Nasal interferon responses to community rhinovirus infections are similar in controls and children with asthma.

BACKGROUND: Rhinovirus (RV) is the main cause of asthma exacerbations in children. Some studies reported that persons with asthma have attenuated interferon (IFN) responses to experimental RV infection compared with healthy individuals. However, responses to community-acquired RV infections in controls and children with asthma have not been compared. OBJECTIVE: To evaluate nasal cytokine responses after natural RV infections in people with asthma and healthy children. METHODS: We compared nasal cytokine expression among controls and children with asthma during healthy, virus-negative surveillance weeks and self-reported RV-positive sick weeks. A total of 14 controls and 21 patients with asthma were studied. Asthma disease severity was based on symptoms and medication use. Viral genome was detected by multiplex polymerase chain reaction. Nasal cytokine protein levels were determined by multiplex assays. RESULTS: Two out of 47 surveillance weeks tested positive for RV, illustrating an asymptomatic infection rate of 5%. A total of 38 of 47 sick weeks (81%) tested positive for the respiratory virus. Of these, 33 (87%) were positive for RV. During well weeks, nasal interleukin 8 (IL-8), IL-12, and IL-1ß levels were higher in children with asthma than controls. Compared with healthy virus-negative surveillance weeks, IL-8, IL-13, and interferon beta increased during colds only in patients with asthma. In both controls and children with asthma, the nasal levels of interferon gamma, interferon lambda-1, IL-1ß, IL-8, and IL-10 increased during RV-positive sick weeks. During RV infection, IL-8, IL-1ß, and tumor necrosis factor-α levels were strongly correlated. CONCLUSION: In both controls and patients with asthma, natural RV infection results in robust type II and III IFN responses.

Association between asthma, obesity, and health behaviors in African American youth.

Background: There is a clear relationship between obesity and asthma, with obesity recognized as a risk factor for asthma. There is mounting evidence, however, that asthma may predict obesity risk via behavioral pathways. Objectives: The purpose of this study was to assess the cross-sectional relationships between asthma, body mass index (BMI) percentile, and behavioral factors including caloric intake, dietary inflammatory index, moderate-vigorous physical activity (MVPA), and sedentary time (SED) among African American adolescents. Methods: A community-based sample of 195 African American youth (ages 11-18 years) were included in this analysis. Asthma status was based on self-report using the International Study of Asthma and Allergies in Children's Phase Three questionnaire. MVPA and SED were measured via accelerometry, and caloric intake and dietary inflammatory index were evaluated with the Food Frequency Questionnaire. Weight status was assessed via BMI percentile using measured weight, height, and CDC growth charts. Results: Adolescents with a history of asthma were significantly more overweight (62% vs. 43%, p = 0.04) and consumed a higher inflammatory diet (1.6 ± 0.3 vs. 1.0 ± 0.2, p = 0.02) than their peers who never had asthma. After adjusting for all covariates, activity and dietary variables, odds ratio analysis revealed adolescents who reported ever having asthma were 3.1 ± 1.5 times as likely to be overweight or obese than adolescents with no asthma history (p = 0.02). Conclusions: Presence of asthma history was associated with increased obesity risk in African American adolescents, independent of behavioral factors. Longitudinal studies are needed to better understand the relationship between asthma and obesity in African American adolescents.

Impact of community respiratory viral infections in urban children with asthma.

BACKGROUND: Upper respiratory tract viral infections cause asthma exacerbations in children. However, the impact of natural colds on children with asthma in the community, particularly in the high-risk urban environment, is less well defined. OBJECTIVE: We hypothesized that children with high-symptom upper respiratory viral infections have reduced airway function and greater respiratory tract inflammation than children with virus-positive low-symptom illnesses or virus-negative upper respiratory tract symptoms. METHODS: We studied 53 children with asthma from Detroit, Michigan, during scheduled surveillance periods and self-reported respiratory illnesses for 1 year. Symptom score, spirometry, fraction of exhaled nitric oxide (FeNO), and nasal aspirate biomarkers, and viral nucleic acid and rhinovirus (RV) copy number were assessed. RESULTS: Of 658 aspirates collected, 22.9% of surveillance samples and 33.7% of respiratory illnesses were virus-positive. Compared with the virus-negative asymptomatic condition, children with severe colds (symptom score ≥5) showed reduced forced expiratory flow at 25% to 75% of the pulmonary volume (FEF25%-75%), higher nasal messenger RNA expression of C-X-C motif chemokine ligand (CXCL)-10 and melanoma differentiation-associated protein 5, and higher protein abundance of CXCL8, CXCL10 and C-C motif chemokine ligands (CCL)-2, CCL4, CCL20, and CCL24. Children with mild (symptom score, 1-4) and asymptomatic infections showed normal airway function and fewer biomarker elevations. Virus-negative cold-like illnesses demonstrated increased FeNO, minimal biomarker elevation, and normal airflow. The RV copy number was associated with nasal chemokine levels but not symptom score. CONCLUSION: Urban children with asthma with high-symptom respiratory viral infections have reduced FEF25%-75% and more elevations of nasal biomarkers than children with mild or symptomatic infections, or virus-negative illnesses.

