity might explain, in part, the high prevalence of atopic asthma in this ethnic group.