Rebecca S. Gruchalla

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.

Counterregulation between the FcεRI Pathway and Antiviral Responses in Human Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) play essential roles in directing immune responses. These cells may be particularly important in determining the nature of immune responses to viral infections in patients with allergic asthma as well those with other atopic diseases. The purposes of this study were 1) to compare the functional capacity of pDCs in patients with one type of allergic disorder, allergic asthma, and controls; 2) to determine whether IgE cross-linking affects antiviral responses of influenza-exposed pDCs; and 3) to determine whether evidence of counterregulation of FcεRIα and IFN-α pathways exists in these cells. pDC function was assessed in a subset of asthma patients and in controls by measuring IFN-α production after exposure of purified pDCs to influenza viruses. FcεRIα expression on pDCs was determined by flow cytometry in blood samples from patients with allergic asthma and controls. pDCs from patients with asthma secreted significantly less IFN-α upon exposure to influenza A (572 versus 2815; p = 0.03), and secretion was inversely correlated with serum IgE levels. Moreover, IgE cross-linking prior to viral challenge resulted in 1) abrogation of the influenza-induced pDC IFN-α response; 2) diminished influenza and gardiquimod-induced TLR-7 upregulation in pDCs; and 3) interruption of influenza-induced upregulation of pDC maturation/costimulatory molecules. In addition, exposure to influenza and gardiquimod resulted in upregulation of TLR-7, with concomitant downregulation of FcεRIα expression in pDCs. These data suggest that counterregulation of FcεRI and TLR-7 pathways exists in pDCs, and that IgE cross-linking impairs pDC antiviral responses.

Acute respiratory health effects of air pollution on children with asthma in US inner cities

BACKGROUND Children with asthma in inner-city communities may be particularly vulnerable to adverse effects of air pollution because of their airways disease and exposure to relatively high levels of motor vehicle emissions. OBJECTIVE To investigate the association between fluctuations in outdoor air pollution and asthma morbidity among inner-city children with asthma. METHODS We analyzed data from 861 children with persistent asthma in 7 US urban communities who performed 2-week periods of twice-daily pulmonary function testing every 6 months for 2 years. Asthma symptom data were collected every 2 months. Daily pollution measurements were obtained from the Aerometric Information Retrieval System. The relationship of lung function and symptoms to fluctuations in pollutant concentrations was examined by using mixed models. RESULTS Almost all pollutant concentrations measured were below the National Ambient Air Quality Standards. In single-pollutant models, higher 5-day average concentrations of NO2, sulfur dioxide, and particles smaller than 2.5 microm were associated with significantly lower pulmonary function. Higher pollutant levels were independently associated with reduced lung function in a 3-pollutant model. Higher concentrations of NO2 and particles smaller than 2.5 microm were associated with asthma-related missed school days, and higher NO2 concentrations were associated with asthma symptoms. CONCLUSION Among inner-city children with asthma, short-term increases in air pollutant concentrations below the National Ambient Air Quality Standards were associated with adverse respiratory health effects. The associations with NO2 suggest that motor vehicle emissions may be causing excess morbidity in this population.

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.

Differential effects of outdoor versus indoor fungal spores on asthma morbidity in inner-city children.

BACKGROUND Although sensitization to fungal allergens is prevalent in inner-city children with asthma, the relationship between fungal exposure and morbidity is poorly understood. OBJECTIVE We examined relationships between fungal sensitization, exposure, and asthma morbidity in inner-city children. METHODS Participants were 5 to 11 years old and enrolled in the Inner-City Asthma Study. This report includes the subset of children with at least 1 positive skin test (PST) response to a fungal allergen extract; for these children, indoor and outdoor airborne culturable fungi levels were measured at baseline and throughout the 2-year study. Asthma morbidity measures were collected prospectively. The primary outcome was symptom days per 2 weeks. RESULTS At baseline, children with a PST response to a fungal allergen extract had significantly more symptom days compared with those without a PST response to any fungal allergen extract (6.3 vs 5.7 days per 2 weeks, P = .04). During the study, increases in total fungal exposure and indoor Penicillium species exposure were associated with increases in symptom days and asthma-related unscheduled visits. Indoor exposures to total fungi and to Penicillium species were associated with significant increases in unscheduled visits, even after controlling for outdoor fungal levels. Adverse effects associated with exposure to a specific fungus were stronger among children with PST responses to that fungal allergen extract compared with those seen in children with negative skin test responses. CONCLUSION Outdoor fungal exposure is primarily associated with increased asthma symptoms and increased risk of exacerbations in this population.

Effect of mouse allergen and rodent environmental intervention on asthma in inner-city children

BACKGROUND Mouse allergens are prevalent in inner-city households, and increasing levels of exposure are associated with sensitization in children with asthma. OBJECTIVES To examine mouse allergen sensitization and exposure in inner-city children, mouse allergen as an independent risk factor for asthma morbidity, and the efficacy of a rodent environmental intervention. METHODS We conducted a subanalysis of children with asthma aged 5 to 11 years enrolled in the Inner-City Asthma Study. After randomization, 150 participants received a home rodent-specific environmental intervention. Asthma morbidity measures were obtained bimonthly. Bedroom dust was collected and analyzed for Mus m 1 at baseline and every 6 months for 2 years. RESULTS Twenty-two percent of children tested positive to mouse. Most bedrooms (80%) had detectable mouse allergen. Sensitization occurred at low levels of exposure. Sensitization and exposure were associated with increased asthma morbidity, including hospitalizations. Mouse allergen levels on the bedroom floor decreased 27.3% (95% confidence interval, -46.1% to -1.9%) in intervention homes. Mouse allergen reduction was associated with less missed school, sleep disruption, and caretaker burden but not symptoms or medical utilization. CONCLUSIONS Mouse allergen is prevalent in inner-city homes. Sensitization seems to occur at low levels of exposure. Mouse allergen is an independent risk factor for asthma morbidity. The described environmental intervention reduced mouse allergen levels and asthma-related sleep and activity disturbance.

