Agustin Calatroni

Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City Children

BACKGROUND Research has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control. METHODS We enrolled inner-city children, adolescents, and young adults with persistent asthma in a randomized, double-blind, placebo-controlled, parallel-group trial at multiple centers to assess the effectiveness of omalizumab, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma. RESULTS Among 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists. CONCLUSIONS When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; ClinicalTrials.gov number, NCT00377572.).

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.

Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations

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.

Association of childhood obesity with atopic and nonatopic asthma: results from the National Health and Nutrition Examination Survey 1999-2006.

BACKGROUND Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure. OBJECTIVE We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school. METHODS A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations (clincaltrials.gov #NCT01430403). Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined. RESULTS Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; 95% CI, 0.25-0.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33-1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02-0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002-0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88). Adverse events were rare and similar among arms. CONCLUSIONS Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.

Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005-2006.

Background. Obesity and asthma prevalence have both risen among children over the last several decades, and research efforts increasingly suggest that obesity is associated with asthma. Some, but not all, studies have shown that the effect of obesity on asthma is stronger among nonatopic individuals than among those with atopy. Systemic inflammation may be a factor in this relationship. Objective. To examine the association of obesity with atopic and nonatopic asthma among U.S. children and to assess the role of C-reactive protein. Design. Nationally representative data from the National Health and Nutrition Examination Survey (NHANES) were used to examine the relationship of weight to current asthma using logistic regression. Overweight was defined as ≥85th percentile of body mass index (BMI)-for-age and obesity was defined as ≥95th percentile of BMI-for-age. The presence of at least one positive allergen-specific immunoglobulin E (IgE) was used to stratify the relationship by atopic status in 2005–2006 data (n = 3387). Setting and Participants. Stratified, multistage probability sampling was used to identify survey participants. This analysis includes children ages 2–19 (n = 16,074) from the 1999–2006 NHANES who have information on BMI and current asthma. Main Outcome Measure. Self-report of doctor-diagnosed current asthma. Results. Obesity was significantly related to current asthma among children and adolescents (odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.33, 2.12). The association was stronger in nonatopic children (OR: 2.46, 95% CI: 1.21, 5.02) than in atopic children (OR: 1.34, 95% CI: 0.70, 2.57) (interaction p value = .09). C-reactive protein levels were associated with current asthma in nonatopic children, but not after adjusting for BMI. Conclusion. Excess weight in children is associated with higher rates of asthma, especially asthma that is not accompanied by allergic disease.

DNA methylation and childhood asthma in the inner city.

BACKGROUND The inability to measure IgE-based sensitivity to all allergens has limited our understanding of what portion of asthma is related to IgE. Total IgE measurement can potentially overcome this limitation. OBJECTIVE We sought to determine the association between total IgE levels and asthma. METHODS The National Health and Nutrition Examination Survey 2005-2006 examined a representative sample of the US population 6 years of age and older. RESULTS The median total IgE level was 40.8 kU/L (interquartile range, 15.5-114 kU/L). Total IgE levels varied with age, sex, race/ethnicity, serum cotinine level, body size, and socioeconomic status. The prevalence of current asthma was 8.8%. The prevalence of atopy was 42.5%, as defined by 15 specific IgEs. The adjusted odds ratio (OR) for asthma with a 10-fold increase in total IgE level was 2.18 (95% CI, 1.66-2.87). Total IgE level predicted asthma only among atopic subjects (OR, 2.41; 95% CI, 1.62-3.60) and not among nonatopic subjects (OR, 1.11; 95% CI, 0.72-1.71; interaction P = .005). Among atopic subjects, the association between total IgE level and asthma became stronger as the number of positive specific IgE test results increased. Asthma was present at even the lowest levels of total IgE, regardless of atopic status. Approximately 92% of atopic subjects were identified by 6 specific IgEs, but to increase the identification to more than 99% required 11 specific IgEs. CONCLUSION Total IgE levels are associated with asthma only among persons who have positive results for at least 1 allergen-specific IgE. Asthma independent of IgE is not uncommon in the US population. The complete identification of atopic subjects in a population requires a large panel of allergen-specific IgEs.

Evidence of pathway‐specific basophil anergy induced by peanut oral immunotherapy in peanut‐allergic children

BACKGROUND Epigenetic marks are heritable, influenced by the environment, direct the maturation of T lymphocytes, and in mice enhance the development of allergic airway disease. Thus it is important to define epigenetic alterations in asthmatic populations. OBJECTIVE We hypothesize that epigenetic alterations in circulating PBMCs are associated with allergic asthma. METHODS We compared DNA methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy control subjects by using DNA and RNA from PBMCs. Results were validated in an independent population of asthmatic patients. RESULTS Comparing asthmatic patients (n = 97) with control subjects (n = 97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL13, RUNX3, and specific genes relevant to T lymphocytes (TIGIT). Among asthmatic patients, 11 differentially methylated regions were associated with higher serum IgE concentrations, and 16 were associated with percent predicted FEV1. Hypomethylated and hypermethylated regions were associated with increased and decreased gene expression, respectively (P < 6 × 10(-12) for asthma and P < .01 for IgE). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma (IL4 and ST2). Methylation marks involved in T-cell maturation (RUNX3), TH2 immunity (IL4), and oxidative stress (catalase) were validated in an independent asthmatic cohort of children living in the inner city. CONCLUSIONS Our results demonstrate that DNA methylation marks in specific gene loci are associated with asthma and suggest that epigenetic changes might play a role in establishing the immune phenotype associated with asthma.

Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children

In Westernized countries, over 1% of the population is allergic to peanuts or tree nuts, which carries a risk of severe allergic reactions. Several studies support the efficacy of peanut oral immunotherapy (OIT) for reducing the clinical sensitivity of affected individuals; however, the mechanisms of this effect are still being characterized. One mechanism that may contribute is the suppression of effector cells, such as basophils. Basophil anergy has been characterized in vitro as a pathway‐specific hyporesponsiveness; however, this has not been demonstrated to occur in vivo.

Development and validation of the Composite Asthma Severity Index—an outcome measure for use in children and adolescents

Background Asthma causes significant morbidity in children, and studies have demonstrated that environmental allergies contribute to increased asthma morbidity.