Differential responses to rhinovirus- and influenza-associated pulmonary exacerbations in patients with cystic fibrosis.

RATIONALE: The mechanism by which viruses cause exacerbations of chronic airway disease and the capacity of patients with cystic fibrosis (CF) to respond to viral infection are not precisely known. OBJECTIVES: To determine the antiviral response to infection in patients with CF. METHODS: Sputum was collected from patients with CF with respiratory exacerbation. Viruses were detected in multiplex polymerase chain reaction (PCR)-based assays. Gene expression of 84 antiviral response genes was measured, using a focused quantitative PCR gene array. MEASUREMENTS AND MAIN RESULTS: We examined 36 samples from 23 patients with respiratory exacerbation. Fourteen samples tested virus-positive and 22 virus-negative. When we compared exacerbations associated with rhinovirus (RV, n = 9) and influenza (n = 5) with virus-negative specimens, we found distinct patterns of antiviral gene expression. RV was associated with greater than twofold induction of five genes, including those encoding the monocyte-attracting chemokines CXCL10, CXCL11, and CXCL9. Influenza was associated with overexpression of 20 genes, including those encoding the cytokines tumor necrosis factor and IL-12; the kinases MEK, TBK-1, and STAT-1; the apoptosis proteins caspase-8 and caspase-10; the influenza double-stranded RNA receptor RIG-I and its downstream effector MAVS; and pyrin, an IFN-stimulated protein involved in influenza resistance. CONCLUSIONS: We conclude that virus-induced exacerbations of CF are associated with immune responses tailored to specific infections. Influenza induced a more potent response consisting of inflammation, whereas RV infection had a pronounced effect on chemokine expression. As far as we are aware, this study is the first to compare specific responses to different viruses in live patients with chronic airway disease.

The Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS): study design and methods.

The Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS) was designed to examine the relationship between near-roadway exposures to air pollutants and respiratory outcomes in a cohort of asthmatic children who live close to major roadways in Detroit, Michigan USA. From September 2010 to December 2012 a total of 139 children with asthma, ages 6-14, were enrolled in the study on the basis of the proximity of their home to major roadways that carried different amounts of diesel traffic. The goal of the study was to investigate the effects of traffic-associated exposures on adverse respiratory outcomes, biomolecular markers of inflammatory and oxidative stress, and how these exposures affect the frequency and severity of respiratory viral infections in a cohort of children with asthma. An integrated measurement and modeling approach was used to quantitatively estimate the contribution of traffic sources to near-roadway air pollution and evaluate predictive models for assessing the impact of near-roadway pollution on children's exposures. Two intensive field campaigns were conducted in Fall 2010 and Spring 2011 to measure a suite of air pollutants including PM2.5 mass and composition, oxides of nitrogen (NO and NO2), carbon monoxide, and black carbon indoors and outdoors of 25 participants' homes, at two area schools, and along a spatial transect adjacent to I-96, a major highway in Detroit. These data were used to evaluate and refine models to estimate air quality and exposures for each child on a daily basis for the health analyses. The study design and methods are described, and selected measurement results from the Fall 2010 field intensive are presented to illustrate the design and successful implementation of the study. These data provide evidence of roadway impacts and exposure variability between study participants that will be further explored for associations with the health measures.

Macrophage/epithelial cell CCL2 contributes to rhinovirus-induced hyperresponsiveness and inflammation in a mouse model of allergic airways disease.

Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1ß, CCL7/MCP-3, CCL19/MIP-3ß, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.

Air change rates and interzonal flows in residences, and the need for multi-zone models for exposure and health analyses.

Air change rates (ACRs) and interzonal flows are key determinants of indoor air quality (IAQ) and building energy use. This paper characterizes ACRs and interzonal flows in 126 houses, and evaluates effects of these parameters on IAQ. ACRs measured using weeklong tracer measurements in several seasons averaged 0.73 ± 0.76 h(-1) (median = 0.57 h(-1), n = 263) in the general living area, and much higher, 1.66 ± 1.50 h(-1) (median = 1.23 h(-1), n = 253) in bedrooms. Living area ACRs were highest in winter and lowest in spring; bedroom ACRs were highest in summer and lowest in spring. Bedrooms received an average of 55 ± 18% of air from elsewhere in the house; the living area received only 26 ± 20% from the bedroom. Interzonal flows did not depend on season, indoor smoking or the presence of air conditioners. A two-zone IAQ model calibrated for the field study showed large differences in pollutant levels between the living area and bedroom, and the key parameters affecting IAQ were emission rates, emission source locations, air filter use, ACRs, interzonal flows, outdoor concentrations, and PM penetration factors. The single-zone models that are commonly used for residences have substantial limitations and may inadequately represent pollutant concentrations and exposures in bedrooms and potentially other environments other where people spend a substantial fraction of time.

