Stephen J. Teach

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.

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

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.

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

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.

Epidemiology of a pediatric emergency medicine research network: the PECARN Core Data Project.

Objective: To examine the epidemiology of pediatric patient visits to emergency departments (ED). Methods: We conducted a cross-sectional study of pediatric ED visits at the participating Pediatric Emergency Care Applied Research Network (PECARN) hospitals in 2002. We provide descriptive characteristics of pediatric ED visits and a comparison of the study database to the National Hospital Ambulatory Medical Care Survey (NHAMCS). Bivariate analyses were calculated to assess characteristics associated with hospital admission, death in the ED, and length of ED visit. We also performed multivariate regression to model the likelihood of admission to the hospital. Results: Mean patient age was 6.2 years; 53.5% were boys; 47.5% black; and 43.2% had Medicaid insurance. The most common ED diagnoses were fever, upper respiratory infection, asthma, otitis media, and viral syndromes. The inpatient admission rate was 11.6%. The most common diagnoses requiring hospitalization were asthma, dehydration, fever, bronchiolitis, and pneumonia. In multivariate analysis, patients who were black or Hispanic, had Medicaid insurance or were uninsured, or were older than 1 year were less likely to be hospitalized. Demographics of the PECARN population were similar to NHAMCS, with notable exceptions of a larger proportion of black patients and of admitted patients from the PECARN EDs. Conclusion: We describe previously unavailable epidemiological information about childhood illnesses and injuries that can inform development of future studies on the effectiveness, outcomes, and quality of emergency medical services for children. Most pediatric ED patients in our study sought care for infectious causes or asthma and were discharged from the ED. Hospital admission rate differed according to age, payer type, race/ethnicity, and diagnosis.

Ask Suicide-Screening Questions (ASQ): A brief instrument for the pediatric emergency department

OBJECTIVE To develop a brief screening instrument to assess the risk for suicide in pediatric emergency department patients. DESIGN A prospective, cross-sectional instrument-development study evaluated 17 candidate screening questions assessing suicide risk in young patients. The Suicidal Ideation Questionnaire served as the criterion standard. SETTING Three urban, pediatric emergency departments associated with tertiary care teaching hospitals. PARTICIPANTS A convenience sample of 524 patients aged 10 to 21 years who presented with either medical/surgical or psychiatric chief concerns to the emergency department between September 10, 2008, and January 5, 2011. MAIN EXPOSURES Participants answered 17 candidate questions followed by the Suicidal Ideation Questionnaire. MAIN OUTCOME MEASURES Sensitivity, specificity, predictive values, likelihood ratios, and area under the receiver operating characteristic curves of the best-fitting combinations of screening questions for detecting elevated risk for suicide. RESULTS A total of 524 patients were screened (344 medical/surgical and 180 psychiatric). Fourteen of the medical/surgical patients (4%) and 84 of the psychiatric patients (47%) were at elevated suicide risk on the Suicidal Ideation Questionnaire. Of the 17 candidate questions, the best-fitting model comprised 4 questions assessing current thoughts of being better off dead, current wish to die, current suicidal ideation, and past suicide attempt. This model had a sensitivity of 96.9% (95% CI, 91.3-99.4), specificity of 87.6% (95% CI, 84.0-90.5), and negative predictive values of 99.7% (95% CI, 98.2-99.9) for medical/surgical patients and 96.9% (95% CI, 89.3-99.6) for psychiatric patients. CONCLUSIONS A 4-question screening instrument, the Ask Suicide-Screening Questions (ASQ), with high sensitivity and negative predictive value, can identify the risk for suicide in patients presenting to pediatric emergency departments.

Racial and ethnic disparities in pediatric appendicitis rupture rate

OBJECTIVES To determine if there are racial/ethnic differences in the rates of appendiceal rupture among the children of two large states. Because rupture is primarily due to delayed diagnosis, differences would suggest disparities in timely access to quality emergency care. METHODS This was an observational, cross-sectional analysis of full-year samples of acute appendicitis cases from California and New York children 4 to 18 years old. Racial/ethnic groups were compared for risk of appendiceal rupture adjusted for biological factors both before and after adjustment for the following socioeconomic, hospital, and admission characteristics: income, insurance, hospital type, and admission source. Results were interpreted in light of census data on the proportion of immigrants in each racial/ethnic group. RESULTS Compared with white children with acute appendicitis, Hispanic and Asian children have higher odds of rupture in California, whereas Asian and black/African American children have higher odds in New York. These differences roughly parallel the within-state proportion of immigrant children in these groups. Adjustments for family, socioeconomic, and hospital characteristics attenuate but do not eliminate disparities. CONCLUSIONS The authors found evidence of significant racial/ethnic disparities in rate of appendiceal rupture, an important and preventable outcome, in two large but dissimilar states. Immigrant groups may be most at risk for delayed emergency care. Future research should focus on immigration and acculturation as risk factors for appendicitis rupture in children.

