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Severe community-acquired pneumonia (CAP) is a common cause of hospitalization in ICU with a high mortality rate, and the incrimination of viruses is an ongoing topic. The aim of the study was to describe the ecology of severe CAP in our ICU, to assess the impact of molecular testing on aetiological diagnosis and to report the prevalence of coinfections. Methods: a single center retrospective study on adult patients admitted in ICU for severe CAP and matching the IDSA/ATS criteria. Available respiratory sample and Legionella urinary antigen test were compulsory. In addition to the laboratory results available, we performed a systematic respiratory panel PCR and legionella culture. The primary endpoint was the proportion of each pathogen identified in the respiratory samples. The secondary endpoints were the proportion of patients for whom respiratory panel molecular tests had an impact on diagnosis and indicated a theoretical modification of the antimicrobial therapy, the proportions of patients with coinfections and mortality.Results: a total of 104 patients were included with a median SAPS II score of 46.5 (IQR 24.5). Severe CAP were documented in 67% cases. The most frequent pathogens were influenza A/B, Streptococcus pneumoniae and rhinovirus. Systematic use of respiratory panel molecular testing benefited to the diagnosis of 28 patients (27%) with 20 cases of viral induced severe CAP and 8 cases of coinfections. It is worth noting that 2 of 6 Legionella severe CAP were only detected by the PCR, these were due to Legionella spp. Overall mortality reached 39% by the 3rd month.Conclusion: two third of the population had a positive aetiological diagnosis and the mortality was high. The three most frequent pathogens were influenza viruses, Streptococcus pneumoniae and rhinovirus.Using respiratory panel PCR tests on all samples helped to improve diagnosis and showed that viral aetiologies were frequent in this cohort of severe CAP.; Les pneumopathies aiguës communautaires (PAC) graves sont une cause fréquente d’hospitalisation en réanimation et grevées d’une importante mortalité. La responsabilité des virus dans cette pathologie est un sujet d’actualité. Les objectifs de cette étude sont de décrire l’écologie locale des PAC graves, d’identifier le rôle des virus et de discuter de l’intérêt de l’utilisation systématique de tests moléculaires à l’admission des patients.Méthode : étude descriptive rétrospective monocentrique incluant des adultes admis en réanimation pour PAC grave, répondant aux critères de l’IDSA/ATS, et ayant un prélèvement respiratoire disponible ainsi qu’un test urinaire antigénique de légionellose. En plus des résultats microbiologiques respiratoires disponibles, nous avons réalisé une analyse moléculaire à spectre respiratoire et une culture spécifique de la légionelle. Le critère d’évaluation principal était la proportion de chaque pathogène détecté sur les prélèvements respiratoires. Les critères d’évaluation secondaires étaient l’apport de l’utilisation systématique de tests moléculaires, la présence de co-infections virus-bactéries et la mortalité.Résultats : au total 104 patients ont été inclus, avec un score SAPS II médian de 46.5 (IQR 24.5). Le diagnostic étiologique a pu être défini dans 67% des cas. Les pathogènes les plus impliqués étaient le virus de la grippe (A/B), Streptococcus pneumoniae et rhinovirus. L’utilisation systématique de tests PCR couvrants les pathogènes respiratoires a bénéficié au diagnostic de 28 patients (27%) avec 20 cas d’infections virales et 8 cas de co-infections. A noter, 2 cas de légionellose grave sur 6 ont été uniquement détectés via la PCR. Celles-ci étaient dues à des Legionella spp. La mortalité a atteint 39% au 3ème mois.Conclusion : deux tiers des patients ont eu un diagnostic étiologique. La mortalité des PAC graves était élevée. Les 3 pathogènes les plus fréquents sont le virus de la grippe, Streptococcus pneumoniae et rhinovirus. Les tests moléculaires ont permis d’améliorer le rendement diagnostique et de mettre en évidence l’implication des virus dans ces PAC graves.

IntroductionCOVID-19 sequelae are numerous and multisystemic, and how to evaluate those symptomatic patients is a timely issue. Klok et al proposed the Post-COVID-19 Functional Status (PCFS) Scale as an easy tool to evaluate limitations related to persistent symptoms. Our aim was to analyse PCFS Scale ability to detect functional limitations and its correlation with quality of life in a cohort of patients, 2–9 months after hospitalisation for COVID-19 hypoxemic pneumonia.MethodsPCFS Scale was evaluated in 121 patients together with quality of life and dyspnoea questionnaires, pulmonary function tests and CT scans.ResultsWe observed a high correlation with multiple questionnaires (Short Form-36, Hospital Anxiety and Depression Scale, modified Medical Research Council, end Borg Six-Minute Walk Test), making the PCFS Scale a quick and global tool to evaluate functional limitations related to various persistent symptoms following COVID-19 pneumonia.DiscussionThe PCFS Scale seems to be a suitable instrument to screen for patients who will require careful follow-up after COVID-19 hypoxemic pneumonia even in the absence of pulmonary sequelae.

Highlights • COVID-19 pneumonia is at risk of transfer in intensive care unit or death • Hydroxychloroquine+azithromycin seems to improve outcome of admitted patients • We report no major cardiac adverse event of this combination therapy, Introduction Interest of anti-infective agents in COVD-19 showed discrepant results. However, there is no evaluation about the impact in changes of practices on the prognosis over time. Methods Single center, retrospective study, conducted from March 5th to April 25th 2020, in adults hospitalized in a medicine ward for a COVID-19. Patient characteristics were compared between 2 periods (before/after March 19th) considering French guidelines issued by learned societies. Aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission in intensive care unit (ICU) and/or death. Results One hundred thirty-two patients were admitted, mean age was 59.0 ± 16.3 years, mean CRP level was 84.0±71.1 mg/L, 46% had a lymphocyte count

International audience; An unusual prevalence of Klebsiella pneumoniae (24%) was observed in 25 adults admitted to the intensive care units of two University Hospitals in the French West Indies, for spontaneous community-acquired bacterial meningitis. All tested isolates had several prominent features of hypervirulent isolates, including rmpa and iuc genes, K1 or K2 capsular serotypes.

International audience; Supported by years of clinical use in some countries and more recently by literature on experimental models, as well as its compassionate use in Europe and in the United States, bacteriophage (phage) therapy is providing a solution for difficult-to-treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce. Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) was treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (ceftriaxone, cefoxitin, or imipenem-cilastatin; intraperitoneal). Healthy mice also received phages alone. The severity of pulmonary edema, acute inflammatory cytokine concentration (blood and lung homogenates), complete blood counts, and bacterial and bacteriophage counts were determined at early (Յ12 h) and late (Ն20 h) time points. The efficacy of bacteriophage to decrease bacterial load was faster than with antibiotics, but the two displayed similar endpoints. Bacteriophage treatment was not associated with overinflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities than did antibiotics. In the absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of antiviral cytokines (gamma interferon [IFN-␥] and interleukin-12 [IL-12]) and chemokines in the lungs but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals. The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to that with antibiotic treatment.

