Jose M. Marin

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2007 and 2011 staging systems: a pooled analysis of individual patient data

BACKGROUNDnThere is no universal consensus on the best staging system for chronic obstructive pulmonary disease (COPD). Although documents (eg, the Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2007) have traditionally used forced expiratory volume in 1 s (FEV1) for staging, clinical parameters have been added to some guidelines (eg, GOLD 2011) to improve patient management. As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aimed to investigate how individual patients were categorised by GOLD 2007 and 2011, and compare the prognostic accuracy of the staging documents for mortality.nnnMETHODSnWe searched reports published from Jan 1, 2008, to Dec 31, 2014. Using data from cohorts that agreed to participate and had a minimum amount of information needed for GOLD 2007 and 2011, we did a patient-based pooled analysis of existing data. With use of raw data, we recalculated all participant assignments to GOLD 2007 I-IV classes, and GOLD 2011 A-D stages. We used survival analysis, C statistics, and non-parametric regression to model time-to-death data and compare GOLD 2007 and GOLD 2011 staging systems to predict mortality.nnnFINDINGSnWe collected individual data for 15u2008632 patients from 22 COPD cohorts from seven countries, totalling 70u2008184 person-years. Mean age of the patients was 63·9 years (SD 10·1); 10u2008751 (69%) were men. Based on FEV1 alone (GOLD 2007), 2424 (16%) patients had mild (I), 7142 (46%) moderate (II), 4346 (28%) severe (III), and 1670 (11%) very severe (IV) disease. We compared staging with the GOLD 2007 document with that of the new GOLD 2011 system in 14u2008660 patients: 5548 (38%) were grade A, 2733 (19%) were grade B, 1835 (13%) were grade C, and 4544 (31%) were grade D. GOLD 2011 shifted the overall COPD severity distribution to more severe categories. There were nearly three times more COPD patients in stage D than in former stage IV (p<0·05). The predictive capacity for survival up to 10 years was significant for both systems (p<0·01) but area under the curves were only 0·623 (GOLD 2007) and 0·634 (GOLD 2011), and GOLD 2007 and 2011 did not differ significantly. We identified the percent predicted FEV1 thresholds of 85%, 55% and 35% as better to stage COPD severity for mortality, which are similar to the ones used previously.nnnINTERPRETATIONnNeither GOLD COPD classification schemes have sufficient discriminatory power to be used clinically for risk classification at the individual level to predict total mortality for 3 years of follow-up and onwards. Increasing intensity of treatment of patients with COPD due to their GOLD 2011 reclassification is not known to improve health outcomes. Evidence-based thresholds should be searched when exploring the prognostic ability of current and new COPD multicomponent indices.nnnFUNDINGnNone.

Protective Cardiovascular Effect of Sleep Apnea Severity in Obesity Hypoventilation Syndrome

BACKGROUNDnObesity hypoventilation syndrome (OHS) is associated with a high burden of cardiovascular morbidity (CVM) and mortality. The majority of patients with OHS have concomitant OSA, but there is a paucity of data on the association between CVM and OSA severity in patients with OHS. The objective of our study was to assess the association between CVM and OSA severity in a large cohort of patients with OHS.nnnMETHODSnIn a cross-sectional analysis, we examined the association between OSA severity based on tertiles of oxygen desaturation index (ODI) and CVM in 302 patients with OHS. Logistic regression models were constructed to quantify the independent association between OSA severity and prevalent CVM after adjusting for various important confounders.nnnRESULTSnThe prevalence of CVM decreased significantly with increasing severity of OSA based on ODI as a continuous variable or ODI tertiles. This inverse relationship between OSA severity and prevalence of CVM was seen in the highest ODI tertile and it persisted despite adjustment for multiple confounders. Chronic heart failure had the strongest negative association with the highest ODI tertile. No significant CVM risk change was observed between the first and second ODI tertiles. Patients in the highest ODI tertile were younger, predominantly male, more obese, more hypersomnolent, had worse nocturnal and daytime gas exchange, lower prevalence of hypertension, better exercise tolerance, and fewer days hospitalized than patients in the lowest ODI tertile.nnnCONCLUSIONSnIn patients with OHS, the highest OSA severity phenotype was associated with reduced risk of CVM. This finding should guide the design of future clinical trials assessing the impact of interventions aimed at decreasing cardiovascular morbidity and mortality in patients with OHS.nnnTRIAL REGISTRYnClinicaltrial.gov; No.: NCT01405976; URL: www.clinicaltrials.gov.