Bronchiolitis Management Before and After the AAP Guidelines

BACKGROUND AND OBJECTIVES: Evidence-based practice guidelines for bronchiolitis management published by the American Academy of Pediatrics in 2006 recommend supportive care with limited diagnostic testing and treatment. We sought to determine the impact of these guidelines on the treatment of hospitalized children. METHODS: We analyzed data on inpatients with bronchiolitis aged 1 to 24 months from the Pediatric Health Information System, an administrative billing database, from November 1, 2004 to March 31, 2012. We compared trends in use of diagnostic and treatment resources before and after the publication of the guidelines by using segmented time series. RESULTS: A total of 41 pediatric hospitals contributed data to yield 130 262 patients; 58% were male, and 59% were publicly insured. Median age was 4.0 months (interquartile range, 2–9). Unadjusted analysis showed improvement in utilization rates before and after guidelines for diagnostic tests and for medications; however, there was no decreased use of antibiotics. A segmented regression analysis also demonstrated differences in rates of change before and after guidelines, with significant improvement for chest radiography, steroids, and bronchodilators (P < .0001). CONCLUSIONS: In a nationally representative cohort of pediatric hospitals, publication of the 2006 American Academy of Pediatrics bronchiolitis guidelines was associated with significant reductions in the use of diagnostic and therapeutic resources.

DNA methylation and childhood asthma in the inner city.

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.

Efficacy of an observation scale in detecting bacteremia in febrile children three to thirty-six months of age, treated as outpatients

OBJECTIVE To assess the efficacy of the Yale Observation Scale (YOS) in detecting occult bacteremia in febrile, ambulatory pediatric patients with no apparent signs or symptoms of severe infection and with no focal infection. DESIGN YOS scores were assigned as part of a prospective, multicenter, randomized, interventional trial of oral and intramuscular antibiotics in preventing the complications of occult bacteremia in febrile children. SETTING Pediatric emergency departments at eight urban medical centers. PARTICIPANTS Children, 3 to 36 months of age with a temperature at least 39.0 degrees C, a nonfocal, non-toxic-appearing illness (or uncomplicated otitis media), treated as outpatients. INTERVENTIONS None. RESULTS There were 6611 assessable patients, who had both a blood culture result and a YOS score assigned. The median YOS score for both patients with bacteremia (n = 192) and patients without bacteremia (n = 6419) was 6, but the mean rank among patients with bacteremia was significantly higher (p < 0.0001). The sensitivity, specificity, and positive and negative predictive values for a YOS score greater than 10 were 5.2%, 96.7%, 4.5%, and 97.1%, respectively. CONCLUSIONS The YOS scores are higher among patients with bacteremia than among patients without bacteremia, but the difference is not clinically useful in detecting occult bacteremia in febrile children, with nonfocal, apparently nontoxic infection, treated as outpatients in this age group.

Laboratory Predictors of Fluid Deficit in Acutely Dehydrated Children

To determine which laboratory studies are most predictive of the fluid deficit in acutely dehydrated children, we studied a convenience sample of 40 children requiring intravenous fluid resuscitation. Nine laboratory studies (serum BUN/cr, total serum C02, serum uric acid, serum anion gap, urine anion gap, venous pH, venous base deficit, urine specific gravity, and fractional excretion of sodium) were individually assessed in simple linear regression models with fluid deficit as the dependent variable. Only the serum BUN/cr and serum uric acid were significantly associated with increasing fluid deficit (r=0.52, P=0.0005 and r=0.35, P=0.03, respectively). The sensitivities and specificities of these two laboratory studies for the detection of >5% fluid deficit were poor. Conventional laboratory studies used to assess dehydration in children are poorly predictive of fluid deficits.