James N. Moy

Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-kappaB.

The promoters of the IL‐8, MCP‐1, and RANTES genes contain binding sites for the redox‐responsive transcription factors AP‐1 and NF‐κB, which have been shown to be important for their expression. In this overview, we present evidence from our laboratories that the stimulus‐specific regulation of these chemokines by the reactive oxidant H2O2, the proinflammatory cytokine TNF‐α, and respiratory syncytial virus (RSV) is mediated in a cell type‐specific manner involving different patterns of AP‐1 and NF‐κB binding activity. Our results demonstrate that H2O2 induction of IL‐8 gene expression is linked with the selective binding of AP‐1 to the IL‐8 promoter, whereas TNF‐α and RSV induction of IL‐8 correlates with the activation of NF‐κB binding. We propose that the differential activation and binding of inducible transcription factors to the promoter regions of chemokine genes provides a critical regulatory mechanism by which the CXC and CC chemokines can be selectively expressed in a cell type‐specific and stimulus‐specific manner. Such a regulatory mechanism of differential chemokine expression could critically influence the site‐ specific recruitment of distinct subsets of leukocytes to sites of inflammation and injury. J. Leukoc. Biol. 65: 291–298; 1999.

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.

C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study

To cite this article: Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, Moy JN, Offenberger J, Jacobson KW, Yang WH, Eidelman F, Janss G, Packer FR, Rojavin MA, Machnig T, Keinecke H‐O, Wasserman RL. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study. Allergy 2011; 66: 1604–1611.

Prevalence and burden of illness for asthma and related symptoms among kindergartners in Chicago public schools

BACKGROUND Asthma mortality rates in poor communities of Chicago are among the highest in the country. Possible explanations include increased asthma prevalence, increased severity, and suboptimal health care. OBJECTIVE To estimate the prevalence of asthma and asthma-related symptoms among inner-city kindergarten children, and to characterize their burden of illness, asthma-related health care access, and pharmacologic treatment. METHODS Cross-sectional survey of parents of kindergartners was conducted in 11 randomly selected Chicago elementary schools. A self-administered 16-item questionnaire was given to parents of kindergartners. Parents who reported doctor-diagnosed asthma or at least one of several key asthma-related symptoms were then interviewed with a supplemental questionnaire examining asthma-related health care and medication use. RESULTS Based on data from 638 children [mean age 5.7 (SD = 0.6) years], the prevalence of diagnosed asthma was 10.8%. Sixteen percent of the respondents reported that their child had wheezed in the past year. The prevalence of asthma-related symptoms unassociated with a diagnosis of asthma was 30.1%. The children with diagnosed asthma had evidence of a high burden of illness: over 40% were reported to have had sleep disturbance due to wheezing > or =1 to 2 nights/week and 86.6% reported acute care visits for respiratory symptoms in the past year. Self-reported access to medical care was high. Over 40% of the children with doctor diagnosed asthma were reported to have used a beta2-agonist in the preceding 2 weeks, and 12.2% used an inhaled anti-inflammatory. CONCLUSIONS These data suggest that asthma prevalence in school-aged children in inner-city communities may be higher than US estimates. The burden of illness experienced by these children is substantial. Also, a large proportion of children were reported to have respiratory symptoms consistent with asthma, and no asthma diagnosis, suggesting possible undiagnosed asthma. While measures of health care access appear to indicate that the majority of children with asthma experience no identified barriers to health care, there is evidence to suggest undertreatment.

Safety, tolerability, and exploratory efficacy of montelukast in 6- to 24-month-old patients with asthma.

ABSTRACT Objective: The purpose of this study was to determine the safety and tolerability profile of montelukast 4-mg oral granules compared with placebo in children aged 6–24 months with asthma. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study. Children 6–24 months of age at first visit with a history of at least three episodes of physician-diagnosed asthma or ‘asthma-like’ symptoms and in need of controller therapy were randomized to either montelukast 4-mg oral granules or placebo once daily in the evening for 6 weeks. The primary variables were the frequency of clinical and laboratory adverse experiences. The exploratory efficacy endpoints included days without β-agonist use, β-agonist use per day, unscheduled physician or hospital visits for asthma, oral corticosteroid rescues for asthma, asthma attacks, discontinuation due to worsening of asthma, and total blood peripheral eosinophil counts. Results: The most common clinical adverse experiences were upper respiratory tract infection, asthma, fever, diarrhea, and vomiting occurring with similar frequencies between treatment groups. There were no clinically meaningful differences between the two treatment groups in clinical or laboratory adverse experiences and no significant differences in frequency of patients with elevated serum transaminases. Differences between the montelukast and placebo treatment groups in the exploratory efficacy endpoints of days without β-agonist use, oral corticosteroid rescues, emergency care, asthma attacks, and discontinuations due to worsening asthma were not significant. Conclusions: Montelukast, 4-mg oral granules, was well tolerated over 6 weeks of treatment in children aged 6–24 months with asthma.

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial

IMPORTANCE Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed. OBJECTIVE To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment. INTERVENTION Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (childs signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period. MAIN OUTCOMES AND MEASURES The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures. RESULTS A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed. CONCLUSIONS AND RELEVANCE Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01272635.

