A novel locus for exertional dyspnoea in childhood asthma.

Most children diagnosed with asthma have respiratory symptoms such as cough, dyspnoea and wheezing, which are also important markers of overall respiratory function. A decade of genome-wide association studies (GWAS) have investigated genetic susceptibility to asthma itself, but few have focused on important respiratory symptoms that characterise childhood asthma.Using whole-genome sequencing (WGS) data for 894 asthmatic trios from a Costa Rican cohort, we performed family-based association tests (FBATs) to assess the association between genetic variants and multiple asthma-relevant respiratory phenotypes: cough, phlegm, wheezing, exertional dyspnoea and exertional chest tightness. We tested whether genome-wide significant associations were replicated in two additional studies: 1) 286 asthmatic trios from the Childhood Asthma Management Program (CAMP), and 2) 2691 African American current or former smokers from the COPDGene study.In the 894 Costa Rican trios, we identified a genome-wide significant association (p=2.16×10-9) between exertional dyspnoea and the single nucleotide polymorphism (SNP) rs10165869, located on chromosome 2q37.3, that was replicated in the CAMP cohort (p=0.023) with the same direction of association (combined p=3.28×10-10). This association was not found in the African American participants from COPDGene. We also found suggestive evidence for an association between SNP rs10165869 and the atypical chemokine receptor 3 (ACKR3).Our finding encourages the secondary association analysis of a wider range of phenotypes that characterise respiratory symptoms in other airway diseases/studies.

Phenotype of Spirometric Impairment in an Aging Population.

RATIONALE: The Global Lung Initiative (GLI) provides age-appropriate criteria for establishing spirometric impairment, including mild, moderate, and severe chronic obstructive pulmonary disease (COPD) and restrictive pattern, but its association with respiratory-related phenotypes has not been evaluated. OBJECTIVES: To evaluate respiratory-related phenotypes in GLI-defined spirometric impairment. METHODS: In COPDGene (N = 10,131 patients; age range, 45-81 yr; average smoking history, 44.3 pack-years), we evaluated spirometry, dyspnea (modified Medical Research Council grade, ≥2), poor respiratory health-related quality of life (St. George's Respiratory Questionnaire total score, ≥25), poor exercise performance (6-minute-walk distance, <391 m), bronchodilator reversibility (FEV1 change, >12% and ≥200 ml), and computed tomography-diagnosed emphysema and gas trapping (>5% and >15% of lung, respectively). MEASUREMENTS AND MAIN RESULTS: GLI established normal spirometry in 5,100 patients (50.3%), mild COPD in 669 (6.6%), moderate COPD in 865 (8.5%), severe COPD in 2,522 (24.9%), and restrictive pattern in 975 (9.6%). Relative to normal spirometry, graded associations with respiratory-related phenotypes were found for mild, moderate, and severe COPD, with respective adjusted odds ratios (95% confidence intervals) as follows: dyspnea-1.31 (1.10-1.56), 2.20 (1.81-2.68), and 10.73 (8.04-14.33); poor respiratory health-related quality of life-1.49 (1.28-1.75), 2.69 (2.08-3.47), and 14.61 (10.09-21.17); poor exercise performance-1.11 (0.94-1.31), 1.58 (1.33-1.88), and 4.58 (3.42-6.12); bronchodilator reversibility-2.76 (2.24-3.40), 5.18 (4.29-6.27), and 6.21 (5.06-7.62); emphysema-4.86 (3.16-7.47), 6.41 (4.09-10.05), and 17.79 (10.79-29.32); and gas trapping-3.92 (3.12-4.93), 5.20 (3.82-7.07), and 16.28 (9.71-27.30). Restrictive pattern was also associated with multiple respiratory-related phenotypes at a level similar to moderate COPD, but it was otherwise not associated with emphysema (0.89 [0.60-1.32]) or gas trapping (1.15 [0.92-1.42]). CONCLUSIONS: GLI-defined spirometric impairment establishes clinically meaningful respiratory disease, as validated by graded associations with respiratory-related phenotypes.

Diagnosing and managing sleep apnea in patients with chronic cerebrovascular disease: a randomized trial of a home-based strategy.

