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Malnutrition is frequent in patients with idiopathic pulmonary fibrosis (IPF). We examined the relationship between malnutrition at diagnosis and all-cause hospitalization, survival, and acute exacerbation in newly diagnosed IPF patients. In this prospective cohort study, the nutritional status of 153 consecutive newly-diagnosed IPF outpatients was evaluated by measuring body mass index (BMI), fat-free mass index (FFMI) with bioelectrical impedance analysis, and food intake with the Self Evaluation of Food Intake (SEFI)®. Diagnosis was taken as the baseline date and malnutrition was defined as an FFMI below 17 (men) or 15 kg/m2 (women). To determine the factors associated with all-cause hospitalization and mortality, univariate Cox regression analyses were performed and variables with P < 0.2 were included in a stepwise multivariable analysis. A quarter (26%; 40/153) of the patients were suffering from malnutrition at baseline, which was more frequent (62%) in patients whose BMI was <25 kg/m2. Patients whose baseline FFMI was low were more likely to be hospitalized (Hazard Ratio (HR) = 1.98 [95% confidence interval, 1.15; 3.41], P = 0.0139) and/or die (HR = 1.79 [1.11; 2.89], P = 0.0165), but their acute exacerbation rate was similar to that of patients with normal FFMIs. Decreased food intake (SEFI®<7) at baseline was associated with all-cause hospitalization (P = 0.003) and mortality (P < 0.0001) during follow-up. Baseline higher gender-age-physiology (GAP) scores (HR = 1.24 [1.01; 1.52], P = 0.0434; HR = 1.71 [1.37; 2.14], P < 0.0001, respectively), lower BMI (HR = 0.89 [0.83; 0.96], P = 0.003; HR = 0.89 [0.82; 0.96], P = 0.003), and decreased food intake (SEFI® score) (HR = 0.81 [0.71; 0.93], P = 0.003; HR = 0.72 [0.64; 0.81], P < 0.0001), but not FFMI, were independently associated with all-cause hospitalization and mortality rates during follow-up. Malnutrition and decreased food intake at IPF diagnosis are associated with all-cause hospitalization and mortality. Future studies will determine whether dedicated interventions to improve food intake and nutritional status could improve outcomes for IPF patients. • The prevalence of malnutrition at idiopathic pulmonary fibrosis (IPF) is frequent (26%). • Malnutrition and decreased food intake at IPF diagnosis are associated with increased hospitalization and mortality. • GAP score, BMI and food intake (SEFI®) are independently associated with all-cause hospitalization and mortality. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility of a chest CT-based body composition analysis in idiopathic pulmonary fibrosis (IPF), and to investigate the respective contribution of lung and muscle CT quantitative analyses to the prognosis of IPF.Method: A total of 71 IPF patients were recruited at diagnosis. All patients underwent a standard chest CT-scan and a bioelectrical impedance analysis considered as reference standard for estimating malnutrition through the use of the fat-free mass index (FFMI). The skeletal muscle index (SMI) was measured on chest-CT at the level of the first lumbar vertebra by two radiologists. Lung fibrosis extent was quantified by three radiologists in consensus. The extent of emphysema, the pulmonary artery to aorta (PA/AO) diameter ratio and lymph node enlargement were also reported. Mortality and hospitalization over a 14-month follow-up were recorded.Results: A low FFMI defining malnutrition was identified in 26.8% of patients. SMI was significantly lower in these patients (p<0.001) and was correlated with FFMI (r=0.637, p<0.001). Interobserver agreement of SMI measurement was very good (ICC=0.91). For diagnosing malnutrition, SMI showed a 0.79 sensitivity, a 0.69 specificity, a 0.48 PPV and a 0.90 NPV. In univariate analysis, fibrosis extent was significantly associated with death, while SMI did not reach significance. In multivariate analysis, fibrosis extent and PA/AO ratio were independently associated with hospitalization.Conclusions: SMI measured on chest CT could be a reliable tool to exclude malnutrition in IPF. A quantitative analysis of both fibrosis and skeletal muscle may allow holistic management of IPF patients. [ABSTRACT FROM AUTHOR]