Background: the recommended duration of antibiotic treatment for community-acquired pneumonia (CAP) in France is 7 to 14 days whereas other countries suggest shorter therapy. Objective: to compare the duration of antibiotic treatment by Amoxicillin or Amoxicillin-clavulanic acid for 7 days or less and for more than 7 days, on the symptoms duration of CAP in outpatients. Methods: this is an ancillary study from a prospective observational cohort study (CAPA Study) in adult outpatients with CAP describing a low severity disease. Only patients receiving Amoxicillin or Amoxicillin-clavulanic acid were included. The primary outcome was a composite score calculated by adding the duration of key symptoms of pneumonia: fever > 38.5°C, persistent cough, chest pain, dyspnoea and weakness impacting daily activities. Results: Amoxicillin or Amoxicillin-clavulanic acid was prescribed in 432 patients, 73 patients were treated for 7 days or less and 358 during more than 7 days. Mean (SD) duration of key symptoms of low severity CAP was 26.4 days (19.2) in the Amoxicillin or Amoxicillinclavulanic acid group treated for = 7 days versus 29.1 days (22.8) in the group treated for more than 7 days without any significant difference between the two groups (p=0.66), adjusting with variables significantly associated with the outcome. Conclusion: the duration of antibiotic treatment may not impact on the duration of key symptoms of low severity CAP. Regarding our results and those of others studies which have demonstrated the effectiveness of short course antibiotic treatment, the French guidelines should be reviewed.; Contexte : en France, la durée d’antibiotique recommandée dans le traitement des pneumopathies aiguës communautaires est de 7 à 14 jours alors que d’autres pays recommandent une durée plus courte. Objectif : comparer l’impact de la durée d’une antibiothérapie par Amoxicilline ou Amoxicilline-Acide clavulanique pendant =7 jours et pendant >7 jours sur la durée des symptômes cliniques principaux de pneumopathie. Méthodes : étude ancillaire d’une étude de cohorte observationnelle prospective (CAPA study) chez des adultes présentant une pneumopathie de faible sévérité en ambulatoire. Seuls les patients ayant reçu de l’Amoxicilline ou l’association Amoxicilline-acide clavulanique ont été inclus. Le critère de jugement principal était un score composite obtenu en additionnant les durées des symptômes cliniques principaux de pneumopathie, c’est-à-dire la fièvre>38,5°C, la toux persistante, la douleur thoracique, la dyspnée et la fatigue avec retentissement sur les activités de la vie quotidienne. Résultats : l’amoxicilline ou l’Amoxicilline-Acide clavulanique a été prescrit chez 432 patients, 73 ont été traité pendant =7 jours et 358 pendant >7 jours. La durée moyenne (écart-type) des symptômes cliniques principaux de pneumopathie était de 26.4 jours (19.1) dans le groupe ayant reçu l’antibiotique pendant =7 jours versus 29.1 jours (22.8) dans le groupe traité pendant >7 jours, sans différence significative entre les 2 groupes (p=0,66), après ajustement avec les variables significativement associées au critère de jugement principal. Conclusion : la durée de l’antibiothérapie ne semble pas avoir d’impact sur la durée des symptômes cliniques principaux des pneumopathies aiguës communautaires de faible sévérité. Au regard de nos résultats et de ceux des autres études ayant démontré l’efficacité des traitements antibiotiques de courte durée, il serait nécessaire de réviser les recommandations françaises.

International audience; RATIONALE: Pulmonary fibrosis is a devastating as yet untreatable disease. We previously investigated the endogenous mediators released on lung injury and showed that uric acid is a danger signal activating Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in lung inflammation and fibrosis (Gasse et al., Am J Respir Crit Care Med 2009;179:903-913). OBJECTIVES: Here we address the role of extracellular adenosine triphosphate (eATP) in pulmonary inflammation and fibrosis. METHODS: ATP was quantified in bronchoalveolar lavage fluid (BALF) of control subjects and patients with idiopathic pulmonary fibrosis. The contribution of eATP as a danger signal was assessed in a murine model of lung fibrosis induced by airway-administered bleomycin (BLM), an intercalating agent that causes DNA strand breaks. MEASUREMENTS AND MAIN RESULTS: Fibrotic patients have elevated ATP content in BALF in comparison with control individuals. In mice, we report an early increase in eATP levels in BALF on BLM administration. Modulation of eATP levels with the ATP-degrading enzyme apyrase greatly reduced BLM-induced inflammatory cell recruitment, lung IL-1β, and tissue inhibitor of metalloproteinase (TIMP)-1 production, while administration of ATP-γS, a stable ATP derivative, enhanced inflammation. P2X(7) receptor-deficient mice presented dramatically reduced lung inflammation, with reduced fibrosis markers such as lung collagen content and matrix-remodeling proteins TIMP-1 and matrix metalloproteinase-9. The acute inflammation depends on a functional pannexin-1 hemichannel protein. In vitro, ATP is released by pulmonary epithelial cells on BLM-induced stress and this is partly dependent on the presence of functional P2X(7) receptor and pannexin-1 hemichannel. CONCLUSIONS: ATP released from BLM-injured lung cells constitutes a major endogenous danger signal that engages the P2X(7) receptor/pannexin-1 axis, leading to IL-1β maturation and lung fibrosis.

Soares, Alexandre Learth Coelho, Fernando Rodrigues Guabiraba, Rodrigo Kamal, Mamdouh Vargaftig, B Boris Li, Lily Li, Jian Tavares-de-Lima, Wothan Ryffel, Bernhard Augusta, Ga. Shock. 2010 Sep;34(3):306-13. doi: 10.1097/SHK.0b013e3181cdc585.; International audience; Intestinal ischemia-reperfusion (I/R) injury may cause acute systemic and lung inflammation. Here, we revisited the role of TNF-alpha in an intestinal I/R model in mice, showing that this cytokine is not required for the local and remote inflammatory response upon intestinal I/R injury using neutralizing TNF-alpha antibodies and TNF ligand-deficient mice. We demonstrate increased neutrophil recruitment in the lung as assessed by myeloperoxidase activity and augmented IL-6, granulocyte colony-stimulating factor, and KC levels, whereas TNF-alpha levels in serum were not increased and only minimally elevated in intestine and lung upon intestinal I/R injury. Importantly, TNF-alpha antibody neutralization neither diminished neutrophil recruitment nor any of the cytokines and chemokines evaluated. In addition, the inflammatory response was not abrogated in TNF and TNF receptors 1 and 2-deficient mice. However, in view of the damage on the intestinal barrier upon intestinal I/R with systemic bacterial translocation, we asked whether Toll-like receptor (TLR) activation is driving the inflammatory response. In fact, the inflammatory lung response is dramatically reduced in TLR2/4-deficient mice, confirming an important role of TLR receptor signaling causing the inflammatory lung response. In conclusion, endogenous TNF-alpha is not or minimally elevated and plays no role as a mediator for the inflammatory response upon ischemic tissue injury. By contrast, TLR2/4 signaling induces an orchestrated cytokine/chemokine response leading to local and remote pulmonary inflammation, and therefore disruption of TLR signaling may represent an alternative therapeutic target.

International audience; Benzo(a)pyrene (BP) is an environmental contaminant known to favor airway inflammation likely through up-regulation of pro-inflammatory cytokines. The present study was designed to characterize its effects toward interleukin-8 (IL-8), a well-established pulmonary inflammatory cytokine. In primary human macrophages, BP was shown to induce IL-8 expression at both mRNA and secretion levels in a dose-dependent manner. Such an up-regulation was likely linked to aryl hydrocarbon receptor (AhR)-activation since BP-mediated IL-8 induction was reduced after AhR expression knock-down through RNA interference. Moreover, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation experiments showed BP-triggered binding of AhR to a consensus xenobiotic responsive element (XRE) found in the human IL-8 promoter. Finally, BP administration to mice led to over-expression of keratinocyte chemoattractant (KC), the murine functional homologue of IL-8, in lung. It also triggered the recruitment of neutrophils in bronchoalveolar lavage (BAL) fluids, which was however fully abolished in the presence of a chemical antagonist of the KC/IL-8 receptors CXCR1/CXCR2, thus supporting the functional and crucial involvement of KC in BP-induced lung inflammation. Overall, these data highlight an AhR-dependent regulation of IL-8 in response to BP that likely contributes to the airway inflammatory effects of this environmental chemical.

