[The Overlap Syndrome: association of COPD and Obstructive Sleep Apnoea]. / L' "Overlap Syndrome": association de bronchopneumopathie chronique obstructive et de syndrome d'apnées obstructives du sommeil.

Chronic obstructive pulmonary disease (COPD) and the obstructive sleep apnoea-hypopnoea syndrome (OSAHS) are both common diseases affecting respectively 10 and 5% of the adult population over 40 years of age. Their coexistence, which is denominated "Overlap Syndrome", can be expected to occur in about 0.5% of this population. Two recent epidemiologic studies have shown that the prevalence of OSAHS is not higher in COPD than in the general population, and that the coexistence of the two conditions is due to chance and not through a pathophysiological linkage. Patients with "overlap" have a higher risk of sleep-related O(2) desaturation than do patients with COPD alone and the same degree of bronchial obstruction. They have an increased risk of developing hypercapnic respiratory failure and pulmonary hypertension when compared with patients with OSAHS alone and with patients with "usual" COPD. In patients with overlap, hypoxaemia, hypercapnia, and pulmonary hypertension can be observed in the presence of mild to moderate bronchial obstruction, which is different from "usual" COPD. Treatment of the overlap syndrome consists of nasal continuous positive airway pressure or nocturnal non-invasive ventilation (NIV), with or without nocturnal O(2). Patients who are markedly hypoxaemic during the daytime (PaO(2)<55-60 mmHg) should be given conventional long-term O(2) therapy in addition to nocturnal ventilation.

Cor pulmonale.

The term "cor pulmonale" is still popular but there is presently no consensual definition and it seems more appropriate to define the condition by the presence of pulmonary hypertension (PH) resulting from diseases affecting the structure and/or the function of the lungs: PH results in right ventricular enlargement and may lead with time to right heart failure (RHF). Chronic obstructive pulmonary disease (COPD) is the first cause of cor pulmonale, far before idiopathic pulmonary fibrosis and obesity-hypoventilation syndrome. In chronic respiratory disease (CRD) PH is "pre-capillary," due to an increase of pulmonary vascular resistance (PVR). The first cause of increased PVR is chronic long-standing alveolar hypoxia which induces pulmonary vascular remodeling. The main characteristic of PH in CRD and particularly in COPD is its mild to moderate degree, resting pulmonary artery mean pressure (PAP) in a stable state of the disease usually ranging between 20 and 35 mmHg. However, PH may worsen during exercise, sleep, and exacerbations of the disease. These acute increases in afterload can favor the development of RHF. A minority (<5%) of COPD patients exhibit severe or "disproportionate" PH (PAP >40 mmHg), the mechanism of which is not well understood. At present long-term oxygen therapy (LTOT) is the logical treatment of PH since alveolar hypoxia is considered to be the major determinant of the elevation of PAP and PVR. LTOT stabilizes or at least attenuates and sometimes reverses the progression of PH, but PAP seldom returns to normal. Vasodilators (prostacyclin, endothelin receptor antagonists, sildenafil, nitric oxide) could be considered in patients with severe PH but controlled studies in this field are presently lacking.

Pulmonary hypertension in COPD.

Mild-to-moderate pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD); such a complication is associated with increased risks of exacerbation and decreased survival. Pulmonary hypertension usually worsens during exercise, sleep and exacerbation. Pulmonary vascular remodelling in COPD is the main cause of increase in pulmonary artery pressure and is thought to result from the combined effects of hypoxia, inflammation and loss of capillaries in severe emphysema. A small proportion of COPD patients may present with "out-of-proportion" pulmonary hypertension, defined by a mean pulmonary artery pressure >35-40 mmHg (normal is no more than 20 mmHg) and a relatively preserved lung function (with low to normal arterial carbon dioxide tension) that cannot explain prominent dyspnoea and fatigue. The prevalence of out-of-proportion pulmonary hypertension in COPD is estimated to be very close to the prevalence of idiopathic pulmonary arterial hypertension. Cor pulmonale, defined as right ventricular hypertrophy and dilatation secondary to pulmonary hypertension caused by respiratory disorders, is common. More studies are needed to define the contribution of cor pulmonale to decreased exercise capacity in COPD. These studies should include improved imaging techniques and biomarkers, such as the B-type natriuretic peptide and exercise testing protocols with gas exchange measurements. The effects of drugs used in pulmonary arterial hypertension should be tested in chronic obstructive pulmonary disease patients with severe pulmonary hypertension. In the meantime, the treatment of cor pulmonale in chronic obstructive pulmonary disease continues to rest on supplemental oxygen and a variety of measures aimed at the relief of airway obstruction.

