The Effect of Nasal High Flow Therapy on Minute Ventilation in Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Nasal high-flow therapy (HFT) has been shown to improve daytime breathing mechanics in healthy adults as well as the lung function and quality of life in chronic obstructive pulmonary disease (COPD) patients. METHOD: We hypothesized that improved breathing mechanics with HFT may further reduce minute ventilation (i.e. decreased work of breathing) during sleep in patients with COPD. In COPD participants we examined the dose effect of HFT (within night randomization of HFT level; 0, 10, 20 and 30L/min) on minute ventilation, oxyhemaglobin saturation and transcutaneous carbon dioxide during wake and sleep. We assessed overnight polysomnography with and without HFT on two separate nights. Paired t-tests were used to compare overnight sleep quality with and without HFT. The association between ventilatory variables and HFT level was assessed using regression analysis. RESULTS: During sleep, HFT decreased minute ventilation by 0.63±0.02L/min per 10L/min nasal airflow by reducing tidal volume (37±6mL per 10L/min; p<0.001) without affecting respiratory rate (p=0.9) or arterial CO2 (p=0.7). In contrast, during wakefulness reductions in minute ventilation (0.85±0.04L/min per 10L/min) was due to respiratory rate reduction along with prolongation in expiratory time. CONCLUSION: The reduction in minute ventilation is greater with higher dead-space volumes (r=0.50; p<0.02) and during wakefulness suggesting that ventilatory responses to HFT are mediated through a reduction in dead-space ventilation. The reduction in ventilation in response to HFT is large enough to reduce respiratory loads. Reducing respiratory loads may avert muscle fatigue, preserve respiratory function, or prevent development of respiratory failure.

Indoor heat exposure in Baltimore: does outdoor temperature matter?

Heat exposure of a population is often estimated by applying temperatures from outdoor monitoring stations. However, this can lead to exposure misclassification if residents do not live close to the monitoring station and temperature varies over small spatial scales due to land use/built environment variability, or if residents generally spend more time indoors than outdoors. Here, we compare summertime temperatures measured inside 145 homes in low-income households in Baltimore city with temperatures from the National Weather Service weather station in Baltimore. There is a large variation in indoor temperatures, with daily-mean indoor temperatures varying from 10 °C lower to 10 °C higher than outdoor temperatures. Furthermore, there is only a weak association between the indoor and outdoor temperatures across all houses, indicating that the outdoor temperature is not a good predictor of the indoor temperature for the residences sampled. It is shown that much of the variation is due to differences in the availability of air conditioning (AC). Houses with central AC are generally cooler than outdoors (median difference of - 3.4 °C) while those with no AC are generally warmer (median difference of 1.4 °C). For the collection of houses with central or room AC, there is essentially no relationship between indoor and outdoor temperatures, but for the subset of houses with no AC, there is a weak relationship (correlation coefficient of 0.36). The results presented here suggest future epidemiological studies of indoor exposure to heat would benefit from information on the availability of AC within the population.

Nasal high flow, but not supplemental O2, reduces peripheral vascular sympathetic activity during sleep in COPD patients.

INTRODUCTION: Patients with COPD have increased respiratory loads and altered blood gases, both of which affect vascular function and sympathetic activity. Sleep, particularly rapid eye movement (REM) sleep, is known to exacerbate hypoxia and respiratory loads. Therefore, we hypothesize that nasal high flow (NHF), which lowers ventilatory loads, reduces sympathetic activity during sleep and that this effect depends on COPD severity. METHODS: We performed full polysomnography in COPD patients (n=17; FEV1, 1.6±0.6 L) and in matched controls (n=8). Participants received room air (RA) at baseline and single night treatment with O2 (2 L/min) and NHF (20 L/min) in a random order. Finger pulse wave amplitude (PWA), a measure of vascular sympathetic tone, was assessed by photoplethysmography. Autonomic activation (AA) events were defined as PWA attenuation ≥30% and indexed per hour for sleep stages (AA index [AAI]) at RA, NHF, and O2). RESULTS: In COPD, sleep apnea improved following O2 (REM-apnea hypopnea index [AHI] with RA, O2, and NHF: 18.6±20.9, 12.7±18.1, and 14.4±19.8, respectively; P=0.04 for O2 and P=0.06 for NHF). REM-AAI was reduced only following NHF in COPD patients (AAI-RA, 21.5±18.4 n/h and AAI-NHF, 9.9±6.8 n/h, P=0.02) without changes following O2 (NHF-O2 difference, P=0.01). REM-AAI reduction was associated with lung function expressed as FEV1 and FVC (FEV1: r=-0.59, P=0.001; FEV1/FVC: r=-0.52 and P=0.007). CONCLUSION: NHF but not elevated oxygenation reduces peripheral vascular sympathetic activity in COPD patients during REM sleep. Sympathetic off-loading by NHF, possibly related to improved breathing mechanics, showed a strong association with COPD severity.

Domestic exposure to endotoxin and respiratory morbidity in former smokers with COPD.

