Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Effect of obesity on sinonasal disease in asthma.

OBJECTIVE: Sinonasal disease can contribute to poor asthma control. There are reports that link obesity with an increased prevalence of sinonasal disease, but no studies evaluating the severity of sinonasal disease in obese asthmatics, and how this impacts asthma control. The purpose of the current study was to determine if obesity is associated with increased severity of sinonasal disease, and/or affects response to nasal corticosteroid treatment in asthma. METHODS: This study included 236 adults participating in a 24-week randomized, double-masked, placebo-controlled study of nasal mometasone for the treatment of poorly controlled asthma. Sinonasal disease severity was assessed using validated questionnaires, and compared in participants of differing BMIs. Eosinophilic inflammation was assessed using markers in nasal lavage, serum and exhaled nitric oxide. Response to treatment was compared in different BMI groups. RESULTS: Obesity had no effect on the severity of sinonasal disease symptoms in asthmatics (Sino-Nasal Outcome Test 22 (SNOT 22) score [mean ± SD] 35.4 ± 18.5, 40.2 ± 22.8, and 39.1 ± 21.7, p = 0.43, in lean, overweight and obese participants), nor on nasal, bronchial or systemic markers of allergic inflammation. Nasal steroids had some limited effects on symptoms, lung function and inflammatory markers in lean participants, but no detectable effect was found in obese patients. CONCLUSIONS: Obesity does not affect severity of sinonasal disease in patients with asthma; the association of sinonasal disease symptoms with increased asthma severity and markers of Type 2 inflammation are consistent across all BMI groups. The response of obese patients to nasal corticosteroids requires further study.

Can a simple test of functional capacity add to the clinical assessment of diabetes?

AIM: To identify impairment in functional capacity associated with complicated and non-complicated diabetes using the 6-min walk distance test. METHODS: We enrolled 111 adults, aged ≥40 years, with Type 2 diabetes from a hospital facility and 150 healthy control subjects of similar age and sex from a community site in Lima, Peru. All participants completed a 6-min walk test. RESULTS: The mean age of the 261 participants was 58.3 years, and 43.3% were male. Among those with diabetes, 67 (60%) had non-complicated diabetes and 44 (40%) had complications such as peripheral neuropathy, retinopathy or nephropathy. The mean unadjusted 6-min walk distances were 376 m and 394 m in adults with and without diabetes complications, respectively, vs 469 m in control subjects (P<0.001). In multivariable regression, the subjects with diabetes complications walked 84 m less far (95% CI -104 to -63 m) and those without complications walked 60 m less far (-77 to -42 m) than did control subjects. When using HbA1c level as a covariate in multivariable regression, participants walked 13 m less far (-16.9 to -9.9 m) for each % increase in HbA1c . CONCLUSIONS: The subjects with diabetes had lower functional capacity compared with healthy control subjects with similar characteristics. Differences in 6-min walk distance were even apparent in the subjects without diabetes complications. Potential mechanisms that could explain this finding are early cardiovascular disease or deconditioning.

Chronic exposure to biomass fuel smoke and markers of endothelial inflammation.

Indoor smoke exposure may affect cardiovascular disease (CVD) risk via lung-mediated inflammation, oxidative stress, and endothelial inflammation. We sought to explore the association between indoor smoke exposure from burning biomass fuels and a selected group of markers for endothelial inflammation. We compared serum concentrations of amyloid A protein, E-selectin, soluble intercellular adhesion molecule 1 (ICAM-1) and VCAM-1, von Willebrand factor (vWF), and high-sensitivity C-reactive protein (hs-CRP) in 228 biomass-exposed vs. 228 non-exposed participants living in Puno, Peru. Average age was 56 years (s.d. = 13), average BMI was 26.5 kg/m(2) (s.d. = 4.4), 48% were male, 59.4% completed high school, and 2% reported a physician diagnosis of CVD. In unadjusted analysis, serum levels of soluble ICAM-1 (330 vs. 302 ng/ml; P < 0.001), soluble VCAM-1 (403 vs. 362 ng/ml; P < 0.001), and E-selectin (54.2 vs. 52.7 ng/ml; P = 0.05) were increased in biomass-exposed vs. non-exposed participants, respectively, whereas serum levels of vWF (1148 vs. 1311 mU/ml; P < 0.001) and hs-CRP (2.56 vs. 3.12 mg/l; P < 0.001) were decreased, respectively. In adjusted analyses, chronic exposure to biomass fuels remained positively associated with serum levels of soluble ICAM-1 (P = 0.03) and VCAM-1 (P = 0.05) and E-selectin (P = 0.05), and remained negatively associated with serum levels of vWF (P = 0.02) and hs-CRP (P < 0.001). Daily exposure to biomass fuel smoke was associated with important differences in specific biomarkers of endothelial inflammation and may help explain accelerated atherosclerosis among those who are chronically exposed.

