A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Candidate genes for COPD in two large data sets.

Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV1 % predicted and FEV1/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.

Quality of life measured with a generic instrument (Short Form-36) improves following pulmonary rehabilitation in patients with COPD.

STUDY OBJECTIVES: The purpose of this study was to evaluate the effects of a 3-week comprehensive pulmonary rehabilitation program on quality of life as measured by the Short Form-36 (SF-36) in patients with COPD. DESIGN AND SETTING: We report on the outcomes of 37 consecutive patients referred for pulmonary rehabilitation at a respiratory specialty medical center. PATIENTS: Thirty-seven patients (mean age, 66 years) with COPD and severe airflow limitation (mean +/- SE FEV(1), 29.6 +/- 1.8% of predicted) were studied. INTERVENTIONS: Rehabilitation consisted of a 3-week pulmonary rehabilitation program incorporating 12 exercise sessions, each of which included bicycle ergometer exercise training, upper-extremity training, strength training, and stretching, along with psychosocial counseling and education. MEASUREMENTS AND RESULTS: The Health Status Index (SF-36) and 6-min walk test were completed before and after rehabilitation. There was an improvement in five of the nine quality-of-life subscales of the SF-36 following pulmonary rehabilitation. Although there was an improvement in functional capacity as measured by the 6-min walk, there was no correlation between improvement in quality of life and improvement in functional capacity. There was no correlation between FEV(1) and improvement in walk distance, but there was a correlation between FEV(1) and improvement in SF-36 physical function and energy/fatigue subscales. CONCLUSION: Health-related quality of life assessed by the SF-36, a general measure of quality of life, improves following an intensive 3-week pulmonary rehabilitation program. Use of the SF-36 allows comparison of the results of pulmonary rehabilitation to therapeutic interventions in patients with other medical disorders.

Improved exercise performance following lung volume reduction surgery for emphysema.

Lung volume reduction surgery (LVRS) for emphysema has been suggested to improve patient lung function and activity. The short-term impact of LVRS on exercise performance was evaluated using maximal and submaximal steady-state exercise testing in 27 patients with severe hypoxemic chronic obstructive pulmonary disease (COPD), along with measurements of patient function, dyspnea, and quality of life. LVRS significantly improved exercise performance, due to ventilatory improvements associated with increased ventilatory reserve, enhanced tidal volume recruitment, and improved alveolar ventilation. Preoperative measurements of ventilatory reserve and dead space ventilation during exercise testing were closely associated with improved exercise performance. Improvements in patient dyspnea, walk distances, and quality of life also occurred following LVRS and were associated with improvements in exercise performance. Surgical mortality from LVRS was low (4%), but short-term all-cause mortality was increased (19%). Short-term mortality was associated with reduced expiratory muscle strength and markedly elevated dead space ventilation. We conclude that LVRS produces significant improvements in exercise performance, dyspnea, and quality of life in selected patients with COPD. Physiologic prediction of patients most likely to survive for an extended period and have significant benefit following LVRS may also be possible.

Core body temperature is normal in chronic fatigue syndrome.

BACKGROUND: Subjects with chronic fatigue syndrome (CFS) frequently report symptoms of subnormal body temperature and low-grade fever. We conducted a study to determine whether CFS subjects manifest any abnormality of core body temperature (CBT) that might help explain their fatigue. METHODS: Continuous 24-hour recordings of CBT measured every 5 min were performed in 7 subjects meeting the Centers for Disease Control definition of CFS. Three additional groups were studied: normal controls, subjects with seasonal allergy, and subjects with major depression. Subjects (n = 7) in each group were age-, sex-, and weight-matched to the CFS group and had normal basal metabolic rates, thyroid function, and 24-hour urinary free cortisol excretions. CBT was measured with an ingestible radio frequency transmitter pill and a belt-worn receiver-logger. Each pill was factory-calibrated to +/- 0.1 degree C and field-calibrated with a water bath calibration prior to use. RESULTS: The 24-hour mean calibration-adjusted CBTs of each group were not significantly different (control: 37.00 +/- 0.17 degrees C; CFS: 37.04 +/- 0.31 degrees C; allergy: 37.15 +/- 0.18 degrees C; depression: 37.16 +/- 0.18 degrees C). Similarly, the mean peak and trough circadian temperatures were not statistically different. The mean 24-hour profile of CBT for each group showed a similar circadian rhythm. In simultaneously collected blood samples, each group showed a similar circadian profile of serum cortisol with a peak occurring at 08:00. CONCLUSIONS: Subjects with CFS have normal CBT despite frequent self-reports of subnormal body temperature and low-grade fever.

Respiratory tract infection complicating transtracheal oxygen therapy.

