Showing papers by "National Jewish Health published in 2008"

Outcomes for COPD pharmacological trials: From lung function to biomarkers

Abstract: The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Idiopathic nonspecific interstitial pneumonia: Report of an American thoracic society project

Abstract: Rationale: The American Thoracic Society/European Respiratory Society International Consensus Classification panel identified the clinical entity idiopathic nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis and recommended further study.Objectives: We hypothesized that idiopathic NSIP is an autoimmune disease and the lung manifestation of undifferentiated connective tissue disease (UCTD), a recently described, distinct entity.Methods: We studied 28 consecutive patients with idiopathic interstitial pneumonia (IIP) enrolled in the University of California, San Francisco Interstitial Lung Disease Center who met prespecified criteria for UCTD, as follows: at least one clinical manifestation of connective tissue disease, serologic evidence of systemic inflammation in the absence of clinical infection, and absence of sufficient American College of Rheumatology criteria for another connective tissue disease. Medical record reviews, evaluation of radiographs, and scoring of lung biopsies were p...

Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.

Abstract: Rationale: An efficacious medical therapy for idiopathic pulmonary fibrosis (IPF) remains elusive.Objectives: To explore the efficacy and safety of etanercept in the treatment of IPF.Methods: This was a randomized, prospective, double-blind, placebo-controlled, multicenter exploratory trial in subjects with clinically progressive IPF. Primary endpoints included changes in the percentage of predicted FVC and lung diffusing capacity for carbon monoxide corrected for hemoglobin (DlCOHb) and change in the alveolar to arterial oxygen pressure difference P(a–a)O2 at rest from baseline over 48 weeks.Measurements and Main Results: Eighty-eight subjects received subcutaneous etanercept (25 mg) or placebo twice weekly as their sole treatment for IPF. No differences in baseline demographics and disease status were detected between treatment groups; the mean time from first diagnosis was 13.6 months and mean FVC was 63.9% of predicted. At 48 weeks, no significant differences in efficacy endpoints were observed betwee...

IL-17A Produced by γδ T Cells Plays a Critical Role in Innate Immunity against Listeria monocytogenes Infection in the Liver

Abstract: IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4+ Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR γδ T cells expressing TCR Vγ4 or Vγ6. Interestingly, TCR γδ T cells expressing both IFN-γ and IL-17A were hardly detected, indicating that the IL-17A-producing TCR γδ T cells are distinct from IFN-γ-producing γδ T cells, similar to the distinction between Th17 and Th1 in CD4+ T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR γδ T cells, which is important in innate immunity in the liver.

Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease.

Abstract: Rationale: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families.Objectives: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD.Methods: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema.Measurements and Main Results: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non–COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P ≤ 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV1 ...

Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation

Abstract: Five to ten percent of asthma cases are poorly controlled chronically and refractory to treatment, and these severe cases account for disproportionate asthma-associated morbidity, mortality, and he...

Efficacy of infliximab in extrapulmonary sarcoidosis: Results from a randomised trial

Abstract: The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5 mg x kg(-1) body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.

Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing

Abstract: Background Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. Objectives We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. Methods In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. Results The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices. Conclusions In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.

Airway Lipoxin A4 Generation and Lipoxin A4 Receptor Expression Are Decreased in Severe Asthma

Abstract: Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A4 (LXA4) is an arachidonic acid–derived mediator that serves as an agonist for resolution of inflammation.Objectives: Airway levels of LXA4, as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma.Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA4 receptors were monitored by flow cytometry.Measurements and Main Results: Individuals with severe asthma had significantly less LXA4 in bronchoalveolar lavage fluids (11.2 ± 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 ± 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthm...

Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.

Abstract: The purpose of the workshop was to identify still obscure or novel cellular components of the lung, to determine cell function in lung development and in health that impacts on disease, and to decide promising avenues for future research to extract and phenotype these cells. Since robust technologies are now available to identify, sort, purify, culture, and phenotype cells, progress is now within sight to unravel the origins and functional capabilities of lung cells in developmental stages and in disease. The Workshop's agenda was to first discuss the lung's embryologic development, including progenitor and stem cells, and then assess the functional and structural cells in three main compartments of the lung: (1) airway cells in bronchial and bronchiolar epithelium and bronchial glands (basal, secretory, ciliated, Clara, and neuroendocrine cells); (2) alveolar unit cells (Type 1 cells, Type 2 cells, and fibroblasts in the interstitium); and (3) pulmonary vascular cells (endothelial cells from different vascular structures, smooth muscle cells, and adventitial fibroblasts). The main recommendations were to: (1) characterize with better cell markers, both surface and nonsurface, the various cells within the lung, including progenitor cells and stem cells; (2) obtain more knowledge about gene expression in specific cell types in health and disease, which will provide insights into biological and pathologic processes; (3) develop more methodologies for cell culture, isolation, sorting, co-culture, and immortalization; and (4) promote tissue banks to facilitate the procurement of tissue from normal and from diseased lung for analysis at all levels.

Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood Asthma Management Program (CAMP) study.

Abstract: OBJECTIVE. Systemic corticosteroids are known to induce osteoporosis and increase the risk for fractures in adults and children. Inhaled corticosteroids have been shown to increase the risk for osteoporosis and fractures in adults at risk; however, long-term prospective studies of children to assess risks of multiple short courses of oral corticosteroids and chronic inhaled corticosteroids have not been performed. Thus, we assessed the effects of multiple short courses of oral corticosteroids and long-term inhaled corticosteroids on bone mineral accretion over a period of years. METHODS. This was a cohort follow-up study for a median of 7 years of children who had mild-to-moderate asthma and initially were randomly assigned into the Childhood Asthma Management Program trial. Serial dual-energy radiograph absorptiometry scans of the lumbar spine for bone mineral density were performed for all patients. Annual bone mineral accretion was calculated for 531 boys and 346 girls who had asthma and were aged 5 to 12 years at baseline (84% of the initial cohort). RESULTS. Oral corticosteroid bursts produced a dosage-dependent reduction in bone mineral accretion (0.052, 0.049, and 0.046 g/cm2 per year) and an increase in risk for osteopenia (10%, 14%, and 21%) for 0, 1 to 4, and ≥5 courses, respectively, in boys but not girls. Cumulative inhaled corticosteroid use was associated with a small decrease in bone mineral accretion in boys but not girls but no increased risk for osteopenia. CONCLUSIONS. Multiple oral corticosteroid bursts over a period of years can produce a dosage-dependent reduction in bone mineral accretion and increased risk for osteopenia in children with asthma. Inhaled corticosteroid use has the potential for reducing bone mineral accretion in male children progressing through puberty, but this risk is likely to be outweighed by the ability to reduce the amount of oral corticosteroids used in these children.

Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial.

Abstract: Rationale: Airway inflammation in asthma is associated with increased activated CD25+ T cells, IL-2, and soluble IL-2 receptors (IL-2Rs).Objectives: A randomized, double-blinded, placebo-controlled study was used to evaluate the safety and efficacy of daclizumab, a humanized IgG1 monoclonal antibody against the IL-2R α chain (CD25) of activated lymphocytes, in adults with moderate to severe persistent asthma.Methods: Patients with obstructive pulmonary functions, despite inhaled corticosteroids (ICS), were switched to equivalent dose inhaled triamcinolone acetate acetonide (TAA). Patients dependent on ICS were randomized (3:1) to daclizumab (intravenous loading dose, 2 mg/kg, then 1 mg/kg) or placebo every 2 weeks, added to stable-dose TAA through Week 12 (Treatment Period 1). Over Weeks 12–20 (Treatment Period 2), patients tapered TAA while on the study drug, and were followed for 16 weeks off the study drug.Measurements and Main Results: Among 115 evaluable patients (88 daclizumab, 27 placebo), groups h...

Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis.

Abstract: Rationale: Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis.Objectives: To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis.Methods: Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity).Measurements and Main Results: The mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and o...

Knowns and Unknowns of the Alveolus

Abstract: Our current alveolar paradigm includes three highly specialized cell populations. Alveolar type I cells are flat, elongated cells that presumably enable gas exchange. Alveolar type II cells are small, cuboidal cells with metabolic, secretory, progenitor, and immunologic functions. Alveolar fibroblasts secrete extracellular matrix proteins that support alveolar structure. These cells work together to facilitate respiration. Many years of high-quality research have defined our understanding of alveolar biology. However, there is much to be determined about the factors controlling cellular phenotypes and crosstalk. Moreover, specific questions remain regarding origin, repopulation, and previously unrecognized functions of each cell. This article summarizes the current data for each cell type and highlights areas that would benefit from further investigation.

Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study

Abstract: Background Clinical trials in children with moderate-to-severe persistent asthma are limited. Objective We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing. Methods The budesonide dose (with salmeterol [50 μg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 μg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction. Results Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated. Conclusion Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid–sparing alternative in children with moderate-to-severe persistent asthma.

