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SUMMARYThe objective of this study was to determine how clinicians make use of the modern multiplex PCR assays (MPAs) to manage patients hospitalized for community-acquired pneumonia (CAP). We studied the use of MPAs in 1648 patients hospitalized for CAP over a 3-year period at the moment of the setup of the new PCR assay. We observed that the use of MPAs for the identification of multiple respiratory pathogens marks a radical change in the investigation of CAP etiology. Surprisingly, the contribution of MPAs to the medical decision-making process varies drastically according to the units of care.

International audience; By 2020, chronic obstructive pulmonary disease (COPD) will be the third cause of mortality. Extrapulmonary comorbidities influence the prognosis of patients with COPD. Tobacco smoking is a common risk factor for many comorbidities, including coronary heart disease, heart failure and lung cancer. Comorbidities such as pulmonary artery disease and malnutrition are directly caused by COPD, whereas others, such as systemic venous thromboembolism, anxiety, depression, osteoporosis, obesity, metabolic syndrome, diabetes, sleep disturbance and anaemia, have no evident physiopathological relationship with COPD. The common ground between most of these extrapulmonary manifestations is chronic systemic inflammation. All of these diseases potentiate the morbidity of COPD, leading to increased hospitalisations and healthcare costs. They can frequently cause death, independently of respiratory failure. Comorbidities make the management of COPD difficult and need to be evaluated and treated adequately. Extrapulmonary comorbidities are common in COPD and influence prognosis; we propose an exhaustive comorbidities review

To the Editor: Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia, accounting for 40% of all cases in individuals >65 years of age. Thoracic complications of CLL can be classified into three groups: 1) infectious complications, which are by far the most frequent and are directly related to the severity of immunodeficiency secondary either to leukaemia or therapy; 2) pleural effusions that are either in CLL localisation or related to venous or lymphatic compression caused by a mass or lymph node, and 3) specific bronchopulmonary involvement secondary to lymphocytic infiltration. Specific bronchopulmonary involvement due to chronic lymphocytic leukaemia (or pathologic leukaemic bronchopulmonary infiltration (LBPI)) is rare and there are few reports in the literature. We report the cases of six patients with CLL and bronchopulmonary leukaemic infiltrates who needed specific treatment due to the severity of respiratory symptoms. The patients’ characteristics are summarised in table S1 in the online supplementary material. All patients gave their written informed consent for inclusion in this report. The six patients were all males. Mean age was 70 years (range 64–74 years). Patient 1 was a current smoker (40 pack-years) and patients 4 and 6 were former smokers (10 PA). CLL had been diagnosed in all patients through a combination of blood hyperlymphocytosis, characteristic lymphocyte morphology and immunophenotyping carried out in the Haematology Department (Tours university Hospital, Tours, France), an average of 6.2 years previously (range 3–14 years). At diagnosis, none of the patients presented with respiratory symptoms or computed tomography (CT) scan abnormalities indicative of LBPI. Patients 1, 2, 4, 5 and 6 had a previous pulmonary history of infectious pneumonia. Only patient 1 had never received specific CLL treatment. All …

Gastro-oesophageal reflux has long been suspected of implication in the genesis and progression of idiopathic pulmonary fibrosis (IPF). We hypothesised that hiatal hernia may be more frequent in IPF than in other interstitial lung disease (ILD), and that hiatal hernia may be associated with more severe clinical characteristics in IPF.We retrospectively compared the prevalence of hiatal hernia on computed tomographic (CT) scans in 79 patients with IPF and 103 patients with other ILD (17 scleroderma, 54 other connective tissue diseases and 32 chronic hypersensitivity pneumonitis). In the IPF group, we compared the clinical, biological, functional, CT scan characteristics and mortality of patients with hiatal hernia (n=42) and without hiatal hernia (n=37).The prevalence of hiatal hernia on CT scan at IPF diagnosis was 53%, similar to ILD associated with scleroderma, but significantly higher than in the two other ILD groups. The size of the hiatal hernia was not linked to either fibrosis CT scan scores, or reduction in lung function in any group. Mortality from respiratory causes was significantly higher among IPF patients with hiatal hernia than among those without hiatal hernia (p=0.009).Hiatal hernia might have a specific role in IPF genesis, possibly due to pathological gastro-oesophageal reflux.

