Advances in pulmonary hypertension diagnosis and risk stratification.

editorial reviewedPulmonary hypertension (PH) is a common clinical condition linked to chronic cardiopulmonary illnesses. It must be distinguished from pulmonary arterial hypertension (PAH), a rare disease characterized by a specific involvement of the pulmonary arterial bed. An early diagnosis and accurate classification by a multidisciplinary team are necessary for a multimodal and individualized therapy approach. This article aims to provide a summary of the most recent ESC/ERS recommendations published in 2022.L’hypertension pulmonaire (HTP) est une entité clinique fréquemment retrouvée chez les patients atteints d’affections cardio-pulmonaires chroniques. Elle est à différentier de l’hypertension artérielle pulmonaire (HTAP) qui est, quant à elle, une maladie rare caractérisée par une atteinte spécifique du lit artériel pulmonaire. Une identification précoce et une classification correcte, en équipe pluridisciplinaire, sont primordiales pour une prise en charge thérapeutique multimodale et personnalisée. Cet article a pour but de résumer, de façon pratique, les dernières recommandations des sociétés européennes de cardiologie (ESC) et de pneumologie (ERS) publiées en 2022

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

AG has received support by NordForsk Nordic Trial Alliance (NTA) grant, by Academy of Finland Fellow grant N. 323116 and the Academy of Finland for PREDICT consortium N. 340541. The Richards research group is supported by the Canadian Institutes of Health Research (CIHR) (365825 and 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation (CFI), the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS). TN is supported by a research fellowship of the Japan Society for the Promotion of Science for Young Scientists. GBL is supported by a CIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarship. JBR is supported by an FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, the Medical Research Council, the European Union, the National Institute for Health Research-funded BioResource and the Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London. The Biobanque Québec COVID19 is funded by FRQS, Genome Québec and the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé. These funding agencies had no role in the design, implementation or interpretation of this study. The COVID19-Host(a)ge study received infrastructure support from the DFG Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)” (DFG Grant: “EXC2167”). The COVID19-Host(a)ge study was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). Genotyping in COVID19-Host(a)ge was supported by a philantropic donation from Stein Erik Hagen. The COVID GWAs, Premed COVID-19 study (COVID19-Host(a)ge_3) was supported by "Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"and also by the Instituto de Salud Carlos III (CIBERehd and CIBERER). Funding comes from COVID-19-GWAS, COVID-PREMED initiatives. Both of them are supported by "Consejeria de Salud y Familias" of the Andalusian Government. DMM is currently funded by the the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018). The Columbia University Biobank was supported by Columbia University and the National Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Columbia University. The SPGRX study was supported by the Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150. The GEN-COVID study was funded by: the MIUR grant “Dipartimenti di Eccellenza 2018-2020” to the Department of Medical Biotechnologies University of Siena, Italy; the “Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119; and philanthropic donations to the Department of Medical Biotechnologies, University of Siena for the COVID-19 host genetics research project (D.L n.18 of March 17, 2020). Part of this research project is also funded by Tuscany Region “Bando Ricerca COVID-19 Toscana” grant to the Azienda Ospedaliero Universitaria Senese (CUP I49C20000280002). Authors are grateful to: the CINECA consortium for providing computational resources; the Network for Italian Genomes (NIG) (http://www.nig.cineca.it) for its support; the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/); the Genetic Biobank of Siena, member of BBMRI-IT, Telethon Network of Genetic Biobanks (project no. GTB18001), EuroBioBank, and RD-Connect, for managing specimens. Genetics against coronavirus (GENIUS), Humanitas University (COVID19-Host(a)ge_4) was