Thoracic lymphadenopathy (LA) has been identified as a key prognostic factor in interstitial lung disease (ILD) of all-cause. Crystalline silica is a risk factor of systemic sclerosis (SSc). The association of a history of crystalline silica exposure with chest high-resolution computed tomography (HRCT) features and thoracic LA are still to be determined in SSc patients. We performed an observational study to assess the association of lifetime exposure to silica, with chest HRCT characteristics in a population of SSc patients fulfilling the 2013 ACR/EULAR classification criteria for SSc. A specific questionnaire based on a multidisciplinary approach was used to assess occupational and non-occupational exposure to silica in 100 consecutive SSc patients. Clinical characteristics and chest HRCT at diagnosis and at the latest visit were evaluated to assess the association of silica exposure with disease characteristics. 16% of the overall population and 58% of men had an occupation with specific high silica exposure. A higher silica exposure score was associated with the combination of mediastinal and hilar LA on HRCT (OR=8.09, 95%CI=2.01–32.52, P = 0.002). More than 12% of the patients had a combination of mediastinal and hilar LA on HRCT. This marker of silica exposure was predictive of worsening of pulmonary involvement in univariate analysis (OR=5.86, 95%CI=1.64–20.89, P = 0.007) and multivariate analysis (OR=4.57, 95%CI =1.12–18.60, P = 0.034). In patients with SSc, the combination of mediastinal and hilar LA on HRCT was associated with exposure to silica and was also significantly associated with a more severe evolution of ILD. [ABSTRACT FROM AUTHOR]

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the alveoli accumulation of surfactants proteins and lipids, which diagnosis is confirmed by the presence of GM-CSF antibodies in serum. PAP can be evoked when its characteristic images on chest computed-tomography (CT) are present: bilateral and multifocal ground-glass opacities and crazy-paving appearance. Patients with PAP are at an increased risk of opportunistic infections caused by Nocardia, mycobacteria and fungal pathogens due to impaired processing of pulmonary surfactant. We here report a typical case of newly diagnosed autoimmune PAP, with initial indication to realize a whole-lung lavage. Despite this treatment the patient presented a marked clinical worsening, with increasing need for oxygen and finally the need for mechanical ventilation. The chest CT was controlled and found to be typical of PAP, while the search for opportunistic infections remained negative. Finally, SARS-CoV-2 PCR was performed on bronchoalveolar lavage fluid, and was positive, whereas it had previously been negative twice. Our case report highlights the difficulty of distinguishing SARS-CoV-2 infection in the context of PAP, as the chest CT features are similar. We believe that a SARS-CoV-2 RT-PCR should be systematically realized in case of respiratory deterioration in PAP patients. [ABSTRACT FROM AUTHOR]

Study objective There is no consensus about the management of large spontaneous pneumothoraces. Guidelines recommend either needle aspiration or chest tube drainage and most patients are hospitalized. We assess the efficiency of ambulatory management of large spontaneous pneumothoraces with pigtail catheters. Methods From February 2007 to January 2011, all primary and secondary large spontaneous pneumothoraces from Lorient's hospital (France) were managed with pigtail catheters with a 1-way valve. The patients were discharged immediately and then evaluated every 2 days according to a specific algorithm. Results Of the 132 consecutive patients (110 primary, 22 secondary), 103 were exclusively managed as outpatients, with full resolution of the pneumothorax by day 2 or 4, which represents an ambulatory success rate of 78%. Mean time (SD) of drainage was 3.4 days (1.8). Seven patients were initially hospitalized but quickly discharged and had full resolution by day 2 or 4, leading to a total success rate of 83%. The use of analgesics was low. The 1-year recurrence rate was 26%. If successful, this outpatient management is potentially cost saving, with a mean cost of $926, assuming up to 2 outpatient visits and 1 chest radiograph, compared with $4,276 if a chest tube was placed and the patient was admitted to the hospital for 4 days. Conclusion Ambulatory management with pigtail catheters with 1-way valves could be a reasonable first-line of treatment for large spontaneous pneumothoraces. Compared with that of other studies, our protocol does not require hospitalization and is cost saving. [ABSTRACT FROM AUTHOR]