[Obesity-hypoventilation syndrome]. / Syndrome obésité-hypoventilation.

INTRODUCTION: The obesity-hypoventilation syndrome (OHS), or alveolar hypoventilation in the obese, has been described initially as the "Pickwickian syndrome". It is defined as chronic alveolar hypoventilation (PaO2<70 mmHg, PaCO2 > or =45 mmHg) in obese patients (body mass index>30 kg/m2) who have no other respiratory disease explaining the hypoxemia-hypercapnia. BACKGROUND: The large majority of obese subjects are not hypercapnic, even in case of severe obesity (>40 kg/m2). There are three principal causes, which can be associated, explaining alveolar hypoventilation in obese subjects: high cost of respiration and weakness of the respiratory muscles (probably the major cause), dysfunction of the respiratory centers with diminished chemosensitivity, long-term effects of the repeated episodes of obstructive sleep apneas observed in some patients. The role of leptin (hormone produced by adipocytes) in the pathogenesis of this syndrome, has been recently advocated. OHS is generally observed in subjects over 50 years. Its prevalence has markedly increased in recent years, probably due to the present "epidemic" of obesity. The diagnosis is often made after an episode of severe respiratory failure. Comorbidities, favored by obesity, are very frequent: systemic hypertension, left heart diseases, diabetes. VIEWPOINT: OHS must be distinguished from obstructive sleep apnea syndrome (OSAS) even if the two conditions are often associated. OSAS may be absent in certain patients with OHS (20% of the patients in our experience). On the other hand obesity may be absent in certain patients with OSAS. CONCLUSION: Losing weight is the "ideal" treatment of OHS but in fact it cannot be obtained in most patients. Nocturnal ventilation (continuous positive airway pressure and mainly bilevel non invasive ventilation) is presently the best treatment of OHS and excellent short and long-term results on symptoms and arterial blood gases have been recently reported.

[Pulmonary hypertension of chronic respiratory disease]. / Hypertension pulmonaire des affections respiratoires chroniques.

Pulmonary hypertension of chronic respiratory disease is defined as elevation of the mean resting pulmonary artery pressure to over 20 mm Hg. It is the commonest cause of pre-capillary pulmonary hypertension on account of the high prevalence of chronic obstructive pulmonary disease. It is primarily due to alveolar hypoxia that leads to remodelling of the distal pulmonary vasculature and consequently to an increase in pulmonary resistance. It is not as severe as idiopathic pulmonary hypertension. The mean pulmonary artery pressure is usually moderately increased (20-35 mm Hg) when patients are seen during a stable period of the disease. There are, however, more severe cases of pulmonary hypertension called, in some cases, disproportionate but these are uncommon. Increased right ventricular afterload can lead to the development of right ventricular failure that is a definite prognostic factor. The clinical symptoms of pulmonary hypertension are at a secondary level compared with those of the causal disease. Non-invasive diagnosis depends on Doppler echocardiography. Currently the most effective treatment is long term oxygen therapy (16-18 hr/24 hr). This improves or, at least stabilises, the pulmonary hypertension.

[Pleural effusion complicating a totally implanted venous device]. / Un épanchement pleural liquidien compliquant une chambre à cathéter implantable.

INTRODUCTION: Totally implanted venous devices (TIVD) are an essential tool for repeated intravenous treatments such as chemotherapy for cancer and antibiotics for cystic fibrosis. CASE REPORT: A woman of 76 years was treated for bronchiectasis, colonised by Pseudomonas aeruginosa, with courses of intravenous antibiotics. On account of poor peripheral veins a TIVD was implanted. The implantation and subsequent antibiotic injections were uncomplicated. Three years later a further course of antibiotics was prescribed. As no reflux of blood was obtained on puncturing the device the position of the catheter was checked radiologically. The patient complained of right shoulder pain following each infusion. The chest x-ray showed a pleural effusion. The sudden onset of the effusion, the absence of signs of infection and the patient's good clinical condition suggested pleural extravasation of the antibiotic infusion from the TIVD. Pleural aspiration yielded 1400 mls of watery fluid. Injection of contrast into the TIVD confirmed intra-pleural extravasation. CONCLUSION: When using a TIVD it is important to bear in mind the possibility of late pleural complications.