BACKGROUND: Obstructive sleep apnea is common and associated with poor outcomes after stroke or transient ischemic attack (TIA). We sought to determine whether the intervention strategy improved sleep apnea detection, obstructive sleep apnea (OSA) treatment, and hypertension control among patients with chronic cerebrovascular disease and hypertension. METHODS: In this randomized controlled strategy trial intervention, patients received unattended polysomnography at baseline, and patients with OSA (apnea-hypopnea index ≥5 events/h) received auto-titrating continuous positive airway pressure (CPAP) for up to 1 year. Control patients received usual care and unattended polysomnography at the end of the study, to identify undiagnosed OSA. Both groups received 24-h blood pressure assessments at baseline and end of the study. "Excellent" CPAP adherence was defined as cumulative use of ≥4 h/night for ≥70% of the nights. RESULTS: Among 225 randomized patients (115 control; 110 intervention), 61.9% (120/194) had sleep apnea. The strategy successfully diagnosed sleep apnea with 97.1% (102/105) valid studies; 90.6% (48/53, 95% CI 82.7-98.4%) of sleep apnea was undiagnosed among control patients. The intervention improved long-term excellent CPAP use: 38.6% (22/57) intervention versus 0% (0/2) control (p < 0.0001). The intervention did not improve hypertension control in this population with well-controlled baseline blood pressure: intervention, 132.7 mmHg (±standard deviation, 14.1) versus control, 133.8 mmHg (±14.0) (adjusted difference, -1.1 mmHg, 95% CI (-4.2, 2.0)), p = 0.48). CONCLUSIONS: Patients with cerebrovascular disease and hypertension have a high prevalence of OSA. The use of portable polysomnography, and auto-titrating CPAP in the patients' homes, improved both the diagnosis and the treatment for sleep apnea compared with usual care but did not lower blood pressure.

Development, Validation, and Assessment of an Ischemic Stroke or Transient Ischemic Attack-Specific Prediction Tool for Obstructive Sleep Apnea.

BACKGROUND: Screening instruments for obstructive sleep apnea (OSA), as used routinely to guide clinicians regarding patient referral for polysomnography (PSG), rely heavily on symptomatology. We sought to develop and validate a cerebrovascular disease-specific OSA prediction model less reliant on symptomatology, and to compare its performance with commonly used screening instruments within a population with ischemic stroke or transient ischemic attack (TIA). METHODS: Using data on demographic factors, anthropometric measurements, medical history, stroke severity, sleep questionnaires, and PSG from 2 independently derived, multisite, randomized trials that enrolled patients with stroke or TIA, we developed and validated a model to predict the presence of OSA (i.e., Apnea-Hypopnea Index ≥5 events per hour). Model performance was compared with that of the Berlin Questionnaire, Epworth Sleepiness Scale (ESS), the Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender instrument, and the Sleep Apnea Clinical Score. RESULTS: The new SLEEP Inventory (Sex, Left heart failure, ESS, Enlarged neck, weight [in Pounds], Insulin resistance/diabetes, and National Institutes of Health Stroke Scale) performed modestly better than other instruments in identifying patients with OSA, showing reasonable discrimination in the development (c-statistic .732) and validation (c-statistic .731) study populations, and having the highest negative predictive value of all in struments. CONCLUSIONS: Clinicians should be aware of these limitations in OSA screening instruments when making decisions about referral for PSG. The high negative predictive value of the SLEEP INventory may be useful in determining and prioritizing patients with stroke or TIA least in need of overnight PSG.

Observational Study of Obstructive Sleep Apnea in Wake-Up Stroke: The SLEEP TIGHT Study.

