Susceptibility to exacerbation in chronic obstructive pulmonary disease

Background Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. Methods We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End points (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both)or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Results Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient"s recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Conclusions Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials .gov number, NCT00292552.)

Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study.

Patients with chronic obstructive pulmonary disease (COPD) often develop weight loss, which is associated with increased mortality. Recombinant human growth hormone (rhGH) treatment has been proposed to improve nitrogen balance and to increase muscle strength in these patients. The aim of this study was to assess the effects of rhGH administration on the nutritional status, resting metabolism, muscle strength, exercise tolerance, dyspnea, and subjective well-being of underweight patients with stable COPD. Sixteen patients attending a pulmonary rehabilitation program (age: 66 +/- 9 yr; weight: 77 +/- 7% of ideal body weight; FEV1: 39 +/- 13% of predicted) were randomly treated daily with either 0.15 IU/kg rhGH or placebo during 3 wk in a double-blind fashion. Measurements were made at the beginning (DO) and at the end (D21) of treatment and 2 mo later (D81). Body weight was similar in the two groups during the study, but lean body mass was significantly higher in the rhGH group at D21 (p < 0.01) and D81 (p < 0.05). The increase in lean body mass was 2.3 +/- 1.6 kg in the rhGH group and 1.1 +/- 0.9 kg in the control group at D21 and 1.9 +/- 1.6 kg in the rhGH group and 0.7 +/- 2.1 kg in the control group at D81. At D21, the resting energy expenditure was increased in the rhGH group (107.8% of DO, p < 0.001 compared with the control group). At D21 and D81, the changes in maximal respiratory pressures, handgrip strength, maximal exercise capacity, and subjective well-being were similar in the two groups. At D21, the 6-min walking distance decreased in the rhGH group (-13 +/- 31%) and increased in the control group (+10 +/- 14%; p < 0.01). We conclude that the daily administration of 0.15 IU/kg rhGH during 3 wk increases lean body mass but does not improve muscle strength or exercise tolerance in underweight patients with COPD.

An unusual cause of hemoptysis--aberrant origin of the left pulmonary artery from the ascending aorta in the adult.

Aberrant origin of a pulmonary artery from the ascending aorta is an uncommon congenital vascular malformation with poor survival without surgery. In this case report, we describe the unusual late diagnosis of this congenital malformation in an otherwise asymptomatic young man presenting with mild hemoptysis. We review the natural and modified history of this defect and the relevant aspects of follow-up in adult life.

Hipertensión y edema pulmonar de altura. Rol de la disfunción endotelial y de la programación fetal [Pulmonary hypertension and lung edema at high altitude. Role of endothelial dysfunction and fetal programming].

High altitude constitutes an exciting natural laboratory for medical research. While initially, the aim of high-altitude research was to understand the adaptation of the organism to hypoxia and find treatments for altitude-related diseases, over the past decade or so, the scope of this research has broadened considerably. Two important observations led to the foundation for the broadening of the scientific scope of high-altitude research. First, high-altitude pulmonary edema (HAPE) represents a unique model which allows studying fundamental mechanisms of pulmonary hypertension and lung edema in humans. Secondly, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary and systemic vascular dysfunction at an early stage. Here, we review studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning lung edema and pulmonary hypertension and to the first direct demonstration of fetal programming of vascular dysfunction in humans.

Distal trisomy 14 (q24 --> qter) and aorto-pulmonary window: a case report and review of the literature.

A newborn female with partial trisomy for the distal part of the long arm of the chromosome 14 (14q24 --> qter) resulting from a paternal balanced translocation (3;14) is described. We compare her phenotype with eight other individuals with trisomy 14q24 --> qter.

Chronic obstructive pulmonary disease in never-smoking animal farmers working inside confinement buildings

BACKGROUND: In animal farming, respiratory disease has been associated with indoor air contaminants and an excess in FEV1 decline. Our aim was to determine the characteristics and risk factors for chronic obstructive pulmonary disease (COPD) in never-smoking European farmers working inside animal confinement buildings. METHODS: A sample of participants in the European Farmers' Study was selected for a cross-sectional study assessing lung function and air contaminants. Dose-response relationships were assessed using logistic regression models. RESULTS: COPD was found in 18 of 105 farmers (45.1 SD 11.7 years) (17.1%); 8 cases (7.6%) with moderate and 3 cases (2.9%) with severe disease. Dust and endotoxin showed a dose-response relationship with COPD, with the highest prevalence of COPD in subjects with high dust (low=7.9%/high=31.6%) and endotoxin exposure (low=10.5%/high=20.0%). This association was statistically significant for dust in the multivariate analysis (OR 6.60, 95% CI 1.10-39.54). CONCLUSION: COPD in never-smoking animal farmers working inside confinement buildings is related to indoor dust exposure and may become severe. [Authors]