Prevalence and risk factors for allergic rhinitis in two resource-limited settings in Peru with disparate degrees of urbanization.

BACKGROUND: Allergic rhinitis is a disease with a high global disease burden, but risk factors that contribute to this condition are not well understood. OBJECTIVE: To assess the prevalence and risk factors of allergic rhinitis in two Peruvian populations with disparate degrees of urbanization. METHODS: We conducted a population-based, cross-sectional study on 1441 children aged 13-15 years at enrollment (mean age 14.9 years, 51% boys) to investigate the prevalence of allergic disease. We used a standardized, Spanish validated questionnaire to determine the prevalence of allergic rhinitis and asked about sociodemographics and family history of allergies. Children also underwent spirometry, exhaled nitric oxide, allergy skin testing to 10 common household allergens and provided a blood sample for measurement of 25OH vitamin D and total serum IgE. RESULTS: Overall prevalence of allergic rhinitis was 18% (95% CI 16% to 20%). When stratified by site, the prevalence of allergic rhinitis was 23% Lima vs. 13% in Tumbes (P < 0.001); however, this difference was no longer significant after controlling for subject-specific factors (P = 0.95). There was a strong association with other allergic diseases: 53% of children with asthma had allergic rhinitis vs. 15% in those without asthma (P < 0.001) and 42% of children with eczema vs. 17% of those without eczema (P < 0.001). Important risk factors for allergic rhinitis were parental rhinitis (adjusted OR = 3.0, 95% CI 1.9-4.7 for 1 parent and adjusted OR = 4.4, 95% CI 1.5-13.7 for 2 parents); allergic sensitization to common household aeroallergens (1.6, 1.1-2.3); being overweight (1.5, 1.0-2.3); exhaled nitric oxide ≥ 20 ppb (1.9, 1.3-2.7); and total serum IgE ≥ 95th percentile (2.4, 1.2-4.8). Population attributable risk of important factors for allergic rhinitis were 25% for high exhaled nitric oxide, 22% for allergic sensitization to common household aeroallergens, 22% for paternal rhinitis, 10% for being overweight and 7% for an elevated total serum IgE. CONCLUSION AND CLINICAL RELEVANCE: Allergic rhinitis was prevalent in both settings, and important risk factors include elevated exhaled nitric oxide, allergic sensitization to common household aeroallergens, parental rhinitis, being overweight and high total serum IgE. When considering subject-specific factors, the difference in prevalence between the urban and rural settings became non-important.

25-hydroxy vitamin D levels are associated with childhood asthma in a population-based study in Peru.

BACKGROUND: Vitamin D deficiency may be associated with an increased risk of asthma. OBJECTIVE: We studied the association between 25-hydroxy (25-OH) vitamin D deficiency and asthma prevalence in two Peruvian populations close to the equator but with disparate degrees of urbanization. METHODS: We conducted a population-based study in 1441 children in two communities in Peru, of which 1134 (79%) provided a blood sample for 25-OH vitamin D analysis. RESULTS: In these 1134 children, mean age was 14.8 years; 52% were boys; asthma and atopy prevalence was 12% in Lima vs. 3% in Tumbes (P < 0.001) and 59% in Lima vs. 41% in Tumbes (P < 0.001), respectively; and, mean 25-OH vitamin D level was 20.8 ng/mL in Lima vs. 30.1 ng/mL in Tumbes (P < 0.001). Prevalence of 25-OH vitamin D deficiency (< 20 ng/mL) was 47% in Lima vs. 7% in Tumbes (P < 0.001). In multi-variable logistic regression, we found that lower 25-OH vitamin D levels were associated with an increased odds of asthma (OR = 1.7 per each 10 ng/mL decrease in 25-OH vitamin D levels, 95% CI 1.2-2.6; P < 0.01). In stratified analyses, the association between lower 25-OH vitamin D levels and asthma was limited to children with atopy (OR = 2.2, 95% CI 1.3-3.6) and not in those without atopy (OR = 0.9, 95% CI 0.5-2.0). We did not find associations between 25-OH vitamin D levels and other clinical biomarkers for asthma, including exhaled nitric oxide, total serum IgE and pulmonary function. CONCLUSION AND CLINICAL RELEVANCE: Both asthma and 25-OH vitamin D deficiency were common among children living in Lima (latitude = 12.0 °S) but not among those in Tumbes (3.6 °S). The relationship between 25-OH vitamin D deficiency and asthma was similar in both sites and was limited among children with atopy. Future supplementation trials may need to consider stratification by atopy at the time of design.

Pharmacogenetics of asthma controller treatment.

