Muscle loss phenotype in COPD is associated with adverse outcomes in the UK Biobank.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with systemic consequences that can cause a muscle loss phenotype (MLP), which is characterized by the loss of muscle mass, muscle strength, or loss of both muscle and fat mass. There are limited data comparing the individual traits of MLP with clinical outcomes in a large unbiased cohort of COPD patients. Our aim was to determine the proportion of patients who met criteria for MLP in an unbiased sample of COPD patients at the population-level. We also determined if specific MLP features were associated with all-cause and COPD-related mortality. METHODS: A retrospective population-based cohort analysis of the UK Biobank was performed. COPD was defined by a FEV1/FVC ratio < 0.7, physician established diagnosis of COPD, or those with a COPD-related hospitalization before baseline assessment. MLP included one or more of the following: 1) Low fat-free mass index (FFMI) on bioelectric impedance analysis (BIA) or 2) Appendicular skeletal muscle index (ASMI) on BIA, 3) Low muscle strength defined by handgrip strength (HGS), or 4) Low muscle and fat mass based on body mass index (BMI). Cox regression was used to determine the association between MLP and all-cause or COPD-related mortality. All models were adjusted for sex, age at assessment, ethnicity, BMI, alcohol use, smoking status, prior cancer diagnosis and FEV1/FVC ratio. RESULTS: There were 55,782 subjects (56% male) with COPD followed for a median of 70.1 months with a mean(± SD) age at assessment of 59 ± 7.5 years, and FEV1% of 79.2 ± 18.5. Most subjects had mild (50.4%) or moderate (42.8%) COPD. Many patients had evidence of a MLP, which was present in 53.4% of COPD patients (34% by ASMI, 26% by HGS). Of the 5,608 deaths in patients diagnosed with COPD, 907 were COPD-related. After multivariate adjustment, COPD subjects with MLP had a 30% higher hazard-ratio for all-cause death and 70% higher hazard-ratio for COPD-related death. CONCLUSIONS: Evidence of MLP is common in a large population-based cohort of COPD and is associated with higher risk for all-cause and COPD-related mortality.

Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease.

BACKGROUND: Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age-related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD. METHODS: To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome-wide association study (GWAS) of fat free mass index (FFMI) in 32 426 non-Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity-associated (FTO) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (n = 3656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes. RESULTS: Multiple SNPs located in the FTO gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene AC090771.2, which transcribes long non-coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A > T in the FTO gene (ß = 0.151, SE = 0.021, P = 1.40 × 10-12 for UK Biobank |ß= 0.220, SE = 0.041, P = 9.99 × 10-8 for COPDGene) and chr 18 SNP rs11664369C > T nearest to the AC090771.2 gene (ß = 0.129, SE = 0.024, P = 4.64 × 10-8 for UK Biobank |ß = 0.203, SE = 0.045, P = 6.38 × 10-6 for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of FTO lowered myotube diameter and induced a senescence-associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia. CONCLUSIONS: Genetic polymorphisms of FTO and AC090771.2 were associated with sarcopenia in COPD in independent cohorts. Knockdown of FTO in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD.

Quantitative Computed Tomography Assessment of Pectoralis and Erector Spinae Muscle Area and Disease Severity in Chronic Obstructive Pulmonary Disease Referred for Lung Volume Reduction.

Patients with advanced chronic obstructive pulmonary disease (COPD) develop skeletal muscle loss (sarcopenia) that is associated with adverse clinical outcomes including mortality. We evaluated if thoracic muscle area is associated with clinical outcomes in patients with severe COPD. We analyzed consecutive patients with severe COPD undergoing evaluation for lung volume reduction from 2015 to 2019 (n = 117) compared to current and former smoking controls undergoing lung cancer screening with normal lung function (n = 41). Quantitative assessments of pectoralis muscle (PM) and erector spinae muscle (ESM) cross sectional area (CSA) were related to clinical outcomes including composite endpoints. Our results showed a reduction in PM CSA but not ESM CSA was associated with the severity of GOLD stage of COPD. Current smokers demonstrated reduced PM CSA which was similar to that in COPD patients who were GOLD stages 3 and 4. PM CSA was associated positively with FEV1, FEV1% predicted, FVC, DLCO, and FEV1/FVC ratio, and was associated negatively with the degree of radiologic emphysema. ESM correlated positively with DLCO, RV/TLC (a marker of hyperinflation), and correlated negatively with radiologic severity of emphysema. Kaplan-Meier analysis showed that reductions in PM but not ESM CSA was associated with the composite end point of mortality, need for lung volume reduction, or lung transplant. In conclusion, in well-characterized patients with severe COPD referred for lung volume reduction, PM CSA correlated with severity of lung disease, mortality, and need for advanced therapies. In addition to predicting clinical outcomes, targeting sarcopenia is a potential therapeutic approach in patients with severe COPD.