Monoclonal antibody (mAb) therapeutics have tremendous potential to benefit patients with lung diseases, for which there remains substantial unmet medical need. To capture the current state of mAb research and development in the area of respiratory diseases, the Research Center of Respiratory Diseases (CEPR-INSERM U1100), the Laboratory of Excellence “MAbImprove,” the GDR 3260 “Antibodies and therapeutic targeting,” and the Grant Research program ARD2020 “Biotherapeutics” invited speakers from industry, academic and government organizations to present their recent research results at the Therapeutic Monoclonal Antibodies for Respiratory Diseases: Current challenges and perspectives congress held March 31 – April 1, 2016 in Tours, France.

Ribavirin is an old drug that was developed and approved in the late 1980s to treat respiratory syncitial virus infections. It can be administered orally, intravenously, or by inhalation using a nebulizer. At the time it was developed, continuous nebulization was considered a valuable method to

COPD is a slowly progressive chronic respiratory disease causing an irreversible decrease in air flow. The main cause is smoking, which provokes inflammatory phenomena in the respiratory tract. COPD is a serious public health issue, causing high morbidity, mortality and disability. Related comorbidities are linked to ageing, common risk factors and genetic predispositions. A combination of comorbidities increases healthcare costs. For instance, patients with more than two comorbidities represent a quarter of all COPD sufferers but account for half the related health costs. Our review describes different comorbidities and their impact on the COPD prognosis. The comorbidities include: cardiovascular diseases, osteoporosis, denutrition, obesity, ageing, anemia, sleeping disorders, diabetes, metabolic syndrome, anxiety-depression and lung cancer. The prognosis worsens with one or more comorbidities. Clinicians are faced with the challenge of finding practical and appropriate ways of treating these comorbidities, and there is increasing interest in developing a global, multidisciplinary approach to management. Managing this chronic disease should be based on a holistic, patient-centred approach and smoking cessation remains the key factor in the care of COPD patients.

Introduction Les exacerbations d’asthme correspondent à des aggravations rapides des symptômes respiratoires et sont responsables d’une morbidité et mortalité importantes. Les infections virales figurent parmi les causes les plus fréquentes des exacerbations mais les données épidémiologiques sont, dans leur grande majorité, issues de cohorte de pays tempérés. Peu de données sont disponibles dans les pays tropicaux malgré une augmentation de la prévalence de l’asthme dans ces régions ces dernières années. Méthodes Dans cette étude observationnelle réalisée sur l’année 2015, l’épidémiologie virale de patients adultes hospitalisés pour exacerbation d’asthme a été comparée entre la ville de Saint Pierre à la Réunion (climat tropical) et de Tours (climat tempéré). Un portage viral était recherché à l’entrée à l’hôpital par polymerase chain reaction (PCR) multiplex sur aspiration nasopharyngée. Seize virus ont été analysés : VRS A et B, rhinovirus, métapneumovirus, myxovirus influenzae A, H1N1, H5N1, parainfluenzae de 1 à 4, coronavirus 229E, NL63 et OC43, adénovirus, entérovirus. À la Réunion, le panel de virus recherché comprenait en plus coronavirus HKU1, bocavirus et paréchovirus. Résultats Au total, 100 patients ont été inclus dont 62 à Saint Pierre et 38 à Tours. La présence d’au moins un virus est retrouvé dans les aspirations naso-pharyngées chez 53 % des patients à Tours et 31 % des patients à Saint Pierre (p

Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations.