[Use of linezolid for the treatment of lung infections in adults with cystic fibrosis]. / Utilisation du linézolide dans le traitement des infections broncho-pulmonaires du patient adulte atteint par la mucoviscidose.

INTRODUCTION: Linezolid, a new antistaphylococcal agent for oral or intravenous administration is active against Staphylococcus aureus with limited sensitivity to glycopeptides. The purpose of the present work was to compare data in the literature with practical clinical experience with the use of linezolid for lung infections in adult cystic fibrosis patients with the objective of developing local guidelines for use. MATERIAL AND METHODS: This retrospective clinical study was conducted in the adult pneumology department of a university hospital. RESULTS: The main clinical signs leading to prescription of linezolid were aggravating cough, bronchial obstruction, and exercise-induced fatigue. Among 42 cystic fibrosis patients, six aged 24+/-3 years were given 22 treatments of linezolid. Two patients were given the drug once and the others 2, 4, 5, and 9 times, 600 mg b.i.d. Mean duration of treatment with linezolid was 16+/-5 days. Among the six patients, two presented meti-R S. aureus infection. For twelve cases, clinical improvement was observed; and in two others the situation worsened leading to interruption of linezolid. CONCLUSIONS: There are few reports in the literature on use of linezolid in cystic fibrosis patients. Writing internal guidelines for our department has enabled standardized use: 600 mg b.i.d. p.o. for 14 days as second-line treatment for bronchial exacerbation of S. aureus infection.

[Pulmonary hypertension associated with disorders of the respiratory system]. / Hypertension pulmonaire des affections respiratoires chroniques.

Pulmonary hypertension associated with disorders of the respiratory system is defined by a pulmonary artery mean pressure above 20 mmHg at rest in stable disease. The most frequent form of precapillary pulmonary hypertension is associated with chronic obstructive pulmonary disease, because of its high prevalence. Pulmonary vascular remodeling occurs in the small pulmonary arteries and is due mainly to chronic alveolar hypoxia. Pulmonary hypertension associated with disorders of the respiratory system is usually mild to moderate, with resting pulmonary artery mean pressure ranging between 20 and 35 mm Hg. It may increase markedly during sleep, exercise or exacerbation of respiratory failure, however. Abrupt postload elevation can lead to right heart failure, an indisputable indicator of prognosis. Because the symptoms of pulmonary hypertension are minimal relative to those of the chronic hypoxic lung disease, noninvasive diagnosis is difficult, particularly in patients with chronic obstructive pulmonary disease. Oxygen therapy (at least 16 h/day) is currently the best treatment for this type of pulmonary arterial hypertension.

[Physiological functional tests to evaluate pulmonary arterial hypertension]. / Explorations fonctionnelles dans l'hypertension artérielle pulmonaire.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare and complex disease, which requires careful diagnostic evaluation. STATE OF THE ART: Most patients have a mild decrease in lung volumes and a moderate decrease in carbon monoxide transfer factor. Mild to moderate arterial hypoxaemia, is often present, associated with a mild respiratory alkalosis. When hypoxaemia is severe, it may represent an intracardiac shunt. Right heart catheterisation is required to confirm the diagnosis and in most cases shows a significant elevation of pulmonary artery pressure due to an increase in pulmonary vascular resistance. The haemodynamic profile and the response to an acute pulmonary vasodilator challenge are determinants of prognosis. Finally, exercise capacity which is usually assessed by the six minute walk test provides an overall functional measure of disease severity, response to therapy, and progression. PERSPECTIVES: Functional evaluation of the heart using echocardiography will play an increasing role in the evaluation of PAH. CONCLUSIONS: Physiological measurements in PAH have several objectives. They form part of the diagnostic definition, allow the exclusion of other conditions and are tools for the assessment of severity, prognosis and response to therapy.

[Coagulation disorders and arterial thromboembolic events in non-small-cell lung cancer. A case report]. / Anomalies de la coagulation et événements thromboemboliques artériels dans le cancer bronchique non à petites cellules. A propos d'une observation.