Muscle loss contributes to higher morbidity and mortality in COPD: An analysis of national trends.

BACKGROUND AND OBJECTIVE: COPD is the third most common cause of death worldwide and fourth most common in the United States. In hospitalized patients with COPD, mortality, morbidity and healthcare resource utilization are high. Skeletal muscle loss is frequent in patients with COPD. However, the impact of muscle loss on adverse outcomes has not been systematically evaluated. We tested the hypothesis that patients hospitalized for COPD exacerbation with, compared to those without, a secondary diagnosis of muscle loss phenotype (all ICD-9 codes associated with muscle loss including cachexia) will have higher mortality and cost of care. METHODS: The NIS database of hospitalized patients in 2011 (1 January-31 December) in the United States was used. The impact of a muscle loss phenotype on in-hospital mortality, LOS and cost of care for each of the 174 808 hospitalizations for COPD exacerbations was analysed. RESULTS: Of the subjects admitted for a COPD exacerbation, 12 977 (7.4%) had a secondary diagnosis of muscle loss phenotype. A diagnosis of muscle loss phenotype was associated with significantly higher in-hospital mortality (14.6% vs 5.7%, P < 0.001), LOS (13.3 + 17.1 vs 5.7 + 7.6, P < 0.001) and median hospital charge per patient ($13 947 vs $6610, P < 0.001). Multivariate regression analysis showed that muscle loss phenotype increased mortality by 111% (95% CI: 2.0-2.2, P < 0.001), LOS by 68.4% (P < 0.001) and the direct cost of care by 83.7% (P < 0.001) compared to those without muscle loss. CONCLUSION: In-hospital mortality, LOS and healthcare costs are higher in patients with COPD exacerbations and a muscle loss phenotype.

Implementation of Protocolized Care in ARDS Improves Outcomes.

BACKGROUND: Treatments for ARDS that improve patient outcomes include use of lung-protective ventilation, prone ventilation, and conservative fluid management. Implementation of ARDS protocols via educational programs might improve adherence and outcomes. The objective of this study was to investigate the effects of an ARDS protocol implementation on outcomes and adherence with ARDS guidelines. METHODS: This was a single-center, interventional, comparative study before and after protocol implementation. Staff education for the ARDS protocol was implemented between June 2014 and May 2015. A retrospective cohort analysis was conducted during between January 2012 and May 2014 (pre-protocol) and between June 2015 and June 2017 (post-protocol). A total of 450 subjects with ARDS were included. After propensity score matching, 432 subjects were analyzed. Of those, 330 subjects were treated after protocol implementation. RESULTS: The median (interquartile range [IQR]) plateau pressure and tidal volume over the first 3 d decreased significantly after protocol implementation (30.5 [IQR 24.2-33] vs 25.5 [IQR 21.7-30], P = .01 and 7.65 vs 7.4 mL/kg predicted body weight, P = .032, respectively). The percentage of subjects with unsafe tidal volume (> 10 mL/kg predicted body weight) decreased (14.4% vs 5.8%, P = .02). The percentage of subjects with safe plateau pressure (≤ 30 cm H2O) increased (47.4% vs 76.5%, P < .001). PEEP deviation from the ARDSNet PEEP/[Formula: see text] table was significantly lower after the implementation. Mortality at 28 and 90 days improved after implementation (53.9% vs 41.8% and 61.8% vs 48.2%, respectively). Adjusted odds ratios for 28-d and 90-d mortality were 0.47 (95% CI 0.28-0.78) and 0.45 (95% CI 0.27-0.76), respectively. CONCLUSIONS: ARDS protocol implementation was associated with improved survival and rate of adherence.

Lower lobe lung volume reduction surgery: a case report.

Lung volume reduction surgery (LVRS) is an option for select patients with advanced chronic obstructive pulmonary disease (COPD). Current guidelines recommend LVRS for patients with appropriate physiology and heterogeneous distribution of emphysema predominately involving upper lobes. We present an unusual case of a 72-year-old male with an advanced COPD who suffered with recurrent exacerbations despite optimal medical management. He underwent a two-stage bilateral lower lobe LVRS for heterogeneous lower lobe emphysema via video-assisted thoracoscopic (VATS) approach. This resulted in a significant subjective as well as objective improvement in his pulmonary functions, 6-min walk distance and subsequent discontinuation of supplemental oxygen.

