Endocan and its major catabolite cleaved endocan are reported as potential biomarkers of pneumonia in the setting of critical illness. However, very little is known about their accuracy to discriminate microbiologically confirmed ventilator-associated pneumonia (VAP) at the time of clinical suspicion. The objective of this study was to evaluate the performance of endocan and cleaved endocan for the early discrimination of microbiologically confirmed VAP. In a pre-planned ancillary analysis of the single-center prospective observational SOH-VAP cohort (NCT03434821) which was conducted at the University hospital of Lille from March 2018 to April 2022, patients presenting with a clinical suspicion of VAP leading to microbiological respiratory sampling were included. Endocan and cleaved endocan were measured on EDTA plasma collected on the day of VAP clinical suspicion. The performance of these biomarkers and of the endocan cleavage ratio (ECR) was determined by comparing values obtained in patients with microbiologically confirmed VAP to those without microbiological confirmation, and by establishing ROC curves. We enrolled 47 patients with microbiologically confirmed VAP and 67 patients without microbiological confirmation. No significant differences were found when comparing endocan, cleaved endocan, and ECR values between confirmed and non-confirmed VAP (median [IQR] = 5 [2.7; 9.6] ng/mL vs. 4.7 [2.5; 8.5] ng/mL, p = 0.86 for endocan; 1.2 [0; 2] ng/mL vs. 1 [0; 2] ng/mL, p = 0.71 for cleaved endocan; and 0.06 [0; 0.32] vs. 0.07 [0; 0.29], p = 0.94 for ECR). Areas under the ROC curves for differentiating confirmed and non-confirmed VAP were respectively calculated at 0.51 (95% CI: 0.4-0.62) for endocan, 0.52 (95% CI: 0.43-0.64) for cleaved endocan, and 0.52 (95% CI: 0.41-0.63) for ECR. Our results do not support the use of endocan nor cleaved endocan for the early detection of microbiologically confirmed VAP at the time of clinical suspicion.

Alpha-1 Antitrypsin Deficiency (AATD) is a rare, underdiagnosed genetic disorder caused by pathogenic variants of the SERPINA1 gene, which can lead to reduced levels and/or dysfunctional forms of the Alpha-1 Antitrypsin (AAT) protein. Accurate AATD diagnosis is critical due to its implications for pulmonary and hepatic health. However, diagnostic practices vary across laboratories, particularly in the detection and reporting of rare variants. This study aimed to evaluate the consistency and reliability of AATD diagnostic testing across European laboratories through a non-commercial external quality assessment (EQA)-like initiative. Seven European laboratories participated in six assessment rounds between 2019 and 2021. Each round involved blinded analysis of serum and dried blood spot (DBS) samples using local standard operating procedures. Tests included AAT and C-reactive protein quantification, isoelectric focusing for AAT phenotyping, and genotyping/sequencing for common and rare SERPINA1 variants. Interrater agreement was assessed using Fleiss’ kappa statistic. Allele error rates were calculated for each variant and Kruskal-Wallis tests were used to compare AAT concentrations across laboratories. For common variants (M [normal], S [p.E288V], and Z [p.E366K]), interlaboratory concordance was high, with Fleiss’ kappa values indicating almost perfect agreement (0.85–1.00). Genotyping and sequencing error rates for these variants were zero. However, detection of rare variants (e.g., MProcida [p.L65P], MHeerlen [p.P393L], and MWurzburg [p.P393S]) was inconsistent, with error rates ranging from 0.14 to 0.29. Sequencing was more effective than phenotyping or simple genotyping for rare variant identification. AAT concentration measurements were generally consistent across laboratories, though DBS samples showed more variability. Reporting nomenclature also varied widely, highlighting the need for standardisation. This initiative demonstrated strong interlaboratory agreement in detecting common AATD variants but revealed challenges in identifying and reporting rare variants. The findings support the need for SERPINA1 sequencing in AATD diagnostics and the adoption of standardised nomenclature. Centralised testing in validated reference laboratories is also recommended to ensure diagnostic accuracy and consistency across Europe.

