[Use of murine models for the study of obstructive sleep apnea syndrome in Down syndrome]. / Utilisation des modèles murins pour l'étude du syndrome d'apnées obstructives du sommeil dans le syndrome de Down.

Down syndrome (DS), or trisomy 21, is a genetic disorder caused by the presence of an extra copy of chromosome 21, leading to various characteristic physical features as well as developmental and cognitive delays. Obstructive sleep apnea syndrome (OSAS) is a common disorder in both adult and pediatric patients with DS. Several characteristics of DS may contribute to the development or worsening of OSAS. Numerous murine models of DS exist. A number of studies have explored apneas and the risk of upper airway obstruction in these models, but up until now, only in adulthood.

[The impact of obesity on respiratory function]. / Impact fonctionnel respiratoire de l'obésité.

The respiratory impact of obesity can be both symptomatic (resting and exertional breathlessness) and functional (pulmonary function at rest and on exercise). The prevalence of breathlessness is increased in adult obese individuals, ∼50% at rest and ∼75% on exertion (mMRC score>0). Pulmonary function abnormalities in obese adults include reduced functional residual capacity (FRC) and expiratory residual volume (ERV), and less frequently reduced total lung capacity (a restrictive defect, with TLC below the 5th percentile of predicted is present in around 15% in severe obese adults), with normal residual volume (RV). Airflows are barely affected by obesity, but bronchial hyperresponsiveness (BHR) is very prevalent, which may be due to the loss of bronchoprotective effect of deep inspiration in obesity (mechanical pathophysiology of BHR). In children, the modifications of lung volumes seen are quite different: TLC is normal while FRC and RV are reduced, explaining the increase in FVC. FEV1/FVC is therefore reduced by obesity, without true airflow obstruction (dysanaptic growth). Resting oxygen consumption (V'O2) is increased due to obesity and normally increases with exercise. Maximum V'O2 is normal or weakly reduced in obese patients; on the other hand, the increase in respiratory load increases the oxygen cost of ventilation, which tends to be rapid, both at rest and during exertion. Finally, it should be noted that there is only limited statistical correlation between exercise dyspnoea and respiratory function abnormalities in obesity.

[Pulmonary function testing of dyspnea complaint by the pulmonologist]. / Investigation fonctionnelle respiratoire de la dyspnée chronique par le pneumologue.

Dyspnea results from an imbalance between ventilatory demand (linked to CO2 production, PaCO2 set-point and wasted ventilation-physiological dead space) and ventilatory capacity (linked to passive-compliance, resistance-and active-respiratory muscles-components of the respiratory system). Spirometry and static lung volumes investigate ventilatory capacity only. Ventilatory demand (increased for instance in all pulmonary vascular diseases due to increased physiological dead space) is not evaluated by these routine measurements. DLCO measurement, which evaluates both demand and capacity, depicts the best statistical correlation to dyspnea, for instance in obstructive and interstitial pulmonary diseases. Dyspnea has multiple domains and is inherently complex and weakly explained by resting investigations: explained variance is below 50%. The diagnostic strategy investigating dyspnea has to distinguish complaints related or not to exercise because dyspnea can occur independently from any effort. Cardiopulmonary exercise testing (V'O2, V'CO2, V'E and operating lung volumes measurements) allows the assessment of underlying pathophysiological mechanisms leading to functional impairment and can contribute to unmask potential underlying mechanisms of unexplained dyspnea although its "etiological diagnostic value" for dyspnea remains a challenging issue.

[Guidelines for methacholine provocation testing]. / Recommandations pour le test de provocation bronchique à la méthacholine en pratique clinique, à partir de l'âge scolaire.

Bronchial challenge with the direct bronchoconstrictor agent methacholine is commonly used for the diagnosis of asthma. The "Lung Function" thematic group of the French Pulmonology Society (SPLF) elaborated a series of guidelines for the performance and the interpretation of methacholine challenge testing, based on French clinical guideline methodology. Specifically, guidelines are provided with regard to the choice of judgment criteria, the management of deep inspirations, and the role of methacholine bronchial challenge in the care of asthma, exercise-induced asthma, and professional asthma.