Alterations of the Arginine Metabolome in Asthma

Abstract: Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation. Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity. Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FENO), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated. Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FENO and serum arginase activity. However, Arg bioavailability was positively associated with FENO only in healthy control subjects; Arg bioavailability was unrelated to FENO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma. Conclusions :U nlike FENO, Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.

Longitudinal Change in the BODE Index Predicts Mortality in Severe Emphysema

Abstract: Rationale: The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients. Objectives: To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival. Methods: Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components. Measurements and Main Results: The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components. Conclusions: The mBODE demonstrates short- and intermediate-term responsiveness to intervention in severe chronic obstructive pulmonary disease. Increase in mBODE of more than 1 point from baseline to 6, 12, and 24 months of follow-up was predictive of subsequent mortality. Change in mBODE may prove a good surrogate measure of survival in therapeutic trials in severe chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).

The Effect of Lung Volume Reduction Surgery on Chronic Obstructive Pulmonary Disease Exacerbations

Abstract: Rationale: Lung volume reduction surgery (LVRS) has been demonstrated to provide a functional and mortality benefit to a select group of subjects with chronic obstructive pulmonary disease (COPD). The effect of LVRS on COPD exacerbations has not been as extensively studied, and whether improvement in postoperative lung function alters the risk of disease exacerbations is not known. Objectives: To examine the effect, and mechanism of potential benefit, of LVRS on COPD exacerbations by comparing the medical and surgical cohorts of the National Emphysema Treatment Trial (NETT). Methods: A COPD exacerbation was defined using Centers for Medicare and Medicaid Services data and International Classification of Diseases, Ninth Revision, discharge diagnosis. Measurements and Main Results: There was no difference in exacerbation rate or time to first exacerbation between the medical and surgical cohorts during the year before study randomization (P = 0.58 and 0.85, respectively). Postrandomization, the surgical cohort experienced an approximate 30% reduction in exacerbation frequency (P = 0.0005). This effect was greatest in those subjects with the largest postoperative improvement in FEV1 (P = 0.04) when controlling for changes in other spirometric measures of lung function, lung capacities, and room air arterial blood gas tensions. Finally, LVRS increased the time to first exacerbation in both those subjects with and those without a prior history of exacerbations (P = 0.0002 and P < 0.0001, respectively). Conclusions: LVRS reduces the frequency of COPD exacerbations and increases the time to first exacerbation. One explanation for this benefit may be the postoperative improvement in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).

Ibuprofen-Induced Patent Ductus Arteriosus Closure: Physiologic, Histologic, and Biochemical Effects on the Premature Lung

Abstract: OBJECTIVE. The goal was to study the pulmonary, biochemical, and morphologic effects of a persistent patent ductus arteriosus in a preterm baboon model of bronchopulmonary dysplasia. METHODS. Preterm baboons (treated prenatally with glucocorticoids) were delivered at 125 days of gestation (term: 185 days), given surfactant, and ventilated for 14 days. Twenty-four hours after birth, newborns were randomly assigned to receive either ibuprofen (to close the patent ductus arteriosus; n = 8) or no drug (control; n = 13). RESULTS. After treatment was started, the ibuprofen group had significantly lower pulmonary/systemic flow ratio, higher systemic blood pressure, and lower left ventricular end diastolic diameter, compared with the control group. There were no differences in cardiac performance indices between the groups. Ventilation index and dynamic compliance were significantly improved with ibuprofen. The improved pulmonary mechanics in ibuprofen-treated newborns were not attributable to changes in levels of surfactant protein B, C, or D, saturated phoshatidylcholine, or surfactant inhibitory proteins. There were no differences in tracheal concentrations of cytokines commonly associated with the development of bronchopulmonary dysplasia. The groups had similar messenger RNA expression of genes that regulate inflammation and remodeling in the lung. Lungs from ibuprofen-treated newborns were significantly drier (lower wet/dry ratio) and expressed 2.5 times more epithelial sodium channel protein than did control lungs. By 14 days after delivery, control newborns had morphologic features of arrested alveolar development (decreased alveolar surface area and complexity), compared with age-matched fetuses. In contrast, there was no evidence of alveolar arrest in the ibuprofen-treated newborns. CONCLUSIONS. Ibuprofen-induced patent ductus arteriosus closure improved pulmonary mechanics, decreased total lung water, increased epithelial sodium channel expression, and decreased the detrimental effects of preterm birth on alveolarization.