International audience; Backround: Glycopeptides given intravenously achieve low airway concentrations. Nebulization of teicoplanin may be an efficient way of delivering a high concentration of this antibiotic to the lung. This multistep study assessed the feasibility of teicoplanin nebulization during mechanical ventilation by evaluating: the stability of its antibiotic effect; epithelial tolerance; lung deposition and systemic absorption in ventilated pigs. Nebulized and non-nebulized teicoplanin activity was tested on Staphylococcus aureus cultures. The cytotoxic effect of teicoplanin on human respiratory epithelial cells was assessed by measuring lactate dehydrogenase activity released, cell viability, and transepithelial electrical resistance. Volume median diameter of particles of nebulized teicoplanin was measured by laser diffraction during mechanical ventilation. The deposited mass of teicoplanin nebulized with a vibrating mesh nebulizer in ventilated piglets was assessed by scintigraphy. Blood pharmacokinetics of teicoplanin administered either intravenously or by nebulization was compared. No decrease of antibiotic activity was observed after nebulization. In vitro cytotoxicity of teicoplanin was only observed with 1000 times the dose recommended for intravenous administration. Volume median diameter of particles was 2.5±0.1 μm. Of the initial nebulizer charge of teicoplanin, 24±7% was present in the lungs of ventilated pigs after the nebulization. Amount absorbed in blood was low (3.4%±0.9%) after nebulization, and blood stream elimination half-life value was 25.4 h. Teicoplanin was administered efficiently by nebulization during mechanical ventilation, without any effect on its pharmacological properties or any cytotoxicity. The pharmacokinetic parameters are promising in view of its time-dependent killing process. All the results of our multi-step study highlighted the potential of teicoplanin to be nebulized during mechanical ventilation.

Most monoclonal antibodies (mAbs) are administered to patients intravenously to ensure high bioavailability as rapidly as possible. The airways, however, are an attractive delivery route for mAbs for the treatment of lung diseases, making it possible to increase their concentration in the target organ while limiting their systemic passage. Several challenges must be overcome for translation into clinical practice. For example, the drug and device must be paired for the efficient and reliable deposition of a pharmacologically active and safe mAb in the lung region of interest. Mesh nebulizers appear to be the most effective aerosol-producing devices for delivering large amounts of biopharmaceutical while limiting protein instability during nebulization. We used metrological and analytic methods to analyze the effect of both antibody concentration and surfactant addition on aerosol performance and antibody integrity. These two factors had a limited effect on aerosol performance, but affected antibody aggregation. The addition of surfactants to antibody formulations at concentrations appropriate for lung administration markedly reduced the formation of medium or large aggregates, as shown by dynamic light scattering and fluorescence microscopy. Aggregation was also dependent on the type of mesh nebulizer, highlighting the need to optimize drug and device together.

International audience; Invasive pulmonary aspergillosis remains a matter of great concern in oncology/haematology, intensive care units and organ transplantation departments. Despite the availability of various diagnostic tools with attractive features, new markers of infection are required for better medical care. We therefore looked for potential pulmonary biomarkers of aspergillosis, by carrying out two-dimensional (2D) gel electrophoresis comparing the proteomes of bronchial-alveolar lavage fluids (BALF) from infected rats and from control rats presenting non-specific inflammation, both immunocompromised. A bioinformatic analysis of the 2D-maps revealed significant differences in the abundance of 20 protein spots (ANOVA P-value0.8). One of these proteins, identified by mass spectrometry, was considered of potential interest: inter-alpha-inhibitor H4 heavy-chain (ITIH4), characterised for the first time in this infectious context. Western blotting confirmed its overabundance in all infected BALF, particularly at early stages of murine aspergillosis. Further investigations were carried on rat serum, and confirmed that ITIH4 levels increased during experimental aspergillosis. Preliminary results in human samples strengthened this trend. To our knowledge, this is the first description of the involvement of ITIH4 in aspergillosis.

International audience; Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream.

