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Objectives Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and as facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), the data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of inflammasomes and IL-1–related cytokines. We aimed to analyse ROS production in neutrophils from patients with GPA and investigate its association with IL-1–related cytokines and the autoantigen PR3. Methods Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production in whole blood of patients with active GPA was evaluated and compared with that in the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1–related cytokines as well as inflammasome-related proteins were analysed. Results We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1–related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients. Conclusion Our data suggests that ROS production and regulation of inflammasomes in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target. Trial registration ClinicalTrials.gov, https://www.clinicaltrials.gov , NCT01862068. [ABSTRACT FROM AUTHOR]

Author(s): Maxens Decavèle [sup.1] [sup.2], Valérie Gounant [sup.2] [sup.3] [sup.4], Jocelyne Fleury Feith [sup.2] [sup.5], Michel Febvre [sup.2] [sup.3], Jean-Marc Naccache [sup.2] [sup.3], Antoine Parrot [sup.1] [sup.2] [sup.3], Muriel Fartoukh [...]

Background and objective: Poly(A)‐specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations. Methods: We performed a retrospective, observational, non‐interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network. Results: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N‐acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range −363 to −148). After a median follow‐up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation‐free survival was 54 months (95% CI 29 to ∞). Extra‐pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation. Conclusion: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed. The pulmonary phenotypes of 31 patients with interstitial lung disease (ILD) and heterozygous poly(A)‐specific ribonuclease (PARN) mutations in this cohort were heterogeneous, but idiopathic pulmonary fibrosis was the most frequent diagnosis. Haematological and hepatic features were less frequent than in patients affected with telomerase reverse transcriptase (TERT)‐ or telomerase RNA component (TERC)‐associated ILDs. [ABSTRACT FROM AUTHOR]

Chronic interstitial lung abnormalities have been described in sickle cell disease (SCD) and attributed to repetitive episode of acute chest syndrome. We report a series of 22 cases of diffuse cystic lung disease in SCD with a case-control study to hunt for mechanism. On pathological analysis of a surgical lung biopsy of the index case, the bronchioles had the appearance of constrictive bronchiolitis. Pulmonary function test results revealed lower forced expiratory flow from 25% to 75% of vital capacity in cases versus controls. These findings suggest a bronchiolar mechanism that was not associated with more acute chest syndrome. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-related pneumonitis (ICI-P) during cancer treatment is rarely observed (<5%). ICI-P is more often observed in patients with nonsmall cell lung cancer (NSCLC) than in those with other cancers. Likewise, it is more common in those receiving programmed cell death (PD)-1/PD-1 ligand inhibitors rather than cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors alone. The frequency of ICI-P is higher when anti-PD-1 and anti-CTLA-4 are administered concomitantly. Despite the low fatality rate (≈13%), ICI-P is the leading cause of ICI-related deaths. This narrative review focuses on the epidemiology, clinical and radiological presentation and prognosis of ICI-P occurring in patients, especially those with advanced NSCLC. Emphasis is placed on the differences in terms of frequency or clinical picture observed depending on whether the ICI is used as monotherapy or in combination with another ICI or chemotherapy. Other pulmonary complications observed in cancer patients, yet not necessarily immune-related, are reviewed, such as sarcoid-like granulomatosis, tuberculosis or other infections. A proposal for pragmatic management, including differential diagnosis and therapeutic strategies, is presented, based on the ICI-P series reported in the literature and published guidelines. [ABSTRACT FROM AUTHOR]

