The GOLD Summit on chronic obstructive pulmonary disease in low- and middle-income countries.

Chronic obstructive pulmonary disease (COPD) is one of the top three causes of death worldwide, but governments and non-governmental organisations have not given its prevention and treatment the priority it requires. This is particularly true in low- and middle-income countries, where most of the people suffering from this disease live. The United Nations (UN) has targeted a reduction of premature deaths from non-communicable diseases (NCDs) by a third by 2030; however, a coordinated UN/World Health Organization (WHO) strategy to address the burden of COPD (one of the most important NCDs) is still lacking. To explore the extent of the problem and inform the development of policies to improve the situation, the Board of Directors of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) held a 1-day Summit. The key themes that emerged were the need to ensure accurate data on prevalence, raise awareness of the disease among the public, healthcare professionals and governments, including the fact that COPD aetiology goes beyond smoking (and other inhaled pollutants) and includes poor lung development in early life, and ensure that spirometry and both pharmacological and non-pharmacological therapies are available and affordable. Here, we present the actions that must be taken to address the impact of COPD. We believe that the WHO is particularly well-positioned to co-ordinate an attack on COPD, and GOLD will do all it can to help and rally support.

The Impact of Alemtuzumab and Basiliximab Induction on Patient Survival and Time to Bronchiolitis Obliterans Syndrome in Double Lung Transplantation Recipients.

We examined the effect of alemtuzumab and basiliximab induction therapy on patient survival and freedom from bronchiolitis obliterans syndrome (BOS) in double lung transplantation. The United Network for Organ Sharing database was reviewed for adult double lung transplant recipients from 2006 to 2013. The primary outcome was risk-adjusted all-cause mortality. Secondary outcomes included time to BOS. There were 6117 patients were identified, of whom 738 received alemtuzumab, 2804 received basiliximab, and 2575 received no induction. Alemtuzumab recipients had higher lung allocation scores compared with basiliximab and no-induction recipients (41.4 versus 37.9 versus 40.7, p < 0.001) and were more likely to require mechanical ventilation before to transplantation (21.7% versus 6.5% versus 6.2%, p < 0.001). Median survival was longer for alemtuzumab and basiliximab recipients compared with patients who received no induction (2321 versus 2352 versus 1967 days, p = 0.001). Alemtuzumab (hazard ratio 0.80, 95% confidence interval 0.67-0.95, p = 0.009) and basiliximab induction (0.88, 0.80-0.98, p = 0.015) were independently associated with survival on multivariate analysis. At 5 years, alemtuzumab recipients had a lower incidence of BOS (22.7% versus 55.4 versus 55.9%), and its use was independently associated with lower risk of developing BOS on multivariate analysis. While both induction therapies were associated with improved survival, patients who received alemtuzumab had greater median freedom from BOS.

Blunted expression of miR-199a-5p in regulatory T cells of patients with chronic obstructive pulmonary disease compared to unaffected smokers.

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal regulatory T cell (T(reg)) response and increases in T helper type 1 (Th1) and Th17 cell responses. It is unclear if dysregulation of microRNAs (miRNA) within T(reg) cells contributes to the abnormal inflammatory response in COPD. In this study, we aimed to compare the miRNA profile of COPD T(reg) cells with that of healthy controls and to explore the function of differentially expressed miRNAs. We first obtained T(reg) and T effector cells (Teff ) from peripheral blood of non-smokers, unaffected current smokers and COPD current smokers. Then, we assessed their miRNA expression by microarray analysis followed by real-time reverse transcription-polymerase chain reaction (RT-PCR) validation of particular miRNAs. Six and 96 miRNAs were expressed differentially in COPD T(reg) cells versus T(reg) cells of healthy non-smokers and healthy smokers, whereas no differences were found in miRNA expression in T(eff) cells. We found that miR-199a-5p was repressed by approximately fourfold in T(reg) cells of COPD patients compared to healthy smokers (P < 0·05). In addition, miR-199a-5p was over-expressed in T(reg) cells compared to Teff cells (P < 0·001) and had significant over-representation of its target genes in the T(reg) transcriptome, being associated with the transforming growth factor (TGF)-ß activation pathway (P < 0·01). We also confirmed the function of miR-199a5p in an in-vitro loss-of-function cell model running TaqMan® arrays of the human TGF-ß pathway. These findings suggest that the abnormal repression of miR-199a-5p in patients with COPD compared to unaffected smokers may be involved in modulating the adaptive immune balance in favour of a Th1 and Th17 response.

