Characterisation and prognosis of undiagnosed chronic obstructive pulmonary disease patients at their first hospitalisation.

BACKGROUND: Under-diagnosis of COPD is an important unmet medical need. We investigated the characteristics and prognosis of hospitalised patients with undiagnosed COPD. METHODS: The PAC-COPD cohort included 342 COPD patients hospitalised for the first time for an exacerbation of COPD (2004-2006). Patients were extensively characterised using sociodemographic, clinical and functional variables, and the cohort was followed-up through 2008. We defined "undiagnosed COPD" by the absence of any self-reported respiratory disease and regular use of any pharmacological respiratory treatment. RESULTS: Undiagnosed COPD was present in 34% of patients. They were younger (mean age 66 vs. 68 years, p = 0.03), reported fewer symptoms (mMRC dyspnoea score, 2.1 vs. 2.6, p < 0.01), and had a better health status (SGRQ total score, 29 vs. 40, p < 0.01), milder airflow limitation (FEV1% ref., 59% vs. 49%, p < 0.01), and fewer comorbidities (two or more, 40% vs. 56%, p < 0.01) when compared with patients with an established COPD diagnosis. Three months after hospital discharge, 16% of the undiagnosed COPD patients had stopped smoking (vs. 5%, p = 0.019). During follow-up, annual hospitalisation rates were lower in undiagnosed COPD patients (0.14 vs. 0.25, p < 0.01); however, this difference disappeared after adjustment for severity. Mortality was similar in both groups. CONCLUSIONS: Undiagnosed COPD patients have less severe disease and lower risk of re-hospitalisation when compared with hospitalised patients with known COPD.

Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins.

BACKGROUND: Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins. METHODS: Whole exome sequencing analysis was carried out in a large U.S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy. RESULTS: A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U.S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin. CONCLUSIONS: Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.

Echocardiographic abnormalities in patients with COPD at their first hospital admission.

Cardiovascular disease accounts for significant morbidity and mortality in chronic obstructive pulmonary disease (COPD). Its prevalence and mechanisms of association have not been elucidated. The study aimed to assess the prevalence of echocardiographic abnormalities and potential risk factors in patients with COPD at their first exacerbation requiring hospital admission. Transthoracic echocardiography was prospectively performed in 342 patients (forced expiratory volume in 1 s 52 ± 16% predicted) 3 months after discharge. Significant cardiac alterations were present in 64% of patients; 27% left- and 48% right-heart disorders. The most common were right ventricle enlargement (30%) and pulmonary hypertension (19%). Left ventricle enlargement was present in 6%, left ventricle systolic dysfunction in 13%, left ventricle diastolic impairment in 12% and left atrial dilatation in 29%. Echocardiographic abnormalities were unrelated to COPD severity and were more frequent in patients with self-reported cardiac disease. They were also observed in 63% of patients with no known cardiac disease or cardiovascular risk factors other than smoking. We conclude that cardiac abnormalities are highly prevalent in COPD patients at the time of their first severe exacerbation, even in the absence of established cardiac disease or cardiovascular risk factors. Considering the prognostic and therapeutic implications of cardiac comorbidity, echocardiography should be considered in the assessment of patients with clinically significant COPD.

[Validation of the Yale Physical Activity Survey in chronic obstructive pulmonary disease patients]. / Validación del cuestionario de actividad física de Yale en pacientes con enfermedad pulmonar obstructiva crónica.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) perform limited physical activity. Surprisingly, there is a lack of research in COPD about the validity of physical activity questionnaires. Our aim was to validate the Yale Physical Activity Survey in COPD patients in order to quantify and classify their levels of physical activity. METHODS: 172 COPD patients from 8 university hospitals in Spain wore an accelerometer (SenseWear(®)Pro(2)Armband) for 8 days and answered the questionnaire 15 days later. Statistical analyses used to compare both tools measures included: (i) Spearman's correlation coefficient, (ii) intraclass correlation coefficient (ICC) and Bland-Altman plots, (iii) distribution of accelerometer measurements according to tertiles of the questionnaire, and (iv) receiver operating characteristic (ROC) curves to detect sedentary patients. RESULTS: 94% of participants were men, 28% were active smokers and 7% were currently working. Mean (standard deviation) age was 70 (8) years, mean post-bronchodilator FEV(1) was 52 (15)% predicted, and median (p25-p75) steps taken was 5,702 (3,273-9,253) steps per day(-1). Spearman correlations were low to moderate (from 0.29 to 0.52, all P<.001). ICCs showed weak agreement (from 0.34 to 0.40, all P<.001). A wide variability in agreement was observed in the Bland-Altman plots. Significant differences in accelerometer measurements were found according to questionnaire tertiles (all P<.001). The area under the ROC for identifying sedentarism was 0.71 (95% CI: 0.63-0.79). CONCLUSIONS: The Yale Physical Activity Survey may be a valid tool to classify, but not to quantify, physical activity performed by COPD patients. The summary index of this questionnaire, based on seven short questions, shows the best validity properties. This suggests that it should be considered a screening tool to identify patients at risk for sedentarism.

Physical activity and clinical and functional status in COPD.

BACKGROUND: The mechanisms underlying the benefits of regular physical activity in the evolution of COPD have not been established. Our objective was to assess the relationship between regular physical activity and the clinical and functional characteristics of COPD. METHODS: Three hundred forty-one patients were hospitalized for the first time because of a COPD exacerbation in nine teaching hospitals in Spain. COPD diagnosis was confirmed by spirometry under stable conditions. Physical activity before the first COPD hospitalization was measured using the Yale questionnaire. The following outcome variables were studied under stable conditions: dyspnea, nutritional status, complete lung function tests, respiratory and peripheral muscle strength, bronchial colonization, and systemic inflammation. RESULTS: The mean age was 68 years (SD, 9 years), 93% were men, 43% were current smokers, and the mean postbronchodilator FEV(1) was 52% predicted (SD, 16% predicted). Multivariate linear regression models were built separately for each outcome variable and adjusted for potential confounders (including remaining outcomes if appropriate). When patients with the lowest quartile of physical activity were compared to patients in the other quartiles, physical activity was associated with significantly higher diffusing capacity of the lung for carbon monoxide (Dlco) [change in the second, third, and fourth quartiles of physical activity, compared with first quartile (+ 6%, + 6%, and + 9% predicted, respectively; p = 0.012 [for trend])], expiratory muscle strength (maximal expiratory pressure [Pemax]) [+ 7%, + 5%, and + 9% predicted, respectively; p = 0.081], 6-min walking distance (6MWD) [+ 40, + 41, and + 45 m, respectively; p = 0.006 (for trend)], and maximal oxygen uptake (Vo(2)peak) [+ 55, + 185, and + 81 mL/min, respectively; p = 0.110 (for trend)]. Similarly, physical activity reduced the risk of having high levels of circulating tumor necrosis factor alpha (odds ratio, 0.78, 0.61, and 0.36, respectively; p = 0.011) and C-reactive protein (0.70, 0.51, and 0.52, respectively; p = 0.036) in multivariate logistic regression. CONCLUSIONS: More physically active COPD patients show better functional status in terms of Dlco, Pemax, 6MWD, Vo(2)peak, and systemic inflammation.

Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies.

Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.