Transtracheal oxygen is generally well tolerated in patients with chronic hypoxemia. Minor complications are common, but there are few reports of serious respiratory tract infections associated with transtracheal oxygen therapy. We describe four patients with interstitial lung disease who had frequent lower respiratory tract infections requiring hospitalization after initiation of transtracheal oxygen therapy.

Mechanical ventilation in the home.

Despite advances in the application of mechanical ventilation as a short-term, life-saving technique, intensive care units are increasingly faced with patients who cannot be weaned from ventilatory assistance and who require mechanical ventilation as a long-term, life-supporting necessity. Because of limited resources in health care facilities for the management of chronic ventilator-assisted individuals, home care has become an important option. With careful selection of appropriate candidates, home care for ventilator-assisted individuals can result in not only decreased respiratory symptoms, reduction in hospitalization, and improved physiologic measures, but also an improved quality of life with substantial survival and a reduction in the costs of medical care.

Transtracheal oxygen decreases inspired minute ventilation.

Although patients using transtracheal oxygen (TTO2) frequently report decreased dyspnea and improved exercise tolerance, the mechanism for these effects is unknown. We hypothesized that these patients might have decreased inspired minute ventilation (VI), and this might be one mechanism for their decreased dyspnea and improved exercise tolerance. The effects of TTO2 on VI were studied in seven patients with chronic hypoxemia; two had chronic obstructive lung disease and five had severe restrictive disorders. VI, exhaled minute ventilation (VE), respiratory rate (RR), tidal volume (VT), earlobe O2 saturation (O2 sat), and arterial blood gases were measured while patients received varying amounts of oxygen either transtracheally or by mouth to achieve equivalent degrees of oxygenation. With TTO2 VI was reduced compared to VI with mouth O2 at similar levels of PaO2. As TTO2 flow rate increased, VI decreased; at 6 L/min O2 delivered transtracheally, mean VI was reduced by 54 +/- 7.0%. Reduction in VI was due to decreased VT; RR did not change. To determine if air delivered transtracheally decreased VI, five patients were studied while receiving air transtracheally or by mouth. With transtracheal air, VI was significantly less than VI obtained while breathing air by mouth. We conclude that VI is decreased when oxygen or air is delivered directly into the trachea and that VI decreases as transtracheal flow increases. This effect is not due solely to changes in oxygenation. Decreased dyspnea and improved exercise tolerance in patients using TTO2 may be due to decreased VI and decreased inspiratory work of breathing.

Criteria for establishing units for chronic ventilator-dependent patients in hospitals.

These guidelines were developed by the American Association for Respiratory Care in response to a request by the Health Care Financing Administration for professional assistance in defining criteria for establishment of demonstration units for management of chronic ventilator-dependent patients in hospitals. Although the exact method by which these demonstration units (3 to 5 in number) will be selected has not been announced, these guidelines will have an important role in assuring that appropriate sites are chosen and that patient selection and data collection are adequate to document the possible benefits of such units.

Pulmonary rehabilitation: myth or reality?

Pulmonary rehabilitation is an art of medical practice incorporating many therapeutic modalities with the goal of improving the patient's functional ability. The gains to be realized and the basis for improvement following pulmonary rehabilitation are detailed in this article.

Rehabilitation and home care for ventilator-assisted individuals.

An increasing number of patients with chronic irreversible respiratory disorders are receiving mechanical ventilation in the home. Rehabilitation prior to hospital discharge allows improved independence and mobility in the home for these individuals.

Dyssynchronous breathing during arm but not leg exercise in patients with chronic airflow obstruction.

Some patients with chronic airflow obstruction experience dyspnea with mild arm exercise but not with more-intense leg exercise. To investigate why these patients have limited endurance during arm exertion, we studied ventilatory responses to exercise with unsupported arms in 12 patients with chronic airflow obstruction (mean [+/- SD] forced expiratory volume in one second, 0.68 +/- 0.28 liters). Unloaded leg cycling was also studied for comparison. In the five patients who had the most severe airflow obstruction, arm exercise was limited by dyspnea after 3.3 +/- 0.7 minutes, and dyssynchronous thoracoabdominal breathing developed. In the other seven patients, arm exercise was limited by the sensation of muscle fatigue after 6.1 +/- 2.0 minutes (P less than 0.05), and dyssynchronous breathing did not occur. None of the 12 patients had dyssynchronous breathing during unloaded leg cycling. Maximal transdiaphragmatic pressure, a measure of diaphragmatic fatigue, declined similarly after arm and leg exercise in both groups. During unsupported arm work, the accessory muscles of inspiration help position the torso and arms. We hypothesize that the extra demand placed on these muscles during arm exertion leads to early fatigue, an increased load on the diaphragm, and dyssynchronous thoracoabdominal inspirations. This sequence may contribute to dyspnea and limited endurance during upper-extremity exercise.