Low CD4/CD8 Ratio in Bronchus-Associated Lymphoid Tissue Is Associated with Lung Allograft Rejection.

Background. Bronchus-associated lymphoid tissue (BALT) has been associated with lung allograft rejection in rat transplant models. In human transplant recipients, BALT has not been linked to clinically significant rejection. We hypothesize that the immunohistochemical composition of BALT varies with the presence of acute lung allograft rejection. Methods. We retrospectively examined 40 human lung allograft recipients transplanted from 3/1/1999 to 6/1/2008. Patients were grouped by frequency and severity of acute rejection based on International Society of Heart Lung Transplant (ISHLT) criteria. Transbronchial biopsies were reviewed for BALT by a blinded pathologist. BALT if present was immunohistochemically stained to determine T-and B-cell subpopulations. Results. BALT presence was associated with an increased frequency of acute rejection episodes in the first year after transplantation. Patients with a lower CD4/CD8 ratio had an increased rejection rate; however, BALT size or densities of T-cell and B-cell subpopulations did not correlate with rejection rate. Conclusion. The presence of BALT is associated with an increased frequency of rejection one year after transplant. The lower the CD4/CD8 ratio, the more acute rejection episodes occur in the first year after transplantation. The immunohistochemical composition of BALT may predict patients prone to frequent episodes of acute cellular rejection.

Biologic lung volume reduction therapy for advanced homogeneous emphysema.

This report summarises phase 2 trial results of biologic lung volume reduction (BioLVR) for treatment of advanced homogeneous emphysema. BioLVR therapy was administered bronchoscopically to 25 patients with homogeneous emphysema in an open-labelled study. Eight patients received low dose (LD) treatment with 10 mL per site at eight subsegments; 17 received high dose (HD) treatment with 20 mL per site at eight subsegments. Safety was assessed in terms of medical complications during 6-month follow-up. Efficacy was assessed in terms of change from baseline in gas trapping, spirometry, diffusing capacity, exercise capacity, dyspnoea and health-related quality of life. There were no deaths or serious medical complications during the study. A statistically significant reduction in gas trapping was observed at 3-month follow-up among HD patients, but not LD patients. At 6 months, changes from baseline in forced expiratory volume in 1 s (-8.0+/-13.93% versus +13.8+/-20.26%), forced vital capacity (-3.9+/-9.41% versus +9.0+/-13.01%), residual volume/total lung capacity ratio (-1.4+/-13.82% versus -5.4+/-12.14%), dyspnoea scores (-0.4+/-1.27 versus -0.8+/-0.73 units) and St George's Respiratory Questionnaire total domain scores (-4.9+/-8.3 U versus -12.2+/-12.38 units) were better with HD than with LD therapy. BioLVR therapy with 20 mL per site at eight subsegmental sites may be a safe and effective therapy in patients with advanced homogeneous emphysema.

Prevalence and clinical correlates of bronchoreversibility in severe emphysema.

Chronic obstructive pulmonary disease (COPD) exhibits airflow obstruction that is not fully reversible. The importance of bronchoreversibility remains controversial. We hypothesised that an emphysematous phenotype of COPD would be associated with decreased bronchoreversibility. 544 patients randomised to the medical arm of the National Emphysema Treatment Trial formed the study group. Participants underwent multiple measurements of bronchoreversibility on a mean of four sessions over 1.91 yrs. They were also characterised by measures of symptoms, quality of life and quantitative measures of emphysema by computed tomography. Mean baseline forced expiratory volume in 1 s (FEV(1)) in this patient population is 24% predicted. 22.2% of patients demonstrated bronchoreversibility on one or more occasions using American Thoracic Society/European Respiratory Society criteria. Few patients (0.37%) had bronchoreversibility on all completed tests. Patients who demonstrated bronchoreversibility were more likely to be male, and have better lung function and less emphysema. 64% of patients demonstrated large (> or =400 mL) changes in forced vital capacity (FVC). In a severe emphysema population, bronchoreversibility as defined by change in FEV(1) is infrequent, varies over time, and is more common in males and those with less severe emphysema. Improvements in FVC, however, were demonstrated in the majority of patients.