Introduction: Aspiration pneumonia (AP) is a complication of coma that can have chemical and/or bacterial clinical presentation. Quick determination of inhalation type may avoid unjustified antibiotic therapy. Procalcitonin (PCT) is an interesting biomarker to differentiate sepsis and inflammation. Our study aimed at evaluating the PCT assay value in the diagnosis of AP. Methods: Prospective, single-­‐center study, in 103 patients admitted to intensive care for coma. AP was diagnosed upon a positive bacteriological sampling and suggestive clinical picture (radiological infiltrate, fever, cough, sputum, dyspnea, pleuritic pain, encephalopathy, pulmonary condensation syndrome, leukocytosis). Assays of PCT, CRP and leukocytosis were carried out at H0, H6, H12, D1 and up to ICU discharge. The areas under the ROC curve (AUC) and likelihood ratios (LRs) were calculated for the threshold values to the best compromise of sensitivity and specificity. Results: In patients with AP, PCT significantly increased from H0 to D3. PCT’s AUC at H0, H6 and D2 were greater than those of CRP and leukocytes with respectively: (0.63 versus 0.58 and 0.53); (0.69 versus 0.63 and 0.54) and (0.73 versus 0.72 and 0.58). At H12, AUC demonstrated (0.68 versus 0.70 and 0.58) and at H24 (0.69 versus 0.73 and 0.66). LR of PCT were: H0 (0.068 ng / mL, 1, LR+, LR-­‐ 0.7); H6 (0.09 ng / mL, LR+ 2, LR-­‐ 0.5); H12 (0.13 ng / mL, LR+ 2.3, LR-­‐ 0.5); H24 (0.19 ng / mL, LR+ 3.5, LR-­‐0.5) and Day 2 (0.1 ng / mL, LR+ 2.7, LR-­‐ 0.4). Conclusion: PCT measurement is better than CRP and leukocytosis in the early dignosis of AP. Its moderate diagnostic value limits its contribution in the initiation antibiotic therapy in this context.; Introduction : La pneumonie d’inhalation (PI) est une complication des comas pouvant prendre une forme chimique et/ou bactérienne. Déterminer rapidement le type d’inhalation permettrait d’éviter une antibiothérapie injustifiée. La procalcitonine (PCT) est un biomarqueur capable de différentier sepsis et inflammation. L’objectif de notre travail était d’évaluer l’intérêt de son dosage pour le diagnostic de PI. Matériel et Méthode : Essai prospectif, monocentrique, chez 103 patients admis en réanimation pour coma. La PI était retenue devant un prélèvement bactériologique positif et une clinique évocatrice. La PCT, la CRP et la leucocytose étaient dosées à H0, H6, H12, J1 et jusqu’à la sortie de réanimation. Les aires sous la courbe ROC (AUC) et les rapports de vraisemblance (RV) étaient calculés pour les valeurs seuils des meilleurs compromis de sensibilité et spécificité. Résultats : La PCT s’élevait dès H0 en cas de PI, significativement jusqu’à J3. Les AUC de la PCT à H0, H6 et J2 étaient supérieures à celles de la CRP et des leucocytes avec (0,63 versus 0,58 et 0,53), (0,69 versus 0,63 et 0,54) et (0,73 versus 0,72 et 0,58). À H12, on retrouvait AUC (0,68 versus 0,70 et 0,58) et H24 (0,69 versus 0,73 et 0,66). Les RV de la PCT étaient : H0 (seuil 0,068 ng/mL, RV+ 1,7, RV-­‐ 0,7), H6 (seuil 0,09 ng/mL, RV+ 2, RV-­‐ 0,5), H12 (seuil 0,13 ng/mL, RV+ 2,3, RV-­‐ 0,5), H24 (seuil 0,19 ng/mL, RV+ 3,5, RV-­‐ 0,5), J2 (seuil 0,1 ng/mL, RV+ 2,7, RV-­‐ 0,4). Conclusion : Le dosage précoce de la PCT est supérieur à celui de la CRP et des leucocytes pour le diagnostic de PI. Son intérêt demeure modéré et limite son apport dans la prescription d’une antibiothérapie dans ce contexte.

International audience; Advances in high-throughput DNA sequencing allow for a comprehensive analysis of bacterial genes that contribute to virulence in a specific infectious setting. Such information can yield new insights that affect decisions on how to best manage major public health issues such as the threat posed by increasing antimicrobial drug resistance. Much of the focus has been on the consequences of the selective advantage conferred on drug-resistant strains during antibiotic therapy. It is thought that the genetic and phenotypic changes that confer resistance also result in concomitant reductions in in vivo fitness, virulence, and transmission. However, experimental validation of this accepted paradigm is modest. Using a saturated transposon library of Pseudomonas aeruginosa, we identified genes across many functional categories and operons that contributed to maximal in vivo fitness during lung infections in animal models. Genes that bestowed both intrinsic and acquired antibiotic resistance provided a positive in vivo fitness advantage to P. aeruginosa during infection. We confirmed these findings in the pathogenic bacteria Acinetobacter baumannii and Vibrio cholerae using murine and rabbit infection models, respectively. Our results show that efforts to confront the worldwide increase in antibiotic resistance might be exacerbated by fitness advantages that enhance virulence in drug-resistant microbes.

International audience; BACKGROUND: Many low-risk patients with pneumonia are hospitalized despite recommendations to treat such patients in the outpatient setting. OBJECTIVE: To identify the factors associated with the hospitalization of low-risk patients with pneumonia. METHODS: We analyzed data collected by retrospective chart review for 1,889 low-risk patients (Pneumonia Severity Index [PSI] risk classes I to III without evidence of arterial oxygen desaturation) enrolled in a cluster-randomized trial conducted in 32 emergency departments. RESULTS: Overall, 845 (44.7%) of all low-risk patients were treated as inpatients. Factors independently associated with an increased odds of hospitalization included PSI risk classes II and III, the presence of medical or psychosocial contraindications to outpatient treatment, comorbid conditions that were not contained in the PSI (cognitive impairment, history of coronary artery disease, diabetes mellitus, or pulmonary disease), multilobar radiographic infiltrates, and home therapy with oxygen, corticosteroids, or antibiotics before presentation. While 32.8% of low-risk inpatients had a contraindication to outpatient treatment and 47.1% had one or more preexisting treatments, comorbid conditions, or radiographic abnormalities not contained in the PSI, 20.1% had no identifiable risk factors for hospitalization other than PSI risk class II or III. CONCLUSIONS: Hospital admission appears justified for one-third of low-risk inpatients based upon the presence of one or more contraindications to outpatient treatment. At least one-fifth of low-risk inpatients did not have a contraindication to outpatient treatment or an identifiable risk factor for hospitalization, suggesting that treatment of a larger proportion of such low-risk patients in the outpatient setting could be achieved without adversely affecting patient outcomes.

International audience; BACKGROUND:The process and effectiveness of knowledge translation (KT) interventions targeting policymakers are rarely reported. In Cambodia, a low-income country (LIC), an intervention aiming to provide evidence-based knowledge on pneumonia to health authorities was developed to help update pediatric and adult national clinical guidelines. Through a case study, we assessed the effectiveness of this KT intervention, with the goal of identifying the barriers to KT and suggest strategies to facilitate KT in similar settings.METHODS:An extensive search for all relevant sources of data documenting the processes of updating adult and pediatric pneumonia guidelines was done. Documents included among others, reports, meeting minutes, and email correspondences. The study was conducted in successive phases: an appraisal of the content of both adult and pediatric pneumonia guidelines; an appraisal of the quality of guidelines by independent experts, using the AGREE-II instrument; a description and modeling of the KT process within the guidelines updating system, using the Unified Modeling Language (UML) tools 2.2; and the listing of the barriers and facilitators to KT we identified during the study.RESULTS:The first appraisal showed that the integration of the KT key messages in pediatric and adult guidelines varied with a better efficiency in the pediatric guidelines. The overall AGREE-II quality assessments scored 37% and 44% for adult and pediatric guidelines, respectively. Scores were lowest for the domains of 'rigor of development' and 'editorial independence.' The UML analysis highlighted that time frames and constraints of the involved stakeholders greatly differed and that there were several missed opportunities to translate on evidence into the adult pneumonia guideline. Seventeen facilitating factors and 18 potential barriers to KT were identified. Main barriers were related to the absence of a clear mandate from the Ministry of Health for the researchers and to a lack of synchronization between knowledge production and policy-making.CONCLUSIONS:Study findings suggest that stakeholders, both researchers and policy makers planning to update clinical guidelines in LIC may need methodological support to overcome the expected barriers.

International audience; BackgroundAn epidemic of measles broke out in France in 2008. We designed a retrospective study focusing on adults hospitalized for measles in 2010/2011.MethodsA case was any patient aged more than 15 years, hospitalized (September 2010 to September 2011) with a typical rash or a biological diagnosis. Data was collected with standardized questionnaires in participating hospitals.ResultsFour hundred and sixty cases were reported: sex-ratio (M/F) = 0.93, median age 26 years (σ = 8.8). Twenty-nine cases were severe (6.5%), 27 of which hospitalized in an ICU. Three hundred and twelve (68%) cases had elevated serum transaminases (EST), 155 (34%) cases had pneumonia, 34 (7%) cases had elevated serum creatinin (ESC), four (0.9%) cases had elevated serum amylase and lipase (ESAL), and three (0.7%) cases had neurological symptoms. One hundred and four (23%) patients presented simultaneously with EST and pneumonia. One patient presenting with severe pneumonia died (0.2%). One hundred and ten (24%) patients received antibiotics during a median seven days.ConclusionMeasles can present as various syndromes in adults and be responsible for a high burden during outbreaks. The immediate outcome is favorable in most patients. Long-term outcome needs further investigations to identify possible late complications.; ContexteUne épidémie de rougeole est survenue en France, de 2008 à 2011. Nous avons mené une étude rétrospective, sur les adultes hospitalisés pour rougeole.MéthodesUn cas était un patient âgé de plus de 15 ans, hospitalisé (septembre 2010 à septembre 2011) présentant un rash typique ou un diagnostique biologique. Les données ont été recueillies grâce à un questionnaire standardisé, dans les centres hospitaliers participants.RésultatsQuatre cent soixante cas ont été recueillis: sex-ratio (M/F) = 0,93, âge médian 26 ans (σ = 8,8). Vingt-neuf cas ont été graves (6,5 %), dont 27 hospitalisés en soins intensifs. 312 (68 %) cas ont présenté des transaminases sériques élevées, 155 (34 %) cas ont présenté une pneumonie, 34 (7 %) cas avaient une créatininémie élevée, quatre (0,9 %) cas avaient des amylasémies et lipasémies élevées, et trois (0,7 %) cas avaient des symptômes neurologiques. Cent quatre (23 %) patients ont présenté simultanément des transaminases élevées et une pneumonie. Une patiente avec une pneumonie grave est décédée (0,2 %). Cent dix (24 %) patients ont reçu une antibiothérapie pendant une durée médiane de sept jours.ConclusionLa rougeole de l’adulte peut se présenter sous des formes cliniques variées et peut être un important fardeau de santé publique en cas d’épidémie. Le pronostic immédiat est favorable chez la plupart des patients. Un suivi à long terme est cependant nécessaire afin d’identifier de possibles complications tardives.