The interpatient variability in response to asthma controllers is significant and associates with pharmacogenomic variability. The goal of the present study was to identify novel variants that associate with response to common asthma controllers: fluticasone, combination of fluticasone + salmeterol and montelukast with single nucleotide polymorphisms (SNPs) in ß2-adrenergic receptor, corticosteroid and leukotriene pathway candidate genes. Participants in a large clinical trial of step-down strategies volunteered for this pharmacogenetic study. A total of 169 SNPs in 26 candidate genes were genotyped in 189 Caucasian participants with asthma who took either fluticasone (100 µg bid), fluticasone propionate (100 µg) + salmeterol (50 µg) (FP/Salm) or montelukast (5 or 10 mg) each night for 16 weeks. Primary outcomes were the slopes of plots of Asthma Control Questionnaire (ACQ) scores versus time following randomization; and the percent change in percent predicted FEV1 (ΔFEV1%pred) from enrollment to the end of the study. Associations between SNPs and outcomes were analyzed using general linear models. False discovery rate and Bonferroni corrections were used to correct for multiple comparisons. In all, 16 SNPs in seven genes were significantly associated with outcomes. For FP/Salm, three SNPs in CHRM2 associated with ACQ slope (P=2.8 × 10⁻5), and rs1461496 in HSPA8 associated with ΔFEV1%pred. For fluticasone, five SNPs in CRHR1 (P=1.9 × 10⁻4), and three SNPs in COL2A1 associated with ACQ slope and ΔFEV1%pred, respectively. For montelukast, four SNPs in CHRM2 associated with ΔFEV1%pred and predicted an opposite effect compared with fluticasone (P=9 × 10⁻³). The present study indentified several novel SNPs that associate with response to common asthma controllers, and support further pharmacogenomic study and the use of genetic variants to personalize asthma treatment.

ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma.

BACKGROUND: Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy, but its impact on disease control remains unclear. OBJECTIVE: We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score. METHODS: We analysed 270 children, 6- to 17-years old, with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels. RESULTS: Of all children, 14.8% (40/270) (and 28% (38/135) of African Americans) carried two non-5-repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 vs. 30 nmol/mol creatinine, P = 0.0134), significantly worse FEV1% predicted (84 vs. 91, P = 0.017) and a trend towards worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (r = -0.192, P = 0.009). CONCLUSION AND CLINICAL RELEVANCE: Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.

The minimal important difference of exercise tests in severe COPD.

Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease (COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4-6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St George's Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohen's effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1-20.1 m), 24.2 m (95% CI 23.4-25.4 m), 24.6 m (95% CI 23.4-25.7 m) and 26.4 m (95% CI 25.4-27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0-2.4 W), 3.2 W (95% CI 3.0-3.4 W), 3.2 W (95% CI 3.0-3.4 W) and 3.3 W (95% CI 3.0-3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26 ± 2 m for 6MWD and 4 ± 1 W for MCEC for patients with severe COPD.

Supplementation with vitamin A early in life and subsequent risk of asthma.

Animal models suggest that vitamin A deficiency affects lung development adversely and promotes airway hyperresponsiveness, and may predispose to an increased risk of asthma. We examined the long-term effects of vitamin A supplementation early in life on later asthma risk. In 2006-2008, we revisited participants from two cohorts in rural Nepal who were enrolled in randomised trials of vitamin A supplementation. The first cohort received vitamin A or placebo for <16 months during their pre-school years (1989-1991). The second cohort was born to mothers who received vitamin A, ß-carotene or placebo before, during and after pregnancy (1994-1997). At follow-up, we asked about asthma symptoms and performed spirometry. Out of 6,421 subjects eligible to participate, 5,430 (85%) responded to our respiratory survey. Wheezing prevalence during the previous year was 4.8% in participants aged 9-13 yrs and 6.6% in participants aged 14-23 yrs. We found no differences between the vitamin A supplemented and placebo groups from either trial in the prevalence of lifetime or current asthma and wheeze or in spirometric indices of obstruction (p ≥ 0.12 for all comparisons). Vitamin A supplementation early in life was not associated with a decreased risk of asthma in an area with chronic vitamin A deficiency.

Associations of IL6 polymorphisms with lung function decline and COPD.

BACKGROUND: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. METHODS: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV(1)) over 5 years and baseline FEV(1) at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). RESULTS: In the LHS, three IL6 SNPs were associated with decline in FEV(1) (0.023< or =p< or =0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01< or =p< or =0.04 in additive genetic models). CONCLUSION: The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV(1) and susceptibility to COPD in smokers.

Leptin receptor polymorphisms and lung function decline in COPD.

Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.

Hypothalamic motivational systems: fixed or plastic neural circuits?