Milk marketing policy options for the dairy industry in New England.

New England dairy farmers are under intense price pressure resulting from important growth in milk production from lower cost of production Southwest states as well as by retailers' market power. Agricultural officials and legislative bodies in New England and in other Northeast US states are aware of these pressures and have been reacting with emergency dairy farm aid, following a very low 2006 milk price, and with state legislations in an attempt to address perceived excess retailing margins for fluid milk. In this paper, we suggest that a sigmoid demand relationship exists for fluid milk. This demand relationship would explain fluid milk asymmetric price transmission, high-low pricing, and the creation of a large retailing margin (chain surplus) often observed for fluid milk. It is also argued that a sigmoid demand relationship offers an opportunity for state legislators to help Northeast dairy farmers capturing a larger share of the dollar of the consumers through various policy options. Therefore, 5 milk market channel regulatory mechanisms (status quo, price gouging, supply control, fair share policy, and chain surplus return) are discussed and compared. The supply control mechanism was found the most effective at redistributing the chain surplus, associated with the sigmoid demand relationship for fluid milk, to dairy farmers. However, this option is unlikely to be politically acceptable in the United States. Second-best options for increasing dairy farmers' share of the consumers' dollar are the fair price policy and the chain surplus return. The former mechanism would distribute the chain surplus between retailers, processors, and farmers, whereas the latter would distribute it between consumers, retailers, and farmers. Remaining mechanisms would either transfer the chain surplus to retailers (status quo) or to consumers (price gouging).

Estimating pulmonary artery pressures by echocardiography in patients with emphysema.

In patients with emphysema being evaluated for lung volume reduction surgery, Doppler echocardiography has been used to screen for pulmonary hypertension as an indicator of increased peri-operative risk. To determine the accuracy of this test, the present authors compared the results of right heart catheterisations and Doppler echocardiograms in 163 patients participating in the cardiovascular substudy of the National Emphysema Treatment Trial. Substudy patients had both catheterisation and Doppler echocardiography performed before and after randomisation. In 74 paired catheterisations and echocardiograms carried out on 63 patients, the mean values of invasively measured pulmonary artery systolic pressures and the estimated right ventricular systolic pressures were similar. However, using the World Health Organization's definitions of pulmonary hypertension, echocardiography had a sensitivity of 60%, specificity of 74%, positive predictive value of 68% and a negative predictive value of 67% compared with the invasive measurement. Bland-Altman analysis revealed a bias of 0.37 kPa with 95% limits of agreement from -2.5-3.2 kPa. In patients with severe emphysema, echocardiographic estimates of pulmonary artery pressures correlate very weakly with right heart catheterisations, and the test characteristics (e.g. sensitivity, specificity, etc.) of echocardiographic assessments are poor.

Weaning units: lessons from North America?

In the United Kingdom over 5% of critical care beds are occupied by stable patients weaning from mechanical ventilation. In North America, diagnosis related groups (DRGs) were introduced over a decade ago. These provided an economic impetus to develop more cost effective regional weaning centres. The imminent introduction of Payment By Results may encourage similar developments in the UK. The evidence for weaning centres is reviewed and detailed organisational and outcome data from two North American centres presented. These units differ from UK critical care units in terms of nurse : patient ratios and types and numbers of ancillary staff. Limited data, mostly from North America, suggest that weaning centres may be better at improving outcome in ventilator-dependent patients compared with standard critical care. The existing evidence is not conclusive and highlights the need for UK-based studies on organisational approaches to the provision of weaning and longer term critical care.

Discrepancy between severity of lung impairment and seniority on the lung transplantation list.