Background: Idiopathic tracheal stenosis (ITS) is a rare condition representing a difficult therapeutic challenge. Endoscopic management is a therapeutic option but long-term results are not established. The aim of this retrospective multicenter study was to analyze long-term outcome after endoscopic management of ITS. Methods: Nine institutions involved in interventional bronchoscopy were contacted and asked to identify ITS endoscopically treated. A standard form was used to report the main characteristics and long-term outcome after endoscopic management. Results: Twenty-three patients, 96% women, aged 45 ± 16 years, were endoscopically treated for ITS. Time between first symptoms and diagnosis was 19 ± 18 months. Bronchoscopy showed a weblike (61%) or complex (39%) stenosis, located in the upper part of the trachea, mainly in the cricoid area. Endoscopic treatment included mechanical dilation only (52%) or associated with laser or electrocoagulation (30%) and stent placement (18%). All procedures were efficient. The follow-up after endoscopic management was 41 ± 34 months. The ITS recurrence occurred in 30% at 6 months, 59% at 2 years, and 87% at 5 years, with a delay of 14 ± 16 months. The treatment of recurrence (n = 13) included endoscopic management in 12 cases. Conclusions: Endoscopic management of ITS provides a safe and efficient therapeutic option but late recurrences are frequent and require long-term follow-up. [ABSTRACT FROM AUTHOR]

Pulmonary alveolar proteinosis (PAP) is a rare parenchymal pulmonary disease, characterized by the accumulation of surfactant material in alveoli. Rare cases of pulmonary alveolar proteinosis have been reported following the use of sirolimus. All published cases have been described following solid organ transplantation, and symptoms improved quickly after treatment's cessation. We describe a case of PAP secondary to sirolimus treating graft-versus-host reaction in a patient who received a stem cell transplant for chronic lymphocytic leukemia. Pulmonary alveolar proteinosis was cured after stopping sirolimus without any other therapeutic management. PAP can be a rare but serious side effect of sirolimus. It is important to rule out other causes of primary or secondary PAP before suggesting a toxic drug cause. The main challenge is to quickly diagnose this side effect to stop exposure to the toxic agent. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Up to now, no treatment can stop the progression of IPF. Vitamin D3 (VD) reduces experimental lung fibrosis in murine models and depletion of vitamin D3 might be associated with the reduced survival of patients with IPF. In this context, we determined if VD can prevent the pro-fibrotic functions of human lung fibroblasts (HLFs) isolated from patients with IPF. IPF and control HLFs were derived from surgical lung biopsies collected from patients with IPF or with primary lung cancer, respectively. VD (3-100 nM) markedly reduced the basal and PDGF-induced proliferation of HLFs. VD also altered cell cycle by increasing the percentage of IPF HLFs arrested in the G0/G1 phase, and by downregulating the expression of various cell cycle regulatory proteins. In addition, VD barely prevented the TGF-β1-induced differentiation in HLFs. At 100 nM, VD slightly reduced the expression of the pro-fibrotic marker α-smooth muscle actin, and had no effect on fibronectin and collagen-1 expression. In contrast, 100 nM VD strongly inhibited the aerobic glycolytic metabolism induced by TGF- β1. Finally, VD reduced both the secretion of lactate, the levels of lactate deshydrogenase mRNA and the activity of intracellular LDH in IPF HLFs. In conclusion, our study shows that VD reduced pro-fibrotic functions of HLFs. These findings suggest that it might be interesting to assess the potential clinical benefits of vitamin D supplementation in patients with IPF, especially on lung function decline. [ABSTRACT FROM AUTHOR]