The role of exhaled 3-nitrotyrosine (3-NT) beyond the severe asthma phenotype remains largely unexplored. Associations of exhaled 3-NT with allergy and with various asthma characteristics were studied in 792 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA, 40% current asthmatics, 56% allergic, 36% adult-onset asthma). Asthma characteristics were defined using questionnaires, and allergy by a positive skin prick test. 3-NT was analyzed as categorical, continuous and ratio (3-NT/tyrosine) variables. Cross-sectional analyses showed that high 3-NT levels were associated with an increased risk of current asthma (adjusted(a)OR [95%CI] = 1.61 [1.09-2.38], particularly in non-allergic asthma (aOR = 2.19 [1.09-4.41]), and no association was found with allergy. Results were consistent across all 3-NT expressions. Longitudinal analyses showed that high 3-NT levels were associated with persistent current asthma at 10-year follow-up. Our results advance understanding of the mechanisms underlying asthma phenotypic heterogeneity, thereby opening new perspectives in its management.

Objective: The relationship between ventilator-associated events (VAE) and microaspiration in intubated patients has not be studied. The objective of this study was to evaluate the relationship between abundant microaspiration of oropharyngeal secretions or gastric contents and the incidence of VAE. Patients and methods: This was a post hoc analysis of the BESTCUFF study, which was a multicenter, cluster randomized, cross-over, controlled, open-label trial in adult patients ventilated for over 48 h. All tracheal aspirates were sampled for 48 h following enrollment, with quantitative measurement of pepsin and alphaamylase. VAE were identified using National Healthcare Safety Network criteria, based on PEEP or FiO2 variations compared to stable parameters in previous days. The primary objective was to assess the relationship between abundant global microaspiration and the incidence of VAE, adjusted for pre-specified confounding factors (sex, SAPS II score and Glasgow coma scale). Results: 261 patients were included, of which 31 (11.9%) developed VAE, with an overall median age of 65 (interquartile range 52-74), a majority of male patients (164, 62.8%), a median SAPS II score of 50 [40-61], a median SOFA score of 8 [5-11], and acute respiratory failure as main reason for ICU admission (117, 44.8%).The incidence of VAE was not significantly associated with abundant global microaspiration (adjusted cause-specific hazard ratio (cHR): 1.55 [0.46-5.17), abundant gastric microaspiration (adjusted cHR: 1.24 [0.61-2.53), or with abundant oropharyngeal microaspiration (adjusted HR: 1.07 [0.47-2.42]). Conclusions: Our results suggest no significant association between abundant global, gastric or oropharyngeal microaspiration and the incidence of VAE. Implications for clinical practice: This study underscores that measuring microaspiration in intubated critically ill patients might not be useful to predict the diagnosis of VAE or to evaluate interventions aiming at preventing these complications.

Introduction Les variations du gène FLNA sont responsables de pathologies rares appelées filaminopathies, le plus souvent responsables d’épilepsie et de malformations congénitales. Diverses atteintes respiratoires ont été rapportées en population pédiatrique (détresse respiratoire aiguë néonatale, dysplasie bronchopulmonaire, emphysème…). Chez l’adulte, seuls quelques cas d’emphysème ont été décrits. Notre hypothèse est que les variations de FLNA pourraient être associées à la présence d’emphysème à l’âge adulte. L’objectif de notre étude était d’évaluer la fréquence et les caractéristiques de l’emphysème chez les patients avec variation de FLNA. Méthodes Nous avons conduit une étude prospective transversale monocentrique chez les patients adultes (>18 ans) porteurs d’une variation pathogène du gène FLNA suivis au CHU de Lille (CPP 2022-A00972-41). Les patients inclus ont bénéficié (1) d’une recherche exhaustive d’exposition respiratoire à des substances responsables d’emphysème (tabagisme actif ou passif, expositions domestiques et professionnelles), (2) d’un scanner thoracique interprété par les radiologues thoraciques et d’une quantification du volume d’emphysème par un logiciel, (3) d’explorations fonctionnelles respiratoires (EFR) comprenant spirométrie, pléthysmographie, DLCO et oscillomètrie respiratoire. En cas d’emphysème, ils bénéficiaient d’une recherche de déficit en alpha-1-antitrypsine (DAAT) et d’un séquençage du gène PTPN6. L’objectif principal était de déterminer la fréquence de l’emphysème. Les objectifs secondaires étaient la description des caractéristiques de l’emphysème (type, répartition et sévérité), des EFR, et de la fréquence de l’emphysème inexpliqué, défini par l’absence de cause secondaire. Résultats Parmi les 29 adultes identifiés dans le centre de référence régional, 10 présentaient des critères de non-inclusion, 5 ont refusé de participer, et 4 n’ont pas donné de réponse. Au total, dix patientes ont été incluses. La fréquence de l’emphysème était de 70 % (n=7). La seule exposition retrouvée chez les patientes atteintes d’emphysème était le tabagisme passif, chez 3 patientes. Aucune n’avait de DAAT ni de variation de PTPN6. L’emphysème était donc inexpliqué dans 57 % des cas (n=4). L’emphysème était majoritairement centrolobulaire (n=4) et prédominait dans les régions supérieures (n=4). Le volume médian d’emphysème était de 8,8 % (IQ 3,0–18,0 %) du volume pulmonaire total. Chez les patients avec emphysème, les EFR révélaient une limitation des débits expiratoires (VEMS et, ou VEMS/CVFlimite supérieure de la normale (LSN)) dans 57 % des cas (n=4), une diminution de la DLCO dans 71 % des cas (n=5) et une dysfonction des petites voies aériennes (R5–R20 >0,07kPa/L/s) dans 71 % des cas (n=5). Conclusion Nos résultats suggèrent que les femmes adultes avec variation pathogène hétérozygote du gène FLNA auraient fréquemment de l’emphysème et devraient bénéficier d’un dépistage systématique et de mesures de protection respiratoire (vaccinations, sevrage tabagique). Ces variations pourraient également être une cause d’emphysème familial ou inexpliqué chez les femmes.