BACKGROUND: Wake-up stroke (WUS) accounts for a quarter of all ischemic strokes. Its conspicuous occurrence during sleep suggests that WUS may be associated with obstructive sleep apnea (OSA). We investigated the potential association among WUS, OSA, and measures of sympathetic hyperactivity. METHODS: This is a cross-sectional analysis of data from the Sleep Apnea in Transient Ischemic Attack and Stroke (SLEEP TIGHT) study. Ischemic stroke patients were divided into WUS and non-WUS groups. Participants underwent polysomnography and ambulatory blood pressure monitoring. Collected data included demographic, medical, stroke characteristics (including severity by National Institutes of Health Stroke Scale), cholesterol, serum catecholamines, C-reactive protein, interleukin-6, B-type natriuretic peptide, blood pressure, and polysomnographic (apnea-hypopnea index (AHI); measures of hypoxia). Because both stroke and OSA affect men and women to varying degrees, the cohort was considered as a whole and by gender stratification. RESULTS: Among 164 participants, 30.3% had WUS. The mean age was 62.0 ± 11.3 and the mean body mass index was 30.2 ± 7.9 kg/m2. One-hundred-and-five participants (63.6%) were males and 92 participants (56.8%) were Caucasian. Neither AHI nor OSA (AHI ≥5) frequency differed between WUS and non-WUS groups. Men tended to be more likely than women to have WUS (74.0 vs. 59.6%; p = 0.08), but this was not statistically significant. In gender-stratified analyses, men with WUS compared to men with non-WUS had significantly higher rates of severe OSA (AHI >30: 45.0 vs. 17.6%; p = 0.03) and tended toward more 3% oxygen desaturation events (57.0 ± 63.9 vs. 31.8 ± 22.9; p = 0.06). These differences were not seen in women. WUS patients tended to be of the male gender (74.0 vs. 59.6%; p = 0.08). History of stroke, hypertension, diabetes, dyslipidemia, or atrial fibrillation, serum catecholamines, and inflammatory biomarkers was no different between the groups. Low-density lipoprotein (LDL) was significantly higher in WUS (114.5 ± 36.3 vs. 101.4 ± 37.6; p = 0.04). Baseline diastolic blood pressure (DBP) was significantly greater in the WUS group. There was no difference in systolic or ambulatory blood pressure (including nighttime blood pressure) between WUS and non-WUS groups. CONCLUSIONS: WUS may be associated with severe OSA with more oxygen desaturation in men but not in women. WUS may be associated with high DBP and increased LDL cholesterol.

Phenotype of normal spirometry in an aging population.

RATIONALE: In aging populations, the commonly used Global Initiative for Chronic Obstructive Lung Disease (GOLD) may misclassify normal spirometry as respiratory impairment (airflow obstruction and restrictive pattern), including the presumption of respiratory disease (chronic obstructive pulmonary disease [COPD]). OBJECTIVES: To evaluate the phenotype of normal spirometry as defined by a new approach from the Global Lung Initiative (GLI), overall and across GOLD spirometric categories. METHODS: Using data from COPDGene (n = 10,131; ages 45-81; smoking history, ≥10 pack-years), we evaluated spirometry and multiple phenotypes, including dyspnea severity (Modified Medical Research Council grade 0-4), health-related quality of life (St. George's Respiratory Questionnaire total score), 6-minute-walk distance, bronchodilator reversibility (FEV1 % change), computed tomography-measured percentage of lung with emphysema (% emphysema) and gas trapping (% gas trapping), and small airway dimensions (square root of the wall area for a standardized airway with an internal perimeter of 10 mm). MEASUREMENTS AND MAIN RESULTS: Among 5,100 participants with GLI-defined normal spirometry, GOLD identified respiratory impairment in 1,146 (22.5%), including a restrictive pattern in 464 (9.1%), mild COPD in 380 (7.5%), moderate COPD in 302 (5.9%), and severe COPD in none. Overall, the phenotype of GLI-defined normal spirometry included normal adjusted mean values for dyspnea grade (0.8), St. George's Respiratory Questionnaire (15.9), 6-minute-walk distance (1,424 ft [434 m]), bronchodilator reversibility (2.7%), % emphysema (0.9%), % gas trapping (10.7%), and square root of the wall area for a standardized airway with an internal perimeter of 10 mm (3.65 mm); corresponding 95% confidence intervals were similarly normal. These phenotypes remained normal for GLI-defined normal spirometry across GOLD spirometric categories. CONCLUSIONS: GLI-defined normal spirometry, even when classified as respiratory impairment by GOLD, included adjusted mean values in the normal range for multiple phenotypes. These results suggest that among adults with GLI-defined normal spirometry, GOLD may misclassify normal phenotypes as having respiratory impairment.

