Survival after inpatient or outpatient pulmonary rehabilitation in patients with fibrotic interstitial lung disease: a multicentre retrospective cohort study.

BACKGROUND: The impact of pulmonary rehabilitation (PR) on survival in patients with fibrotic interstitial lung disease (ILD) is unknown. Given the challenges conducting a large randomised controlled trial, we aimed to determine whether improvement in 6-minute walk distance (6MWD) was associated with better survival. METHODS: This retrospective, international cohort study included patients with fibrotic ILD participating in either inpatient or outpatient PR at 12 sites in 5 countries. Multivariable models were used to estimate the association between change in 6MWD and time to death or lung transplantation accounting for clustering by centre and other confounders. RESULTS: 701 participants (445 men and 256 women) with fibrotic ILD were included. The mean±SD ages of the 196 inpatients and 505 outpatients were 70±11 and 69±12 years, respectively. Baseline/changes in 6MWD were 262±128/55±83 m for inpatients and 358±125/34±65 m for outpatients. Improvement in 6MWD during PR was associated with lower hazard rates for death or lung transplant on adjusted analysis for both inpatient (HR per 10 m 0.94, 95% CI 0.91 to 0.97, p<0.001) and outpatient PR (HR 0.97, 95% CI 0.95 to 1.00, p=0.042). Participation in ≥80% of planned outpatient PR sessions was associated with a 33% lower risk of death (95% CI 0.49% to 0.92%). CONCLUSIONS: Patients with fibrotic ILD who improved physical performance during PR had better survival compared with those who did not improve performance. Confirmation of these hypothesis-generating findings in a randomised controlled trial would be required to definitely change clinical practice, and would further support efforts to improve availability of PR for patients with fibrotic ILD.

Cardiovascular Outcomes and All-Cause Mortality in Patients with Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease (Overlap Syndrome).

RATIONALE: The combined impact of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) on cardiovascular outcomes remains controversial. OBJECTIVES: We determined whether the combined presence of COPD and severe OSA defined by the apnea-hypopnea index (AHI) or degree of nocturnal hypoxemia is associated with increased hazards of cardiovascular events and mortality. METHODS: Prospectively collected data from adults with suspected OSA who underwent sleep study between 1994 and 2010 were linked to provincial administrative data to determine a presence of COPD and composite outcome. Exposures of interest were: 1) AHI greater than 30, and 2) 10 or more minutes of sleep time spent with oxygen saturation (SaO2) less than 90%. The primary outcome was a composite of hospitalization due to myocardial infarction, stroke, congestive heart failure, cardiac revascularization procedures, or death from any cause. Using Cox regression and controlling for confounders, hazards were compared between four groups: AHI greater than 30 with COPD, AHI greater than 30 without COPD, AHI less than or equal to 30 with COPD, and AHI less than or equal to 30 without COPD (reference). A similar approach was used for the degree of nocturnal hypoxemia. Relative excess risk due to interaction (RERI) was calculated. To adjust for the effect of positive airway pressure treatment, given that information on its acceptance, but not adherence, was available, a separate analysis was conducted only on untreated individuals who never claimed a positive airway pressure device. RESULTS: Among 10,149 participants, 30% had AHI greater than 30, 25% spent at least 10 minutes of sleep with SaO2 less than 90%, and 12% had COPD. Over a median of 9.4 years, 16.4% developed an outcome. In the total sample, a greater hazard of outcome was observed in individuals with COPD who spent at least 10 minutes of sleep with SaO2 less than 90% (hazard ratio, 1.91; 95% confidence interval [CI], 1.60 to 2.28) but not with AHI greater than 30; a synergistic effect was found in women (RERI, 1.18; 95% CI, 0.05 to 2.30), but not men (RERI, -0.08; 95% CI, -0.47 to 0.32). The highest hazard of outcome was associated with the co-occurrence of AHI greater than 30 and COPD in untreated individuals (hazard ratio, 2.01; 95% CI, 1.55 to 2.62); a synergistic effect was not found. CONCLUSIONS: In adults with suspected OSA, the co-occurrence of nocturnal hypoxemia and COPD was associated with an increased hazard of cardiovascular events and mortality with a synergistic effect found only in women.

Magnitude of exercise capacity and quality of life improvement following repeat pulmonary rehabilitation in patients with COPD.