Mycoplasma pneumoniae induces airway epithelial cell expression of MUC5AC in asthma.

Abstract: As excess mucin expression can contribute to the exacerbation of asthma, the present authors hypothesised that Mycoplasma pneumoniae significantly induces MUC5AC (the major airway mucin) expression in airway epithelial cells isolated directly from asthmatic subjects. A total of 11 subjects with asthma and six normal controls underwent bronchoscopy with airway brushing. Epithelial cells were cultured at an air-liquid interface and incubated with and without M. pneumoniae for 48 h, and in the presence and absence of nuclear factor (NF)-kappaB and a toll-like receptor (TLR)2 inhibitor. Quantitative PCR was performed for MUC5AC and TLR2 mRNA. MUC5AC protein and total protein were determined by ELISA. M. pneumoniae exposure significantly increased MUC5AC mRNA and protein expression after 48 h in epithelial cells isolated from asthmatic, but not from normal control subjects, at all concentrations as compared to unexposed cells. TLR2 mRNA expression was significantly increased in asthmatic epithelial cells at 4 h compared with unexposed cells. NF-kappaB and TLR2 inhibition reduced MUC5AC expression to the level of the unexposed control in both groups. Mycoplasma pneumoniae exposure significantly increased MUC5AC mRNA and protein expression preferentially in airway epithelial cells isolated from asthmatic subjects. The toll-like receptor 2 pathway may be involved in this process.

IL10 polymorphisms are associated with airflow obstruction in severe α1-antitrypsin deficiency

Abstract: Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1)

Initiation of antiretroviral therapy at CD4 cell counts >/=350 cells/mm3 does not increase incidence or risk of peripheral neuropathy, anemia, or renal insufficiency.

Abstract: Background: US guidelines recommend deferring initiation of highly active antiretroviral therapy (HAART) for most patients with CD4 counts >350 cells/mm 3 in part because of concerns about antiretroviral toxicity. Methods: Incidence rates of peripheral neuropathy, anemia, and renal insufficiency in a cohort of 2165 patients followed more than 3 years (mean) were analyzed in multivariate Cox proportional hazards models by CD4 cell counts at initiation of HAART. A nested cohort of 895 patients restricted to study participants who did or did not start HAART within a CD4 cell count stratum were also compared. Results: Incidence and risks of all 3 comorbidities decreased with initiation of HAART at CD4 counts >200 cells/mm 3 versus <200 cells/mm 3 . Incidence and risks of renal insufficiency were similar with HAART initiation at CD4 counts ≥ 350 cells/mm 3 versus 200 to 349 cells/mm 3 , but risk of peripheral neuropathy and anemia were further decreased in persons starting HAART at a CD4 count ≥350 cells/mm 3 . The incidence of these conditions was highest during the first 6 months of treatment at any CD4 cell count and declined up to 19-fold with further therapy. Discussion: Initiating HAART at CD4 cell counts ≥200 cells/mm 3 reduced the incidence and risk of the 3 comorbid conditions and for anemia and peripheral neuropathy as well by starting at CD4 counts ≥350 cells/mm 3 . The incidence of each condition decreased rapidly and remained low with increasing time on HAART.

Addressing Heavy Drinking in Smoking Cessation Treatment: A Randomized Clinical Trial.