BACKGROUND: Organ allocation for lung transplantation, based mainly on accrued time on a waiting list, may not be an equitable system of organ allocation. To provide an objective view of the current practice concerning lung allocation, and timing for transplantation, we examined illness severity and list seniority in patients on a lung transplantation waiting list. METHODS: Adult patients awaiting lung transplantation underwent testing for mean pulmonary artery pressure (mPpa), maximum oxygen consumption (VO2 max), 6-minute walk distance (6MWD), forced expiratory volume in 1 second, mean partial pressure of carbon dioxide, partial pressure of oxygen/fractional concentration of inspired oxygen, and diffusing capacity of the lung for carbon monoxide. Relationships between physiological variables and waiting list rankings were then determined. RESULTS: Thirty-four patients were tested and there was no correlation between time spent waiting on the list and mPpa (r=0.01; P=.94), VO2 max percentage predicted (r=0.07; P=.71), or 6MWD (r=0.15; P=.42). Many patients with functional impairments as indicated by low maximum VO2 or by short 6MWD are scheduled to receive their transplant after patients with levels that indicate a lower degree of risk. When compared with a hypothetical reranking based on mean Ppa, 24 of the 34 patients (71%) on our current waiting list were found to be 5 positions higher or lower than this new risk-based ranking. Sixteen patients (47%) were 10 or more positions away from their hypothetical severity-based ranking, and 9 (26%) were at least 15 positions out of place. Sixteen of the 34 patients were ranked lower than they would be based on a severity of illness using the pulmonary artery pressure alone, 17 were ranked higher than "should be" based on pulmonary artery mean, and only 1 patient (ranked in position 15) was appropriately positioned based on seniority and severity of disease based on PA mean. CONCLUSION: Rank order for lung transplantation has no relationship with illness severity, and the discrepancy between disease severity and seniority on the lung waiting list may compromise overall outcomes in the lung transplantation population.

Fluid milk processing costs: current state and comparisons.

An economic-engineering model is used to derive the theoretically minimum cost of processing and distributing fluid white milk for the state of Maine. This model represents a state-of-the-art milk processing facility and is used to evaluate three questions: 1) the components of total processing costs; 2) whether the cost of milk processing declines with increasing plant size; and 3) the minimum processing volume to financially justify inplant blow-molding technology. The model indicates that significant savings in per-container processing costs can be achieved by increasing plant size. However, distribution costs, related to the geographical distribution of consumer demand and plant location in the state of Maine do not favor large centralized plants. In addition, this model is compared with results published in 1993 to evaluate cost trends over a 7-yr period. The model indicates import shifts to more technologically advanced processing equipment and a dramatic increase in labor costs. Overall, processing costs have risen 2.9% annually above the rate of inflation. Dairies that are unable to respond to increased labor costs through capital investment and expansion will likely find it more difficult to remain competitive in the milk processing industry.

Quality of life in survivors of prolonged mechanical ventilatory support.

OBJECTIVE: To examine the long-term quality of life (QOL) in a group of patients after prolonged mechanical ventilatory support. DESIGN: Prospective cohort study. SETTING: Outpatient follow-up. PATIENTS: Survivors of prolonged mechanical ventilatory support who were discharged from a ventilator rehabilitation unit (VRU). INTERVENTIONS: Measurement of health-related QOL using the Sickness Impact Profile (SIP). MEASUREMENTS AND MAIN RESULTS: Forty-six patients were contacted approximately 2 yrs after their discharge from the VRU and asked to complete the SIP. Twenty-five patients (age, 59 +/- 17 yrs; duration of mechanical ventilatory support, 45 +/- 36 days [mean +/- sd]) agreed to participate in this study and completed the SIP questionnaire 23 +/- 18 months after their discharge from the VRU. Patients' VRU stay was 29 +/- 21 days. Two patients were discharged with nocturnal ventilatory support, and the rest were completely weaned of mechanical ventilatory support before discharge. Fifteen patients (60%) were discharged to home, eight patients (32%) were discharged to a rehabilitation facility, and two patients (8%) were discharged to a skilled-care facility. Most patients had mild dysfunction, and the global SIP score was 12 +/- 10, the physical dimension score was 12 +/- 12, and the psychosocial dimension score was 9 +/- 11 (SIP scores range from 0 to 100, with higher scores indicating worse QOL). Subgroup analysis showed that postoperative patients had lower SIP scores compared with patients with chronic respiratory diseases (global SIP, 7 +/- 6 vs. 19 +/- 8; p <.05). Moreover, the patients in the postoperative group were older, but had similar SIP scores as patients who had acute lung injury (17 +/- 15). Global SIP scores correlated with age (r = -.40; p =.046), but not with duration of mechanical ventilatory support (r = -.23) or VRU admission Acute Physiology and Chronic Health Evaluation II scores (r = -.39; p =.06). CONCLUSIONS: In survivors of prolonged mechanical ventilatory support, using specific selection criteria shows that there is minimal impairment in the QOL at long-term follow-up. Although some patients continue to have moderate to severe limitations, it is the cause of respiratory failure and the underlying disease, rather than duration of ventilatory support, that have a significant impact on QOL.