Bronchoscopic lung volume reduction with valves: What should the internist know?

Traditional therapies for emphysema such as bronchodilators and anti-inflammatory drugs have limited value due to permanent structural changes in the emphysematous lung that result in hyperinflation. Surgical lung volume reduction partially corrects hyperinflation by removing emphysematous lung and is an option in selected patients, but it carries a risk of morbidity and death. Valve therapy is a less-invasive option that involves bronchoscopic implantation of 1-way valves in emphysematous lung segments to allow air flow and mucus clearance in the direction of central airways. The authors review the rationale, evidence, and applications of valve therapy.

Repair of iatrogenic pulmonary vein occlusion with a vascularized atrial flap.

Pulmonary vein obstruction is a rare condition, most commonly reported following pulmonary vein catheter ablation for atrial arrhythmia. This novel technique for treatment of pulmonary venous obstruction has the advantage of utilizing an autologous vascularized flap with intact endothelium for reconstruction of the pulmonary vein and to prevent restenosis.

Predictors of Response to Endobronchial Coil Therapy in Patients With Advanced Emphysema.

BACKGROUND: The Lung Volume Reduction Coil Treatment in Patients With Emphysema (RENEW) trial reported improvements in quality of life, pulmonary function, and exercise performance following endobronchial coil treatment. OBJECTIVES: The purpose of this post hoc analysis was to identify baseline predictors, including quantitative CT measures, that identify patients most likely to significantly benefit from endobronchial coil therapy. METHODS: Quantitative CT analysis by an independent radiology laboratory and a qualitative evaluation by five blinded experts of the baseline thoracic CT imaging were performed. Univariate and multivariate logistic regression analyses were performed to elucidate characteristics associated with clinical response. RESULTS: In total, 125 patients underwent coil treatment and had evaluable 12-month follow-up results. Of these, 78 patients received treatment of lobes with the highest emphysematous destruction determined by quantitative CT analysis (quantitative visual match [QVM]+), and 47 received treatment in at least one lobe that was not the most destroyed (QVM-). From the 78 patients with QVM+ treatment, a subgroup of 50 patients (64%) was identified with baseline residual volume > 200% predicted, emphysema score > 20% low attenuation area, and absence of airway disease. In this subgroup, greater lobar residual volume reduction in the treated lobes was achieved, which was associated with significant mean ± SE improvement in FEV1 (15.2 ± 3.1%), St. George's Respiratory Questionnaire (-12 ± 2 points), and residual volume (-0.57 ± 0.13 L). DISCUSSION: This post hoc analysis found that both significant hyperinflation (residual volume ≥ 200% predicted) and CT analysis are critical for patient selection and treatment planning for endobronchial coil therapy. Quantitative CT analysis is important to identify optimal lobar treatment and to exclude patients with insufficient emphysema (< 20% low attenuation area), whereas visual assessment identifies patients with signs of airway disease associated with worse outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01608490; URL: www.clinicaltrials.gov.

Supplemental oxygen in patients with stable chronic obstructive pulmonary disease: evidence from Nocturnal Oxygen Treatment Trial to Long-term Oxygen Treatment Trial.

PURPOSE OF REVIEW: Oxygen therapy was the first treatment shown to prolong life in patients with chronic obstructive pulmonary disease (COPD) and has been joined by lung volume reduction surgery in selected patients with emphysema, smoking cessation, and potentially noninvasive ventilation in chronic hypercapneic respiratory failure. Although there is consensus around the survival-enhancing effect of supplemental oxygen (SupplO2) for patients with chronic severe hypoxemia at rest, the impact of SupplO2 for COPD patients with moderate hypoxemia and exertional desaturation had been less clear. RECENT FINDINGS: The recently published Long-term Oxygen Treatment Trial (LOTT) showed no benefit of SupplO2 for the composite outcome of survival and all-cause hospitalizations, or for component outcomes, severe COPD exacerbations, or quality of life in COPD patients with moderate resting hypoxemia or room air normoxemia with exercise desaturation. SUMMARY: Results of the LOTT challenge the practice of prescribing SupplO2 for patients with COPD and moderate resting hypoxemia or isolated exertional desaturation. In the context that LOTT may not have recruited patients for whom SupplO2 conferred subjective benefit, there may be a role for short-term trials of SupplO2 with assessment of subjective benefit in such patients.

α1-Antitrypsin Deficiency.