Abstract: The positive association between cigarette smoking and alcohol use has been well documented (eg, Chiolero, Wietlisbach, Ruffieux, Paccaud, & Cornuz, 2006; Dawson, 2000; Falk, Yi, & Hiller-Sturmhofel, 2006; Friedman, Tekawa, Klatsky, Sidney, & Armstrong, 1991) Almost 20% of current smokers consume five or more drinks on one occasion at least once per month, compared to about 65% of nonsmokers (Dawson, 2000) The combined negative effects of excessive drinking and smoking on health outcomes are substantial For example, smoking and heavy drinking combine to produce especially negative consequences on brain morphology and function (Durazzo, Cardenas, Studholme, Weiner, & Meyerhoff, 2007; Meyerhoff et al, 2006), and smoking negates the cardioprotective effects of regular drinking (Ebbert, Janney, Sellers, Folsom, & Cerhan, 2005; Schroder, Marrugat, Elosua, & Covas, 2002) Furthermore, a multiplicative effect operates when smoking is combined with heavy drinking, conferring markedly greater risk for oral, pharyngeal, laryngeal, and esophageal cancers relative to just smoking, just drinking, or neither smoking nor drinking (Pelucchi, Gallus, Garavello, Bosetti, & La Vecchia, 2006) Greater alcohol use is associated with decreased odds of smoking cessation (Hymowitz et al, 1997; Osler, Prescott, Godtfredsen, Hein, & Schnohr, 1999; Sorlie & Kannel, 1990; Zimmerman, Warheit, Ulbrich, & Buhl Auth, 1990) and is a strong prospective predictor of smoking relapse among self-quitters (Garvey, Bliss, Hitchcock, Heinold, & Rosner, 1992; Ockene et al, 2000) Current alcohol use (Humfleet, Munoz, Sees, Reus, & Hall, 1999; Sherman, Wang, & Nguyen, 1996; Smith, Kraemer, Miller, Debusk, & Taylor, 1999) and current binge drinking (Murray, Istvan, Voelker, Rigdon, & Wallace, 1995) at the start of a smoking cessation treatment and use of alcohol after treatment (Humfleet et al, 1999) are negatively associated with abstinence, although there has been an exception (Hughes & Oliveto, 1993) In treatment samples, approximately one quarter of smoking lapses occur in contexts involving alcohol use (Baer & Lichtenstein, 1988; Borland, 1990; Shiffman, 1982) A number of recent clinical trials have examined smoking cessation interventions initiated during alcoholism treatment Results have indicated that these interventions do not harm treatment outcome and may even be associated with better drinking outcomes (Prochaska, Delucchi, & Hall, 2004), though there have been exceptions (eg, Joseph, Willenbring, Nugent, & Nelson, 2004) However, relatively little attention has been devoted to smokers who drink heavily but are not alcohol dependent The US Department of Health and Human Services guidelines for treating tobacco dependence recommend that smokers reduce or avoid drinking alcohol as much as possible when making a quit attempt (Fiore, Bailey, Cohen, & et al, 2000) However, clinicians currently have little guidance as to how to address heavy drinking in smoking cessation treatment as no empirical studies have been published to date in this area Brief motivationally-focused behavioral interventions have been shown to reduce drinking (McCrady, 2000; Moyer, Finney, Swearingen, & Vergun, 2002; Whitlock, Polen, Green, Orleans, & Klein, 2004) among drinkers who are not seeking treatment for alcohol problems and especially among those with less severe alcohol problems (Moyer et al, 2002) Incorporating brief interventions into smoking cessation treatment for nondependent heavy drinkers may be efficacious both in reducing drinking and in improving smoking cessation outcomes Towards this end, the aim of the current study was to test the efficacy of a smoking cessation treatment that incorporated a brief alcohol intervention, which focused on the risks of smoking relapse associated with drinking and the negative effects of continued heavy drinking This randomized clinical trial involved 236 non-alcohol dependent, heavy drinking smokers who were recruited from the community and were seeking smoking cessation treatment Participants were randomized to either standard smoking cessation treatment (ST), which included provision of the nicotine patch, or an equivalent standard treatment that also incorporated a brief alcohol intervention (ST-BI) Treatment conditions were matched on amount of contact time and participants were followed for 26 weeks after their smoking quit date We hypothesized that ST-BI, compared to ST, would result in higher rates of point prevalence smoking abstinence at 2, 8, 16, and 26 weeks after quit date and a lower number of alcoholic drinks consumed per week In addition, we hypothesized that ST-BI, relative to ST, would result in lower rates of initial lapses to smoking that involved alcohol use during treatment Finally, we examined two potential moderators of treatment effects on smoking: level of drinking prior to treatment and intention to change drinking These analyses were considered exploratory as there are theoretical reasons to expect either stronger or weaker effects of ST-BI at higher levels of each variable For pretreatment drinking, the emphasis of ST-BI on alcohol use might be especially relevant for relatively heavier drinkers; on the other hand, asking these very heavy drinkers to change both drinking and smoking simultaneously might prove overly difficult For intention to change drinking, ST-BI might be relatively more effective for those who intend to change drinking because it reinforces the expectations of such smokers that changing alcohol use may facilitate smoking cessation; on the other hand, ST-BI could be less effective for these smokers because the information in ST-BI is redundant with their intentions

Estrogen Determines Sex Differences in Airway Responsiveness after Allergen Exposure

Abstract: The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. ICI182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17β-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin 1 receptor antagonist...

