Gordon R. Bloomberg

Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial

BACKGROUND Preliminary evidence is equivocal about the role of exhaled nitric oxide (NO) in clinical asthma management. We aimed to assess whether measurement of exhaled NO, as a biomarker of airway inflammation, could increase the effectiveness of asthma treatment, when used as an adjunct to clinical care based on asthma guidelines for inner-city adolescents and young adults. METHODS We did a randomised, double-blind, parallel-group trial at ten centres in the USA. We screened 780 inner-city patients, aged 12-20 years, who had persistent asthma. All patients completed a run-in period of 3 weeks on a regimen based on standard treatment. 546 eligible participants who adhered to treatment during this run-in period were then randomly assigned to 46 weeks of either standard treatment, based on the guidelines of the National Asthma Education and Prevention Program (NAEPP), or standard treatment modified on the basis of measurements of fraction of exhaled NO. The primary outcome was the number of days with asthma symptoms. We analysed patients on an intention-to-treat basis. This trial is registered with clinicaltrials.gov, number NCT00114413. FINDINGS During the 46-week treatment period, the mean number of days with asthma symptoms did not differ between the treatment groups (1.93 [95% CI 1.74 to 2.11] in the NO monitoring group vs 1.89 [1.71 to 2.07] in the control group; difference 0.04 [-0.22 to 0.29], p=0.780). Other symptoms, pulmonary function, and asthma exacerbations did not differ between groups. Patients in the NO monitoring group received higher doses of inhaled corticosteroids (difference 119 mug per day, 95% CI 49 to 189, p=0.001) than controls. Adverse events did not differ between treatment groups (p>0.1 for all adverse events). INTERPRETATION Conventional asthma management resulted in good control of symptoms in most participants. The addition of fraction of exhaled NO as an indicator of control of asthma resulted in higher doses of inhaled corticosteroids, without clinically important improvements in symptomatic asthma control.

Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing.

BACKGROUND Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. OBJECTIVES We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. METHODS In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. RESULTS The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices. CONCLUSIONS In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.

Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-City Cohort

RATIONALE Stress-elicited disruption of immunity begins in utero. OBJECTIVES Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families). METHODS Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age). MEASUREMENTS AND MAIN RESULTS Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than

Asthma control, adiposity, and adipokines among inner-city adolescents.

15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-alpha to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-gamma. CONCLUSIONS Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.

Risk Factors for Asthma Morbidity and Mortality in a Large Metropolitan City

BACKGROUND There is an association between adiposity and asthma prevalence, but the relationship to asthma control is unclear. OBJECTIVES We sought to understand the relationships among adiposity, sex, and asthma control in inner-city adolescents with asthma. METHODS We prospectively followed 368 adolescents with moderate-to-severe asthma (ages 12-20 years) living in 10 urban areas for 1 year. Asthma symptoms and exacerbations were recorded, and pulmonary function and exhaled nitric oxide levels were measured every 6 weeks. Adiposity measures (body mass index [BMI] and dual-energy X-ray absorptiometric scans) were made, and blood was collected for measurement of allergy markers, adiponectin, leptin, TNF-alpha, IL-6, and C-reactive protein levels. RESULTS More than 60% of female subjects and 50% of male subjects were above the 85th percentile of BMI for age. Higher BMI was associated with more symptom days (R = 0.18, P = .02) and exacerbations (R = 0.18, P = .06) among female subjects only. Adiponectin was inversely related to asthma symptoms (R = -0.18, P < .05) and exacerbations (R = -0.20, P < .05) and positively with FEV(1)/forced vital capacity ratio (R = 0.15, P < .05) in male subjects only independent of body size. There was no relationship between adiposity or adipokines and total IgE levels, blood eosinophil counts, and exhaled nitric oxide levels. Dual-energy X-ray absorptiometry provided little additional value in relating adiposity to asthma outcome in this population of adolescents. CONCLUSION Adiposity is associated with poorer asthma control in female subjects. Adiponectin is associated with improved asthma control in male subjects.

Predictors of repeat hospitalizations in children with asthma: the role of psychosocial and socioenvironmental factors.

Morbidity and mortality due to asthma continues to increase despite advances in understanding the pathophysiology and treatment of the disease. We evaluated the potential risk factors for asthma morbidity and mortality in a large metropolitan city (St. Louis, MO) using small area geographic analysis. We found that the risk of hospitalization for children with asthma was 8.4 times greater (95% confidence interval [CI] 7.0–9.9) in lower socioeconomic zip code areas and 5.3 times greater (95% CI 4.7–5.9) in those zip codes with a higher percentage of African Americans. Similarly, the risk of death due to asthma was 6.4 times greater in the lower socioeconomic zip code areas (95% CI 3.4–12.1). Lower socioeconomic status and African American race are strong risk factors for hospitalization and mortality from asthma. Public policy and healthcare resources need to be organized and directed more efficiently to this population.