International audience; Tumour Necrosis Factor (TNF) is critical for host control of M. tuberculosis, but the relative contribution of TNF from innate and adaptive immune responses during tuberculosis infection is unclear. Myeloid versus T-cell-derived TNF function in tuberculosis was investigated using cell type-specific TNF deletion. Mice deficient for TNF expression in macrophages/neutrophils displayed early, transient susceptibility to M. tuberculosis but recruited activated, TNF-producing CD4(+) and CD8(+) T-cells and controlled chronic infection. Strikingly, deficient TNF expression in T-cells resulted in early control but susceptibility and eventual mortality during chronic infection with increased pulmonary pathology. TNF inactivation in both myeloid and T-cells rendered mice critically susceptible to infection with a phenotype resembling complete TNF deficient mice, indicating that myeloid and T-cells are the primary TNF sources collaborating for host control of tuberculosis. Thus, while TNF from myeloid cells mediates early immune function, T-cell derived TNF is essential to sustain protection during chronic tuberculosis infection.

International audience; Probe-based confocal laser endomicroscopy (pCLE) allows microscopic imaging of the alveoli during bronchoscopy. The objective of the study was to assess the diagnostic accuracy of pCLE for amiodarone-related pneumonia (AMR-IP). Alveolar pCLE was performed in 36 nonsmoking patients, including 33 consecutive patients with acute or subacute interstitial lung disease (ILD), of which 17 were undergoing treatment with amiodarone, and three were amiodarone-treated patients without ILD. Nine out of 17 patients were diagnosed with high-probability AMR-IP (HP-AMR-IP) by four experts, and three separate observers. Bronchoalveolar lavage findings did not differ between HP-AMR-IP and low-probability AMR-IP (LP-AMR-IP) patients. In HP-AMR-IP patients, pCLE showed large (>20 μm) and strongly fluorescent cells in 32 out of 38 alveolar areas. In contrast, these cells were observed in only two out of 39 areas from LP-AMR-IP patients, in one out of 59 areas from ILD patients not receiving amiodarone and in none of the 10 areas from amiodarone-treated patients without ILD (p

Despite many therapeutic interventions, ventilator-acquired pneumonias (VAP) are frequent in ICU and are associated with major morbidity and mortality. Sepsis causes a time-dependent modification of the inflammatory response. This reprogramming could promote the occurrence of a secondary infection and worsen the prognosis. In animals, peritonitis is associated with an alteration of pulmonary immunity and an increasing mortality from secondary pneumonia.To investigate, in humans, the potential involvement of previous intra-abdominal infection (IIA) in preventing or promoting VAP, we realized a prospective observational study using data from a multicenter database (OUTCOMEREA), including all patients admitted in ICU for severe sepsis or septic shock who required mechanical ventilation for at least seventy-two hours. 2623 patients were included, of which 290 had an IIA. 862 patients (33%) developed a VAP, 56 (19%) in the IIA group and 806 (34%) in the no-IIA group (p < 0.01). VAP, after a sepsis, occurred less frequently and later in patients with IIA. The occurrence of IIA, in comparison with another sepsis, is a protective factor against VAP (HR = 0.643 [0.478 – 0.863], p = 0,003). There is, however, no significant difference between the groups in terms of ICU mortality (28% versus 32%, p = 0.16).In this study, the presence of an abdominal sepsis, in a context of severe sepsis or septic shock, was associated with a lower incidence of later VAP. These results have to be confirmed in others studies, especially prospective. They open interesting new research directions.; Les pneumonies acquises sous ventilation mécanique (PAVM) sont une complication fréquente en réanimation et sont associées à une morbidité importante pour les patients. Leur incidence reste élevée malgré les efforts de prévention mis en place. Le sepsis induit une modification de la réponse inflammatoire au cours du temps. Cette reprogrammation pourrait favoriser la survenue d’une seconde infection et en aggraver le pronostic. Chez l’animal, la survenue d’une péritonite altère les défenses pulmonaires et augmente la mortalité d’une pneumonie secondaire.Afin d’étudier, chez l’homme, l’effet d’une infection intra-abdominale (IIA) sur la susceptibilité aux PAVM, nous avons réalisé une étude multicentrique, sur la base de données Outcomerea, incluant tous les patients admis en réanimation avec un sepsis sévère ou un choc septique et ayant été ventilés au moins soixante douze heures. 2623 patients ont été inclus, dont 290 avec une IIA. 862 patients (33%) ont développé une PAVM, parmi lesquels 56 (19%) dans le groupe IIA et 806 (34%) dans le groupe sans IIA (p

International audience; OBJECTIVE: This study charted incidence trends of hospital-acquired (HA) pneumonia, bacteraemia and urinary tract infections (UTI) in a haematology department. METHODS: Prospective surveillance of hospital-acquired infections (HAI) was undertaken in a 42-bed haematology department of a university hospital. All patients hospitalized ≥48 hours between 1(st) January 2004 and 31(st) December 2010 were included. Definitions of HAI were based on a standardized protocol. The incidence was the number of events per 1000 patient-days at risk; only the first HAI was counted. Multivariate Poisson regression was fitted to assess temporal trends. RESULTS: Among 3 355 patients (58 063 patient-days at risk) included, 1 055 (31%) had HAI. The incidence of HA pneumonia, HA bacteraemia and HA UTI was respectively 3.3, 12.0 and 2.9 per 1000 patient-days at risk. HA bacteraemia incidence increased by 11% (95% confidence interval: +6%, +15%, P

International audience; CONTEXT: Titanium dioxide nanoparticles (nano-TiO(2)) and ethanol vapors are air contaminants with increasing importance. The presence of a pathological pulmonary condition, such as asthma, may increase lung susceptibility to such contaminants. OBJECTIVE: This study aimed to investigate if exposure to inhaled ethanol vapors or nano-TiO(2) can modulate the rat pulmonary inflammatory response resulting from an allergic asthmatic reaction. MATERIALS AND METHODS: Brown Norway rats were sensitized (sc) and challenged (15 min inhalation, 14 days later) with chicken egg ovalbumin (OVA). Leukocytes were counted in bronchoalveolar lavages (BAL) performed at 6, 24, 36, 48 and 72 h following the challenge and either after ethanol exposures (3000 ppm, 6 h/day, daily) or at 48 h (peak inflammation) for nano-TiO(2) exposures (9.35 mg/m(3) aerosol for 6 and 42 h after the OVA challenge). For the nano-TiO(2) exposures, plasma and BAL cytokines were measured and lung histological analyzes were performed. RESULTS: Exposure to ethanol did not significantly affect BAL leukocytes after OVA challenge. Exposure to nano-TiO(2) significantly decreased BAL leukocytes compared to OVA-challenged controls. Plasma and BAL IL-4, IL-6, and INF-γ levels were also decreased in the nano-TiO(2) group. DISCUSSION: While ethanol vapors do not modify the pulmonary inflammation in rats during an asthmatic response, a surprising protective effect for agglomerated nano-TiO(2) was observed. A putative mechanistic basis involving a decrease in the Th2 response caused by OVA is proposed. CONCLUSION: Allergic pulmonary inflammation is not up-regulated by inhalation of the pollutants ethanol and nano-TiO(2). On the contrary, nano-TiO(2) decreases lung inflammation in asthmatic rats.