International audience; Neutrophil serine proteases in cystic fibrosis (CF) lung secretions partially resist inhibition by natural and exogenous inhibitors, mostly because DNA impairs their control. Cationic polypeptides display the property of condensing DNA and retain antimicrobial properties. We hypothesized that DNA condensation by cationic polypeptides in CF sputum would result in a better control of CF inflammation and infection.OBJECTIVES:We examined whether poly-L-lysine would compact DNA in CF lung secretions and liquefy CF sputum, improve the control of extracellular proteases by exogenous inhibitors, and whether it displays antibacterial properties toward CF-associated bacteria.METHODS:We used fluorogenic methods to measure proteolytic activities and inhibition by protease inhibitors in whole sputum homogenates from patients with CF before and after treatment with poly-L-lysine. Antibacterial properties of poly-L-lysine were measured in bacterial cultures and in whole CF sputum. Poly-L-lysine toxicity was evaluated after aerosolization by histologic analysis, flow cytometry, and quantification of proinflammatory cytokines.MEASUREMENTS AND MAIN RESULTS:Poly-L-lysine compacts CF sputum DNA, generating a liquid phase that improves ciliary beating frequency at the lung epithelial surface, and allows the control of neutrophil elastase and cathepsin G by their natural inhibitors. It retains antimicrobial properties against Pseudomonas aeruginosa and Staphylococcus aureus at doses that induce no inflammation in the mouse lung after aerosol administration.CONCLUSIONS:Poly-L-lysine may be an alternative to dornase-α to liquefy sputum with added benefits because it helps natural inhibitors to better control the deleterious effects of extracellularly released neutrophil serine proteases and has the ability to kill bacteria in CF sputum.

International audience; Aim: Intranasal aerosol administration of drugs is widely used by ENT specialists. Although clinical evidence is still lacking, intranasal nebulization appears to be an interesting therapeutic option for local drug delivery, targeting anatomic sites beyond the nasal valve. The sonic nebulizer NL11SN associates a 100 Hertz (Hz) sound to the aerosolization to improve deposition in the nasal/paranasal sinuses. The aim of the present study was: to evaluate in vivo the influence of associating a 100 Hz sound on sinus ventilation and nasal and pulmonary aerosol deposition in normal volunteers, and; to quantify in vitro aerosol deposition in the maxillary sinuses in a plastinated head model. Material and methods: Scintigraphic analysis of 81mKr gas ventilation and of sonic aerosol (99mTc-DTPA) deposition using the NL11SN was performed in vivo in seven healthy volunteers. In parallel, NL11SN gentamicin nebulization was performed, with or without associated 100 Hz sound, in a plastinated human head model; the gross amount of gentamicin delivered to the paranasal sinuses was determined by fluorescence polarization immunoassay. Results: Associating the 100 Hz sound to 81mKr gas ensured paranasal sinus ventilation in healthy volunteers. 99mTc-DTPA particles nebulized with the NL11SN were deposited predominantly in the nasal cavities (2/3, vs 1/3 in the lungs). In vitro, the use of NL11SN in sonic mode increased gentamicin deposition threefold in the plastinated model sinuses (P < 0.002); the resulting antibiotic deposit would be sufficient to induce a local therapeutic effect. Conclusion: The NL11SN nebulizer ensured preferential nasal cavity aerosol deposition and successfully targeted the maxillary sinuses.

Lung cancer is the leading cause of cancer-related death worldwide. The efficacy of current systemic treatments is limited, with major side effects and only modest survival improvements. Aerosols routinely used to deliver drugs into the lung for treating infectious and inflammatory lung diseases have never been used to deliver monoclonal antibodies to treat lung cancer. We have shown that cetuximab, a chimeric anticancer anti-EGFR mAb, is suitable for airway delivery as it resists the physical constraints of aerosolization, and have evaluated the aerosol delivery of cetuximab in vivo.We developed an animal model of lung tumor sensitive to cetuximab by injecting Balb/c Nude mice intratracheally with A431 cells plus 10 mM EDTA and analyzed the distribution, pharmacokinetics and antitumor efficacy of cetuximab aerosolized into the respiratory tract.Aerosolized IgG accumulated durably in the lungs and the tumor, but passed poorly and slowly into the systemic circulation. Aerosolized cetuximab also limited the growth of the mouse tumor. Thus, administering anticancer mAbs via the airways is effective and may limit systemic side effects.Delivery of aerosolized-mAbs via the airways deserves further evaluation for treating lung cancers.