Socioeconomic, Family, and Pediatric Practice Factors That Affect Level of Asthma Control

This study examined relationships between psychosocial factors and asthma rehospitalization patterns in 115 children (ages 4-15) who had > or = 1 hospitalization during the study period. Lifetime history of hospitalizations and new hospitalizations during a 1-year follow-up period were measured, controlling for baseline asthma symptoms and medications. Prospectively, caretaker characteristics (lower sense of mastery, being less emotionally bothered by asthma) predicted greater likelihood of future asthma hospitalizations. Lifetime history of hospitalizations was associated with family impacts (greater family strain and family conflict greater financial strain) as well as caretaker characteristics (greater personal strain, beliefs about not being able to manage ones childs asthma). These findings could help guide future interventions targeted at the subgroup of children who represent a high proportion of asthma hospitalizations.

Parental Characteristics, Somatic Fetal Growth, and Season of Birth Influence Innate and Adaptive Cord Blood Cytokine Responses

BACKGROUND. Multiple issues play a role in the effective control of childhood asthma. OBJECTIVE. To identify factors related to the level of asthma control in children receiving asthma care from community pediatricians. PATIENTS AND METHODS. Data for 362 children participating in an intervention study to reduce asthma morbidity were collected by a telephone-administered questionnaire. Level of asthma control (well controlled, partially controlled, or poorly controlled) was derived from measures of recent impairment (symptoms, activity limitations, albuterol use) and the number of exacerbations in a 12-month period. Data also included demographic characteristics, asthma-related quality of life, pediatric management practices, and medication usage. Univariable and multivariable analyses were used to identify factors associated with poor asthma control and to explore the relationship between control and use of daily controller medications. RESULTS. Asthma was well controlled for 24% of children, partially controlled for 20%, and poorly controlled for 56%. Medicaid insurance, the presence of another family member with asthma, and maternal employment outside the home were significant univariable factors associated with poor asthma control. Medicaid insurance had an independent association with poor control. Seventy-six percent of children were reported by parents as receiving a daily controller medication. Comparison of guideline recommended controller medication with current level of asthma control indicated that a higher step level of medication would have been appropriate for 74% of these children. Significantly lower overall quality-of-life scores were observed in both parents and children with poor control. CONCLUSIONS. Despite substantial use of daily controller medication, children with asthma continue to experience poorly controlled asthma and reduced quality of life. Although Medicaid insurance and aspects of family structure are significant factors associated with poorly controlled asthma, attention to medication use and quality-of-life indicators may further reduce morbidity.

The Urban Environment and Childhood Asthma (URECA) birth cohort study: design, methods, and study population

BACKGROUND Immunologic responses at birth likely relate to subsequent risks for allergic diseases and wheezing in infancy; however, the influences of parental characteristics and prenatal factors on neonatal immune responses are incompletely understood. OBJECTIVE This study investigates potential correlations between urban parental, prenatal, and perinatal factors on innate and adaptive stimuli-induced cytokine responses. METHODS Five hundred sixty and 49 children of parents with and without allergic disease or asthma, respectively, were enrolled into a prospective birth cohort study (Urban Environment and Childhood Asthma). Cord blood mononuclear cells were incubated with innate and adaptive immune stimuli, and cytokine responses (ELISA) were compared with season of birth, parental characteristics, in utero stressors, and fetal growth. RESULTS Many cytokine responses varied by season of birth, including 2-fold to 3-fold fluctuations with specific IFN-alpha and IFN-gamma responses. Birth weight was inversely associated with IFN-gamma responses to respiratory syncytial virus (R = -0.16), but positively associated with IL-8 responses to a variety of innate stimuli (R = 0.08-0.12). Respiratory syncytial virus-induced cytokine responses were 21% to 54% lower in children of mothers with asthma. Cytokine responses were generally lower in babies born to parents with allergy/asthma. CONCLUSIONS Innate cytokine responses are associated with parental allergic or airway disease, somatic fetal growth, ethnicity, and season of birth. Collectively, these findings suggest that urban prenatal exposures and familial factors affect the development of the fetal immune system.

Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma

BackgroundThe incidence and morbidity of wheezing illnesses and childhood asthma is especially high in poor urban areas. This paper describes the study design, methods, and population of the Urban Environment and Childhood Asthma (URECA) study, which was established to investigate the immunologic causes of asthma among inner-city children.Methods and ResultsURECA is an observational prospective study that enrolled pregnant women in central urban areas of Baltimore, Boston, New York City, and St. Louis and is following their offspring from birth through age 7 years. The birth cohort consists of 560 inner-city children who have at least one parent with an allergic disease or asthma, and all families live in areas in which at least 20% of the population has incomes below the poverty line. In addition, 49 inner-city children with no parental history of allergies or asthma were enrolled. The primary hypothesis is that specific urban exposures in early life promote a unique pattern of immune development (impaired antiviral and increased Th2 responses) that increases the risk of recurrent wheezing and allergic sensitization in early childhood, and of asthma by age 7 years. To track immune development, cytokine responses of blood mononuclear cells stimulated ex vivo are measured at birth and then annually. Environmental assessments include allergen and endotoxin levels in house dust, pre- and postnatal maternal stress, and indoor air nicotine and nitrogen dioxide. Nasal mucous samples are collected from the children during respiratory illnesses and analyzed for respiratory viruses. The complex interactions between environmental exposures and immune development will be assessed with respect to recurrent wheeze at age 3 years and asthma at age 7 years.ConclusionThe overall goal of the URECA study is to develop a better understanding of how specific urban exposures affect immune development to promote wheezing illnesses and asthma.