Identification of COPD Patients at High Risk for Lung Cancer Mortality Using the COPD-LUCSS-DLCO

BACKGROUNDnThe COPD-Lung Cancer Screening Score (COPD-LUCSS) is a tool designed to help identify patients with COPD with the highest risk of developing lung cancer (LC). The COPD-LUCSS includes the determination of radiological emphysema, a potential limitation for its implementation in clinical practice. The diffusing capacity for carbon monoxide (DLCO) is a surrogate marker of emphysema and correlates well with CT-determined emphysema.nnnOBJECTIVEnTo explore the use of the COPD-LUCSS using the DLCO instead of radiological emphysema, as a tool to identify patients with COPD at higher risk of LC death.nnnMETHODSnThe Body Mass Index, Airflow Obstruction, Dyspnea, Exercise Performance international cohort database was analyzed. By logistic regression analysis, we confirmed that the other parameters included in the COPD-LUCSS (age > 60, pack-years > 60, BMI < 25) were independently associated with LC death. We selected the best cutoff value for DLCO that independently predicted LC death. We then integrated the new COPD-LUCSS-DLCO assigning points to each parameter according to its hazard ratio value in the Cox regression model. The score ranges from 0 to 8 points.nnnRESULTSnBy regression analysis, age > 60, BMI <25 kg/m(2), pack-year history > 60, and DLCO < 60% were independently associated with LC diagnosis. Two COPD-LUCSS-DLCO risk categories were identified: low risk (scores 0-3) and high risk (scores 3.5-8). In comparison to patients at low risk, risk of death from LC increased 2.4-fold (95% CI, 2.0-2.7) in the high-risk category.nnnCONCLUSIONSnThe COPD-LUCSS using DLCO instead of CT-determined emphysema is a useful tool to identify patients with COPD at risk of LC death and may help in its implementation in clinical practice.

Prognostic assessment in COPD without lung function: the B-AE-D indices

Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function. The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988). Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer–Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer–Lemeshow test all p>0.05). The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk. The B-AE-D indices allow a simple and accurate assessment of COPD-related risk in the absence of lung function http://ow.ly/XFBox

Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease

BACKGROUNDnPatients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference.nnnMETHODSnAfter a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, postbronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores.nnnMAIN OUTCOMESnReceiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points.nnnFINDINGSnA total of 18,577 patients with COPD [72.0% male; mean age: 66.3xa0years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points.nnnCONCLUSIONSnThe application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed.

Airflow reversibility and long-term outcomes in patients with COPD without comorbidities

BACKGROUNDnThe forced expiratory volume at first second (FEV(1)) during spirometry reflects the severity of chronic obstructive pulmonary disease (COPD) and is known to be an important prognostic factor. It is uncertain whether the response to short-acting bronchodilators may predict long-term outcomes such as hospitalizations and mortality.nnnMETHODSnWe retrospectively studied a total of 1203 consecutive COPD patients without significant comorbidities during a mean (±SD) of 69 ± 39 months of follow-up. At baseline the subjects were classified as those with positive or negative bronchodilator test (BDT) and also in quartiles of absolute bronchodilator response to 400 μg of salbutamol. Hospital visits and mortality were the end points.nnnRESULTSnA positive bronchodilator test was observed in 332 (27.6%) of the patients. There were 73 (21.9%) deaths in patients with a positive BDT versus 253 (28.7%) in those with a negative BDT (p = 0.04). In adjusted Cox regression analysis a positive BDT was significantly associated with a prolonged time to first hospitalization. After stratifying the population by quartiles of response to BDT, a dose-response relationship was observed with the best outcomes in the quartile with highest level of airflow reversibility, even after controlling for age, sex, BMI, smoking status and baseline postbronchodilator FEV(1).nnnCONCLUSIONSnIn a large population of well characterized COPD patients without significant comorbidities, those demonstrating higher levels of reversibility at baseline presented better long-term outcomes even after controlling for other known prognostic factors.