[Digital action plan for asthma exacerbations (PANAME)]. / Plan d'action numérique pour l'asthme en exacerbation : PANAME.

BACKGROUND: A written action plan (WAP) reduces emergency visits for asthma exacerbations. However, a WAP is underused and often focused on asthma control. The innovation is an AppWeb that includes an expert software aimed at diagnosing the level of severity of asthma exacerbations and delivering a personalized digital action plan (DAP) when patients are in urgent need of medical advice. Symptoms describing the level of severity of asthma exacerbations and the consequent treatments have been established by working groups of the French Respiratory Societies (SPLF and SP2A for adults and children, respectively). The main objective of the study is to evaluate the effect of the DAP on the frequency of urgent medical attendance. Secondary objectives are to evaluate adherence to the DAP compared to a WAP and the qualitative satisfaction of patients using the DAP. METHODOLOGY: A randomized, prospective, comparative, multicenter study on two parallel groups, conducted in private practice and in hospitals. In both arms, asthmatic patients (240 children aged 6 to 12 years and 270 adults aged 18 to 50 years) with severe asthma exacerbation(s) during the previous year and an Internet connection via a smartphone or a tablet computer, will have at their disposal a WAP and one arm will have, in addition, the DAP. Included patients will be followed up every three months for one year. EXPECTED RESULTS: A decrease in the number of urgent medical attendances and better adherence in the WAP+DAP group compared to the WAP group.

[Mechanisms of non-specific airway hyperresponsiveness: Methacholine-induced alterations in airway architecture]. / Mécanismes de l'hyperréactivité bronchique non spécifique : modifications de l'architecture des voies aériennes induites par la méthacholine.

Multiple mechanisms drive non-specific airway hyperresponsiveness in asthma. At the organ level, methacholine inhalation induces a complex bronchomotor response involving both bronchoconstriction and, to some extent, paradoxical bronchodilatation. This response is heterogeneous both serially, along a single bronchial axis, and in parallel, among lung regions. The bronchomotor response to methacholine induces contraction of distal airways as well as focal airway closure in select lung territories, leading to anatomically defined ventilation defects and decreased vital capacity. In addition, loss of the bronchoprotector and bronchodilator effects of deep inspirations is a key contributor to airway hyperresponsiveness in asthma.

[Interpretation and use of routine pulmonary function tests: Spirometry, static lung volumes, lung diffusion, arterial blood gas, methacholine challenge test and 6-minute walk test]. / Interprétation et utilisation des explorations fonctionnelles respiratoires de routine de l'adulte : spirométrie, volumes non mobilisables, diffusion, hématose, test de provocation bronchique à la métacholine et test de marche.

Resting pulmonary function tests (PFT) include the assessment of ventilatory capacity: spirometry (forced expiratory flows and mobilisable volumes) and static volume assessment, notably using body plethysmography. Spirometry allows the potential definition of obstructive defect, while static volume assessment allows the potential definition of restrictive defect (decrease in total lung capacity) and thoracic hyperinflation (increase in static volumes). It must be kept in mind that this evaluation is incomplete and that an assessment of ventilatory demand is often warranted, especially when facing dyspnoea: evaluation of arterial blood gas (searching for respiratory insufficiency) and measurement of the transfer coefficient of the lung, allowing with the measurement of alveolar volume to calculate the diffusing capacity of the lung for CO (DLCO: assessment of alveolar-capillary wall and capillary blood volume). All these pulmonary function tests have been the subject of an Americano-European Task force (standardisation of lung function testing) published in 2005, and translated in French in 2007. Interpretative strategies for lung function tests have been recommended, which define abnormal lung function tests using the 5th and 95th percentiles of predicted values (lower and upper limits of normal values). Thus, these recommendations need to be implemented in all pulmonary function test units. A methacholine challenge test will only be performed in the presence of an intermediate pre-test probability for asthma (diagnostic uncertainty), which is an infrequent setting. The most convenient exertional test is the 6-minute walk test that allows the assessment of walking performance, the search for arterial desaturation and the quantification of dyspnoea complaint.