• La spondyloarthrite et la sacro-iliite sont régulièrement associées à la sarcoïdose, en particulier en présence de lombalgie inflammatoire. • Une atteinte granulomateuse des os pelviens mimant une sacro-iliite peut survenir dans la sarcoïdose ; la présence de changements unilatéraux sur la radiographie suggère une atteinte granulomateuse. • L'existence d'une arthropathie de l'articulation sacro-iliaque associée à la sarcoïdose reste sujette à discussion. • Les modalités d'imagerie utilisées pour évaluer l'articulation sacro-iliaque dans la sarcoïdose sont encore hétérogènes. Sarcoïdose et spondyloarthrite (SpA) sont fréquemment associées, et des granulomes ont été décrits au niveau des os iliaques. Nous proposons ici une revue systématique de la littérature sur les manifestations rhumatologiques axiales de la sarcoïdose. Cette revue systématique de la littérature a été réalisée dans les bases de données PubMed et Cochrane Library. Les recommandations PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) ont été appliquées pour l'examen des rapports de cas et des études transversales. Résultats Au total, 41 articles remplissaient les critères définis. Trois études transversales sur l'association SpA-sarcoïdose ont montré une prévalence de sacro-iliite et de SpA de 12,9 à 44,8 % et de 12,9 à 48,3 %, respectivement, dans les sous-groupes de lombalgie inflammatoire (LI). Cependant, les définitions de la LI et les modalités d'imagerie de l'articulation sacro-iliaque (ASI) étaient hétérogènes (radiographie ou imagerie par résonance magnétique), la radiographie étant la principale technique (78 % des cas) employée pour diagnostiquer la sacro-iliite. Trente-et-un rapports de cas sur l'association sarcoïdose-sacro-iliite ont été identifiés, représentant 35 patients. Les critères de l'ASAS pour la SpA étaient remplis dans la moitié des cas (16/32), et le HLA-B27 était positif dans 46 % des cas (12/26). La sarcoïdose est apparue postérieurement aux symptômes sacro-iliaques chez 47 % des patients. L'atteinte unilatérale était significativement plus fréquente dans les sept cas de granulome des os sacro-iliaques que dans le groupe sarcoïdose-sacro-iliite (p < 0,001). L'analyse de la littérature a démontré de façon probante l'existence d'une association SpA-sarcoïdose, ce qui incite à accorder une attention particulière aux patients atteints de sarcoïdose et faisant état d'une LI. La présence d'une sacro-iliite unilatérale devrait faire suspecter une atteinte osseuse granulomateuse distincte de la sacro-iliite. Les modalités d'imagerie mises en œuvre pour étudier l'ASI chez les patients présentant une sarcoïdose étaient hétérogènes et des études supplémentaires sont nécessaires. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis and spondyloarthritis (SpA) have been regularly associated. Bone iliac granulomas have also been described. We propose herein a systematic review of rheumatologic axial manifestations of sarcoidosis.Methods: PubMed and the Cochrane Library were used to conduct this systematic literature review. Case reports and cross-sectional studies were reviewed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.Results: A total of 41 articles were eligible. Three cross-sectional studies on the association between SpA and sarcoidosis showed a prevalence of sacroiliitis and SpA ranging from 12.9 to 44.8% and 12.9 to 48.3% in inflammatory back pain (IBP) subgroups, respectively. However, the IBP definitions and sacroiliac joint (SIJ) imaging modalities (X-rays or magnetic resonance imaging) were heterogeneous, and X-ray was mainly used for sacroiliitis diagnosis (in 78% of cases). Thirty-one case-report articles of the sarcoidosis-sacroiliitis association were identified, representing 35 patients. ASAS criteria for SpA were met in half of cases (16/32) and 46% (12/26) had HLA B27 positivity. Sarcoidosis occurred after sacroiliac symptoms in 47% of cases. In the seven case-report articles with granulomatous sacroiliac bone involvement, unilateral involvement seemed higher than in the sarcoidosis-sacroiliitis group.Conclusion: Literature analysis found a good evidence of the association between SpA and sarcoidosis, and special attention should be given to patients reporting IBP. Unilateral sacroiliitis may raise suspicion of granulomatous bone involvement, distinct from sacroiliitis. Imaging modalities used to study the SIJ in patients with sarcoidosis have been heterogeneous and further investigation is needed. [ABSTRACT FROM AUTHOR]