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The use of recombinant GM-CSF in the treatment of pulmonary alveolar proteinosis (PAP) has been reported recently in Thorax 1,2 in cases with anti-GM-CSF antibodies. We report the successful use of GM-CSF in a patient with no GM-CSF antibodies, which provides further evidence for considering GM-CSF as a possible keystone to the treatment of PAP. A 35 year old man with a past history of idiopathic marrow aplasia treated with antilymphocytic serum in 1983 and Mycobacterium avium systemic infection presented in February 1999 with a 4 month history of dyspnoea. A diagnosis of PAP was suspected from the HRCT scan which showed …

Background PAPRICA is a research program designed to estimate the impact on the health of patients with chronic respiratory insufficiency of a prevention strategy based on notification of ozone pollution. The first year of this study was conducted during the 2003 heat wave, and high temperatures were therefore considered as a confounding factor in the data analysis. The aim of the present study was to assess the relationship between ozone and temperature in order to propose a methodology to distinguish between the effects of ozone and temperature on the impact of a prevention strategy with regard to ozone pollution. Methods Multivariate analyses were used to identify associated climate and ozone pollution profiles. This descriptive method is of great value to highlight the complexity of interactions between these parameters. Results Ozone concentration and temperature were strongly correlated, but the health impact of ozone pollution alone will be evaluated by focusing on situations characterized by ozone concentrations above 110 μg/m3/8h (air quality guidelines to protect human health defined by the French legislation) and temperatures lower than 26°C, below the discomfort threshold. Conclusion The precise relationship between ambient ozone concentration and temperature identified during the PAPRICA 2003 study period will be used in analysing the PAPRICA health data.

Summary Amiodarone-induced pulmonary toxicity (APT) is a serious adverse event that can lead to death. The aims of our study are to determine factors associated with mortality and to describe outcome and sequelae of patients with APT. Methods Forty-six patients with APT were divided into two groups according to survival at day 90 for a clinical, functional, biological and radiological comparaison. We then evaluated the evolution of 15 survivors at a median of three months [1–6 months] and/or 12 months [8–36 months]. Results Mortality of APT at day 90 was 37% (17 patients) and was linked to the speed of onset of symptoms and a high HRCT alveolar score. Angiotensin system antagonist treatment was prescribed significantly more in the survival group ( p = 0.042, HR 0.34 (95% CI 0.12–0.96)). In surviving patients, dyspnea, vital capacity and HRCT alveolar score improved significantly while HRCT fibrosis score deteriorated gradually during the first six months. At the end of the study, all the surviving patients presented functional and/or radiological sequelae. Conclusions Severity of APT is linked to the extent and speed of onset of pulmonary damage. After the initial episode, the patients who survived improved slowly but with persistent sequelae.

SummaryA new anticholinergic aerosol containing 0.5mg ipratropium bromide dissolved in 1mL of solution has been produced with the purpose of decreasing nebulization time for patients compared to the traditional formulation which is twice as voluminal (0.5mg/2mL, Boehringer-Ingelheim, France). The aim of this study was to compare aerosol characteristics (inhaled mass, particle size distribution and nebulization time) of these two formulations of ipratropium bromide, nebulized alone and with terbutaline (5mg/2mL, Astra Zeneca, Sweden), to determine whether the new formulation was equivalent to the old one. Four different jet nebulizers were used: PariLC+®, Atomisor NL9M®, Sidestream® and Mistyneb®. Statistical analysis of the results showed that for all types of nebulizer, the inhaled mass of ipratropium bromide 0.5mg/1mL was significantly lower than the inhaled mass of ipratropium bromide 0.5mg/2mL, and that there was no statistical difference between the inhaled mass of ipratropium bromide 0.5mg/1mL+terbutaline 5mg/2mL and the inhaled mass of ipratropium bromide 0.5mg/2mL+terbutaline 5mg/2mL. The study also showed that the new formulation of ipratropium bromide (0.5mg/1mL) mixed with terbutaline allowed a 26% decrease in nebulization time compared to the old formulation (0.5mg/2mL) mixed with terbutaline without changing aerosol characteristics (inhaled mass and particle size distribution). This leads to the conclusion that a 2mL minimum volume is required for nebulization, and that nebulization of ipratropium bromide 0.5mg/1mL alone must be avoided.