Ethnic differences in respiratory impairment.

OBJECTIVE: Spirometric Z scores by lambda-mu-sigma (LMS) rigorously account for age-related changes in lung function. Recently, the Global Lung Function Initiative (GLI) expanded LMS spirometric Z scores to multiple ethnicities. Hence, in aging populations, the GLI provides an opportunity to rigorously evaluate ethnic differences in respiratory impairment, including airflow limitation and restrictive pattern. METHODS: Using data from the Third National Health and Nutrition Examination Survey, including participants aged 40-80, we evaluated ethnic differences in GLI-defined respiratory impairment, including prevalence and associations with mortality and respiratory symptoms. RESULTS: Among 3506 white Americans, 1860 African Americans and 1749 Mexican Americans, the prevalence of airflow limitation was 15.1% (13.9% to 16.4%), 12.4% (10.7% to 14.0%) and 8.2% (6.7% to 9.8%), and restrictive pattern was 5.6% (4.6% to 6.5%), 8.0% (6.9% to 9.0%) and 5.7% (4.5% to 6.9%), respectively. Airflow limitation was associated with mortality in white Americans, African Americans and Mexican Americans-adjusted HR (aHR) 1.66 (1.23 to 2.25), 1.60 (1.09 to 2.36) and 1.80 (1.17 to 2.76), respectively, but associated with respiratory symptoms only in white Americans-adjusted OR (aOR) 2.15 (1.70 to 2.73). Restrictive pattern was associated with mortality but only in white Americans and African Americans-aHR 2.56 (1.84 to 3.55) and 3.23 (2.06 to 5.05), and associated with respiratory symptoms but only in white Americans and Mexican Americans-aOR 2.16 (1.51 to 3.07) and 2.12 (1.45 to 3.08), respectively. CONCLUSIONS: In an aging population, we found ethnic differences in GLI-defined respiratory impairment. In particular, African Americans had high rates of respiratory impairment that were associated with mortality but not respiratory symptoms.

Respiratory impairment and COPD hospitalisation in older persons: a competing risk analysis.

The aim of the present study was to evaluate, among older persons, the association between respiratory impairment and hospitalisation for chronic obstructive pulmonary disease (COPD), based on spirometric Z-scores, i.e. the LMS (lambda, mu, sigma) method, and a competing risk approach. Using data on 3,563 white participants aged 65-80 yrs (from the Cardiovascular Health Study) we evaluated the association of LMS-defined respiratory impairment with the incident of COPD hospitalisation and the competing outcome of death without COPD hospitalisation, over a 5-yr period. Respiratory impairment included airflow limitation (mild, moderate or severe) and restrictive pattern. Over a 5-yr period, 276 (7.7%) participants had a COPD hospitalisation incident, whereas 296 (8.3%) died without COPD hospitalisation. The risk of COPD hospitalisation was elevated more than two-fold in LMS-defined mild and moderate airflow limitation and restrictive pattern (adjusted HR (95% CI): 2.25 (1.25-4.05), 2.54 (1.53- 4.22) and 2.65 (1.82-3.86), respectively), and more than eight-fold in LMS-defined severe airflow limitation (adjusted HR (95% CI) 8.33 (6.24-11.12)). Conversely, only LMS-defined restrictive-pattern was associated with the competing outcome of death without COPD hospitalisation (adjusted HR (95% CI) 1.68 (1.22-2.32)). In older white persons, LMS-defined respiratory impairment is strongly associated with an increased risk of COPD hospitalisation. These results support the LMS method as a basis for defining respiratory impairment in older persons.