• Intravenous amoxicillin at 6 g/day allowed detectable concentrations in pleural fluid in 90% of cases. • Amoxicillin coefficient of diffusion in pleural fluid was 68%. • Metronidazole achieved excellent pleural diffusion, highly correlated with plasma levels. • Considering causative pathogen MICs, an amoxicillin target of C min or C ss ≥ 5 mg/L in pleural fluid seems appropriate. The pharmacokinetics of antibiotics in pleural fluid during pleural infections has been poorly described. This study aimed to explore amoxicillin and metronidazole diffusion into the pleural space. This was an ambispective, single-centre study that included patients with complicated parapneumonic effusion or pleural empyema managed with repeated therapeutic thoracentesis as first-line treatment between 2014 and 2022. Pleural steady-state or trough concentrations of amoxicillin and metronidazole were measured, with a lower limit of quantification of 5 mg/L. Seventy paired blood and pleural samples were analysed from 40 patients. The median (interquartile range) patient age was 55 years (45–67 years) and 88% were male. The median patient weight was 65.8 kg (57.3–82 kg) and median plasma albumin concentration was 29.7 g/L (23.7–33.9 g/L). Median creatinine clearance was 106 mL/min (95–117 mL/min). Median amoxicillin pleural concentrations in patients treated with oral, bolus and continuous intravenous administrations (6 g/day) were, respectively, 5.2 (<5–6.4), 9.4 (8–13.1) and 10.8 (7.1–13.1) mg/L. Pleural concentrations were <5 mg/L in 5/11 samples (45%) with oral treatment and 6/59 (10%) with intravenous treatment. Median metronidazole pleural concentrations were 18.4 (15.7–22.8) mg/L, with all patients being treated orally (1.5 g/day). Oral metronidazole (1.5 g/day) and intravenous amoxicillin (6 g/day) achieved therapeutic targets in pleural fluid in most cases, but oral amoxicillin did not. [ABSTRACT FROM AUTHOR]

The tyrosine kinase inhibitor, Nintedanib (NTD), has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). In cell-free systems, NTD was recently shown to inhibit kinase activity of the human recombinant colony-stimulating factor 1 (CSF1) receptor (CSF1R) which mediates major functions of pulmonary macrophages. In the present study, we have investigated the effects of NTD on the phenotype of human monocyte-derived macrophages controlled by CSF1 in order to identify its anti-inflammatory properties via CSF1R inhibition. NTD (0.01 to 1 μM) prevented the CSF1-induced phosphorylation of CSF1R and activation of the downstream signaling pathways. NTD, like the CSF1R inhibitor GW2580, significantly decreased the adhesion of macrophages and production of the chemokine ligand (CCL) 2. NTD also altered the polarization of macrophages to classical M1 and alternative M2a macrophages. It reduced the secretion of several pro-inflammatory and/or pro-fibrotic cytokines (IL-1β, IL-8, IL-10 and CXCL13) by M1 macrophages but did not prevent the expression of M1 markers. While NTD (50–200 nM) partially blocked the synthesis of M2a markers (CD11b, CD200R, CD206, and CD209), it did not reduce synthesis of the M2a pro-fibrotic cytokines CCL22 and PDGF-BB, and increased CCL18 release when used at its highest concentration (1 μM). The effects of NTD on macrophage polarization only was partially mimicked by GW2580, suggesting that the drug inhibits other molecules in addition to CSF1R. In conclusion, NTD alters the CSF1-controlled phenotype of human macrophages mainly by blocking the activation of CSF1R that thus constitutes a new molecular target of NTD, at least in vitro. Unlabelled Image • Nintedanib inhibits the activation of CSF1R in human macrophages. • Nintedanib reduces the adherence of human macrophages through CSF1R inhibition. • Nintedanib prevents CCL2 gene expression induced by CSF1 in M0 macrophages. • Nintedanib decreases the production of IL-1b and IL-8 in M1 macrophages. • Nintedanib reduces the expression of M2 markers. [ABSTRACT FROM AUTHOR]