Echocardiographic changes with non-invasive ventilation and CPAP in obesity hypoventilation syndrome

Rationale Despite a significant association between obesity hypoventilation syndrome (OHS) and cardiac dysfunction, no randomised trials have assessed the impact of non-invasive ventilation (NIV) or CPAP on cardiac structure and function assessed by echocardiography. Objectives We performed a secondary analysis of the data from the largest multicentre randomised controlled trial of OHS (Pickwick project, n=221) to determine the comparative efficacy of 2 months of NIV (n=71), CPAP (n=80) and lifestyle modification (control group, n=70) on structural and functional echocardiographic changes. Methods Conventional transthoracic two-dimensional and Doppler echocardiograms were obtained at baseline and after 2 months. Echocardiographers at each site were blinded to the treatment arms. Statistical analysis was performed using intention-to-treat analysis. Results At baseline, 55% of patients had pulmonary hypertension and 51% had evidence of left ventricular hypertrophy. Treatment with NIV, but not CPAP, lowered systolic pulmonary artery pressure (−3.4u2009mm Hg, 95%u2009CI −5.3 to –1.5; adjusted P=0.025u2009vs control and P=0.033u2009vs CPAP). The degree of improvement in systolic pulmonary artery pressure was greater in patients treated with NIV who had pulmonary hypertension at baseline (−6.4u2009mm Hg, 95%u2009CI −9 to –3.8). Only NIV therapy decreased left ventricular hypertrophy with a significant reduction in left ventricular mass index (−5.7u2009g/m2; 95%u2009CI −11.0 to –4.4). After adjusted analysis, NIV was superior to control group in improving left ventricular mass index (P=0.015). Only treatment with NIV led to a significant improvement in 6u2009min walk distance (32u2009m; 95%u2009CI 19 to 46). Conclusion In patients with OHS, medium-term treatment with NIV is more effective than CPAP and lifestyle modification in improving pulmonary hypertension, left ventricular hypertrophy and functional outcomes. Long-term studies are needed to confirm these results. Trial registration number Pre-results, NCT01405976 (https://clinicaltrials.gov/).

Severe Obstructive Sleep Apnea is Associated with Alterations in the Nasal Microbiome and Increase in Inflammation

Rationale: Obstructive sleep apnea (OSA) is associated with recurrent obstruction, subepithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome. Objectives: To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers. Methods: Two large cohorts were used: 1) a discovery cohort of 472 subjects from the WTCSNORE (Seated, Supine and Post‐Decongestion Nasal Resistance in World Trade Center Rescue and Recovery Workers) cohort, and 2) a validation cohort of 93 subjects rom the Zaragoza Sleep cohort. Sleep apnea was diagnosed using home sleep tests. Nasal lavages were obtained from cohort subjects to measure: 1) microbiome composition (based on 16S rRNA gene sequencing), and 2) biomarkers for inflammation (inflammatory cells, IL‐8, and IL‐6). Longitudinal 3‐month samples were obtained in the validation cohort, including after continuous positive airway pressure treatment when indicated. Measurements and Main Results: In both cohorts, we identified that: 1) severity of OSA correlated with differences in microbiome diversity and composition; 2) the nasal microbiome of subjects with severe OSA were enriched with Streptococcus, Prevotella, and Veillonella; and 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of cooccurring microbes that defined communities. Several common oral commensals (e.g., Streptococcus, Rothia, Veillonella, and Fusobacterium) correlated with apnea‐hypopnea index. Three months of treatment with continuous positive airway pressure did not change the composition of the nasal microbiota. Conclusions: We demonstrate that the presence of an altered microbiome in severe OSA is associated with inflammatory markers. Further experimental approaches to explore causal links are needed.