supported by Ricerca Corrente (Italian Ministry of Health), intramural funding (Fondazione Humanitas per la Ricerca). The generous contribution of Banca Intesa San Paolo and of the Dolce&Gabbana Fashion Firm is gratefully acknowledged. Data acquisition and sample processing was supported by COVID-19 Biobank, Fondazione IRCCS Cà Granda Milano; LV group was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation: Testing Marker Utility in Steatohepatitis”, Programme “Photonics” under grant agreement “101016726” for the project “REVEAL: Neuronal microscopy for cell behavioural examination and manipulation”, Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361. DP was supported by Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV). Genetic modifiers for COVID-19 related illness (BeLCovid_1) was supported by the "Fonds Erasme". The Host genetics and immune response in SARS-Cov-2 infection (BelCovid_2) study was supported by grants from Fondation Léon Fredericq and from Fonds de la Recherche Scientifique (FNRS). The INMUNGEN-CoV2 study was funded by the Consejo Superior de Investigaciones Científicas. KUL is supported by the German Research Foundation (LU 1944/3-1) SweCovid is funded by the SciLifeLab/KAW national COVID-19 research program project grant to Michael Hultström (KAW 2020.0182) and the Swedish Research Council to Robert Frithiof (2014-02569 and 2014-07606). HZ is supported by Jeansson Stiftelser, Magnus Bergvalls Stiftelse. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping for the COMRI cohort was performed and funded by the Genotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finland. These funding agencies had no role in the design, implementation or interpretation of this study.Background: There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality—and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.Academy of Finland Fellow grant N. 323116Academy of Finland for PREDICT consortium N. 340541.Canadian Institutes of Health Research (CIHR) (365825 and 409511)Lady Davis Institute of the Jewish General HospitalCanadian Foundation for Innovation (CFI)NIH FoundationCancer Research UKGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS)Japan Society for the Promotion of Science for Young ScientistsCIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarshipFRQS Clinical Research ScholarshipCalcul QuébecCompute CanadaWelcome TrustMedical Research CouncEuropean UnionNational Institute for Health Research-funded BioResourceClinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation TrustKing’s College LondonGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary Initiative in Infection and ImmunityFonds de Recherche Québec Santé(DFG Grant: “EXC2167”)(CompLS grant 031L0165)Stein Erik Hagen"Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"Instituto de Salud Carlos III (CIBERehd and CIBERER)COVID-19-GWASCOVID-PREMED initiatives"Consejeria de Salud y Familias" of the Andalusian GovernmentAndalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018)Columbia UniversityNational Center for Advancing Translational SciencesNIH Grant Number UL1TR001873Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150MIUR grant “Dipartimenti di Eccellenza 2018-2020”“Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119Tuscany Region “Bando Ricerca COVID-19 Toscana”CINECA consortiumNetwork for Italian Genomes (NIG)COVID-19 Host Genetics InitiativeGenetic Biobank of SienaEuroBioBankRD-ConnectRicerca Corrente (Italian Ministry of Health)Fondazione Humanitas per la RicercaBanca Intesa San PaoloDolce&Gabbana Fashion FirmCOVID-19 BiobankFondazione IRCCS Cà Granda MilanoMyFirst Grant AIRC n.16888Ricerca Finalizzata Ministero della Salute RF-2016-02364358Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoEuropean Union (EU) Programme Horizon 2020 (under grant agreement No. 777377)“Photonics” “101016726”Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV)"Fonds Erasme"Fondation Léon FredericqFonds de la Recherche Scientifique (FNRS)Consejo Superior de Investigaciones CientíficasGerman Research Foundation (LU 1944/3-1)SciLifeLab/KAW national COVID-19 research program project (KAW 2020.0182)Swedish Research Council (2014-02569 and 2014-07606)Jeansson Stiftelser, Magnus Bergvalls StiftelseTechnical University of Munich, Munich, GermanyGenotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finlan

Novel method of transpulmonary pressure measurement with an air‑flled esophageal catheter