Résumé L'hypertension artérielle pulmonaire (HTAP) est une pathologie rare, caractérisée par une augmentation des résistances vasculaires pulmonaires. Parmi les multiples étiologies d'HTAP, on retrouve les HTAP induites par la prise de médicaments, principalement représentés par les traitements anorexigènes. Nous rapportons les cas de quatre patients ayant développé une HTAP au cours d'un traitement par léflunomide, molécule prescrite dans le cadre d'une polyarthrite rhumatoïde, d'un rhumatisme psoriasique ou d'une connectivite indifférenciée. Les quatre patients consultaient pour une dyspnée d'installation progressive (stade II à IV de la NYHA au moment du diagnostic) ; l'examen clinique retrouvait des signes cliniques d'insuffisance cardiaque, motivant la réalisation d'une échographie cardiaque. Des signes échographiques évocateurs d'HTAP faisaient réaliser un cathétérisme cardiaque droit, retrouvant une hypertension pulmonaire pré-capillaire (pression artérielle pulmonaire moyenne supérieure à 25 mmHg et une pression artérielle pulmonaire d'occlusion inférieure à 15 mmHg). Le bilan étiologique d'hypertension pulmonaire pré-capillaire était réalisé tel que préconisé par les recommandations internationales ; la réalisation d'une scintigraphie de ventilation-perfusion et d'un angioscanner thoracique permettait d'exclure les diagnostics d'hypertension pulmonaire post-embolique chronique ou en rapport avec une maladie respiratoire chronique. Le diagnostic d'HTAP était alors retenu et les explorations réalisées à visée étiologique étaient négatives. L'imputabilité du léflunomide était finalement retenue. Le traitement incriminé était arrêté pour les quatre patients, et trois d'entre eux ont reçu un traitement spécifique de l'HTAP. L'évolution clinique et/ou hémodynamique était favorable pour l'ensemble des patients. Ces quatre cas ont été déclarés au centre local de pharmacovigilance, permettant de retenir un signal faible. Cela a conduit à la modification de la monographie du léflunomide en ajoutant « hypertension pulmonaire » à la rubrique « effets indésirables » et « de rares cas d'hypertension pulmonaire ont été rapportés pendant un traitement par léflunomide » à la rubrique « mises en garde ». [ABSTRACT FROM AUTHOR]

Introduction: Appropriate identification of subjects who are candidates for spirometry through case-finding questionnaires may help solve the problem of chronic obstructive pulmonary disease misdiagnosis. The performance of case-finding questionnaires depends at least partially on the characteristics of the population used for their development. The use of an accurate threshold for the forced expiratory volume in 1 second / forced vital capacity ratio to define persistent airway obstruction is also vital in ascertaining chronic obstructive pulmonary disease.Methods: Using a population examined between October 2012 and May 2013 that included a large subset of agricultural workers both exposed and unexposed to tobacco smoking, the authors aimed to select a combination of items that would identify persons most likely to have persistent airway obstruction defined as forced expiratory volume in 1 second / forced vital capacity less than the lower limit of normal according to the Global Lung Initiative-2012 equations. Two thirds of the population (n=3,397) were randomly selected to develop a questionnaire, and one third (n=1,698) was reserved for questionnaire validation. Statistical analysis was performed in 2016.Results: The selected items were sex, dyspnea, BMI, tobacco smoking habits, age, history of respiratory diseases, and history of occupation at risk. The C-index of the model was 0.84 (95% CI=0.80, 0.88) for the development population and 0.76 (95% CI=0.66, 0.86) for the validation population. Using the selected items in combination, the sensitivity and specificity in identifying persistent airway obstruction were 76% and 77%, respectively, in the development population (and 68% and 73%, respectively, in the validation population) for a threshold value of 2.50%.Conclusions: This seven-item questionnaire is the first developed from a population comprising a large subset of agricultural workers and using the Global Lung Initiative-2012 equations. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare disorder that can be drug-induced, mostly following treatment by appetite-suppressant drugs. We report four cases of patients who developed PAH following a treatment by leflunomide for rheumatoid arthritis, psoriatic arthritis or undetermined connective tissue disease. All patients described a progressive dyspnea from grade II to IV of NYHA classification; clinical examination found signs of heart failure. PAH was finally diagnosed and confirmed by right heart catheterisation. Haemodynamic explorations found pre-capillary pulmonary hypertension with mean pulmonary arterial pressure above 25mmHg, and pulmonary capillary wedge pressure under 15mmHg. Explorations of this pre-capillary pulmonary hypertension were conducted according to international guidelines: pulmonary or chronic thromboembolic aetiologies were excluded after ventilation/perfusion lung scan and high-resolution computed tomography. All other etiologic explorations were negative. Imputability of leflunomide was finally retained. Leflunomide was stopped for all patients; three of them received specific PAH treatments. A favourable clinical and/or haemodynamic evolution was observed for all patients. The conclusions of the investigations conducted by our pharmacovigilance centre were communicated to the European Medicines Agency, leading to the addition of "pulmonary hypertension" in the paragraph "special warning and precautions of use" of the package leaflet of leflunomide. [ABSTRACT FROM AUTHOR]