Pulmonary involvement in Fabry disease: Overview and perspectives.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A, which leads to storage of sphingolipids in virtually all human cells and consequently to organ dysfunction. Pulmonary involvement is still debated. But, obstructive lung disease is up to ten times more prevalent in patients with FD compared to general public. Also, an accelerated decline in forced expiratory volume in one second (FEV1) over time was observed in these patients. Lysosomal storage of glycosphingolipids is considered leading to small airway disease via hyperplasia of the bronchiolar smooth muscle cells. Larger airways may become involved with ongoing disease process. There is no evidence for involvement of the lung interstitium in FD. The effect of enzyme replacement therapy on respiratory involvement remains to be determined in large, prospective controlled trials.

Endothelin-1 does not mediate the endothelium-dependent hypoxic contractions of small pulmonary arteries in rats.

Various pulmonary artery preparations in vitro demonstrate sustained endothelium-dependent contractions upon hypoxia. To determine whether endothelin-1 could mediate this phenomenon, we examined the effect of bosentan, a new antagonist of both the ETA and ETB subtypes of the endothelin receptor. Small (300 pm) pulmonary arteries from rats were mounted on a myograph, precontracted with prostaglandin F2 alpha and exposed to hypoxia (PO2, 10 to 15 mm Hg, measured on-line) for 45 min. Endothelium-intact control rings exhibited a biphasic response, with a transient initial vasoconstriction (phase 1) followed by a second slowly developing sustained contraction (phase 2). Expressed in percent of the maximal response to 80 mmol/L KCl, the amplitudes of phase 1 (peak tension) and 2 (tension after 45 min of hypoxia) averaged 37 +/- 12% and 17 +/- 14%, respectively (n = 11). In endothelium-denuded rings, phase 1 persisted while the amplitude of phase 2 was reduced to 2 +/- 12% (p < 0.05, n = 8), showing the endothelium dependence of this contraction. Neither phase was significantly decreased in rings treated with 10(-5) mmol/L bosentan (38 +/- 15% and 17 +/- 12%, respectively, n = 6). The PO2 threshold for onset of hypoxic contraction was not significantly different among these three groups and averaged 32 +/- 24 mm Hg. In a separate experiment, we assessed the inhibitory effect of 10(-5) mol/L bosentan on the response to 10(-8) mol/L endothelin-I. Rings treated for 45 min with 10(-8) mol/L endothelin-1 alone exhibited a maximal contraction of 75 +/- 27% (n = 6). This was reduced to 4 +/- 17% (p < 0.01, n = 6) in rings treated with both 10(-8) mol/L endothelin-1 and 10(-5) mol/L bosentan. We conclude that complete blockade of all endothelin receptor subtypes has no effect on either endothelium-dependent or -independent hypoxic contractions in this preparation. This suggests that endothelial factors other than endothelin-I mediate the acute hypoxic contractions of small pulmonary arteries in the rat.

Multiple pulmonary artery aneurysms in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare genetic disorder characterised by multiple hamartomas, caused by inactivating mutations of the TSC1/TSC2 tumour suppressor genes. Classical pulmonary involvement in tuberous sclerosis complex (TSC) consists of lymphangioleiomyomatosis and/or multiple micronodular pneumocyte hyperplasia (MMPH). Association of TSC with pulmonary artery aneurysm (PAA) has been only exceptionally described. We report here the first case of TSC with multiple PAA in combination with MMPH, cardiac rhabdomyomas and bone, skin and brain involvement.

Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes.

Background Chronic obstructive pulmonary disease (COPD) is increasingly considered a heterogeneous condition. It was hypothesised that COPD, as currently defined, includes different clinically relevant subtypes. Methods To identify and validate COPD subtypes, 342 subjects hospitalised for the first time because of a COPD exacerbation were recruited. Three months after discharge, when clinically stable, symptoms and quality of life, lung function, exercise capacity, nutritional status, biomarkers of systemic and bronchial inflammation, sputum microbiology, CT of the thorax and echocardiography were assessed. COPD groups were identified by partitioning cluster analysis and validated prospectively against cause-specific hospitalisations and all-cause mortality during a 4 year follow-up. Results Three COPD groups were identified: group 1 (n ¼ 126, 67 years) was characterised by severe airflow limitation (postbronchodilator forced expiratory volume in 1 s (FEV 1 ) 38% predicted) and worse performance in most of the respiratory domains of the disease; group 2 (n ¼ 125, 69 years) showed milder airflow limitation (FEV 1 63% predicted); and group 3 (n ¼ 91, 67 years) combined a similarly milder airflow limitation (FEV 1 58% predicted) with a high proportion of obesity, cardiovascular disorders, iabetes and systemic inflammation. During follow-up, group 1 had more frequent hospitalisations due to COPD (HR 3.28, p < 0.001) and higher all-cause mortality (HR 2.36, p ¼ 0.018) than the other two groups, whereas group 3 had more admissions due to cardiovascular disease (HR 2.87, p ¼ 0.014). Conclusions In patients with COPD recruited at their first hospitalisation, three different COPD subtypes were identified and prospectively validated:"severe respiratory COPD","moderate respiratory COPD", and"systemic COPD'