Sueño y cáncer

La cantidad y calidad de sueño ha preocupado desde siempre a la humanidad. Se sabe que el sueño es esencial para mantener la vida en general y la vida humana en particular. Todos los pacientes con enfermedades orgánicas agudas y crónicas presentan alteraciones del sueño. En particular, los pacientes con cáncer manifiestan síntomas de cansancio e insomnio pre y post-dormicional. Este editorial no aborda dicho tema, sino al contrario, discute de como los trastornos respiratorios primarios del sueño pueden influir en el desarrollo de cáncer, y cuál es el papel presente y futuro del neumólogo. El ritmo circadiano es una función biológica esencial de todos los seres vivos, y determina los cambios fisiológicos y de comportamiento a lo largo de las 24 h del día. En los mamíferos, el «marcapasos» circadiano está situado dentro del núcleo supraquiasmático (NSQ) en el hipotálamo. La ritmicidad de su funcionamiento está determinada genéticamente y ya existen estudios preliminares sobre la presencia de algunos polimorfismos de genes que determinarían anomalías del ritmo sueño-vigilia. Por otra parte, en personas con trabajos a turnos o altamente expuestas a la luz durante la noche, se han descrito modificaciones epigenéticas en genes claves de la regulación circadiana, que además alteran simultáneamente la transcripción de genes reguladores relacionados con la susceptibilidad a cáncer1. Estudios epidemiológicos llevados a cabo en estos trabajadores, encuentran asociación entre riesgo de cáncer y trabajo a turnos. La información es especialmente consistente en el caso del cáncer de mama2. Los potenciales mecanismos intermedios que explicarían la relación entre trabajos a turno y riesgo de cáncer son desconocidos. Se sabe que la melatonina posee efectos oncogénicos supresores. In vitro, la melatonina aumenta la expresión del gen PER2 uno de cuyos efectos es reducir la producción de -catenina. Esta proteína aumenta los niveles de ciclina D, que activa la proliferación de células neoplásicas. En las propias células tumorales de Ca de mama se han descrito varios receptores para melatonina que afectan a la fisiología tumoral. Tanto en varones como en mujeres que trabajan aThe quantity and quality of sleep has always been a concern for mankind, and it is known to be essential for sustaining life in general and human life in particular. All patients with acute and chronic disease suffer altered sleep patterns. Cancer patients, in particular, suffer fatigue and difficulties falling or staying asleep. This editorial does not address this topic, but instead discusses the influence of primary sleep-disordered breathing on the development of cancer, and the role of the respiratory medicine specialist now and in the future. The circadian rhythm is an essential biological function in all living beings, and determines physiological changes and behavior over a 24-h period. In mammals, the circadian “pacemaker” is located in the suprachiasmatic nucleus (SCN) in the hypothalamus. Circadian rhythms are genetically determined, and preliminary studies have reported the presence of certain genetic polymorphisms that might determine disorders in the sleep–wake pattern. Epigenetic modifications in key genes for circadian regulation have been reported in shift workers and individuals exposed to high levels of light at night, modifications that simultaneously alter the transcription of regulatory genes related with susceptibility to cancer.1 Epidemiological studies performed in these workers have found an association between the risk of cancer, particularly breast cancer,2 and shift work. The intermediary mechanisms that might explain the relationship between shift work and the risk of cancer are unknown. Melatonin is known to have anti-oncogenic effects, and in vitro studies have shown it to increase expression of the PER2 gene which, among other things, reduces the production of -catenine. This protein increases cyclin-D levels, activating the proliferation of neoplastic cells. Various melatonin receptors affecting tumor physiology have been described in breast cancer tumor cells. In both male and female shift workers, melatonin levels at night and in 24-h urine are reduced and fluctuate much less than in day-time workers.3 This finding would support the laboratory