Caring for the older person with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), a common disease in elderly patients, is characterized by high symptom burden, health care utilization, mortality, and unmet needs of patients and caregivers. Respiratory failure and dyspnea may be exacerbated by heart failure, pulmonary embolism, and anxiety; by medication effects; and by other conditions, including deconditioning and malnutrition. Randomized controlled trials, which provide the strongest evidence for guideline recommendations, may underestimate the risk of adverse effects of interventions for older patients with COPD. The focus of guidelines on disease-modifying therapies may not address the full spectrum of patient and caregiver needs, particularly the high rates of bothersome symptoms, risk of functional and cognitive decline, and need for end-of-life care planning. Meeting the many needs of older patients with COPD and their families requires that clinicians supplement guideline-recommended care with treatment decision making that takes into account older persons' comorbid conditions, recognizes the trade-offs engendered by the increased risk of adverse events, focuses on symptom relief and function, and prepares patients and their loved ones for further declines in the patient's health and their end-of-life care. A case of COPD in an 81-year-old man hospitalized with severe dyspnea and respiratory failure highlights both the challenges in managing COPD in the elderly and the limitations in applying guidelines to geriatric patients.

The ratio of FEV1 to FVC as a basis for establishing chronic obstructive pulmonary disease.

RATIONALE: The lambda-mu-sigma (LMS) method is a novel approach that defines the lower limit of normal (LLN) for the ratio of FEV1/FVC as the fifth percentile of the distribution of Z scores. The clinical validity of this threshold as a basis for establishing chronic obstructive pulmonary disease is unknown. OBJECTIVE: To evaluate the association between the LMS method of determining the LLN for the FEV1/FVC, set at successively higher thresholds, and clinically meaningful outcomes. METHODS: Using data from a nationally representative sample of 3,502 white Americans aged 40-80 years, we stratified the FEV1/FVC according to the LMS-LLN, with thresholds set at the 5th, 10th, 15th, 20th, and 25th percentiles (i.e., LMS-LLN5, LMS-LLN10, etc.). We then evaluated whether these thresholds were associated with an increased risk of death or prevalence of respiratory symptoms. Spirometry was not specifically completed after a bronchodilator. MEASUREMENTS AND MAIN RESULTS: Relative to an FEV1/FVC greater than or equal to LMS-LLN25 (reference group), the risk of death and the odds of having respiratory symptoms were elevated only in participants who had an FEV1/FVC less than LMS-LLN(5), with an adjusted hazard ratio of 1.68 (95% confidence interval, 1.34-2.12) and an adjusted odds ratio of 2.46 (95% confidence interval, 2.01-3.02), respectively, representing 13.8% of the cohort. Results were similar for persons aged 40-64 years and those aged 65-80 years. CONCLUSIONS: In white persons aged 40-80 years, an FEV1/FVC less than LMS-LLN5 identifies persons with an increased risk of death and prevalence of respiratory symptoms. These results support the use of the LMS-LLN5 threshold for establishing chronic obstructive pulmonary disease.

Use of lambda-mu-sigma-derived Z score for evaluating respiratory impairment in middle-aged persons.

BACKGROUND: The lambda-mu-sigma (LMS) method calculates the lower limit of normal for spirometric values as the 5th percentile of the distribution of Z scores. Conceptually, LMS-derived Z scores account for normal age-related changes in pulmonary function, including variability and skewness in reference data. Evidence is limited, however, on whether the LMS method is valid for evaluating respiratory impairment in middle-aged persons. OBJECTIVE: To evaluate the association of LMS-defined respiratory impairment (airflow limitation and restrictive pattern) with mortality and respiratory symptoms. METHODS: We analyzed spirometric data from white participants ages 45-64 years in the Third National Health and Nutrition Examination Survey (NHANES III, n = 1,569) and the Atherosclerosis Risk in Communities study (ARIC, n = 8,163). RESULTS: LMS-defined airflow limitation was significantly associated with mortality (adjusted hazard ratios: NHANES III 1.90, 95% CI 1.32-2.72, ARIC 1.28, 95% CI 1.06-1.57), and respiratory symptoms (adjusted odds ratios: NHANES III 2.48, 95% CI 1.75-3.51, ARIC 2.27, 95% CI 1.98-2.62). LMS-defined restrictive-pattern was also significantly associated with mortality (adjusted hazard ratios: NHANES III 1.98, 95% CI 1.08-3.65, ARIC 1.38, 95% CI 1.03-1.85), and respiratory symptoms (adjusted odds ratios: NHANES III 2.34, 95% CI 1.44-3.80, ARIC 1.89, 95% CI 1.46-2.45). CONCLUSIONS: In white middle-age persons, LMS-defined airflow limitation and restrictive-pattern were significantly associated with mortality and respiratory symptoms. Consequently, an approach that reports spirometric values based on LMS-derived Z scores might provide an age-appropriate and clinically valid strategy for evaluating respiratory impairment.