Indoor air pollution has been linked to adverse chronic obstructive pulmonary disease (COPD) health, but specific causative agents have not yet been identified. We evaluated the role of indoor endotoxin exposure upon respiratory health in former smokers with COPD. Eighty-four adults with moderate to severe COPD were followed longitudinally and indoor air and dust samples collected at baseline, 3 and 6 months. Respiratory outcomes were repeatedly assessed at each time point. The associations between endotoxin exposure in air and settled dust and health outcomes were explored using generalizing estimating equations in multivariate models accounting for confounders. Dust endotoxin concentrations in the main living area were highest in spring and lowest in fall, while airborne endotoxins remained steady across seasons. Airborne and dust endotoxin concentrations were weakly correlated with one another (rs  = +0.24, P = 0.005). Endotoxin concentrations were not significantly associated with respiratory symptoms, rescue medication use, quality of life, or severe exacerbations. In vitro whole-blood assays of the pro-inflammatory capacity of PM10 filters with and without endotoxin depletion demonstrated that the endotoxin component of indoor air pollution was not the primary trigger for interleukin-1ß release. Our findings support that endotoxin is not the major driver in the adverse effects of indoor PM upon COPD morbidity.

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.

Home interventions are effective at decreasing indoor nitrogen dioxide concentrations.

UNLABELLED: Nitrogen dioxide (NO2 ), a by-product of combustion produced by indoor gas appliances such as cooking stoves, is associated with respiratory symptoms in those with obstructive airways disease. We conducted a three-armed randomized trial to evaluate the efficacy of interventions aimed at reducing indoor NO2 concentrations in homes with unvented gas stoves: (i) replacement of existing gas stove with electric stove; (ii) installation of ventilation hood over existing gas stove; and (iii) placement of air purifiers with high-efficiency particulate air (HEPA) and carbon filters. Home inspection and NO2 monitoring were conducted at 1 week pre-intervention and at 1 week and 3 months post-intervention. Stove replacement resulted in a 51% and 42% decrease in median NO2 concentration at 3 months of follow-up in the kitchen and bedroom, respectively (P = 0.01, P = 0.01); air purifier placement resulted in an immediate decrease in median NO2 concentration in the kitchen (27%, P < 0.01) and bedroom (22%, P = 0.02), but at 3 months, a significant reduction was seen only in the kitchen (20%, P = 0.05). NO2 concentrations in the kitchen and bedroom did not significantly change following ventilation hood installation. Replacing unvented gas stoves with electric stoves or placement of air purifiers with HEPA and carbon filters can decrease indoor NO2 concentrations in urban homes. PRACTICAL IMPLICATIONS: Several combustion sources unique to the residential indoor environment, including gas stoves, produce nitrogen dioxide (NO2), and higher NO2 concentrations, are associated with worse respiratory morbidity in people with obstructive lung disease. A handful of studies have modified the indoor environment by replacing unvented gas heaters; this study, to our knowledge, is the first randomized study to target unvented gas stoves. The results of this study show that simple home interventions, including replacement of an unvented gas stove with an electric stove or placement of HEPA air purifiers with carbon filters, can significantly decrease indoor NO2 concentrations.

Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables. METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Predictors of airborne endotoxin concentrations in inner city homes.

Few studies have assessed in home factors which contribute to airborne endotoxin concentrations. In 85 inner city Baltimore homes, we found no significant correlation between settled dust and airborne endotoxin concentrations. Certain household activities and characteristics, including frequency of dusting, air conditioner use and type of flooring, explained 36-42% of the variability of airborne concentrations. Measurements of both airborne and settled dust endotoxin concentrations may be needed to fully characterize domestic exposure in epidemiologic investigations.

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.

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.

Analysis of CD4+ T-cell gene expression in allergic subjects using two different microarray platforms.

BACKGROUND: Allergic diseases are thought to involve dysregulated activation of T cells including CD4+ lymphocytes. T-cell activation results in changes in gene expression, but the optimal method to study gene expression profiles in T cells, and how this changes over time, are not known. METHODS: Circulating CD4+ T cells were obtained from subjects with atopic asthma, nonatopic asthma or nonallergic controls, and total mRNA was rapidly isolated. Atopy was defined as positive skin prick test to one of nine allergens. Gene expression was analyzed using hybridization and Affymetrix oligonucleotide arrays (Hu133A and Hu133B chips, n = 84), or by reverse transcription-polymerase chain reaction (RT-PCR) with a pathway-targeted array (Human Th1-Th2-Th3 RT(2) Profiler PCR Array, Superarray, n = 16). RESULTS: Using Affymetrix arrays, it was difficult to discern a dominant allergy-associated profile because of heterogeneity in gene expression profiles. In contrast, a Th2-like signature was evident using RT-PCR arrays with increased expression of expected genes (e.g. IL-4, 5, 9, and 13, all P < 0.05) as well as unexpected gene transcripts (e.g. osteopontin). Gene expression profiles were relatively stable over time in circulating CD4+ T cells from two subjects using both platforms. CONCLUSIONS: Unstimulated CD4+ T cells isolated from allergic subjects express a characteristic profile of genes when analyzed using RT-PCR based microarrays.