Contribution of exhaled nitric oxide measurement in airway inflammation assessment in asthma. A position paper from the French Speaking Respiratory Society.

Nitric oxide (NO) is both a gas and a ubiquitous inter- and intracellular messenger with numerous physiological functions. As its synthesis is markedly increased during inflammatory processes, NO can be used as a surrogate marker of acute and/or chronic inflammation. It is possible to quantify fractional concentration of NO in exhaled breath (FENO) to detect airway inflammation, and thus improve the diagnosis of asthma by better characterizing asthmatic patients with eosinophilic bronchial inflammation, and eventually improve the management of targeted asthmatic patients. FENO measurement can therefore be viewed as a new, reproducible and easy to perform pulmonary function test. Measuring FENO is the only non-invasive pulmonary function test allowing (1) detecting, (2) quantifying and (3) monitoring changes in inflammatory processes during the course of various respiratory disorders, including corticosensitive asthma.

Granulocytic myeloid-derived suppressor cells inversely correlate with plasma arginine and overall survival in critically ill patients.

Critically ill patients display a state of immunosuppression that has been attributed in part to decreased plasma arginine concentrations. However, we and other authors have failed to demonstrate a clinical benefit of L-arginine supplementation. We hypothesize that, in these critically ill patients, these low plasma arginine levels may be secondary to the presence of granulocytic myeloid-derived suppressor cells (gMDSC), which express arginase known to convert arginine into nitric oxide (NO) and citrulline. Indeed, in a series of 28 non-surgical critically ill patients, we showed a dramatic increase in gMDSC compared to healthy subjects (P = 0·0002). A significant inverse correlation was observed between arginine levels and gMDSC (P = 0·01). As expected, gMDSC expressed arginase preferentially in these patients. Patients with high gMDSC levels on admission to the medical intensive care unit (MICU) presented an increased risk of death at day 7 after admission (P = 0·02). In contrast, neither plasma arginine levels, monocytic MDSC levels nor neutrophil levels were associated with overall survival at day 7. No relationship was found between body mass index (BMI) or simplified acute physiology score (SAPS) score, sequential organ failure assessment (SOFA) score or gMDSC levels, eliminating a possible bias concerning the direct prognostic role of these cells. As gMDSC exert their immunosuppressive activity via multiple mechanisms [production of prostaglandin E2 (PGE2 ), interleukin (IL)-10, arginase, etc.], it may be more relevant to target these cells, rather than simply supplementing with L-arginine to improve immunosuppression and its clinical consequences observed in critically ill patients.

[Idiopathic pulmonary fibrosis: diagnosis and treatment in 2013]. / Fibrose pulmonaire idiopathique : prise en charge diagnostique et thérapeutique en 2013.

Idiopathic pulmonary fibrosis (IPF), the etiopathogeny of which is still unknown, is the most frequent and severe of idiopathic interstitial pneumonias. It progressively leads, sometimes more acutely when exacerbations occur, to a restrictive respiratory insufficiency. Its prognosis is very dark with a median survival of 3-5 years. No treatment so far has been curative. Its diagnostic and therapeutic management has been greatly improved due to the technical progress in terms of high-resolution tomodensitometry, to the availability of new drugs with a real antifibrotic potential and to the production of international recommendations. The diagnosis is reached in 2/3 of IPF patients presenting with a typical usual interstitial pneumonitis (UIP) CT-scan pattern. It requires a videothoracoscopic biopsy in the remaining patients. Multidisciplinary discussions are key to a proper diagnosis of IPF. Pirfenidone is presently the only drug with a real antifibrotic potential in mild to moderate forms of the disease (FVC>50% and DLCO>35% predicted). The other ones have proved either inefficient or toxic. It is highly recommended to include patients in innovative targeted protocols. Non-pharmacological management of these patients comprises long-term oxygen therapy, pulmonary rehabilitation and overall lung transplantation. Pulmonary hypertension, to be detected regularly during the follow-up, is associated to a dark prognosis. No specific treatment is efficient in this context. Several comorbidities, particularly frequent in IPF, should be treated when present: gastro-oesophageal reflux, obstructive sleep apnea, emphysema. The particular high frequency of bronchopulmonary cancer should be highlighted.