Résumé: L'objectif de cette étude est d'analyser les données récoltées au cours d'audits environnementaux d'habitat de patients parisiens afin de rechercher des liens entre l'environnement domestique et le diagnostic de pneumopathie interstitielle diffuse (PID). Une étude exploratoire cas-témoins a été effectuée à partir des données de 122 patients audités de 2011 à 2017 : 47 patients étaient atteints de PID et 75 patients témoins étaient atteints de pathologies extra-pulmonaires. Le diagnostic de PID est significativement corrélé à quatre des 14 facteurs examinés (données mesurées ou questionnaires) : présence de plantes dans l'habitat (odds ratio (OR) = 4,14 ; IC 95 % = [1,45 ; 11,81]), présence de pigeons dans l'environnement proche de l'habitat (OR = 3,9 ; IC 95 % = [1,56 ; 9,76]), présence majoritaire de Penicillium spp dans les prélèvements (air, poussière ou surface du logement) (OR = 3,33 ; IC 95 % = [1,41 ; 7,88]) et occupation du logement supérieure à 10 ans (OR = 3,06 ; IC 95 % = [1,34 ; 6,98]). L'audit sur site permet d'identifier des facteurs de risque présents dans l'habitat susceptibles d'affecter la santé des occupants et de préconiser des mesures d'éviction. This study analyzes the data collected during audits of the housing of Parisian patients to highlight links between elements in the habitat and a diagnosis of interstitial lung disease (ILD). An exploratory case-control study was performed with data from 122 patients interviewed from 2011 to 2017: 47 patients had ILD, 75 control patients had extrapulmonary conditions. The diagnosis of ILD was significantly correlated with four of the 14 factors examined (by measurement data and questionnaires): presence of plants in the dwelling (odds ratio (OR) = 4.14; 95% CI = [1.45;11.81]), presence of pigeons near the home (OR = 3.9; 95% IC = [1.56;9.76]), presence of Penicillium spp in the samples (air, dust, or surfaces) (OR = 3.33; 95% IC = [1.41;7.88]), and housing occupancy > 10 years (OR = 3.06; 95% IC = [1.34;6.98]). The on-site audit identified risk factors present in the habitat that could affect the health of the occupants possibly requiring eviction measures. [ABSTRACT FROM AUTHOR]

Background: An important objective on diagnosis of patients with Langerhans cell histiocytosis (LCH) is to determine the extent of disease. However, whether systematic extrathoracic investigation is needed in adult patients with clinically isolated pulmonary LCH (PLCH) has not been evaluated.Methods: In this prospective, multicentre study, 54 consecutive patients with newly diagnosed clinically isolated PLCH were systematically evaluated at inclusion by bone imaging and blood laboratory testing to search for subclinical extrapulmonary LCH involvement. The patients were followed over a 2-year period. At each visit, they were asked about the presence of extrapulmonary manifestations of LCH.Results: In the absence of bone symptoms, the skeletal X-ray survey results were normal for all but two patients who had a localised bone lesion consistent with possible LCH involvement, that remained unchanged over 2 years of follow-up. Whole-body bone scintigraphy did not add information to the plain radiography findings for the detection of asymptomatic bone involvement in isolated PLCH. Conversely, it showed nonspecific focal bone uptake in 18% of the patients, mainly corresponding to post-traumatic or degenerative abnormalities unrelated to LCH. Mild leucocytosis due to neutrophilia was observed in 22% of the patients and was not related to their smoking habits. Three patients had mild isolated lymphocytosis without haematological disease, whereas two patients had mild lymphopaenia. A mild inflammatory biological syndrome was observed in a minority of patients without infection or constitutional symptoms and was not associated with progressive disease. A substantial proportion (24.5%) of the patients had abnormal biological liver test results, including elevated liver enzymes and/or cholestasis, which were not linked to LCH involvement in this cohort.Conclusions: Obtaining a thorough history and performing comprehensive physical examination are essential for staging patients diagnosed with PLCH. In the absence of symptoms or signs suggestive of extrapulmonary LCH involvement, the systematic performing of recommended bone imaging does not appear informative. Although the observed blood laboratory abnormalities were not specifically related to LCH, performing these tests in the diagnostic workup for PLCH is useful because some of these alterations may impact patient management.Trial Registration: ClinicalTrials.gov: No. NCT01225601; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Rationale: Clinical decision making relative to community-acquired pneumonia (CAP) diagnosis is difficult. Chest radiograph is key in establishing parenchymal lung involvement. However, radiologic performance may lead to misdiagnosis, rendering questionable the use of chest computed tomography (CT) scan in patients with clinically suspected CAP. Objectives: To assess whether early multidetector chest CT scan affects diagnosis and management of patients visiting the emergency department with suspected CAP. Methods: A total of 319 prospectively enrolled patients with clinically suspected CAP underwent multidetector chest CT scan within 4 hours. CAP diagnosis probability (definite, probable, possible, or excluded) and therapeutic plans (antibiotic initiation/discontinuation, hospitalization/discharge) were established by emergency physicians before and after CT scan results. The adjudication committee established the final CAP classification on Day 28. Measurements and Main Results: Chest radiograph revealed a parenchymal infiltrate in 188 patients. CAP was initially classified as definite in 143 patients (44.8%), probable or possible in 172 (53.8%), and excluded in 4 (1.2%). CT scan revealed a parenchymal infiltrate in 40 (33%) of the patients without infiltrate on chest radiograph and excluded CAP in 56 (29.8%) of the 188 with parenchymal infiltrate on radiograph. CT scan modified classification in 187 (58.6%; 95% confidence interval, 53.2-64.0), leading to 50.8% definite CAP and 28.8% excluded CAP, and 80% of modifications were in accordance with adjudication committee classification. Because of CT scan, antibiotics were initiated in 51 (16%) and discontinued in 29 (9%), and hospitalization was decided in 22 and discharge in 23. Conclusions: In CAP-suspected patients visiting the emergency unit, early CT scan findings complementary to chest radiograph markedly affect both diagnosis and clinical management. Clinical trial registered with www.clinicaltrials.gov (NCT 01574066). [ABSTRACT FROM AUTHOR]