Antihypertensive medications and physical function in older persons.

BACKGROUND: To further inform benefits and risks of medications on physical function in aging populations, we have evaluated the associations of antihypertensive (antiHTN) class and number used with skeletal muscle function, mobility, sedentary time, and symptoms in older persons. METHODS: Using baseline data from the Lifestyle Interventions and Independence in Elder (LIFE) study (N = 1567, mean age 78.9 years) and multivariable models, we evaluated cross-sectional associations of antiHTN class and number used with physical measures and symptom questionnaires. AntiHTN class included diuretics, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and beta blockers (BB). Physical measures included respiratory muscle weakness (maximal inspiratory pressure), grip weakness (dynamometer), impaired lower extremity proximal muscle strength (chair stands), impaired balance (three-stage test), slow gait (400 m walk), mobility impairment (Short Physical Performance Battery), and high sedentary time (accelerometry). Symptoms included dyspnea and fatigue. Covariates included clinical characteristics and non-antiHTNs. RESULTS: Use of any antiHTN was highly prevalent (n = 1248 [79.6%]). In the antiHTN subgroup, each antiHTN class was well represented (ranging 36.6%-62.7%) and included use of three or more antiHTNs (32.0%). In adjusted models, the only statistically significant associations were use of BB and three or more antiHTNs with high sedentary time: odds ratios (95% confidence intervals) 1.44 (1.12, 1.85) and 1.52 (1.04, 2.23), respectively. CONCLUSION: Use of BB and three or more antiHTNs yielded 44% and 52% increased odds of accelerometry-defined high sedentary time, respectively. Notably, high sedentary time is a risk factor for adverse health outcomes. Thus, future work should evaluate whether high sedentary time mitigates benefits or increases risks, regarding antiHTN use in aging populations.

Re-evaluation of the Uplift Clinical Trial Using Age-Appropriate Spirometric Criteria.

BACKGROUND: The clinical trial of tiotropium in COPD, UPLIFT, enrolled adults with a mean age of 65 years and moderate-to-severe airflow obstruction, based on criteria from the Global Initiative for Chronic Obstructive Lung Disease (GOLD). For the UPLIFT cohort, however, GOLD-based criteria are not age-appropriate. RESEARCH QUESTION: Will the use of more age-appropriate criteria for airflow obstruction from the Global Lung Function Initiative (GLI) modify the spirometric classification of the UPLIFT cohort and, in turn, the mortality effect of tiotropium in COPD? STUDY DESIGN AND METHODS: Baseline spirometric classifications were first cross-tabulated by GLI- and GOLD-based criteria. Next, in GLI- and GOLD-based airflow obstruction, modified intention-to-treat analyses evaluated differences in time to death over 4 years, comparing tiotropium vs placebo. Because treatment response may differ by COPD severity, the mortality effect also was evaluated within stratum defined by GLI- and GOLD-based moderate and severe airflow obstruction. RESULTS: Of 5,898 participants with GOLD-based airflow-obstruction, staged as moderate in 2,739 (46.4%) and severe in 3,156 (53.5%), GLI-based criteria established airflow obstruction in 5,750 (97.5%), staged as moderate in 795 (13.5%) and severe in 4,947 (83.9%). Relative to placebo, tiotropium yielded statistically nonsignificant adjusted hazard ratios (adjHRs) (95% CI) for death of 0.91 (0.80-1.04) and 0.91 (0.79-1.03) in GLI- and GOLD-based airflow obstruction, respectively. However, statistically significant effect modification was observed, but only in GLI-based moderate and severe airflow-obstruction, with tiotropium yielding adjHRs for death of 0.53 (0.34-0.81) and 0.99 (0.86-1.13), respectively. The P value for interaction was .007. INTERPRETATION: Mortality reduction by tiotropium was only statistically significant in GLI-based moderate airflow-obstruction, a group that was underrepresented in UPLIFT because of severity misclassification by the original GOLD-based enrollment criteria.