Background Influenza is an important cause of serious illness and death, particularly in elderly and high-risk groups. Objectives Aim of this study was to identify factors associated with poor outcomes among adults hospitalized in France for laboratory-confirmed seasonal influenza. Study design Patients hospitalized for influenza were identified in a prospective, multicenter study carried out in French hospitals during three consecutive influenza seasons (2012–2015). Influenza virus infection was confirmed by reverse transcription polymerase chain reaction. Sociodemographic and clinical variables were compared according to the virus type and subtype. Risk factors for complications, intensive care unit (ICU) admission and death were analyzed by backward stepwise logistic regression. Results The study population consisted of 566 patients, of whom 56% were older than 65 years and 82% had underlying chronic illnesses. Type A influenza viruses infected 422 patients (75%), including subtype H3N2 in 239 patients (57%). The prior vaccine coverage rate was 38%. Complications occurred in 255 patients (45%), consisting mainly of pneumonia (n = 143, 30%) and respiratory failure (n = 116, 20%). Eighty-three patients (15%) were admitted to an ICU, and the in-hospital mortality rate was 4% (n = 21). Sixty-six patients (12%) received oseltamivir. Age over 65 years was the only identified risk factor for complications. Risk factors for ICU admission were an absence of vaccination, no oseltamivir administration before admission, pre-existing chronic respiratory disease, and current smoking. Age over 65 years and ICU admission were risk factors for death. Conclusions Older individuals and patients with underlying conditions are most at risk of influenza complications. Vaccination and early oseltamivir administration, both of which are recommended for these patients, appear to reduce ICU admissions. [ABSTRACT FROM AUTHOR]

Background Mutations in the telomerase complex ( TERT and TR ) are associated with pulmonary fibrosis and frequent hematologic manifestations. The aim of this study was to characterize the prognosis of lung transplantation in patients with TERT or TR mutations. Methods Patients with documented TERT or TR mutations who received a lung transplant between 2007 and 2013 in France were identified via an exhaustive search of the lung transplantation network, one expert genetic laboratory, and the clinical research network on rare pulmonary diseases. Results There were 9 patients (7 men) with TERT ( n = 6) or TR ( n = 3) mutations who received a single ( n = 8) or a double ( n = 1) lung transplant for pulmonary fibrosis. Median age was 50 years (range, 35–61 years) at diagnosis and 52 years (range, 37–62 years) at the time of lung transplantation. Thrombocytopenia was present in 7 patients before lung transplantation. After lung transplantation, 6 patients developed myelodysplasia and/or bone marrow failure, directly contributing to death in 4 cases. Anemia was observed in 9 patients, and neutropenia was observed in 3 patients. The median survival after lung transplantation was 214 days (range, 59–1,709 days). Conclusions Patients with mutations of the telomerase complex are at high risk of severe hematologic complications after lung transplantation, in particular, bone marrow failure. Specific recommendations should be developed for appropriate guidance regarding hematologic risk assessment before transplantation and management of the post-transplantation immunosuppressive regimen. [ABSTRACT FROM AUTHOR]

Abstract: Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC. [Copyright &y& Elsevier]