Air pollution is an environmental risk factor associated with lung and cardiovascular disease that may be mediated by physiological pathways such as oxidative stress. Previous studies have identified associations between air pollution and biomarkers of oxidative stress (8-OHdG, 4-HNE, and fluorescent oxidation products (FOPs)), as well as lung health marker CC16, in younger and asthmatic populations. The objective of this study of a large population-based sample of non-smoking adults was to explore the relationship between long-term and short-term atmospheric pollution exposures and plasma or urine levels of these biomarkers. Our study was a post-hoc analysis of the cross-sectional ELISABET study from 2011 to 2013. We included non-smoking inhabitants of Lille, France from the ELISABET study. We assessed mean pluri-annual residential and short-term exposures to atmospheric pollution components (PM10, NO2, and O3) and collected several biomarkers (CC16, 8-OHdG, 4-HNE, and fluorescent oxidation products (FOPs)). We searched for associations between pollutants and biomarkers using log-linear robust multivariate regressions. Our work did not show any association between short- or long-term exposure to air pollution components and CC16, 8-OHdG, 4-HNE or FOP in a large (980 subjects) sample of Lille’s general population, despite having sufficient statistical power to replicate previous findings of associations between air pollution and these biomarkers found in younger or asthmatic populations.

Biallelic SERPINA1 Q0 variants lead to early-onset emphysema even in nonsmokers, mandating early-life preventive and therapeutic measures. ZZ patients' lungs on shut-off transcription strategies equating them to "null" variants should also be protected. https://bit.ly/4mIlRL9.

FLNA pathogenic variants lead to various congenital malformations. Pulmonary manifestations were reported in early age. In adults, few cases of emphysema were published. We aimed to assess the frequency and characteristics of emphysema in adults with a pathogenic or probably pathogenic variant in FLNA. We conducted a transversal single-center study. Adults with FLNA pathogenic variant followed in Lille University Hospital were identified among the French rare disease database BaMaRa®. They attended medical examination, non-contrast chest CT-scan and pulmonary function tests (PFT). We collected medical history, tobacco smoking status, occupational and domestic exposures. When emphysema was identified, the PTPN6 gene was sequenced and alpha1antitrypsin deficiency searched. The primary objective of the study was to assess the frequency of emphysema. Secondary objectives were to evaluate emphysema type, distribution and extension, lung function in case of emphysema and the frequency of unexplained emphysema. Among the 29 patients identified, 10 met non-inclusion criteria, 4 declined, 5 could not be reached and so 10 patients were included. The frequency of emphysema was 70 https://clinicaltrials.gov/study/NCT05550844?cond=FLNA rank=1 .