Surgery for chronic obstructive pulmonary disease: the place for lung volume reduction and transplantation.

Lung volume reduction surgery and lung transplantation have been shown to improve lung function, exercise capacity, and quality of life in patients with advanced emphysema. Because the indications for both surgical procedures overlap, lung volume reduction surgery may be used as an alternative treatment or as a "bridge" to lung transplantation. In this article, we discuss patient selection, clinical outcome parameters, and the morbidity and mortality associated with each surgical procedure. We focus on the different preoperative predictors of good and poor outcomes after lung volume reduction surgery, the role of pulmonary rehabilitation, and the preferred surgical techniques for lung volume reduction surgery. An overview of the postoperative care of emphysema patients who undergo single-lung transplantation is also discussed.

Acute respiratory failure after lung volume reduction surgery.

In this study, we characterized patients who developed respiratory failure postoperatively after lung volume reduction surgery (LVRS). We retrospectively reviewed the records of 72 patients who underwent LVRS from February 1995 to February 1998, examining perioperative variables and complications. Twenty-one patients (29%) developed postoperative respiratory failure, five due to hypoxemia, nine due to hypercapnia, and seven secondary to hemodynamic instability. The hospital mortality was 33% among patients who developed respiratory failure. No preoperative clinical or physiologic variable (including percent ideal body weight, serum albumin, prednisone use, lung function, maximal O(2) uptake on exercise testing, 6-min walk distance, and hemodynamic parameters) was predictive of postoperative respiratory failure. Patients who developed respiratory failure were older (63 +/- 7 versus 57 +/- 8 yr, p = 0.01), had longer anesthesia time (188 +/- 96 versus 127 +/- 56 min, p = 0.001), had a higher incidence of coronary artery disease (40% versus 10%, p = 0.001) and performance of concomitant surgical procedures during the LVRS operation (40% versus 2%, p < 0.001) compared with those without respiratory failure. All patients who underwent simultaneous surgery, which were mostly for cardiac disease, developed respiratory failure. Risk factor analysis confirmed that older patients and those undergoing cardiac surgery combined with LVRS are at increased risk for postoperative respiratory failure.

Quantitation of regional ventilation during the washout phase of lung scintigraphy: measurement in patients with severe COPD before and after bilateral lung volume reduction surgery.

STUDY OBJECTIVES: We sought to investigate the effect of lung volume reduction surgery (LVRS) on regional lung ventilation. DESIGN: Retrospective analysis of routinely acquired data before and after LVRS. SETTING: Large, urban, university medical center. PATIENTS: Twenty-nine patients with severe emphysema. INTERVENTION: Bilateral LVRS. MEASUREMENTS AND RESULTS: (133)Xe washout curves during lung scintigraphy exhibit a biphasic pattern (the first component of the washout curve [m(r)] corresponds to an initial rapid phase in washout that reflects larger airways emptying, and the second component [m(s)] reflects a slower phase of washout that is attributed to gas elimination via smaller airways). We analyzed six standardized regions of the lung (upper, mid, and lower zones of the right and left lung), and calculated m(r) and m(s) for each lung region. The mean (+/- SE) baseline FEV(1) was 0.69+/-0.04 L, total lung capacity (TLC) was 139 +/-4% predicted, and the residual volume (RV)/TLC ratio was 65+/-2%. The mean improvement in FEV(1) 3 months post-LVRS was 38%. Post-LVRS, m(r) and m(s) increased in 79 and 74 lung regions, respectively, and there was no relationship with respect to lung regions that had or had not been operated on. The increase in m(s), however, significantly correlated with the increase in FEV(1) (r = 0.66; p<0.0001) and the decrease in RV/TLC (r = -0.67; p<0.0001). An increase in m(s) also correlated with a decrease in PaCO(2) (r = -0.39; p = 0.03), but m(r) showed no relationship with any parameter. CONCLUSIONS: Small airways ventilation in lung regions that had and had not been operated on is associated with a greater improvement in lung mechanics following LVRS.

Correlation of changes in quality of life after lung volume reduction surgery with changes in lung function, exercise, and gas exchange.