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.

A randomized clinical trial of clinician feedback to improve quality of care for inner-city children with asthma

CONTEXT. Barriers impede translating recommendations for asthma treatment into practice, particularly in inner cities where asthma morbidity is highest. METHODS. The purpose of this study was to test the effectiveness of timely patient feedback in the form of a letter providing recent patient-specific symptoms, medication, and health service use combined with guideline-based recommendations for changes in therapy on improving the quality of asthma care by inner-city primary care providers and on resultant asthma morbidity. This was a randomized, controlled clinical trial in 5- to 11-year-old children (n = 937) with moderate to severe asthma receiving health care in hospital- and community-based clinics and private practices in 7 inner-city urban areas. The caretaker of each child received a bimonthly telephone call to collect clinical information about the childs asthma. For a full year, the providers of intervention group children received bimonthly computer-generated letters based on these calls summarizing the childs asthma symptoms, health service use, and medication use with a corresponding recommendation to step up or step down medications. We measured the number and proportion of scheduled visits resulting in stepping up of medications, asthma symptoms (2-week recall), and health care use (2-month recall). RESULTS. In this population, only a modest proportion of children whose symptoms warranted a medication increase actually had a scheduled visit to reevaluate their asthma treatment. However, in the 2-month interval after receipt of a step-up letter, 17.1% of the letters were followed by scheduled visits in the intervention group compared with scheduled visits 12.3% of the time by the control children with comparable clinical symptoms. Asthma medications were stepped up when indicated after 46.0% of these visits in the intervention group compared with 35.6% in the control group, and when asthma symptoms warranted a step up in therapy, medication changes occurred earlier among the intervention children. Among children whose medications were stepped up at any time during the 12-month study period, those in the intervention group experienced 22.1% fewer symptom days and 37.9% fewer school days missed. The intention-to-treat analysis showed no difference over the intervention year in the number of symptom days, yet there was a trend toward fewer days of limited activity and a significant decrease in emergency department visits by the intervention group compared with controls. This 24% drop in emergency department visits resulted in an intervention that was cost saving in its first year. CONCLUSIONS. Patient-specific feedback to inner-city providers increased scheduled asthma visits, increased asthma visits in which medications were stepped up when clinically indicated, and reduced emergency department visits.

Immunochemical analysis of sulfonamide drug allergy: Identification of sulfamethoxazole-substituted human serum proteins

BACKGROUND Sulfonamides undergo oxidative metabolism to yield reactive metabolites that haptenate proteins readily. Although it has been shown that sulfonamide metabolites bind covalently to murine microsomes, sulfonamide-conjugated serum proteins have not been analyzed in the peripheral blood of treated individuals. OBJECTIVE We hypothesized that during treatment with sulfamethoxazole, intracellular proteins are haptenated by drug metabolites, and some of these are destined for secretion into the serum. METHODS Using antibodies specific for sulfamethoxazole and an alkaline phosphatase immunoblotting technique, we attempted to demonstrate the presence of sulfamethoxazole-substituted proteins in the serum of individuals during a course of treatment. RESULTS Five days into therapy, serum protein haptenation by sulfamethoxazole was demonstrated in two of the three individuals studied. In addition, Western blot analysis revealed that haptenation is not indiscriminate, but highly selective. A single 30 kd protein is the target of haptenation in all instances. A kinetic analysis revealed that substituted proteins can be detected early, within hours of administration. Moreover, haptenated proteins remain detectable in the serum 48 hours after discontinuation of the drug. CONCLUSION The results presented here constitute the first direct evidence that sulfonamides, on being metabolized, covalently haptenate human serum proteins during a course of therapy.

Psychiatric Symptomatology and Disorders in Caregivers of Children With Asthma

OBJECTIVE. The prevalence of asthma and asthma-related mortality has increased in recent years. Data suggest an association between psychiatric symptoms in the caregiver and asthma-related hospitalizations in the child. We examined the prevalence of psychiatric symptoms and disorders and their relationship to asthma-related service utilization in caregivers of children hospitalized for asthma. PATIENTS AND METHODS. Caregivers (n = 175) were assessed during the child’s hospitalization. The number of asthma-related hospitalizations, emergency department visits, and unscheduled clinic visits in the past 12 months was obtained. The Brief Symptom Inventory, an assessment of psychiatric symptoms including somatic, anxiety, and depression subscales, and the Mini International Neuropsychiatric Interview, a structured clinical interview for psychiatric disorders, were administered. RESULTS. Mean age of the caregivers was 34.2 ± 7.3 years; 96.0% were women; 15.4% were white, 57.7% were black, and 26.3% were Hispanic. A total of 47.9% had incomes less than