FEV1 as a Standalone Spirometric Predictor and the Attributable Fraction for Death in Older Persons.

BACKGROUND: Commonly used thresholds for staging FEV1 have not been evaluated as standalone spirometric predictors of death in older persons. Specifically, the proportion of deaths attributed to a reduced FEV1, when staged by commonly used thresholds in L, percent of predicted (% pred), and Z scores, has not been previously reported. METHODS: In 4,232 white persons ≥ 65 y old, sampled from the Cardiovascular Health Study, FEV1 was stratified as stage 1 (FEV1 ≥ 2.00 L, ≥80% pred, and Z score ≥-1.64), stage 2 (FEV1 1.50-1.99 L, 50-79%pred, and Z score -2.55 to -1.63), and stage 3 (FEV1 < 1.50 L, < 50% pred, and Z score < -2.55). Notably, a Z score threshold of -1.64 defines normal-for-age lung function as the lower limit of normal (ie, 5th percentile of distribution), and accounts for differences in age, sex, height, and ethnicity. Next, adjusted odds ratios and average attributable fractions for 10-y all-cause mortality were calculated, comparing FEV1 stages 2 and 3 against stage 1, expressed in L, % pred, and Z scores. The average attributable fraction estimates the proportion of deaths attributed to a predictor by combining the prevalence of the predictor with the relative risk of death conferred by that predictor. RESULTS: FEV1 stage 2 and 3 in L, % pred, and Z scores yielded similar adjusted odds ratios of death: 1.40-1.51 for stage 2 and 2.35-2.66 for stage 3. Conversely, FEV1 stages 2 and 3 in L, % pred, and Z scores differed in prevalence: 12.8-28.6% for stage 2 and 6.4-17.5% for stage 3, and also differed in the adjusted average attributable fraction for death: 3.2-6.4% for stage 2 and 4.5-9.1% for stage 3. CONCLUSIONS: In older persons, the proportion of deaths attributed to a reduced FEV1 is best stratified by Z score staging thresholds because these yield a similar relative risk of death but a more age- and sex-appropriate prevalence of FEV1 stage.

Diffusing capacity in normal-for-age spirometry and spirometric impairments, using reference equations from the global lung function initiative.

BACKGROUND: Reference equations from the Global Lung Function Initiative (GLI) are now available for both spirometry and diffusion. However, respiratory phenotypes defined by GLI-based measures of diffusion have not yet been evaluated in GLI-based normal-for-age spirometry or spirometric impairments. METHODS: We evaluated cross-sectional data from 2100 Caucasians, aged 40-85 years. GLI-based spirometric categories included normal-for-age and the impairments of restrictive-pattern and three-level severity of airflow-obstruction (mild, moderate, severe). GLI-based diffusion included diffusing capacity of the lung for carbon monoxide (DLCO) and measured components of alveolar volume (VA) and transfer coefficient (KCO): DLCO = [VA]x[KCO]. Using multivariable regression models, adjusted odds ratios (adjORs) for DLCO, VA, and KCO < lower limit of normal (LLN) were calculated for spirometric impairments, relative to normal-for-age spirometry. RESULTS: Relative to normal-for-age spirometry, the restrictive-pattern increased the adjORs (95% confidence intervals) for DLCO and VA < LLN-4.61 (3.62, 5.85) and 15.53 (11.8, 20.4), respectively, but not for KCO < LLN-1.02 (0.79, 1.33). Also relative to normal-for-age spirometry, airflow-obstruction from mild to severe increased the adjORs for DLCO < LLN-from 1.22 (0.80, 1.86) to 6.63 (4.91, 8.95), for VA < LLN-from 1.37 (0.85, 2.18) to 7.01 (5.20, 9.43), and for KCO < LLN-from 2.04 (1.33, 3.14) to 3.03 (2.29, 3.99). Notably, in normal-for-age spirometry, 34.5%, 19.7%, and 25.3% of participants had DLCO, VA, or KCO < LLN, respectively. CONCLUSION: Abnormal diffusion is most prevalent in spirometric impairments but also occurs in normal-for-age spirometry. These results further inform the respiratory phenotypes of GLI-based spirometric categories and, in turn, the spirometric evaluation of respiratory disease.