STUDY OBJECTIVES: To evaluate correlations between improvement in quality of life (QOL) in patients with severe COPD before and after they undergo lung volume reduction surgery (LVRS) with changes in pulmonary function tests, gas exchange, exercise performance, and alterations in medical management. DESIGN: Case-series analysis. SETTING: University hospital. PATIENTS: Forty-two patients (mean [+/- SD] age, 56+/-8 years; 53% women) with severe airflow obstruction (FEV(1), 0.62+/-0.2 L), and moderate to severe hyperinflation (total lung capacity [TLC], 6.9+/-1.7 L). INTERVENTION AND MEASUREMENTS: All patients underwent bilateral LVRS via median sternotomy. Measurements of lung function, symptom-limited cardiopulmonary exercise testing, the total distance the patient was able to walk in 6 min in a corridor, and sickness impact profile (SIP) scores were made before and 3 months after LVRS. SIP scores are inversely proportional to the level of function and QOL. RESULTS: Compared to baseline, FEV(1) increased (0.87+/-0.3 vs. 0.62+/-0.2 L, respectively; p<0.01) while residual volume significantly decreased (3.2+/-1.8 vs. 6.3+/-1.2 L, respectively; p<0.004) at 3 months post-LVRS. On cardiopulmonary exercise testing, values increased from baseline to post-LVRS for total exercise time (9.0+/-2.2 vs. 6.0+/-1.5 min, respectively; p = 0.045), maximum oxygen uptake (VO(2)) (16+/-3 vs. 11+/-2 mL/kg/min, respectively; p = 0.01), and maximum minute ventilation (VE) (33+/-9 vs. 28+/-5 L/min, respectively; p = 0.03). The percentage change in the oxygen cost of breathing (VO2/VE ratio) from low to high workloads during exercise was significantly lower after LVRS (p = 0.002). There was no significant change in oxygenation after LVRS (PaO(2)/fraction of inspired oxygen, 331+/-27 vs. 337+/-39, respectively; p = 0.76), but PaCO(2) tended to be lower (41+/-9 vs. 48+/-6 mm Hg, respectively; p = 0.07). Overall SIP scores were significantly lower after LVRS than before (8+/-4 vs. 15+/-2, respectively; p = 0.002). Changes in SIP scores correlated with the change in VO2/VE ratio from low to high workloads, with patients having the smallest changes in VO2/VE ratio having the smallest changes in SIP scores after LVRS (r = 0.6; p = 0.01). Improved or lower SIP scores also tended to correlate with a reduction in residual volume/TLC ratio (r = 0.45; p = 0.09), and there was a linear correlation with a statistically significant Pearson r value with decreased steroid requirements (r = 0.7; p = 0.001). Moreover, changes in psychological SIP subscore tended to correlate with diminished oxygen requirements post-LVRS (r = 0.45; p = 0.09). However, there was no significant correlation between changes in SIP scores and routine measurements of lung function, exercise performance, or gas exchange. CONCLUSION: There is an association between an improvement in QOL and reduced hyperinflation after LVRS. Reduced hyperinflation may lead to more efficient work of breathing during exercise and, therefore, to an increased ability to perform daily activities. Changes in QOL scores correlate best with behaviorally based variables that directly affect the patient's well-being, such as systemic steroid administration.

Effects of long-term oxygen therapy on mortality and morbidity.

In general, based on the above studies of the effects of supplemental oxygen on reducing mortality and improving sleep and exercise function in certain patient groups, patients whose disease is stable on a full medical regimen with PaO2 < or = 55 mm Hg (SaO2 < or = 88%) should be considered for LTOT. Patients with PaO2 of 55-59 mm Hg with signs of tissue hypoxemia (i.e., cor pulmonale, polycythemia, impaired cognition) should also be considered for LTOT. Oxygen therapy should also be considered for those who desaturate during sleep or exercise. These guidelines have been adopted by Medicare as reimbursement criteria and have also been endorsed by the American Thoracic Society. Indications for LTOT endorsed by the American Thoracic Society and published in the "Standards for the Diagnosis and Care of Patients with COPD" are shown in Table 6. More research is required to investigate the use of supplemental oxygen in patients who suffer nocturnal desaturation but do not have signs of end organ dysfunction, those who have an improvement in dyspnea with supplemental oxygen, and in normoxemic patients with impaired exercise performance who improve while inspiring supplemental oxygen.