IFN-γ Production during Initial Infection Determines the Outcome of Reinfection with Respiratory Syncytial Virus

Abstract: Rationale: Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-γ production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown. Objectives: To define the role of IFN-γ in the development of RSV-mediated airway hyperresponsiveness (AHR) and lung histopathology in mice. Methods: Wild-type (WT) and IFN-γ knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway responses were assessed on Day 6 after the primary or secondary infection. Measurements and Main Results: Both WT and IFN-γ knockout mice developed similar levels of AHR and airway inflammation after primary infection. After reinfection, IFN-γ knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-γ during primary infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-γ knockout mice. Adoptive transfer of WT T cells into IFN-γ knockout mice before primary infection restored IFN-γ production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-γ during primary neonatal infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection. Conclusions: IFN-γ production during primary RSV infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-γ during primary infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.

HLA and environmental interactions in sarcoidosis.

Abstract: Sarcoidosis is a systemic granulomatosis of unknown etiology despite being described over 100 years ago. While both genetic predisposition and environmental exposures have been proposed as playing a role in this disease, there have not been any systematic investigations of gene-environmental interaction in this disease. In the ACCESS dataset, detailed environmental histories and high resolution HLA class II typing were performed on 476 cases of newly diagnosed sarcoidosis and 476 matched controls from the patients’ community. We evaluated gene-environmental interactions in exposures or HLA class II alleles that were present in > 5% of the population and had an odd ratio of > 1.0. Four exposures and four HLA Class II alleles met these criteria and were evaluated. Significant interaction was observed between HLA DRB1*1101 and insecticide exposure at work (p < 0.10) and suggestive interaction was observed between HLA DRB1*1101 and exposure to mold and musty odors and DRB1*1501 and insecticide exposure at work (P < 0.15). In addition, HLA DRB1*1101 and insecticide exposure at work was associated with extrapulmonary sarcoidosis, specifically cardiac sarcoidosis and hypercalcemia (p<0.05) and HLA DRB1*1101 and exposure to molds and musty odors was associated with pulmonary only sarcoidosis (P < 0.05). These studies suggest that sarcoidosis is due to an interaction of genetic predisposition and environmental exposure in at least some cases of sarcoidosis. Future studies in defined phenotypes of sarcoidosis may be necessary to define environmental and genetic associations with sarcoidosis.

Time series analysis of treatment adherence patterns in individuals with obstructive sleep apnea.

Abstract: Adherence to medical recommendations is often suboptimal, making examination of adherence data an important scientific concern. Studies that attempt to predict or modify adherence often face the problem that adherence as a dependent variable is complex and non-normally distributed. Traditional statistical approaches to adherence data may mask individual variability that may guide clinician and researcher’s development of adherence interventions. In this study, we employ time series analysis to examine adherence patterns objectively in patients with obstructive sleep apnea (OSA). Although treatment adherence is poor in OSA, state-of-the-art adherence monitoring allows a comprehensive examination of objective data. The purpose of the study is to determine the number and types of adherence patterns seen in a sample of patients with OSA receiving positive airway pressure (PAP). Seventy-one moderate to severe OSA participants with 365 days of treatment data were studied. Adherence patterns could be classified into seven categories: (1) Good Users (24%), (2) Slow Improvers (13%), (3) Slow Decliners (14%), (4) Variable Users (17%), (5) Occasional Attempters (8%), (6) Early Drop-outs (13%), and (7) Non-Users (11%). Time series analysis provides a useful method for examining adherence while maintaining a focus on individual differences. Implications for future research are discussed.

Predicting worsening asthma control following the common cold.

Abstract: The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean±sd increase in mini-ACQ score of 0.69±0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

The role of food allergy in atopic dermatitis.

Abstract: Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease affecting more than 10% of all children. Sensitization to foods triggers isolated skin symptoms in about 30% of children. These symptoms include immediate reactions within minutes after ingesting food without exacerbation of AD and early and late exacerbations of AD. It is important to identify clinically relevant sensitizations to foods using skin prick tests, a specific IgE blood test (ImmunoCAP; Phadia, Portage, MI, USA), and double-blind, placebo-controlled food challenges to initiate appropriate dietary interventions and avoid unnecessary dietary restrictions. Children with AD triggered by food allergens demonstrate a distinct immune response upon stimulation of their peripheral blood mononuclear cells with food allergen. A defective skin barrier and increased intestinal permeability appear to facilitate allergen sensitization. Appropriate skin care to maintain skin barrier function and dietary avoidance of highly allergenic foods during infancy may help to prevent allergen sensitization, thereby reducing the severity of AD and food allergies.