Sima K. Ramratnam

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations

Rationale: 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. Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. Methods: 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. Measurements and Main Results: 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. Conclusions: 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).

Prematurity, atopy, and childhood asthma in Puerto Ricans.

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.

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 Childrens 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 Childrens 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). 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.

Children and Adults With Frequent Hospitalizations for Asthma Exacerbation, 2012-2013: A Multicenter Observational Study.

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.

Parental Numeracy and Asthma Exacerbations in Puerto Rican 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.

Underuse of guideline-recommended long-term asthma management in children hospitalized to the intensive care unit: a multicenter observational study

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.

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.

Relationships Among Maternal Stress and Depression, Type 2 Responses, and Recurrent Wheezing at Age 3 Years in Low Income Urban Families.

Rationale: Maternal depression and prenatal and early life stress may influence childhood wheezing illnesses, potentially through effects on immune development. Objectives: 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. Methods: 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. Measurements and Main Results: 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. Conclusions: 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.

Income Is an Independent Risk Factor for Worse Asthma Outcomes

Background: Socioeconomic status (SES) is associated with asthma morbidity in observational studies, but the factors underlying this association are uncertain. Objective: We investigated whether 3 SES correlates—low income, low education, and high perceived stress—were independent risk factors for treatment failure and asthma exacerbations in the context of a randomized controlled trial. Methods: The effect of low SES (household income of <

Variation in asthma care at hospital discharge by race/ethnicity groups

50,000/y and household educational level of less than a Bachelors degree) and high perceived stress (defined as a score of >20 on a perceived stress scale) on asthma morbidity was analyzed in 381 participants by using Poisson regression models. The primary outcome was treatment failure (defined in the trial protocol as a significant clinical or airflow deterioration), and the secondary outcome was asthma exacerbations requiring systemic corticosteroids. Results: Fifty‐four percent of participants had a low income, 40% had a low educational level, and 17% had high perceived stress levels. Even after adjusting for race and other important confounders, participants with lower income had higher rates of both treatment failures (rate ratio, 1.6; 95% CI, 1.1‐2.3; P = .03) and exacerbations (rate ratio, 1.9; 95% CI, 1.1‐3.3; P = .02). Adherence with inhaled corticosteroids was similarly high for both income categories. Education and perceived stress were not significantly associated with either outcome. Conclusions: In the context of a randomized controlled trial, participants with lower income were more likely to experience adverse asthma outcomes independent of education, perceived stress, race, and medication adherence.