Certain coagulation disorders can occur in patients with cancer and thromboembolic complications are frequent. We report the case of a 53-Year-old patient with metastatic adenocarcinoma of the lung treated with chemotherapy who presented several cerebral arterial thromboembolic events leading to death a few weeks after the initial diagnosis of cancer. This case illustrates the important role of certain satellite disorders related to coagulation activation: non-bacterial thrombotic endocarditis, disseminated intravascular coagulation, anti-phospholipid antibody syndrome. The role of anticancer chemotherapy as a favoring factor for thromboembolic events is also emphasized in patients with non-small-cell lung cancer.

Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension.

Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary haemorrhagic telangiectasia related to a mutation within the endoglin gene is described. This report highlights the critical role of the TGF-beta signalling pathway in this condition.

Allelic imbalance at loci containing FGFR, FGF, c-Met and HGF candidate genes in non-small cell lung cancer sub-types, implication for progression.

Fibroblast growth factors (FGF), hepatocyte growth factor (HGF) and their receptors, FGFR and c-Met, are essential components of the regulatory networks between the epithelium and mesenchyme in embryonic lung, but their respective roles in tumour growth are not clear. We performed allelotyping at loci containing the candidate genes FGFR-1-2-3-4, FGF-1-2-7-10, c-Met and HGF in 36 non-small cell lung cancer (NSCLC) (20 squamous-cell carcinomas (SQC) and 16 adenocarcinomas (ADC)), by surrounding each locus with two microsatellites (MS), as close as possible to the genes of interest. Unexpectedly, SQC and ADC were frequently altered at all of these loci, and SQC showed more simultaneously altered loci. In ADC, alterations at the 15q13-22 locus (FGF7 candidate gene) were significantly more frequent. Thus, these loci showed different patterns of molecular alterations between SQC and ADC. Finally, alterations at loci containing FGFR and HGF candidate genes were inversely correlated to the lymph node status in SQC and ADC, respectively.

Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease.

BACKGROUND: The serotonin transporter (5-HTT) is involved in the pulmonary artery smooth muscle hyperplasia that leads to pulmonary hypertension (PH). Because hypoxia and 5-HTT gene polymorphism control 5-HTT expression, we examined 5-HTT gene polymorphism and PH in hypoxemic patients with advanced chronic obstructive pulmonary disease (COPD). METHODS AND RESULTS: In 103 patients with COPD recruited in France (n=67) and the UK (n=36), we determined 5-HTT gene polymorphism and pulmonary artery pressure (PAP) measured during right heart catheterization (France) or Doppler echocardiography (UK). Ninety-eight subjects from the 2 countries served as control subjects. The distribution of 5-HTT gene polymorphism did not differ between patients and control subjects. In patients carrying the LL genotype, which is associated with higher levels of 5-HTT expression in pulmonary artery smooth muscle cells than the LS and SS genotypes, PH was more severe than in LS or SS patients. Mean PAP values in patients from France with the LL, LS, and SS genotypes were 34+/-3, 23+/-1, and 22+/-2 mm Hg (mean+/-SEM), respectively (P<0.01). Corresponding systolic PAP values in the UK were 40+/-3, 28+/-3, and 24+/-3 mm Hg, respectively (P<0.01). Compared with control subjects, platelet 5-HTT protein was increased in COPD patients in proportion to the hypoxemia level, and strong 5-HTT immunostaining was observed in remodeled pulmonary arteries from COPD patients. CONCLUSIONS: 5-HTT gene polymorphism appears to determine the severity of PH in hypoxemic patients with COPD. Because PH is an important prognostic factor in this disease, recognition of patients at risk for PH should be helpful in managing COPD.

[Long-term oxygen therapy for chronic respiratory failure. Rationale, indications, modalities]. / L'oxygénothérapie de longue durée dans l'insuffisance respiratoire chronique.