The existence of alpha-1 antitrypsin variants with apparently unremarkable phenotypes and serum concentrations, contrasting with a clinical picture suggestive of a severe deficiency, led us to investigate whether in these cases there was a reduction or even suppression of the capacity of alpha-1 antitrypsin to inhibit elastase. To this end, in two different laboratories, we adapted and validated a method for measuring the functional activity of alpha-1 antitrypsin, based on spectrophotometric kinetic analysis of the inhibition by serum alpha-1 antitrypsin of the hydrolytic activity of porcine pancreatic elastase on a chromogenic substrate. This method has proved to be robust, reproducible and transferable and made possible to define, on the basis of an analysis of a hospital population, a functionality index with a confidence interval comprised between 0.87 and 1.2, allowing to identify subjects likely to have a functional deficiency of alpha-1 antitrypsin, whether this deficiency being of a genetic origin without any quantitative or phenotypic translation, or whether being acquired under the effect of external agents (cigarette smoke or viruses).

Alpha-1 antitrypsin (A1AT) is the major circulating serine protease inhibitor. Hypersialylated glycoforms (HSG) are produced to boost A1AT anti-inflammatory and anti-protease properties. Their occurrence and prognostic impact outside severe COVID-19 or community-acquired pneumonia are unknown. Our aim was to clarify the occurrence of A1AT functional deficiency and HSG in patients admitted into intensive care unit (ICU) for any cause. A1AT and elastase inhibitory capacity (EIC) were measured in serum. Functional A1AT deficiency was defined by a measured EIC/calculated EIC Ratio ≤0.85. HSG were identified by isoelectrofocusing and quantified by gel densitometry. A total of 248 serum samples was analyzed, 173 from COVID-19 and 75 from non COVID-19 patients. A functional A1AT deficiency occurred 3-fold more frequently in non-COVID-19 than in COVID-19 patients: 18.7 % vs 6.9 % and was not associated with more frequent S/Z deficient alleles. Functional deficiency was also more frequent in deceased than alive patients in COVID-19 group. M0 and M1 HSG of A1AT occurred in around half of patients but the relative proportion of M1 significantly increased in deceased vs alive patients only in the non-COVID-19 group explaining the absence of worsening of the functional deficiency. In conclusion, our study shows that a functional A1AT deficiency is more frequently observed in patients admitted to the ICU for a cause unrelated to COVID-19, as well as in those with an unfavorable evolution. Among the latter, only those admitted for non-COVID-19 tried to compensate the functional deficiency by increasing the proportion of M1 HSG of A1AT.

Background: Historically used as a marker for inherited disorders, the current interest in plasma homocysteine measurement lies in its ability to provide valuable information about the metabolic and nutritional status of patients. Specifically, nitrous oxide (N2O) abuse can lead to functional vitamin B12 deficiency by oxidation and increase oxidative stress, resulting in elevated plasma homocysteine levels, which mimic neurological conditions such as Guillain–Barré syndrome. Rapid identification of hyperhomocysteinemia is crucial for timely intervention and avoiding costly, unnecessary treatments. Objective: This study evaluates the performance of a rapid immunoassay technique (Snibe) compared to mass spectrometry (LC-MS/MS) for measuring plasma homocysteine levels in patients with nitrous oxide abuse and non-inherited caused of elevated homocysteine, aiming to enhance differential diagnosis related to oxidative stress. Methods: 235 patients from Lille University Hospital were included. EDTA blood samples were collected and analyzed using both rapid immunoassay (Snibe) and LC-MS/MS. Neurological assessment was performed using the peripheral neuropathy disability (PND) score. Results: Firstly, significant elevations in plasma homocysteine levels were observed in patients abusing nitrous oxide measured by LC-MS/MS. Secondly, the immunoassay provided rapid results, essential for early clinical decision-making, but tended to underestimate high values compared to LC-MS/MS. A good correlation was found between the methods for low and moderate values. Conclusion: The immunoassay tended to underestimate high-value samples compared to LC-MS/MS, which is a common problem with the competitive methodology. The rapid immunoassay technique is effective for initial screening and early intervention, aiding in the differential diagnosis of conditions related to oxidative stress. Therefore, it is recommended to use the CLIA method for initial screening and confirm with mass spectrometry if there are abnormal samples. Integrating both techniques can enhance diagnostic accuracy and improve patient outcomes.