A community-based study of tobacco smoke exposure among inner-city children with asthma in Chicago

BACKGROUND Little is known about the level of tobacco exposure and the factors that influence exposure in children with persistent asthma. OBJECTIVE We sought to measure tobacco smoke exposure and determine factors associated with exposure in a large urban sample of asthmatic children. METHODS This cross-sectional study is based on a community-based cohort of 482 children (8-14 years old) with persistent asthma. Caregiver and household tobacco use were reported by the caregiver. Child tobacco smoke exposure was assessed by using salivary cotinine level. Multivariate linear regression of log-transformed salivary cotinine levels were used to characterize the relationship between smoke exposure and caregiver, household, and demographic characteristics. We used a multivariate logistic model to characterize associations with caregiver smoking. RESULTS Overall, 68.5% of children had tobacco smoke exposure. Compared with nonexposed children, those exposed to smoking by a caregiver or another household member had cotinine levels that were 1.68 (95% CI, 1.45-1.94) or 1.40 (95% CI, 1.22-1.62) times higher, respectively. Compared with Hispanic children, African American and white/other children had 1.55 (95% CI, 1.16-2.06) and 1.59 (95% CI, 1.18-2.14) times higher cotinine levels, respectively. Child exposure was also associated with caregiver depression symptoms (odds ratio, 1.01; 95% CI, 1.01-1.02), and higher household income was protective (odds ratio, 0.73; 95% CI, 0.56-0.95). Independent predictors of caregiver smoking included a protective effect of higher education (odds ratio, 0.35; 95% CI, 0.15-0.83) and a positive association with potential problematic drug/alcohol use (odds ratio, 2.30; 95% CI, 1.39-3.83). CONCLUSIONS Tobacco smoke exposure was high in this urban sample of asthmatic children. Caregiver smoking was strongly associated with child exposure and also was associated with lower socioeconomic status, non-Hispanic ethnicity, and depression symptoms.

Cockroach allergy appears early in life in inner-city children with recurrent wheezing

BACKGROUND Cockroach allergy and exposure to high levels of this allergen are important in the increasing asthma-related health problems among young inner-city children. However, there are very little data regarding the prevalence of cockroach allergy in infants and young children with asthma. OBJECTIVE This retrospective study was designed to test the hypothesis that cockroach allergy appears early in life in young children with recurrent wheezing. METHODS We reviewed the medical records of all 196 children (ages 5 months to 16 years) evaluated between January 1995 and September 1997 at the Cook County Hospital Pediatric Allergy Clinic for recurrent wheezing. The patients were assigned into two age groups, less than 4 years old and 4 to 16 years old. The percentages of IgE skin tests positive for common aeroallergens were compared within and between the two age groups. All children in the younger age group were tested for cockroach and dust mites, cat, and dog when indicated by positive environmental history. All children in the older age group were tested for indoor and outdoor allergens. RESULTS Sixty-three children were younger than 4 years of age, and of these, 15 (23.8%) had cockroach allergen sensitivity, compared with only eight patients (12.7%) who were skin test positive to dust mite allergen (P = .01). The youngest patient with a positive reaction to cockroach allergen was 6 months old. Patients with a single allergen skin reactivity were considered as monosensitized. Nine children younger than 4 years of age (14.3%) were monosensitized only to cockroach allergen in contrast to three children (4.8%) who were monosensitized to house-dust mites (P < .05). CONCLUSIONS Our data suggest that cockroach allergen sensitivity starts early in life and may be the only sensitizing allergen in many young inner-city children.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Respiratory syncytial virus and TNFalpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappaB1

BackgroundRespiratory syncytial virus (RSV) infection of airway epithelial cells stimulates the expression and secretion of a variety of cytokines including the chemotactic cytokines interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and RANTES (regulated upon activation, normal T cell expressed and secreted). Chemokines are important chemoattractants for the recruitment of distinct sets of leukocytes to airway sites of inflammation.ResultsWe have shown previously that chemokine expression is regulated in airway epithelial cells (A549) in a stimulus-specific manner in part through the redox-responsive transcription factors AP-1 and NF-κB. In this study, we examined the NF-κB-mediated effects of RSV and the proinflammatory cytokine TNFα on the induction of IL-8, MCP-1 and RANTES chemokine gene expression in A549 epithelial cells. The results demonstrate that RSV induces chemokine expression with distinct kinetics that is associated with a specific pattern of NF-κB binding activity. This distinction was further demonstrated by the differential effects of the NF-κB inhibitors dexamethasone (DEX) and N-acetyl-L-cysteine (NAC). NAC preferentially inhibited RSV induced chemokine expression, whereas DEX preferentially inhibited TNFα induced chemokine expression. DNA binding studies using NF-κB subunit specific binding ELISA demonstrated that RSV and TNFα induced different NF-κB binding complexes containing Rel A (p65) and NF-κB1 (p50). Both TNFα and RSV strongly induced Rel A the activation subunit of NF-κB, whereas only TNFα was able to substantially induce the p50 subunit. Consistent with the expression studies, RSV but not TNFα induction of Rel A and p50 were markedly inhibited by NAC, providing a mechanism by which TNFα and RSV can differentially activate chemokine gene expression via NF-κB.ConclusionsThese data suggest that RSV induction of chemokine gene expression, in contrast to TNFα, involves redox-sensitive NF-κB complexes containing predominantly Rel A.