Abstract: Inorganic arsenic, a major environmental contaminant, exerts immunosuppressive effects towards human cells. We previously demonstrated that relevant environmental concentrations of inorganic arsenic altered morphology and functions of human primary macrophages, suggesting interference with macrophage differentiation program. The goal of this study was to determine global effect of low concentrations of arsenic trioxide (As2O3) on gene expression profile in human primary macrophages, in order to identify molecular targets of inorganic arsenic, especially those relevant of macrophage differentiation process. Using a pan-genomic microarray, we demonstrate that exposure of human blood monocyte-derived macrophages to 1μM As2O3 for 72h, a non-cytototoxic concentration, results in up-regulation of 32 genes and repression of 91 genes. Among these genes, 26 are specifically related to differentiation program of human macrophages. Particularly, we validated that As2O3 strongly alters expression of MMP9, MMP12, CCL22, SPON2 and CXCL2 genes, which contribute to major macrophagic functions. Most of these metalloid effects were reversed when As2O3-treated macrophages were next cultured in arsenic-free medium. We also show that As2O3 similarly regulates expression of this macrophagic gene subset in human alveolar macrophages, the phenotype of which closely resembles that of blood monocyte-derived macrophage. In conclusion, our study demonstrates that environmentally relevant concentrations of As2O3 impair expression of macrophage-specific genes, which fully supports interference of metalloid with differentiation program of human macrophages. [Copyright &y& Elsevier]

Janus kinase (JAK) inhibitors (also termed Jakinibs) constitute a family of small drugs that target various isoforms of JAKs (JAK1, JAK2, JAK3 and/or tyrosine kinase 2 (Tyk2)). They exert anti-inflammatory properties linked, in part, to the modulation of the activation state of pro-inflammatory M1 macrophages. The exact impact of JAK inhibitors on a wider spectrum of activation states of macrophages is however still to be determined, especially in the context of disorders involving concomitant activation of pro-inflammatory M1 macrophages and profibrotic M2 macrophages. This is especially the case in autoimmune pulmonary fibrosis like scleroderma-associated interstitial lung disease (ILD), in which M1 and M2 macrophages play a key pathogenic role. In this study, we directly compared the anti-inflammatory and anti-fibrotic effects of three JAK inhibitors (ruxolitinib (JAK2/1 inhibitor); tofacitinib (JAK3/2 inhibitor) and itacitinib (JAK1 inhibitor)) on five different activation states of primary human monocyte-derived macrophages (MDM). These three JAK inhibitors exert anti-inflammatory properties towards macrophages, as demonstrated by the down-expression of key polarization markers (CD86, MHCII, TLR4) and the limited secretion of key pro-inflammatory cytokines (CXCL10, IL-6 and TNFα) in M1 macrophages activated by IFNγ and LPS or by IFNγ alone. We also highlighted that these JAK inhibitors can limit M2a activation of macrophages induced by IL-4 and IL-13, as notably demonstrated by the down-regulation of the M2a associated surface marker CD206 and of the secretion of CCL18. Moreover, these JAK inhibitors reduced the expression of markers such as CXCL13, MARCO and SOCS3 in alternatively activated macrophages induced by IL-10 and dexamethasone (M2c + dex) or IL-10 alone (M2c MDM). For all polarization states, Jakinibs with inhibitory properties over JAK2 had the highest effects, at both 1 μM or 0.1 μM. Based on these in vitro results, we also explored the effects of JAK2/1 inhibition by ruxolitinib in vivo, on mouse macrophages in a model of HOCl-induced ILD, that mimics scleroderma-associated ILD. In this model, we showed that ruxolitinib significantly prevented the upregulation of pro-inflammatory M1 markers (TNFα, CXCL10, NOS2) and pro-fibrotic M2 markers (Arg1 and Chi3L3). These results were associated with an improvement of skin and pulmonary involvement. Overall, our results suggest that the combined anti-inflammatory and anti-fibrotic properties of JAK2/1 inhibitors could be relevant to target lung macrophages in autoimmune and inflammatory pulmonary disorders that have no efficient disease modifying drugs to date. [ABSTRACT FROM AUTHOR]