Introduction: MicroRNAs are epigenetic regulatory factors capable of silencing the expression of target genes and might mediate the effects of air pollution on health. The objective of the present population-based study was to investigate the association between microRNA expression and long-term, residential exposure to atmospheric PM10 and NO2.Method: We included 998 non-smoking adult participants from the cross-sectional ELISABET survey (2010-2014) in the Lille urban area of France. The mean residential annual pollution levels were estimated with an atmo-spheric dispersion modelling system. Ten microRNAs were selected on the basis of the literature data, together with two housekeeping microRNAs (miR-93-5p and miR-191-5p) and were quantified with RT-qPCRs. Multi-variate linear regression models were used to study the association between microRNAs and air pollution. The threshold for statistical significance (after correction for the FDR) was set to p < 0.1.Results: The mean annual exposure between 2011 and the year of inclusion was 26.4 +/- 2.0 mu g/m3 for PM10 and 24.7 +/- 5.1 mu g/m3 for NO2. Each 2 mu g/m3 increment in PM10 exposure was associated with an 8.6% increment (95%CI [3.1; 14.3]; pFDR = 0.019) in miR-451a expression. A 5 mu g/m3 increment in NO2 exposure was associated with a 5.3% increment ([0.7; 10]; pFDR = 0.056) in miR451a expression, a 3.6% decrement (95%CI [-6.1;-1.1]; pFDR = 0.052) in miR-223-3p expression, a 3.8% decrement (95%CI[-6.8;-0.7]; pFDR = 0.079) in miR-28-3p expression, a 4.3% decrement (95%CI [-7.7;-0.8]; pFDR = 0.055) in miR-146a-5p expression, and a 4.0% decrement (95% CI[-7.4;-0.4]; pFDR = 0.059) in miR-23a-5p expression. The difference between the two housekeeping microRNAs miR-93-5p and miR-191-5p was also associated with PM10 and NO2 exposure. Conclusion: Our results suggest that circulating miRNAs are potentially valuable biomarkers of the effects of air pollution.

Des associations entre marqueurs de stress oxydatif et d'atteinte pulmonaire ont été retrouvées dans des populations vulnérables. L'objectif de ce travail est d'explorer la relation entre les expositions à la pollution atmosphérique résidentielle et à court terme et des marqueurs biologiques d'atteinte pulmonaire et de stress oxydatif chez des adultes non-fumeurs. Nous avons utilisé les données de mesure de stations de pollution et de modélisation d'Atmo-Haut-de-France pour établir l'exposition à court (moyenne de la veille sur la ville) et long terme (moyenne sur l'année glissante précédente au lieu de résidence) à la pollution atmosphérique (PM10, NO2 et O3) d'un échantillon de Lillois de non-fumeurs ayant participé à l'étude transversale ELISABET (2011 à 2013). Nous avons recherché des associations entre les polluants et les biomarqueurs (CC16, 8-OHdG, 4-HNE et produits d'oxydation fluorescents POF) à l'aide de régressions log-linéaires, les pvalues ont été ajustées pour les tests multiples avec la méthode fdr. Pour les modèles dont les résidus étaient mal distribués, des modèles log-linéaires robustes (estimation MM) ont été utilisés comme analyse de sensibilité. Au total, 1004 habitants ont été échantillonnés pour les marqueurs sélectionnés. Une seule association significative entre l'exposition court terme aux PM10 et les POF (320nm) a été trouvée, avec une augmentation de 2,48 % [0,66 %; 4,33 %] (p=0,007) des niveaux de POF pour chaque 10µg/m³ de PM10. Après ajustement pour tests multiples ou en l'analyse de sensibilité robuste l'association étaient non significative. Aucune autre association entre les expositions court ou long-terme et les biomarqueurs n'était significative. Notre travail n'a pas montré d'association significative, malgré une puissance suffisante (99,9 % pour répliquer une étude sur le CC16 chez des adolescents et 99,7 % pour une étude sur les POFs chez des asthmatiques) entre les différents composants de la pollution atmosphérique et le CC16, 8-OHdG, 4-HNE et les produits d'oxydation fluorescents, que ce soit pour une exposition à court ou à long terme dans la population lilloise. Base de données géographiques ; Pollution atmosphérique ; Épidémiologie ; Biomarqueurs ; Biomarqueurs stress oxydatif Les auteurs déclarent ne pas avoir de liens d'intérêts.