BACKGROUND: Maintenance and repeated pulmonary rehabilitation programs (PRPs) for patients with COPD have attempted to prolong PRP benefits beyond 12-24 months. However, there is limited evidence as to the magnitude of benefit or the ideal interval between repeating the program under "real-world" conditions in which patients are referred based on clinical necessity. Therefore, we reviewed the effects of repeating PRP in a physician-referred cohort of patients with COPD. METHODS: A total of 141 individuals with COPD completed PRP twice and 35 completed PRP three times over a 12-year period. We used linear mixed-effects models to quantify the magnitude and change in 6-minute walk distance (6MWD), St George's Respiratory Questionnaire (SGRQ), and Hospital Anxiety and Depression Scale (HADS) for each PRP. One-way analysis of variance with Tukey's post hoc analysis compared the effects of different time intervals on 6MWD, SGRQ, and HADS between PRPs. RESULTS: Despite 39 mL/year average decrease in forced expiratory volume in 1 second, overall 6MWD improved following each PRP (PRP1=58 m, P<0.0001; PRP2=42 m, P<0.0001; PRP3=32 m, P<0.003). Mean SGRQ decreased after PRP1 (-7.0 units; P<0.001) and PRP2 (-4.9 units; P<0.0001) but not after PRP3 (-3.2 units; P=0.10). HADS decreased after PRP1 (-1.9 units; P<0.0001) and PRP2 (-1.7 units; P=0.0001) but not after PRP3 (-0.4 units; P=0.63). CONCLUSION: In physician-referred patients who underwent repeat PRP as clinically required, there were clear benefits in functional exercise capacity following each repeat PRP, which was not affected by the time interval between PRPs. Health-related quality of life and mood improved after the first two PRPs, but not after a third.

Oxygen desaturation and adverse events during 6-min walk testing in patients with COPD.

BACKGROUND AND OBJECTIVE: The 6-min walk test (6MWT) is a simple test assessing functional capacity, but concerns about risks of substantial oxygen desaturation in pulmonary patients have led to non-adherence to the standardised American Thoracic Society guideline. We evaluated the safety of the 6MWT in stable COPD patients and compared the incidence of adverse events in patients with and without substantial exertional hypoxaemia. METHODS: 6MWT data were obtained for 1136 patients with moderate to very severe COPD. Demographics, adverse events, oxygen saturation (SpO2), 6-min walk distance, lung function and quality of life measures were compared between patients with substantial exertional hypoxaemia (nadir SpO2 < 85%) and those without (SpO2 ≥ 85%). Comparisons were made using Mann-Whitney U-test for continuous variables and Fisher's exact test for categorical variables. RESULTS: Twenty-five patients (2.2%) had adverse events, the most common being dizziness, chest tightness, chest pain and palpitations. Substantial exertional hypoxaemia did not increase the incidence of adverse events. No significant morbidity or mortality was recorded. Patients with adverse events had lower baseline SpO2, worse quality of life scores, and higher depression and anxiety scores. However, no significant differences were seen in anthropometric data, spirometric values or SpO2 during and after the 6MWT. CONCLUSIONS: Asymptomatic exertional hypoxaemia is not associated with an increased incidence of adverse events during 6MWT in COPD patients. Our data support the ATS guideline that the 6MWT should be continued in the absence of symptoms and that intermittent oximetry monitoring does not assist in preventing adverse events.

Bin1 SRC homology 3 domain acts as a scaffold for myofiber sarcomere assembly.

In skeletal muscle development, the genes and regulatory factors that govern the specification of myocytes are well described. Despite this knowledge, the mechanisms that regulate the coordinated assembly of myofiber proteins into the functional contractile unit or sarcomere remain undefined. Here we explored the hypothesis that modular domain proteins such as Bin1 coordinate protein interactions to promote sarcomere formation. We demonstrate that Bin1 facilitates sarcomere organization through protein-protein interactions as mediated by the Src homology 3 (SH3) domain. We observed a profound disorder in myofiber size and structural organization in a murine model expressing the Bin1 SH3 region. In addition, satellite cell-derived myogenesis was limited despite the accumulation of skeletal muscle-specific proteins. Our experiments revealed that the Bin1 SH3 domain formed transient protein complexes with both actin and myosin filaments and the pro-myogenic kinase Cdk5. Bin1 also associated with a Cdk5 phosphorylation domain of titin. Collectively, these observations suggest that Bin1 displays protein scaffold-like properties and binds with sarcomeric factors important in directing sarcomere protein assembly and myofiber maturation.