[Lung volume reduction surgery for emphysema and bullous pulmonary emphysema]. / Chirurgie de réduction volumique et des bulles géantes dans l'emphysème pulmonaire.

The improvement of respiratory symptoms for emphysematous patients by surgery is a concept that has evolved over time. Initially used for giant bullae, this surgery was then applied to patients with diffuse microbullous emphysema. The physiological and pathological concepts underlying these surgical procedures are the same in both cases: improve respiratory performance by reducing the high intrapleural pressure. The functional benefit of lung volume reduction surgery (LVRS) in the severe diffuse emphysema has been validated by the National Emphysema Treatment Trial (NETT) and the later studies which allowed to identify prognostic factors. The quality of the clinical, morphological and functional data made it possible to develop recommendations now widely used in current practice. Surgery for giant bullae occurring on little or moderately emphysematous lung is often a simpler approach but also requires specialised support to optimize its results.

[Physiological characteristics associated with previous control in asthmatic children]. / Caractéristiques fonctionnelles associées au contrôle antérieur chez l'enfant asthmatique.

OBJECTIVE: To analyze MEF(50%) (central airways), RV/TLC (distal airways), reversibility of FEV(1) (bronchial tone, REV(FEV1)) and FE(NO) (inflammation) in relation to clinical events in asthmatic children on the assumption that mild symptoms and severe exacerbations in the previous 3 months could be associated with distinct functional characteristics. PATIENTS AND METHODS: A retrospective, single center, out-patient hospital study including all asthmatic children who had complete lung function testing (without and with bronchodilation) during a period of clinical stability, without treatment on the day of the test. RESULTS: Two hundred and forty-five children (11.4±2.4 years) were included: 114 (46%) were asymptomatic, 87 (36%) had minor symptoms and 44 (18%) had had a severe exacerbation in the past 3 months. FEV(1), FEV(1)/FVC and MEF(50%) were not different in these three groups. REV(FEV1) was higher in the symptomatic than in the asymptomatic group (P=0.019), RV/TLC was greater in the exacerbation group than in the asymptomatic group (P=0.019), and FE(NO) was higher in the symptomatic group than in the asymptomatic and exacerbation groups (P=0.006). CONCLUSIONS: In asthmatic children, minor symptoms and severe exacerbation in the previous 3 months are associated with distinct functional characteristics that are not detected by single baseline spirometry without treatment on the day of testing.

Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity.

BACKGROUND: Exhaled NO can be partitioned in its bronchial and alveolar sources, and the latter may increase in the presence of recent asthmatic symptoms and in refractory asthma. The aim of this multicentre prospective study was to assess whether alveolar NO fraction and FE(NO) could be associated with the level of asthma control and severity both at the time of measurement and in the subsequent 3 months. METHODS: Asthma patients older than 10 years, nonsmokers, without recent exacerbation and under regular treatment, underwent exhaled NO measurement at multiple constant flows allowing its partition in alveolar (with correction for back-diffusion) and bronchial origins based on a two-compartment model of NO exchange; exhaled NO fraction at 50 ml/s (FE(NO,0.05)) was also recorded. On inclusion, severity was assessed using the four Global initiative for asthma (GINA) classes and control using Asthma Control Questionnaire (ACQ). Participants were followed-up for 12 weeks, control being assessed by short-ACQ on 1st, 4th, 8th and 12th week. RESULTS: Two-hundred patients [107 children and 93 adults, median age (25th; 75th percentile) 16 years (12; 38)], 165 receiving inhaled corticosteroid, were included in five centres. The two-compartment model was valid in 175/200 patients (87.5%). Alveolar NO and FE(NO,0.05) did not correlate to control on inclusion or follow-up (either with ACQ /short-ACQ values or their changes), nor was influenced by severity classes. Alveolar NO negatively correlated to MEF(25-75%) (rho = -0.22, P < 0.01). CONCLUSION: Alveolar and exhaled NO fractions are not indexes of control or severity in asthmatic children and adults under treatment.

Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-kappaB and endothelin-1.

Pulmonary hypertension is rare in chronic respiratory diseases but has a strong impact on the prognosis and is partly underlined by factors other than hypoxaemia. The aim of the present study was to assess the potential role of endothelin-1 (ET-1) and nuclear factor (NF)-kappaB vasoconstrictive pathways in pulmonary hypertension. The effects of ET-1 receptors blockers (BQ 123 and 788) and of genistein were assessed on response to acetylcholine of pulmonary vascular rings from cystic fibrosis (CF) lung transplant recipients (n = 23). NF-kappaB and ET-1 receptor expression was immunodetected in pulmonary arteries and quantitated using Western blotting. ET-1 vascular content was quantitated using ELISA. In total, 14 out of 23 subjects exhibited strongly impaired pulmonary vasodilation (p<0.01 versus nine out of 23 subjects with a normal response) associated with an activation of ET-1 receptors A and NF-kappaB pathways. Genistein restored vasodilation in subjects with an abnormal response. Pulmonary vascular dysfunction is frequent in end-stage CF, involving the NF-kappaB pathway and that of ET-1 through ET-1 receptor A (ETAR). These data leave a conceptual place for ETAR blockers and isoflavones in the management of the devastating vascular complication of chronic obstructive respiratory diseases such as CF.

Exhaled nitric oxide in cystic fibrosis: relationships with airway and lung vascular impairments.

A reduction of exhaled nitric oxide (NO) fraction and endothelial-mediated dysfunction have been reported in cystic fibrosis (CF). The aims of the present study were to search for relationships between flow-independent NO exchange parameters (bronchial NO flux (J'(aw,NO)) and alveolar NO concentration (C(A,NO))) and lung function tests characterising airflow limitation and pulmonary vascular bed (capillary blood volume and physiological dead space/tidal volume (V(D)/V(T)) ratio on exercise). In total, 34 patients (16 children, 18 adults) with CF, without resting pulmonary hypertension, underwent spirometry, exhaled NO measurement (multiple constant flow analytical method), gas transfer assessment (carbon monoxide and NO, allowing the calculation of capillary volume and membrane conductance) and a graded exercise test with oxygen uptake (V'(O(2))), carbon dioxide production (V'(CO(2))) and arterial blood gas evaluations. Both J'(aw,NO) and C(A,NO )correlated positively with airflow limitation. C(A,NO) correlated positively with capillary/alveolar volume. During exercise, criteria of mild pulmonary vascular disease were evidenced in some patients that participated in exercise limitation (negative correlation between physiological V(D)/V(T) and peak V'(O(2))). C(A,NO )at rest correlated positively with these parameters of wasted ventilation during exercise (physiological V(D)/V(T), minute ventilation (V'(E))/V'(CO(2)) at ventilatory threshold and V'(E)/V'(CO(2)) slope). Flow-independent exhaled NO parameters are linked to airway and early vascular diseases in patients with CF.

Nitric oxide evaluation in upper and lower respiratory tracts in nasal polyposis.

BACKGROUND: A decrease in nasal nitric oxide (NO) and an increase in exhaled NO have been demonstrated in patients with nasal polyposis (NP). OBJECTIVES: The aims were to evaluate the flux of NO from the three compartments of the respiratory tract, namely, upper nasal, lower conducting and distal airways, and to search for relationships between NO parameters and indexes of upper and lower disease activity (bronchial reactivity and obstruction). The effect of medical treatment of polyposis was also evaluated. METHODS: Seventy patients with polyposis were recruited. At baseline, pulmonary function tests (spirometry, plethysmography, bronchomotor response to deep inspiration using forced oscillation measurement of resistance of respiratory system, methacholine challenge, multiple flow rates of exhaled NO and nasal NO measurements) were performed together with an assessment of polyposis [clinical, endoscopic and computed tomography (CT) scores]. RESULTS: Statistical relationships were demonstrated between nasal NO flux and severity scores (clinical: rho=-0.31, P=0.015; endoscopic: rho=-0.57, P<0.0001; CT: rho=-0.46, P=0.0005), and between alveolar NO concentration and distal airflow limitation (FEF(25-75), rho=-0.32, P=0.011). Thirty-six patients were assessed after 11 [7-13] (median [interquartile]) months of medical treatment, demonstrating an improvement in clinical and endoscopic scores, an increase in nasal NO flux, a decrease in NO flux from conducting airways, an improvement in the mild airflow limitation (forced expiratory volume in 1 s, FEF(25-75), even in non-asthmatic patients) and a decrease in the bronchoconstrictor effect of deep inspiration. CONCLUSIONS: The medical treatment of NP improves both airway reactivity and obstruction, whatever the presence of asthma, suggesting a functional link between upper and lower airway functions.