Re-evaluation of combination therapy in chronic obstructive pulmonary disease (COPD).

BACKGROUND: Clinical trials of COPD pharmacotherapy typically involve aging populations with moderate-to-severe COPD, but the latter is often diagnosed by spirometric criteria that are not age-appropriate across the continuum of lung function. We have therefore re-evaluated the clinical effect of combination therapy (salmeterol plus fluticasone) in moderate-to-severe COPD, using more age-appropriate spirometric criteria from the Global Lung Function Initiative (GLI) and trial data from Towards a Revolution in COPD Health (TORCH). METHODS: Of the 6112 TORCH participants, 5688 (93.1%) had GLI-based moderate-to-severe COPD (mean age 64.8 years). The primary outcome was all-cause mortality and the primary comparison was combination therapy vs. placebo. Secondary outcomes included COPD and cardiovascular (CV) mortality and pneumonia. A modified intention-to-treat analysis evaluated differences in time-to-event over a three-year period, using Cox proportional hazards models with statistical significance at p < 0.010 (acknowledging repeated significance testing). RESULTS: Relative to placebo, combination therapy yielded a statistically non-significant reduction in all-cause mortality-adjusted hazard ratio [adjHR] 0.78 (95% confidence interval [CI]: 0.64, 0.95), p = 0.012. Relative to placebo, combination therapy also yielded statistically non-significant reductions in COPD and CV mortality-adjHR 0.75 (95% CI: 0.55, 1.02), p = 0.068 and adjHR 0.76 (95% CI: 0.53, 1.09), p = 0.135, respectively. In contrast, combination therapy yielded a statistically significant increased risk of pneumonia, relative to placebo-adjHR 1.80 (95% CI: 1.46, 2.21), p < 0.001. CONCLUSION: In GLI-based moderate-to-severe COPD, combination therapy yields a statistically significant increased risk of pneumonia but the reductions in mortality are not statistically significant, although could potentially be clinically meaningful.

The Epidemiology of Patient-Reported Hypersomnia in Persons With Advanced Age.

OBJECTIVE: To examine the epidemiology and key demographic and clinical correlates of patient-reported hypersomnia in persons with advanced age. DESIGN: Cross-sectional design. SETTING: Community. PARTICIPANTS: A total of 357 community-dwelling persons from the Yale Precipitating Events Project with a mean age of 84.2 years (range = 78-102 years). MEASUREMENTS: We studied patient-reported hypersomnia, defined categorically by an Epworth Sleepiness Scale (ESS) score of 10 or greater; as well as the severity of hypersomnia symptoms, defined continuously by an ESS score range of 0 to 24 (higher scores denote greater sleepiness). In multivariable regression models, we examined cross-sectional associations between key correlates and ESS score, expressed as categorical and continuous variables. Key correlates included: demographics, education, smoking status, body mass index, self-reported medical conditions, Center for Epidemiologic Studies Depression score, Mini-Mental State Examination score, Physical Activity Scale for the Elderly, restless legs syndrome (RLS), self-reported sleep-disordered breathing (SDB), medications, and Insomnia Severity Index. RESULTS: Mean ESS score for all participants was 6.4. Patient-reported hypersomnia (ESS score ≥10) was established in 82 participants (23.0%)-their mean ESS score was 13.0. In multivariable models, male sex, nonwhite race, arthritis, depressive symptoms, low physical activity, RLS, SDB, central nervous system depressant medications, and insomnia severity were cross-sectionally associated with patient-reported hypersomnia (higher adjusted odds ratios, ranging from 1.93-2.86) and/or with the severity of hypersomnia symptoms (higher ESS scores, ranging from 0.11-2.86 points). CONCLUSION: Patient-reported hypersomnia was prevalent in a sample of community-dwelling persons with advanced age. In addition, based on cross-sectional associations with the ESS score, key demographic and clinical characteristics were identified that may inform screening strategies for hypersomnia in advanced age. J Am Geriatr Soc 67:2545-2552, 2019.