Background: The natural history of pulmonary Langerhans cell histiocytosis (PLCH) has been unclear due to the absence of prospective studies. The rate of patients who experience an early progression of their disease is unknown. Additionally, conflicting effects of smoking cessation on the outcome of PLCH have been reported. Methods: In this prospective, multicentre study, 58 consecutive patients with newly diagnosed PLCH were comprehensively evaluated over a two-year period. Our objectives were to estimate the incidence of early progression of the disease and to evaluate the impact of smoking status on lung function outcomes. Lung function deterioration was defined as a decrease of at least 15% in FEV1 and/or FVC and/or DLCO, compared with baseline values. At each visit, smoking status was recorded based on the patients' self-reports and urinary cotinine measurements that were blinded for the patients. The cumulative incidence of lung function outcomes over time was estimated using the non-parametric Kaplan-Meier method. Multivariate Cox models with time-dependent covariates were used to calculate the hazards ratios of the lung function deterioration associated with smoking status with adjustment for potential confounders. Results: The cumulative incidence of lung function deterioration at 24 months was 38% (22% for FEV1 and DLCO, and 9% for FVC). In the multivariate analysis, smoking status and PaO2 at inclusion were the only factors associated with the risk of lung function deterioration. The patients' smoking statuses markedly changed over time. Only 20% of the patients quit using tobacco for the entire study period. Nevertheless, being a non-smoker was associated with a decreased risk of subsequent lung function deterioration, even after adjustment for baseline predictive factors. By serial lung computed tomography, the extent of cystic lesions increased in only 11% of patients. Conclusions: Serial lung function evaluation on a three- to six-month basis is essential for the follow-up of patients with recently diagnosed PLCH to identify those who experience an early progression of their disease. These patients are highly addicted to tobacco, and robust efforts should be undertaken to include them in smoking cessation programs. [ABSTRACT FROM AUTHOR]

Werner syndrome (WS) is a progeroid or premature aging syndrome characterized by early onset of age-related pathologies and cancer. The average life expectancy of affected people is 52.8 years and tends to increase. The major causes of death are malignancy and myocardial infarction. Increased telomere attrition and decay are thought to play a causative role in the clinical and pathological manifestations of the disease. Although telomere length, with or without germline mutation, is known to be associated with interstitial lung disease, the latter is not associated with WS. To the best of our knowledge, we report the first case describing a WS patient with fatal ILD. This case suggests that older patients with WS could develop ILD. Clinical outcome of WS patients may thus be improved by counselling them regarding smoking cessation or other exposure and by proposing antifibrotic therapy. [ABSTRACT FROM AUTHOR]