International audience; OBJECTIVES: The objective was to compare outcomes associated with early, late, and no admission to the intensive care unit (ICU) for patients hospitalized with community-acquired pneumonia (CAP). METHODS: This was a post hoc analysis of the original data from the Emergency Department Community-Acquired Pneumonia (EDCAP) and Pneumocom-1 prospective multicenter cohort studies of adult patients hospitalized with CAP. Propensity score-adjusted analysis was used to compare 28-day mortality and hospital length of stay (LOS) for 199, 144, and 2,215 patients with early (i.e., ICU admission on the day of emergency department [ED] presentation), late, and no ICU admission. RESULTS: Unadjusted 28-day mortality rates were 13.1, 19.4, and 5.7% for early, late, and no ICU admissions, respectively (p < 0.001). After adjusting for quintile of propensity score, the odds of 28-day mortality were higher for late ICU admissions relative to early ICU admissions (odds ratio [OR] = 2.63; 95% confidence interval [CI] = 1.42 to 4.90), and no ICU admissions (OR = 3.40; 95% CI = 2.11 to 5.48), but did not differ between early and no ICU admissions (OR = 1.29; 95% CI = 0.79 to 2.09). The median hospital LOS was 10 days for early (interquartile range [IQR] = 7 to 18), 15 days for late (IQR 9 to 23), and 6 days (IQR 4 to 9) for no ICU admissions (p < 0.001). CONCLUSIONS: This study suggests that late but not early admission to the ICU is associated with higher 28-day mortality for patients hospitalized with CAP. Patients admitted to the ICU have longer hospital LOS in comparison to those managed on the wards, particularly if they are admitted late to the ICU.

International audience; Dendritic Cells (DC) represent a key lung immune cell population, which play a critical role in the antigen presenting process and initiation of the adaptive immune response. The study of DCs has largely benefited from the joint development of fluorescence microscopy and knock-in technology, leading to several mouse strains with constitutively labeled DC subsets. However, in the lung most transgenic mice do express fluorescent protein not only in DCs, but also in closely related cell lineages such as monocytes and macrophages. As an example, in the lungs of CX(3)CR1(+/gfp) mice the green fluorescent protein is expressed mostly by both CD11b conventional DCs and resident monocytes. Despite this non-specific staining, we show that a shape criterion can discriminate these two particular subsets. Implemented in a cell tracking code, this quantified criterion allows us to analyze the specific behavior of DCs under inflammatory conditions mediated by lipopolysaccharide on lung explants. Compared to monocytes, we show that DCs move slower and are more confined, while both populations do not have any chemotactism-associated movement. We could generalize from these results that DCs can be automatically discriminated from other round-shaped cells expressing the same fluorescent protein in various lung inflammation models.

International audience; The biological functions of human neutrophil proteinase 3 (PR3) remain unclear because of its close structural resemblance to neutrophil elastase and its apparent functional redundancy with the latter. Thus, all natural inhibitors of PR3 preferentially target neutrophil elastase. We have designed a selective PR3 inhibitor based on the sequence of one of its specific, sensitive FRET substrates. This azapeptide, azapro-3, inhibits free PR3 in solution, PR3 bound to neutrophil membranes, and the PR3 found in crude lung secretions from patients with chronic inflammatory pulmonary diseases. But it does not inhibit significantly neutrophil elastase or cathepsin G. Unlike most of azapeptides, this inhibitor does not form a stable acyl-enzyme complex; it is a reversible competitive inhibitor with a K(i) comparable to the K(m) of the parent substrate. Low concentrations (60 μM) of azapro-3 totally inhibited the PR3 secreted by triggered human neutrophils (200,000 cells/100 μL) and the PR3 in neutrophil homogenates and in lung secretions of patients with lung inflammation for hours. Azapro-3 also resisted proteolysis by all proteases contained in these samples for at least 2h.

International audience; Swallowing disorders (or dysphagia) are common in the elderly and their prevalence is often underestimated. They may result in serious complications including dehydration, malnutrition, airway obstruction, aspiration pneumonia (infectious process) or pneumonitis (chemical injury caused by the inhalation of sterile gastric contents). Moreover the repercussions of dysphagia are not only physical but also emotional and social, leading to depression, altered quality of life, and social isolation. While some changes in swallowing may be a natural result of aging, dysphagia in the elderly is mainly due to central nervous system diseases such as stroke, parkinsonism, dementia, medications, local oral and oesophageal factors. To be effective, management requires a multidisciplinary team approach and a careful assessment of the patient's oropharyngeal anatomy and physiology, medical and nutritional status, cognition, language and behaviour. Clinical evaluation can be completed by a videofluoroscopic study which enables observation of bolus movement and movements of the oral cavity, pharynx and larynx throughout the swallow. The treatment depends on the underlying cause, extent of dysphagia and prognosis. Various categories of treatment are available, including compensatory strategies (postural changes and dietary modification), direct or indirect therapy techniques (swallow manoeuvres, medication and surgical procedures).

International audience; IL-33, a new member of the IL-1 family cytokine, is involved in Th2-type responses in a wide range of diseases and signals through the ST2 receptor expressed on many immune cells. Since the effects of IL-33 on DCs remain controversial, we investigated the ability of IL-33 to modulate DC functions in vitro and in vivo. Here, we report that IL-33 activates myeloid DCs to produce IL-6, IL-1b, TNF, CCL17 and to express high levels of CD40, CD80 OX40L and CCR7. Importantly, IL-33-activated DCs prime naive lymphocytes to produce the Th2 cytokines IL-5 and IL-13, but not IL-4. In vivo, IL-33 exposure induces DC recruitment and activation in the lung. Using an OVA-induced allergic lung inflammation model, we demonstrate that the reduced airway inflammation in ST2-deficient mice correlates with the failure in DC activation and migration to the draining LN. Finally, we show that adoptive transfer of IL-33-activated DCs exacerbates lung inflammation in a DC-driven model of allergic airway inflammation. These data demonstrate for the first time that IL-33 activates DCs during antigen presentation and thereby drives a Th2-type response in allergic lung inflammation.

International audience; CONTEXT: The role of stress-dose hydrocortisone in the management of trauma patients is currently unknown. OBJECTIVE: To test the efficacy of hydrocortisone therapy in trauma patients. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized, double-blind, placebo-controlled HYPOLYTE (Hydrocortisone Polytraumatise) study. From November 2006 to August 2009, 150 patients with severe trauma were included in 7 intensive care units in France. INTERVENTION: Patients were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/d for 5 days, followed by 100 mg on day 6 and 50 mg on day 7) or placebo. The treatment was stopped if patients had an appropriate adrenal response. MAIN OUTCOME MEASURE: Hospital-acquired pneumonia within 28 days. Secondary outcomes included the duration of mechanical ventilation, hyponatremia, and death. RESULTS: One patient withdrew consent. An intention-to-treat (ITT) analysis included the 149 patients, a modified ITT analysis included 113 patients with corticosteroid insufficiency. In the ITT analysis, 26 of 73 patients (35.6%) treated with hydrocortisone and 39 of 76 patients (51.3%) receiving placebo developed hospital-acquired pneumonia by day 28 (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.30-0.83; P = .007). In the modified ITT analysis, 20 of 56 patients (35.7%) in the hydrocortisone group and 31 of 57 patients (54.4%) in the placebo group developed hospital-acquired pneumonia by day 28 (HR, 0.47; 95% CI, 0.25-0.86; P = .01). Mechanical ventilation-free days increased with hydrocortisone by 4 days (95% CI, 2-7; P = .001) in the ITT analysis and 6 days (95% CI, 2-11; P < .001) in the modified ITT analysis. Hyponatremia was observed in 7 of 76 (9.2%) in the placebo group vs none in the hydrocortisone group (absolute difference, -9%; 95% CI, -16% to -3%; P = .01). Four of 76 patients (5.3%) in the placebo group and 6 of 73 (8.2%) in the hydrocortisone group died (absolute difference, 3%; 95% CI, -5% to 11%; P = .44). CONCLUSION: In intubated trauma patients, the use of an intravenous stress-dose of hydrocortisone, compared with placebo, resulted in a decreased risk of hospital-acquired pneumonia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00563303.

BackgroundIdiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice.MethodsThe contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.ResultsWe show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+) γδ T cells and to a lesser extent by CD4αβ(+) T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis.ConclusionsOur findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology.

International audience; OBJECTIVE: To describe the aetiology of community-acquired pneumonia (CAP) in hospitalized adult patients in New Caledonia, a French archipelago in the South Pacific. METHODS: Confirmed CAP patients (n=137) were enrolled prospectively. Pathogens were detected by culture, molecular methods, serology on paired sera, immunofluorescence on nasopharyngeal swabs and antigen detection in urine. RESULTS: The aetiology of CAP was determined in 82 of 137 cases (59.8%), of which 31 exhibited two or more pathogens (37.8%). Hundred and seventeen pathogens were detected: Streptococcus pneumoniae was the most common one (41.0%), followed by influenza virus A (22.1%) and Haemophilus influenzae (10.2%). The frequency of atypical bacteria was low (6.0%). The most frequent and significant coinfection was S. pneumoniae with influenza A virus (P=0.004). Influenza virus was detected from nasopharyngeal swabs in four patients (15.4% of patients tested for influenza) and by PCR from pulmonary specimens in 15 patients (57.7%). CONCLUSIONS : Pneumoniae is the leading cause of CAP in New Caledonian adults. Viral-bacterial co-infections involving S. pneumoniae and influenza virus are very common during the winter. Such adult patients hospitalized with CAP are a clear sentinel group for surveillance of influenza. Vaccination against influenza and S. pneumoniae should be strengthened when risk factors are identified.