Eating and drinking were elicited by electrical stimulation through the same electrode in the hypothalamus of a satiated rat. Intensity thresholds for eliciting eating and drinking were different, and both thresholds decreased with repeated testing. These findings suggest an alternative to the hypothesis that the neural organization of hypothalamic drive systems is modified by experience.

Hypothalamic reward mechanism: two first-stage fiber populations with a cholinergic component.

Refractory periods were estimated for fibers of the hypothalamic substrate of brain stimulation reward. Two nonoverlapping populations were evident: a homogeneous fast population and a more heterogeneous slow population. Cholinergic blockade eliminated the contribution of the fast but not the slow fibers, while dopaminergic blockade reduced responding without significantly influencing either directly activated fiber population. These data indicate that the hypothalamic reward substrate is more complex than has been widely appreciated; it contains two or more parallel subsystems, and one of these subsystems has a cholinergic link.

Anatomically distinct opiate receptor fields mediate reward and physical dependence.

Rats never before exposed to opioids rapidly learned to press a lever for microinjections of morphine into the ventral tegmental area. Challenge by a narcotic antagonist produced no signs of physical dependence. Dependence was not seen after long-term morphine infusions into the ventral tegmentum but was seen after similar infusions into the periventricular gray region. Thus a major rewarding property of morphine is independent of the drug's ability to produce physical dependence. These data challenge models of drug addiction that propose physical dependence as necessary for the rewarding effects of opioids.

Increased lever pressing for amphetamine after pimozide in rats: implications for a dopamine theory of reward.

Low and high doses of a dopamine blocking agent had effects on lever pressing for intravenous amphetamine reward which resembled the effects of reward reduction and reward termination, respectively. Noradrenaline blockade had no such effects. A role in central mediation of reward perception is suggested for dopamine but not for noradrenaline.

Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats.

Rats learned to press a lever for intravenous injections of amphetamine or apomorphine. They also learned to avoid the taste of saccharin which was associated with experimenter-administered amphetamine or with self-administered apomorphine. Thus these, and presumably other, self-administered drugs serve as compound pharmacological stimuli, having both positively reinforcing and aversive properties.

Neuroleptic-induced "anhedonia" in rats: pimozide blocks reward quality of food.

The dopamine receptor blocker pimozide attenuated lever-pressing and running for food reward in hungry rats. In each case the characteristic behavior of pimozide-treated rats was the same as that of undrugged rats when reward was simply withheld. Drug-induced performance difficulties were ruled out by the presence of periods of normal responding in drug-treated animals. Pimozide appears to selectively blunt the rewarding impact of food and other hedonic stimuli.

Circulating fibronectin to C-reactive protein ratio and mortality: a biomarker in COPD?

The balance between inflammatory and repair processes is important in maintaining lung homeostasis in chronic obstructive pulmonary disease (COPD). The aim of the present study was to determine whether or not an integrated index of a biomarker involved in inflammation, C-reactive protein (CRP), and another involved in wound repair, fibronectin, may be a good measure to predict clinical outcomes in COPD. Circulating blood levels of CRP and fibronectin were measured in 4,787 individuals with mild-to-moderate COPD who were prospectively followed for >7 yrs after blood collection as part of the Lung Health Study. To assess the balance between repair and inflammation, a simple ratio was calculated by dividing fibronectin levels by CRP levels and a Cox proportional hazards model was used to determine the relationship between this ratio and all-cause and disease-specific causes of mortality. The relationship between the fibronectin to CRP ratio and all-cause mortality was L-shaped. There was an exponential decay in the adjusted hazard function (i.e. the risk of mortality) as the ratio decreased until a value of 148 was reached, beyond which point the hazard function did not change significantly. Similar results were observed for the risk of coronary and cardiovascular mortality. Circulating fibronectin to CRP ratio is significantly associated with all-cause mortality of COPD patients. However, in contrast to other biomarkers, the relationship appears to be L-shaped (and not linear), suggesting a threshold at approximately 150. While promising, future studies are needed to validate this simple index as a biomarker in COPD.

Prevalence of alpha-1 antitrypsin deficiency in poorly controlled asthma--results from the ALA-ACRC low-dose theophylline trial.

In a study comparing low-dose theophylline to montelukast in poorly controlled asthmatics, 285 subjects consented to be screened for alpha-1 antitrypsin deficiency. Of the 284 for which complete data was available, 10.5% carried a deficiency gene and 2.4% were mildly deficient with an alpha-1 antitrypsin serum level of less than 20 mu M. In the non-African-American cohort, an abnormal phenotype occurred in 12% and 2.9% were mildly deficient. Baseline pulmonary function and asthma scores were not significantly different between those with normal and abnormal AAT phenotype. However those with the deficiency tended to show a greater bronchodilator response.