[Measurement of exhaled nitric oxide: methodology]. / Mesure du NO expiré: méthodologie.

INTRODUCTION: The singular relationship between the exhaled nitric oxide (NO) fraction and the expiratory flow rate has both technical (subject of international guidelines) and theoretical (modelling of pulmonary NO exchange) implications. STATE OF THE ART: Guidelines recommend the measurement of exhaled NO at a single, defined, expiratory flow rate (V') against a positive expiratory pressure to ensure velum closure, providing a fraction of exhaled NO, FE(NO,V'). With some oversimplifications concerning the relationship between FENO and V', NO exchange parameters independent of the expiratory flow rate can be calculated based on a two-compartment model: maximum conducting airway NO flux (J'awNO), alveolar NO concentration (CalvNO), and in some conditions, airway NO diffusing capacity (DawNO) and epithelial NO concentration of conducting airways (CawNO). PERSPECTIVES: Technical progress has provided the pulmonologist with simple equipment to allow the determination of the NO output from the respiratory tract. The two-compartment model provides the physiologist with a non-invasive technique for evaluating the contribution of alveolar space and conducting airways. CONCLUSION: The measurement of exhaled NO allows the non-invasive evaluation of a key mediator involved in the regulation of biological processes.

[The place of expired nitric oxide measurements in asthma]. / Place de la mesure du NO expiré dans l'asthme.

INTRODUCTION: The production of nitric oxide (NO) can be assessed by measuring the fraction of NO during a prolonged expiration (FENO) or by estimating other parameters of NO exchange including the alveolar NO concentration (CalvNO). STATE OF THE ART: Changes in the production of NO are seen in association with clinical events (allergen exposure, minor symptoms, acute crises, changes of treatment) and functional (bronchial hyper-reactivity) or pathological (eosinophilia, remodeling markers) features characterising asthmatic phenotypes. PERSPECTIVE: Measurement of NO is a non-invasive tool for the evaluation of atopy, particularly in the course of allergic asthma. The interpretation of a single measurement is limited by the variability of the values associated with a stable state in the allergic population: the use in practice (risk of exacerbation, follow up, adjustment of steroid treatment) depends on analysis of sequential variations in FENO. Calculation of CalvNO may provide information about small airway inflammation and assist the optimal control of the disease. CONCLUSION: Ambulatory measurement of expired NO and the estimation of parameters describing NO exchange, independently of expiratory flow, could become the key evaluations in the monitoring of allergic asthma.

[Off-line exhaled nitric oxide measurement in children]. / Mesure de la fraction expirée de NO chez l'enfant par une analyse extemporanée.

INTRODUCTION: The objective is to test the validity of a tool allowing an offline measurement of the fraction of expired nitric oxide (FENO). The device is a T-tube on which a pressure gauge allows the control of the expiratory flow and whose two side branches have a gauge such as the bags assembled on each one of them fill successively. METHODS: The first phase aims to check that the sample collected in the second bag answers the criteria of analysis of NO during a single expiration and that this measurement can be delayed. The second phase aims to test the feasibility and the repeatability of the offline analysis in children. RESULTS: The device makes it possible to stabilize the expiratory flow at 100 ml/s. The NO concentration in the second bag is stable during 6 hours. The intra measurement coefficient of variation of delayed FENO 0.1 is 7% (N = 19). CONCLUSION: A off line measurement of the exhaled nitric oxide is reliable in asthmatic children.