α1-Antitrypsin deficiency is an autosomal codominant condition that predisposes to emphysema and cirrhosis. The condition is common but grossly under-recognized. Identifying patients' α1-antitrypsin deficiency has important management implications (ie, smoking cessation, genetic and occupational counseling, and specific treatment with the infusion of pooled human plasma α1-antitrypsin). The weight of evidence suggests that augmentation therapy slows the progression of emphysema in individuals with severe α1-antitrypsin deficiency.

Hyperinflation on chest radiograph as a marker of low adherence to positive airway pressure therapy in the overlap syndrome.

BACKGROUND: Positive airway pressure (PAP) in subjects with both obstructive sleep apnea and COPD reduces the risk of pulmonary hypertension, death, and hospitalizations from COPD exacerbations, but adherence to the intervention is low, similar to the experience with noninvasive ventilation in stable COPD. We sought to assess whether hyperinflation on chest radiographs contributes to low adherence to PAP therapy in the overlap syndrome. METHODS: Records of patients with a listed diagnosis of COPD at the time of polysomnography were reviewed. Overlap syndrome was diagnosed when COPD was clinically confirmed with spirometry showing a fixed airway obstruction and when the apnea-hypopnea index was ≥ 5. Hyperinflation was evaluated by a review of the right diaphragm height on a lateral chest radiograph. Adherence was assessed clinically or through device download at a 3-month follow-up, and later adherence was assessed by telephone interviews. A receiver operating curve was used to determine whether diaphragm height was associated with adherence. RESULTS: Twenty-one of 41 subjects (51%) were considered adherent to PAP therapy at the 3-month visit. Adherent subjects were more overweight compared with non-adherent subjects (body mass index of 36.0 ± 5.7 vs 32.0 ± 5.7 kg/m(2), P = .03), sleepier at the onset (Epworth sleepiness scale score of 13.0 ± 5.8 vs 9.4 ± 5.4, P < .05), and less likely to have hyperinflation as defined by a right diaphragm height ≤ 2.45 cm (33% vs 65%, P = .04). The body mass index and initial sleepiness no longer predicted adherence beyond 3 months, but 35% of subjects with a right diaphragm height ≤ 2.45 cm were adherent beyond 3 months compared with 75% of those with a right diaphragm height > 2.45 cm (P = .04 by Fisher exact test). CONCLUSIONS: Hyperinflation is associated with decreased adherence to PAP therapy in the overlap syndrome.

An older patient with bilateral non-traumatic haemothoraces.

This is the case of a patient who presented with bilateral spontaneous haemothoraces. Video-assisted thoracoscopic surgery was performed bilaterally to evacuate the haemothorax and perform biopsies. The patient was diagnosed with bilateral malignant epithelioid hemangioendothelioma of the pleura and pericardium. To our knowledge, this is the first description of bilateral malignant epithelioid hemangioendothelioma of the pleura presenting with haemothoraces and without obvious pulmonary involvement. Malignant epithelioid hemangioendothelioma is a rare form of malignancy that can present with unilateral or bilateral haemothoraces.

Clinically significant variability of serum IgE concentrations in patients with severe asthma.

OBJECTIVE: To determine the magnitude of immunoglobulin E (IgE) variability in a cohort of patients with severe asthma considered for omalizumab therapy. METHODS: Retrospective chart review identified 65 patients with two or more IgE determinations out of the 124 patients referred to the Cleveland Clinic Respiratory Institute for treatment with omalizumab from 2003 to 2011. Patients with conditions known to affect IgE concentrations were excluded. Demographic data, pulmonary function testing, medications, smoking status, and atopy were recorded. The range of variability and percent variability in relation to baseline serum IgE were calculated. RESULTS: The median difference of serum IgE between the minimal and maximal values was 94.9 IU/ml (IQR 26.3-324.1 IU/ml). Percent variability from minimum value had a median of 75.5% (IQR 23.3-152.6%). There was no correlation between age, body mass index, lung function, and IgE variability. Greater variability was associated with female gender (p = .06). There was no association with peripheral eosinophilia, systemic corticosteroid use, and leukotriene modifier use at presentation. The observed variability would have affected omalizumab dosing in 20 out of 42 patients. Six patients who may have qualified at different time points would not have been deemed candidates based on an IgE concentration <30 IU/ml or >700 IU/ml. CONCLUSION: Serum IgE concentration may have clinically significant variability over time, affecting candidacy and dosing of omalizumab. Our findings imply that repeating serum IgE determinations merits consideration for patients whose initial concentrations are <30 or >700 IU/ml. Prospective studies are warranted to delineate the factors that contribute to IgE variability.