International audience; Allergic asthma is a T helper type 2 (T(H)2)-dominated disease of the lung. In people with asthma, a fraction of CD4(+) T cells express the CX3CL1 receptor, CX3CR1, and CX3CL1 expression is increased in airway smooth muscle, lung endothelium and epithelium upon allergen challenge. Here we found that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blocking reagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4(+) T cells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagents prevented airway inflammation in CX3CR1-deficient recipients injected with WT T(H)2 cells. We found that CX3CR1 signaling promoted T(H)2 survival in the inflamed lungs, and injection of B cell leukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient T(H)2 cells into CX3CR1-deficient mice restored asthma. CX3CR1-induced survival was also observed for T(H)1 cells upon airway inflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1 and CX3CL1 may represent attractive therapeutic targets in asthma.

International audience; AIM: To identify the baseline characteristics associated with suppurative complications in children with community-acquired primary pneumonia. METHODS: A retrospective study included all children from 28 days to 15 years old, who presented with community-acquired pneumonia at two French hospitals from 1995 to 2003. Complicated pneumonia was defined by the presence of empyema and/or lung abscess. RESULTS: Of 767 children with community-acquired pneumonia, 90 had suppurative complications: 83 cases of pleural empyema and seven cases of lung abscess. The mean prevalence of complicated pneumonia was 3% during the 1995-1998 period, and then steadily increased following a linear trend to reach 23% in 2003. Children with complicated pneumonia were older and had a longer symptomatic period preceding hospitalization. They were more likely to receive antibiotics, especially aminopenicillins (p < 0.01), and nonsteroidal anti-inflammatory drugs, especially ibuprofen (p < 0.001). In multivariable analysis, ibuprofen was the only preadmission therapy that was independently associated with complicated pneumonia [adjusted OR = 2.57 (1.51-4.35)]. CONCLUSION: This study confirms an association between the use of prehospital ibuprofen and suppurative pneumonic complications.

IL-17-producing T lymphocytes play a crucial role in inflammation, but their possible implication in fibrosis remains to be explored. In this study, we examined the involvement of these cells in a mouse model of lung inflammation and fibrosis induced by silica particles. Upregulation of IL-17A was associated with the development of experimental silicosis, but this response was markedly reduced in athymic, gamma delta T cell-deficient or CD4(+) T cell-depleted mice. In addition, gamma delta T lymphocytes and CD4(+) T cells, but not macrophages, neutrophils, NK cells or CD8 T cells, purified from the lungs of silicotic mice markedly expressed IL-17A. Depletion of alveolar macrophages or neutralization of IL-23 reduced upregulation of IL-17A in the lung of silicotic mice. IL-17R-deficient animals (IL-17R(-/-)) or IL-17A Ab neutralization, but not IL-22(-/-) mice, developed reduced neutrophil influx and injury during the early lung response to silica. However, chronic inflammation, fibrosis, and TGF-beta expression induced by silica were not attenuated in the absence of IL-17R or -22 or after IL-17A Ab blockade. In conclusion, a rapid lung recruitment of IL-17A-producing T cells, mediated by macrophage-derived IL-23, is associated with experimental silicosis in mice. Although the acute alveolitis induced by silica is IL-17A dependent, this cytokine appears dispensable for the development of the late inflammatory and fibrotic lung responses to silica. The Journal of Immunology, 2010, 184: 6367-6377.

IF : 4,12; International audience; This article considers the issue of personalized drug discovery for the orphan disease cystic fibrosis (CF) to deliver a candidate for therapeutic development. CF is a very complicated disease due to numerous anomalies of the gene leading to progressive severity and morbidity. Despite extensive research efforts, 20 years after the cloning of the CF gene, CF patients are still waiting for a curative treatment as prescribed medications still target the secondary manifestations of the disease rather than the gene or the CF transmembrane conductance regulator (CFTR) protein. New therapeutics aimed at improving mutant CFTR functions, also known as 'protein repair therapy' are nevertheless hoped and predicted to replace some of the currently used therapy, while improving the quality of life as well as life expectancy of CF patients. Although there is substantial variability in the cost of treating CF between countries, a protein repair therapy should also alleviate the financial burden of medical costs for CF patients and their families. Finding new drugs or rediscovering old ones for CF is critically dependent on the delivery of molecular and structural information on the CFTR protein, on its mutated version and on the network of CFTR-interacting proteins. The expertise needed to turn compounds into marketable drugs for CF will depend on our ability to provide biological information obtained from pertinent models of the disease and on our success in transferring safe molecules to clinical trials. Predicting a drug-induced response is also an attractive challenge that could be rapidly applied to patients.

Immunocompromised patients who develop invasive filamentous mycotic infections can be efficiently treated if rapid identification of the causative fungus is obtained. We report a case of fatal necrotic pneumonia caused by combined pulmonary invasive mucormycosis and aspergillosis in a 66 year-old renal transplant recipient. Aspergillus was first identified during the course of the disease by cytological examination and culture (A. fumigatus) of bronchoalveolar fluid. Hyphae of Mucorales (Rhizopus microsporus) were subsequently identified by culture of a tissue specimen taken from the left inferior pulmonary lobe, which was surgically resected two days before the patient died. Histological analysis of the lung parenchyma showed the association of two different filamentous mycoses for which the morphological features were evocative of aspergillosis and mucormycosis. However, the definitive identification of the associative infection was made by polymerase chain reaction (PCR) performed on deparaffinized tissue sections using specific primers for aspergillosis and mucormycosis. This case demonstrates that discrepancies between histological, cytological and mycological analyses can occur in cases of combined mycotic infection. In this regard, it shows that PCR on selected paraffin blocks is a very powerful method for making or confirming the association of different filamentous mycoses and that this method should be made available to pathology laboratories.

Lung emphysema and fibrosis are severe complications of chronic obstructive pulmonary disease, and uncontrolled protease activation may be involved in the pathogenesis. Using experimental elastase-induced acute inflammation, we demonstrate here that inflammation and development of emphysema is IL-1R1 and Toll/IL-1R signal transduction adaptor MyD88 dependent; however, TLR recognition is dispensable in this model. Elastase induces IL-1β, TNF-α, keratinocyte-derived chemokine, and IL-6 secretion and neutrophil recruitment in the lung, which is drastically reduced in the absence of IL-1R1 or MyD88. Further, tissue destruction with emphysema and fibrosis is attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Specific blockade of IL-1 by IL-1R antagonist diminishes acute inflammation and emphysema. Finally, IL-1β production and inflammation are reduced in mice deficient for the NALP3 inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and we identified uric acid, which is produced upon elastase-induced lung injury, as an activator of the NALP3/ASC inflammasome. In conclusion, elastase-mediated lung pathology depends on inflammasome activation with IL-1β production. IL-1β therefore represents a critical mediator and a possible therapeutic target of lung inflammation leading to emphysema.

Objective: To compare the 28-day mortality and hospital length of stay of patients with community-acquired pneumonia who were transferred to an intensive care unit on the same day of emergency department presentation (direct-transfer patients) with those subsequently transferred within 3 days of presentation (delayed-transfer patients). Design: Secondary analysis of the original data from two North American and two European prospective, multicenter, cohort studies of adult patients with community-acquired pneumonia. Patients: In all, 453 non-institutionalized patients transferred within 3 days of emergency department presentation to an intensive care unit were included in the analysis. Supplementary analysis was restricted to patients without an obvious indication for immediate transfer to an intensive care unit. Interventions: None. Measurements and Main Results: The sample consisted of 138 delayed-transfer and 315 direct-transfer patients, among whom 150 (33.1%) were considered to have an obvious indication for immediate intensive care unit admission. After adjusting for the quintile of propensity score, delayed intensive care unit transfer was associated with an increased odds ratio for 28-day mortality (2.07; 95% confidence interval, 1.12-3.85) and a decreased odds ratio for discharge from hospital for survivors (0.53; 95% confidence interval, 0.39-0.71). In a propensity-matched analysis, delayed-transfer patients had a higher 28-day mortality rate (23.4% vs. 11.7%; p = 0.02) and a longer median hospital length of stay (13 days vs. 7 days; p

International audience; RATIONALE: Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-1beta production, inflammation, and fibrosis remain poorly understood. OBJECTIVES: To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung. Methods: Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid. MEASUREMENTS AND MAIN RESULTS: Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor. CONCLUSIONS: Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology.

Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis, the etiological agent of anthrax, whose pulmonary form is fatal in the absence of treatment. Inflammatory response is a key process of host defense against invading pathogens. We report here that intranasal instillation of a B. anthracis strain bearing inactive LT stimulates cytokine production and polymorphonuclear (PMN) neutrophils recruitment in lungs. These responses are repressed by a prior instillation of an LT preparation. In contrast, instillation of a B. anthracis strain expressing active LT represses lung inflammation. The inhibitory effects of LT on cytokine production are also observed in vitro using mouse and human pulmonary epithelial cells. These effects are associated with an alteration of ERK and p38-MAPK phosphorylation, but not JNK phosphorylation. We demonstrate that although NF-κB is essential for IL-8 expression, LT downregulates this expression without interfering with NF-κB activation in epithelial cells. Histone modifications are known to induce chromatin remodelling, thereby enhancing NF-κB binding on promoters of a subset of genes involved in immune response. We show that LT selectively prevents histone H3 phosphorylation at Ser 10 and recruitment of the p65 subunit of NF-κB at the IL-8 and KC promoters. Our results suggest that B. anthracis represses the immune response, in part by altering chromatin accessibility of IL-8 promoter to NF-κB in epithelial cells. This epigenetic reprogramming, in addition to previously reported effects of LT, may represent an efficient strategy used by B. anthracis for invading the host., Author Summary Bacillus anthracis, the etiological agent of anthrax, can infect mammals either accidentally or as a potential consequence of a terrorism threat. Pulmonary infection is a life-threatening form of the disease, causing a near 100% mortality rate in the absence of appropriate therapy. Thus, it is important to understand the mechanisms of host defense against B. anthracis. We examined the effects of various B. anthracis strains on lung inflammation in a mouse model of pulmonary anthrax and on human lung epithelial cells, the first barrier of lung against invading pathogens. We showed that a B. anthracis strain expressing lethal toxin inhibits inflammation. In contrast, a strain in which this toxin has been inactivated induces lung inflammation. We next examined the mechanisms involved in the inhibitory effect of lethal toxin. We showed that B. anthracis injects lethal toxin into epithelial cells, blocks the molecules associated on the chromosome, and thus represses production of mediators involved in inflammation. As the latter is a key process in host defense, its alteration by lethal toxin predisposes the host to infection by B. anthracis. This effect on the chromosomal machinery may represent an efficient strategy used by B. anthracis for invading the host.

International audience; BACKGROUND: Common variable immunodeficiency is characterized by recurrent infections and defective immunoglobulin production. METHODS: The DEFI French national study prospectively enrolled adult patients with primary hypogammaglobulinemia. Clinical events before inclusion were retrospectively analyzed at that time. RESULTS: From April 2004 through April 2007, 341 patients were enrolled, 252 of whom had received a diagnosis of common variable immunodeficiency; of those, 110 were male, 142 were female, and 228 were white. The median age at first symptoms was 19 years. The median age at common variable immunodeficiency diagnosis was 33.9 years. The median delay for diagnosis was 15.6 years for the 138 patients with initial symptoms before 1990 and 2.9 years for the 114 patients with initial symptoms from 1990 to the time of the study. The most frequent initial symptoms were upper respiratory tract infections: bronchitis (in 38% of patients), sinusitis (36%), pneumonia (31%), and/or bronchiectasis (14%). Overall, 240 patients had respiratory symptoms. Pneumonia was reported in 147 patients; Streptococcus pneumoniae and Haemophilus influenzae were documented in 46 and 17 cases, respectively. Recurrent or chronic diarrhea was reported in 118 patients. Giardia (35 cases), Salmonella (19), and Campylobacter (19) infections were more frequent in patients with undetectable serum immunoglobulin A (P

International audience; BACKGROUND: Organizing pneumonia is a pulmonary disease with variable clinical and radiological features and with many differential diagnoses. Diagnosis is based on histology obtained by either transbronchial or surgical lung biopsy but these techniques have several disadvantages. The aim of this study was to evaluate the diagnostic yield of CT-guided transthoracic lung biopsy in organizing pneumonia and to compare it to the usual diagnostic tools. METHODS: Six cases of organizing pneumonia diagnosed with CT-guided lung biopsy are reported and discussed. A review of literature concerning the role of CT-guided lung biopsy in the diagnosis of organizing pneumonia was performed. RESULTS: CT-guided transthoracic lung biopsies provided a higher rate of adequate samples than transbronchial biopsies (92-100% versus 77-86%). The samples were larger, which reduced the risks of misdiagnosis and increased the diagnostic yield (88-97% versus 26-55% in pulmonary nodules and 42-100% versus 66-75% in diffuse pulmonary disease). Complications were rare and generally not serious. CONCLUSION: CT-guided transthoracic lung biopsy may be considered in place of transbronchial biopsy in the diagnosis of organizing pneumonia. Surgical lung biopsy remains the reference method for diagnosis.

International audience; OBJECTIVES: To evaluate the diagnostic accuracy of percutaneous computed tomography (CT)-guided coaxial core needle biopsy in patients with nonresolving pulmonary focal air space consolidations and negative fiberoptic bronchoscopy results. METHODS: From 1997 to 2005, 23 patients (11 woman, 12 men; age range, 45 to 81 y; mean age, 66 y) presenting with nonresolving pneumonia persisting more than 8 weeks (mean, 22 wk; range, 8 to 40 wk) with negative fiberscopic results, underwent coaxial percutaneous biopsy using an automated core needle (18-gauge) under CT guidance. Histologic and bacteriologic evaluations were obtained. The final diagnosis was confirmed by surgical pathology, culture results, or clinical follow-up. RESULTS: Specimens adequate for histopathologic evaluations were obtained in 20 (87%) cases. Final diagnoses were lung cancer (n=15) and benign diseases (infectious pneumonia, 3; lipoid pneumonia, 1; Erdheim Chester disease: 1; and nonspecific chronic pneumonia, 3). Diagnostic yield of core needle biopsy was 78% (18 of 23). The sensitivity and specificity for malignancy were 87% and 100%, respectively. Immediate pneumothorax was present in 11 patients of cases, but only 2 patients required pleural drainage. DISCUSSION: CT-guided lung biopsy using a core needle biopsy provides a high degree of diagnostic accuracy and allows specific characterization of nonresolving pulmonary focal air space consolidation.

Acute cigarette smoke exposure of the airways (two cigarettes twice daily for three days) induces acute inflammation in mice. In this study, we show that airway inflammation is dependent on Toll-like receptor 4 and IL-1R1 signaling. Cigarette smoke induced a significant recruitment of neutrophils in the bronchoalveolar space and pulmonary parenchyma, which was reduced in TLR4-, MyD88-, and IL-1R1-deficient mice. Diminished neutrophil influx was associated with reduced IL-1, IL-6, and keratinocyte-derived chemokine levels and matrix metalloproteinase-9 activity in the bronchoalveolar space. Further, cigarette smoke condensate (CSC) induced a macrophage proinflammatory response in vitro, which was dependent on MyD88, IL-1R1, and TLR4 signaling, but not attributable to LPS. Heat shock protein 70, a known TLR4 agonist, was induced in the airways upon smoke exposure, which probably activates the innate immune system via TLR4/MyD88, resulting in airway inflammation. CSC-activated macrophages released mature IL-1β only in presence of ATP, whereas CSC alone promoted the TLR4/MyD88 signaling dependent production of IL-1α and pro-IL-1β implicating cooperation between TLRs and the inflammasome. In conclusion, acute cigarette exposure results in LPS-independent TLR4 activation, leading to IL-1 production and IL-1R1 signaling, which is crucial for cigarette smoke induced inflammation leading to chronic obstructive pulmonary disease with emphysema.

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.

Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation.

International audience; Monosomy 21 is a rare human disease due to gene dosage errors disturbing a variety of physiological and morphological systems including brain, skeletal, immune and respiratory functions. Most of the human condition corresponds to partial or mosaic monosomy suggesting that Monosomy 21 may be lethal. In order to search for dosage-sensitive genes involved in the human pathology, we generated by chromosomal engineering a monosomic mouse for the Prmt2-Col6a1 interval corresponding to the most telomeric part of human chromosome 21. Haploinsufficiency of the 13 genes, located in the 0.5 Mb genetic interval and conserved in man and mouse, caused apparently no morphological defect as observed in patients. However, monosomic mice displayed an enhanced inflammatory response after local intranasal lipopolysaccharide administration with enhanced recruitment of neutrophils and secretion of cytokines such as tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-12p70 and IFN-gamma in the lung as well increased TNF-alpha production after systemic administration. Further analysis demonstrates that monosomic macrophages were involved and that a few genes, Prmt2, Pcnt2, Mcm3ap and Lss located in the region were candidate for the inflammatory response. Altogether, these results demonstrate the existence of dosage-sensitive genes in the Prmt2-Col6a1 region that control the inflammation and the lung function. Furthermore, they point out that similar partial Monosomies 21 in human might have eluded the diagnosis due to the very specific defects observed in this murine model.