Long-term oxygen therapy (LOT) has become quite popular over the last 20 years due to better knowledge of the beneficial effect (improved life expectancy, improved quality of life, stabilization of the pulmonary hypertension) and to technological progress (concentrators, liquid oxygen). Ambulatory techniques have greatly contributed to the widespread use of oxygen therapy as has the decision of the French National Health Insurance System to reimburse this costly treatment. Almost all the studies devoted to the clinical and functional aspects of LOT have concerned patients with chronic obstructive pulmonary disease (COPD). By extension, it is generally accepted that LOT is warranted in other forms of respiratory failure (diffuse fibrosis, cyphoscoliosis, cystic fibrosis, etc.) when blood gas criteria similar to those retained for COPD are present: PaO(2)<=55 mmHg during stable periods with control measurements at lest 3 weeks apart; PaO(2) between 56 and 60 mmHg if there is also an elevated red cell count or pulmonary hypertension, signs of cor pulmonale ou frank hypoxemia during sleep. These consensus indications are widely accepted but other indications remain controversial: should LOT be prescribed for moderate hypoexmia (PaO(2) >=60 mmHg), exercise-induced hyoxemia alone, sleep hypoxemia alone? Appropriate studies are lacking so systematic prescription of LOT cannot be recommended in these three situations. The duration of LOT should be >=16 h/d, and if possible >=18 h/d. It has been established that objective results (life expectancy, improvement in pulmonary hypertension) are better for longer daily treatment. Patient compliance is however often insufficient. In addition to education, the best way to improve patient participation is to strive for improved quality of life with oxygen therapy (portable device, liquid oxygen) in these patients.

[Alveolar hypoventilation in the obese: the obesity-hypoventilation syndrome]. / L'hypoventilation alvéolaire de l'obèse: le syndrome obésité-hypoventilation.

The obesity-hypoventilation syndrome (or alveolar hypoventilation in the obese) is a new name for an old syndrome, Pickwickian syndrome. It is defined as chronic alveolar hypoventilation (PaO(2)<70 mmHg, PaCO(2) > 45 mmHg) in obese patient with a body mass index > 30 kg/m(2) who have no other respiratory disease explaining the gas anomalies. The large majority of obese subjects are not hypercapnic, even in case of severe obesity. There are three principal causes explaining alveolar hypoventilation in obese subjects: high cost of the work of respiration, dysfunction of the respiratory centers, repeated episodes of nocturnal obstructive apnea. The obesity-hypoventilation syndrome is generally found in males aged over 50 years. Exercise-induced breathlessness is a constant finding. Diagnosis is often made after an episode of severe respiratory failure. Associated diseases favored by obesity are frequent: diabetes, high blood pressure, heart disease. By definition, there is a hypoxemia-hypercapnia syndrome persisting after an acute episode. Spirography usually demonstrates moderate volume restriction. Pulmonary hypertension is frequent but not constant. Obesity-hypoventilation syndrome must be distinguished from obstructive sleep apnea, although the two conditions are often associated. Obstructive sleep apnea may be absent in certain patients with obesity-hypoventilation syndrome (we have had several cases) and inversely, obesity is not observed in certain patients with obstructive apnea. It should be recalled that the term Pickwickian syndrome designates obesity-hypoventilation syndrome (with or without obstructive apnea) and not obstructive sleep apnea syndrome.

[Therapeutic management of primary pulmonary hypertension]. / Prise en charge thérapeutique des hypertensions artérielles pulmonaires primitives.

SEVERITY AND TREATMENT: The management of primitive pulmonary hypertension starts by the evaluation of its severity, based on the New York Heart Association's (NYHA) functional classification and right cardiac catheterization data. Hemodynamic criteria of poor prognosis are: an increase in right atrial pressure > 10 mm Hg, a decrease in cardiac output (cardiac index < 2.2 l/min/m2), an increase in pulmonary vascular resistance > to 20 mm Hg/l/min/m2, and saturation of the oxygen content in venous blood < 63%. These prognostic data will condition treatment. CALCIUM CHANNEL BLOCKERS: Are the only vasodilators that have demonstrated efficacy in primitive pulmonary hypertension (PPH). However, only 20% of patients respond to calcium blockers. To determine a positive response to these agents, a carbon monoxide inhalation test is required during right cardiac catheterization. Prescription of calcium channel blockers to non-responders is often responsible for adverse events, from enhanced dyspnoea to sudden death. Continuous intravenous infusion of epoprostenol has considerably improved the prognosis of PPH and related pulmonary hypertension (PH). Despite the constraints, such treatment should be proposed to NYHA functional class III and IV patients not responding to carbon monoxide tests, until new, equally efficient products have been launched on the market. If epoprostenol fails or provokes severe side effects, pulmonary or cardio-pulmonary transplantation should be envisaged.