(1) Background: Pediatric sarcoidosis is a rare and mostly severe disease. Very few pediatric series with a prolonged follow-up are reported. We aimed to evaluate the evolution of pediatric sarcoidosis in adulthood. (2) Material and methods: Patients over 18-years-old with a pediatric-onset sarcoidosis (≤15-year-old) who completed at least a three-year follow-up in French expert centers were included. Clinical information at presentation and outcome in adulthood were studied. (3) Results: A total of 52 patients were included (34 prospectively in childhood and 18 retrospectively in adulthood), with a mean age of 12 (±2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3–44.5). Relapses mostly occurred during treatment decrease (84.5%), others within the three years after treatment interruption (9.1%), and rarely when the disease was stable for more than three years (6.4%). Sarcoidosis was severe in 11 (21.2%) in adulthood. Patients received a high corticosteroid cumulative dose (median 17,900 mg) for a median duration of five years (range 0–32), resulting in mostly mild (18; 35.3%) and rarely severe (2; 3.8%) adverse events. (4) Conclusions: Pediatric-onset sarcoidosis needed a long-term treatment in almost half of the patients. Around one fifth of pediatric-onset sarcoidosis patients had severe sarcoidosis consequences in adulthood. [ABSTRACT FROM AUTHOR]

Interstitial lung disease (ILD) seems to be associated with an increased risk of lung cancer (LC) and to have a poorer prognosis than LC without ILD. The frequency of ILD in an LC cohort and its prognosis implication need to be better elucidated. This retrospective, observational, cohort study evaluated the frequency of ILD among LC patients (LC–ILD) diagnosed over a 2-year period. LC–ILD patients' characteristics were compared to those with LC without ILD (LC–noILD). Lastly, we conducted a case–control study within this cohort, matching three LC–noILDs to each LC–ILD patient, to evaluate the ILD impact on LC patients' prognoses. Among 906 LC patients, 49 (5.4%) also had ILD. Comparing LC–ILD to LC–noILD patients, respectively, more were men (85.7% vs. 66.2%; p = 0.02); adenocarcinomas were less frequent (47.1% vs. 58.7%, p = 0.08); median [range] and overall survival was shorter: (9 [range: 0.1–39.4] vs. 17.5 [range: 0.8–50.4] months; p = 0.01). Multivariate analysis (hazard ratio [95% confidence interval]) retained two factors independently associated with LC risk of death: ILD (1.79 [1.22–2.62]; p = 0.003) and standard-of-care management (0.49 [0.33–0.72]; p < 0.001). Approximately 5% of patients with a new LC diagnosis had associated ILD. ILD was a major prognosis factor for LC and should be taken into consideration for LC management. Further studies are needed to determine the best therapeutic strategy for the LC–ILD population. [ABSTRACT FROM AUTHOR]

Purpose To describe the initial and follow-up CT features of interstitial lung disease associated with anti-synthetase syndrome (AS-ILD). Materials and methods Two independent thoracic radiologists retrospectively analysed thin-section CT images obtained at diagnosis of AS-ILD in 33 patients (17 positive for anti-Jo1, 13 for anti-PL12, and three for anti-PL7 antibodies). They evaluated the pattern, distribution and extent of the CT abnormalities. They also evaluated the change in findings during follow-up (median 27 months; range 13–167 months) in 26 patients. Results At diagnosis, ground-glass opacities (100%), reticulations (87%) and traction bronchiectasis (76%) were the most common CT findings. Consolidations were present in 45% of patients. A non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP) or mixed NSIP-OP CT pattern were observed in 15 out of 33 (45%), seven out of 33 (21%) and eight out of 33 (24%) patients, respectively, whereas the CT pattern was indeterminate in three patients. During follow-up, consolidations decreased or disappeared in 11 out of 12 patients (92%), among which seven within the first 6 months, but honeycombing progressed or appeared in ten out of 26 patients (38%) and overall disease extent increased in nine out of 26 patients (35%). Conclusion CT features at diagnosis of AS-ILD mainly suggest NSIP and OP, isolated or in combination. Consolidations decrease or disappear in most cases but the disease may progress to fibrosis in more than one third of patients. [ABSTRACT FROM AUTHOR]