International audience; BACKGROUND: Low-risk patients with community-acquired pneumonia are often hospitalized despite guideline recommendations for outpatient treatment. METHODS: Using data from a randomized trial conducted in 32 emergency departments, we performed a propensity-adjusted analysis to compare 30-day mortality rates, time to the return to work and to usual activities, and patient satisfaction with care between 944 outpatients and 549 inpatients in pneumonia severity index risk classes I to III who did not have evidence of arterial oxygen desaturation, or medical or psychosocial contraindications to outpatient treatment. RESULTS: After adjusting for quintile of propensity score for outpatient treatment, which eliminated all significant differences for baseline characteristics, outpatients were more likely to return to work (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.5 to 2.6) or, for nonworkers, to usual activities (OR, 1.4; 95% CI, 1.1 to 1.8) than were inpatients. Satisfaction with the site-of-treatment decision (OR, 1.1; 95% CI, 0.7 to 1.8), with emergency department care (OR, 1.4; 95% CI, 0.9 to 1.9), and with overall medical care (OR, 1.1; 95% CI, 0.8 to 1.6) was not different between outpatients and inpatients. The overall mortality rate was higher for inpatients than outpatients (2.6% vs 0.1%, respectively; p < 0.01); the mortality rate was not different among the 242 outpatients and 242 inpatients matched by their propensity score (0.4% vs 0.8%, respectively; p = 0.99). CONCLUSIONS: After adjusting for the propensity of site of treatment, outpatient treatment was associated with a more rapid return to usual activities and to work, and with no increased risk of mortality. The higher observed mortality rate among all low-risk inpatients suggests that physician judgment is an important complement to objective risk stratification in the site-of-treatment decision for patients with pneumonia.

International audience; Carcinoid tumors are the most common endobronchial tumor in the pediatric population, and represent a rare cause of airway obstruction. The authors report two cases of boys aged 10 and 11 years old, who presented with a 12-month history of recurrent pneumonia. Bronchial endoscopy showed an endobronchial tumor. Chest CT-scan identified local extension and lung-associated lesions; octreoscan was performed to detect distant metastases. Histopathological study concluded in typical carcinoid tumor. The outcome after surgical conservative resection is uneventful with a follow-up of 7 and 26 months. Bronchial tumors must be considered in children with recurrent pneumonia or persistant respiratory symptoms, and require CT scan and bronchial endoscopy for their diagnosis.

International audience; We report a case of severe acute primary pulmonary toxoplasmosis in an immunocompetent young man living in Nice (Southern France). The Toxoplasma DNA extracted from the broncho-alveolar lavage fluid allowed a genetic characterization of the responsible strain which displayed an atypical genotype of Toxoplasma gondii. This unusual genetic composition of the parasite may have influenced, among other factors, the severity of the disease.

International audience; AIMS: Although pulmonary involvement is a known cause of morbidity in Niemann-Pick disease, histological features in the lung are not well characterized. The purpose of this study is to document the histological features seen in pulmonary involvement by types B and C Niemann-Pick disease and to correlate them with clinical and imaging data. METHODS AND RESULTS: Surgical lung biopsies from six patients (four with type B and two with type C disease) were reviewed and all showed diffuse endogenous lipid pneumonia, with lesser involvement of the interstitium by fibrosis and foamy macrophage accumulation. In type B disease only, there was also fine cytoplasmic vacuolation within the cytoplasm of ciliated epithelial cells. Neither disease showed foamy changes within pneumocytes. One patient had a bronchial cast removed on whole lung lavage. Electron microscopy showed abnormal lamellar inclusions within lysosomes of affected cells in type B disease. In patients with type C disease, biopsies were undertaken as part of investigations into acute respiratory failure in the context of multiorgan systemic presentation. Three patients with type B disease had clinical disease limited to the lung, all adults (mean age of 40 years) with unexplained diffuse parenchymal lung disease and mainly ground-glass shadowing on high-resolution computed tomography. CONCLUSIONS: Niemann-Pick disease should be considered for any patient with unexplained diffuse endogenous lipid pneumonia, even when disease is limited to the lungs and presentation is during adulthood.

In chronic obstructive pulmonary disease (COPD), exacerbations are generally associated with several causes, including pollutants, viruses, bacteria that are responsible for an excess of inflammatory mediators, and proinflammatory cytokines released by activated epithelial and inflammatory cells. The normal response of the airway surface epithelium to injury includes a succession of cellular events, varying from the loss of the surface epithelium integrity to partial shedding of the epithelium or even complete denudation of the basement membrane. The epithelium then has to repair and regenerate to restore its functions, through several mechanisms, including basal cell spreading and migration, followed by proliferation and differentiation of epithelial cells. In COPD, the remodeling of the airway epithelium, such as squamous metaplasia and mucous hyperplasia that occur during injury, may considerably disturb the innate immune functions of the airway epithelium. In vitro and in vivo models of airway epithelial wound repair and regeneration allow the study of the spatiotemporal modulation of cellular and molecular interaction factors-namely, the proinflammatory cytokines, the matrix metalloproteinases and their inhibitors, and the intercellular adhesion molecules. These factors may be markedly altered during exacerbation periods of COPD and their dysregulation may induce remodeling of the airway mucosa and a leakiness of the airway surface epithelium. More knowledge of the mechanisms involved in airway epithelium regeneration may pave the way to cytoprotective and regenerative therapeutics, allowing the reconstitution of a functional, well-differentiated airway epithelium in COPD.

We previously showed that the seminatural surfactant Curosurf inhibits the in vitro synthesis of secretory type IIA phospholipase A2 (sPLA2-IIA) in alveolar macrophages (AM). These cells are the main source of sPLA2-IIA in a guinea pig model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Here, we investigate the effect of Curosurf on the pulmonary synthesis of sPLA2-IIA in this ALI model. Our results showed that intratracheal administration of LPS (330 μg/kg) induced an increase in pulmonary expression of sPLA2-IIA, which was inhibited when animals received Curosurf (16 mg/guinea pig) 30 min or 8 h after LPS instillation. When AM were isolated from LPS-treated animals and cultured in conditioned medium, they expressed higher levels of sPLA2-IIA than AM from saline-treated animals. This ex vivo sPLA2-IIA expression was significantly reduced when guinea pigs received Curosurf 30 min after LPS instillation. Finally, we examined the effect of Curosurf on pulmonary inflammation measured 8 or 24 h after LPS administration. Curosurf instillation 30 min or 8 h after LPS reversed the increase in tumor necrosis factor-α expression, polymorphonuclear cell extravasation, and protein concentration in bronchoalveolar lavage fluids. Curosurf also decreased the bronchial reactivity induced by LPS. We conclude that Curosurf inhibits the pulmonary expression of sPLA2-IIA and exhibits palliative anti-inflammatory effects in an animal model of ALI.

International audience; Pseudomonas aeruginosa is an opportunistic pathogen involved in nosocomial infections. While a number of studies have demonstrated the roles of TLR2, TLR4 and TLR5 in host defense againt P. aeruginosa infection, the implication of TLR9 in this process has been overlooked. Here, we show that P. aeruginosa DNA stimulates the inflammatory response through TLR9 pathway in both a cell line and primary alveolar macrophages (AMs). This activation requires asparagine endopeptidase- and endosomal acidification. Interestingly, TLR9-/- mice resisted to lethal lung infection by P. aeruginosa, compared to WT C57BL/6 mice. The resistance of TLR9-/- mice to P. aeruginosa infection was associated with: (i) a higher ability of TLR9-/- AMs to kill P. aeruginosa; (ii) a rapid increase in the pro-inflammatory cytokines such as TNFα, IL-1β and IL-6 production; and (iii) an increase in nitric oxide (NO) production and inductible NO synthase expression in AMs. In addition, inhibition of both IL-1β and NO production resulted in a significant decrease of P. aeruginosa clearance by AMs. Altogether these results indicate that TLR9 plays a detrimental role in pulmonary host defense toward P. aeruginosa by reducing the AMs clearance activity and production of IL-1β and NO necessary for bacteria killing.