Pulmonary hypertension associated to sarcoidosis in Switzerland

Introduction: L'hypertension pulmonaire est une complication rare de la sarcoïdose. Elle se rencontre surtout lors d'atteinte pulmonaire associée, particulièrement lorsque celle-ci est avancée. Objectif: Étudier l'épidémiologie et l'évolution clinique des patients souffrant d'hypertension pulmonaire et de sarcoïdose (SAPH) en Suisse. Méthode: Le registre suisse de l'hypertension pulmonaire a été analysé rétrospectivement pour identifier les cas SAPH de 2000 à 2011. Les paramètres cliniques, tels que le sexe, l'âge, le stade radiographique pulmonaire et l'hémodynamique sont étudiés lors de l'inscription des patients dans le registre. La classe fonctionnelle NYHA, la capacité à l'exercice (TM6M), les traitements introduits (oxygénothérapie, traitements spécifiques pour la sarcoïdose et traitements spécifiques pour l'hypertension pulmonaire), la survie et le nombre de transplantations pulmonaires effectués sont étudiés lors du suivi. Résultats: Parmi plus de 977 patients inscrits, 22 répondent aux critères d'inclusion pour la SAPH. La majorité de patients est de sexe féminin et l'âge moyen est de 59,5 +/-29,7. Le stade pulmonaire le plus souvent rencontré est de degré 4. La mPAP au diagnostic est de 44 ± 12.6 mmHg et la saturation veineuse d'oxygène est de 60%. La plupart des patients présentent une classe NYHA de 3 et le TM6M est de 368.6 ± 124.2 m à l'inclusion dans le registre. La durée moyenne du suivi des patients dans le registre est de 19.4 mois (0-57). La médiane est de 14 mois. La classe fonctionnelle NYHA et les moyennes des mètres parcourus ne montrent pas de changements significatifs lors du suivi. Au début de l'étude, comme à la fin, moins de la moitié des patients sont sous oxygénothérapie ; le traitement le plus utilisé pour l'hypertension pulmonaire est la classe des antagonistes de l'endothéline et pour la sarcoïdose les corticostéroïdes. La survie à un an est de 65 % et de 55 % à 3 ans. Pendant la période d'observation 5 patients nécessitent une transplantation pulmonaire, dont 2 sont décédés. La démarche médicamenteuse varie au cours du temps : la tendance récente est de donner plus de médicaments pour l'hypertension pulmonaire et la sarcoïdose et de favoriser les associations. Conclusion: La SAPH est une maladie rare ou tout au moins rarement diagnostiquée avec un sombre pronostic. Le degré d'hypertension est de modéré à sévère avec une limitation à l'effort importante. En cas de symptômes suggestifs chez un patient souffrant de sarcoïdose, un dépistage échocardiographique systématique devrait être proposé.

Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study.

OBJECTIVE: To define therapeutic strategy for management of patients with ischemic stroke due to a high probability of paradoxical embolism through a Patent Foramen Ovale (PFO). METHODS: Since 1988 all consecutive patients with cerebrovascular events and PFO from the Stroke Registry of our population-based primary-care center are prospectively studied and followed. Since 1992, among 118 patients with cryptogenic embolic brain infarct or transient ischemic attack (TIA) and PFO, 32 consecutive patients younger than 60 years who presented at least two of the following criteria were admitted for surgery: history of Valsalva strain before stroke (11); multiple clinical events (13); multiple infarcts on brain Magnetic Resonance Imaging (MRI) (15); atrial septal aneurysm (ASA) (16); large right-to-left shunt (> 50 microbubbles) (12). RESULTS: Operative time 135' +/- 33'. CPB time 34' +/- 14'. Aortic crossclamping time 16' +/- 6'. Post-operative bleeding 485 +/- 170 ml. No homologous blood transfusion required. No neurological, cardiac or renal complications. All patients were followed-up corresponding to a cumulative time of 601 patient-months. This revealed no recurrent vascular events nor silent new brain lesions on brain MRI. Systematic simultaneous contrast Trans Esophageal Echocardiography (TEE)-Trans Cranial Doppler showed a small residual interatrial shunt in two patients. CONCLUSION: Surgical closure of a patent foramen ovale can be accomplished with very low morbidity and reduce efficiently the risk of stroke recurrence. It seems to be the option of choice in selected patients with a higher (> 1.5%/year) risk of stroke recurrence.