Particle Concentrations and Effectiveness of Free-Standing Air Filters in Bedrooms of Children with Asthma in Detroit, Michigan.

Asthma can be exacerbated by environmental factors including airborne particulate matter (PM) and environmental tobacco smoke (ETS). We report on a study designed to characterize PM levels and the effectiveness of filters on pollutant exposures of children with asthma. 126 households with an asthmatic child in Detroit, Michigan, were recruited and randomized into control or treatment groups. Both groups received asthma education; the latter also received a free-standing high efficiency air filter placed in the child's bedroom. Information regarding the home, emission sources, and occupant activities was obtained using surveys administered to the child's caregiver and a household inspection. Over a one-week period, we measured PM, carbon dioxide (CO(2)), environmental tobacco smoke (ETS) tracers, and air exchange rates (AERs). Filters were installed at midweek. Before filter installation, PM concentrations averaged 28 µg m(-3), number concentrations averaged 70,777 and 1,471 L(-1) in 0.3-1.0 and 1-5 µm size ranges, respectively, and the median CO(2) concentration was 1,018 ppm. ETS tracers were detected in 23 of 38 homes where smoking was unrestricted and occupants included smokers and, when detected, PM concentrations were elevated by an average of 15 µg m(-3). Filter use reduced PM concentrations by an average of 69 to 80%. Simulation models representing location conditions show that filter air flow, room volume and AERs are the key parameters affecting PM removal, however, filters can achieve substantial removal in even "worst" case applications. While PM levels in homes with asthmatic children can be high, levels can be dramatically reduced using filters.

Prevalence of asthma and chronic respiratory symptoms among Alaska Native children.

STUDY OBJECTIVES: To quantify the prevalence and impact of chronic respiratory symptoms among predominantly Alaska Native (AN)/American Indian (AI) middle school students. DESIGN: School-based prevalence assessment using the International Study of Asthma and Allergy in Children survey, with supplemental video material and added questions about productive cough, exposure to tobacco smoke, and the functional impact of symptoms. SETTING: The Yukon-Kuskokwim delta region of western Alaska. PARTICIPANTS: A total of 466 children in the sixth to ninth grades, 81% of whom are AN/AI (377 children). INTERVENTIONS: No study intervention. RESULTS: Among the 377 AN/AI children, 40% reported one of the following three categories of chronic respiratory disease: physician-diagnosed asthma, 7.4%; asthma-like symptoms (ALS) without an asthma diagnosis, 11.4%; and chronic productive cough (CPC) without asthma diagnosis or symptoms, 21.5%. Symptom prevalence differed substantially between the largest town in the region and rural villages. After an adjustment for demographic factors, exposure to environmental tobacco smoke, active tobacco smoking, and self-report of atopy, village residents were 63% less likely to have ALS (p = 0.009), and had a twofold greater risk of CPC (p < 0.001) compared to children living in the town. Children with respiratory symptoms experienced sleep disturbances and accessed clinic visits for respiratory problems more often than did asymptomatic children. CONCLUSIONS: Chronic respiratory symptoms are very common among AN children. CPC is an important nonasthmatic respiratory condition in this population. The differing patterns of respiratory illness within this region may help to elucidate the specific risk factors for asthma and chronic bronchitis in children.

Early radiographic and clinical features associated with bronchiectasis in children.

Bronchiectasis among children living in developing regions is associated with respiratory infections during early childhood, but specific risk factors that precede childhood bronchiectasis are not fully characterized. We hypothesized that severe respiratory syncytial viral (RSV) infection in infancy would increase the risk of bronchiectasis among Alaska Native children in rural Alaska. This was a follow-up cohort study of a 1993-1996 case-control study of RSV-hospitalized case patients and their controls. For each 5-8-year-old former case-patient and control subject, we reviewed medical records, interviewed parents, performed physical examinations and spirometry, collected sera, and analyzed all historical chest radiographs. Ten (11%) RSV cases and 10 (9%) controls had radiographic evidence of bronchiectasis. The mean age at radiographic diagnosis of bronchiectasis was 3.3 years (range, 1.2-6.1 years). Children were more likely to develop bronchiectasis if their chest radiographs, when they were < 2 years of age, showed lung parenchymal densities (RR = 3.9, P < 0.013), persistent parenchymal densities > 6 months' duration (RR = 3.0, P = 0.02), or infiltrates on multiple episodes (test for trend, P = 0.003). Radiographic features of hyperinflation and atelectasis among children < 2 years old were not associated with eventual bronchiectasis. A single severe infection with RSV alone did not predispose Alaska Native infants to bronchiectasis. Childhood bronchiectasis was associated with lung and hence airway injury, manifested on radiographs by parenchymal densities or "pneumonia" rather than by hyperinflation or atelectasis.