Background: There is a strong rationale for proposing transpulmonary pressureguided protective ventilation in acute respiratory distress syndrome. The reference esophageal balloon catheter method requires complex in vivo calibration, expertise and specifc material order. A simple, inexpensive, accurate and reproducible method of measuring esophageal pressure would greatly facilitate the measure of transpulmonary pressure to individualize protective ventilation in the intensive care unit. Results: We propose an air-flled esophageal catheter method without balloon, using a disposable catheter that allows reproducible esophageal pressure measurements. We use a 49-cm-long 10 Fr thin suction catheter, positioned in the lower-third of the esophagus and connected to an air-flled disposable blood pressure transducer bound to the monitor and pressurized by an air-flled infusion bag. Only simple calibration by zeroing the transducer to atmospheric pressure and unit conversion from mmHg to cmH2O are required. We compared our method with the reference balloon catheter both ex vivo, using pressure chambers, and in vivo, in 15 consecutive mechanically ventilated patients. Esophageal-to-airway pressure change ratios during the dynamic occlusion test were close to one (1.03±0.19 and 1.00±0.16 in the controlled and assisted modes, respectively), validating the proper esophageal positioning. The Bland– Altman analysis revealed no bias of our method compared with the reference and good precision for inspiratory, expiratory and delta esophageal pressure measurements in both the controlled (largest bias −0.5 cmH2O [95% confdence interval: −0.9; −0.1] cmH2O; largest limits of agreement −3.5 to 2.5 cmH2O) and assisted modes (largest bias −0.3 [−2.6; 2.0] cmH2O). We observed a good repeatability (intra-observer, intraclass correlation coefcient, ICC: 0.89 [0.79; 0.96]) and reproducibility (inter-observer ICC: 0.89 [0.76; 0.96]) of esophageal measurements. The direct comparison with pleural pressure in two patients and spectral analysis by Fourier transform confrmed the reliability of the air-flled catheter-derived esophageal pressure as an accurate surrogate of pleural pressure. A calculator for transpulmonary pressures is available online. Conclusions: We propose a simple, minimally invasive, inexpensive and reproducible method for esophageal pressure monitoring with an air-flled esophageal catheter without balloon. It holds the promise of widespread bedside use of transpulmonary pressure-guided protective ventilation in ICU patients

Inflammation during COVID-19.

Infection due to SARS-CoV-2 is associated with clinical features of diverse severity. Severe disease includes biological criteria of both inflammation and coagulation activation, and high circulating levels of pro- and anti-inflammatory cytokines. The most critical patients present with acute respiratory distress syndrome and multiple organ failure, resembling bacterial sepsis. Clinical trials have shown that steroids reduce mortality of severe cases, suggesting that inflammation as a mechanism of defense against viral invasion is excessive rather than insufficient. Several molecules targeting more specific pathways than steroids are under evaluation. Those reducing interleukin 6 activity have a certain degree of effectiveness. Anticoagulants and fibrinolytics have moderate impact on the hypercoagulation state. Like for bacterial sepsis, future trials will attempt therapy "individualization" based on biomarkers, but we still lack precision diagnostic tools.: L’infection par le virus SARS-CoV-2 entraîne des tableaux de gravité variable. La biologie des formes graves comporte des critères d’inflammation et d’activation de la coagulation, ainsi que la circulation des cytokines pro- et anti-inflammatoires en grande quantité. Les formes les plus sévères comportent un syndrome de détresse respiratoire aiguë, voire une défaillance multiviscérale qui ressemble au sepsis d’origine bactérienne. Les essais thérapeutiques effectués dans ces formes graves indiquent que les corticoïdes en réduisent la mortalité, ce qui suggère que l’état hyper-inflammatoire peut être excessif plutôt qu’insuffisant dans notre défense contre l’infection virale. Plusieurs molécules plus sélectives que les corticoïdes sont à l’étude. Celles qui réduisent l’activité de l’interleukine 6 ont une certaine efficacité. L’état hyper-coagulable est peu influencé par les traitements anti-coagulants ou fibrinolytiques. Comme dans le sepsis bactérien, l’évolution se fera vers plus d’individualisation des traitements à partir de certains biomarqueurs, mais cette pratique se heurte encore à un manque de précision dans les outils diagnostiques

Pulmonary arterial hypertensiony

peer reviewedPulmonary arterial hypertension (PAH) is a rare vascular lung disease with a complex etiopathogeny characterized by an increased pulmonary arterial pressure of 25 mmHg or above assessed by right heart catheterization. The diagnosis is difficult due to the atypical presentation with shortness of breath requiring a sequential approach bringing at the end the clinician to perform a right heart catheterization. Nowadays, several therapies have proven to be efficient for treating PAH. Recently, international recommendations have moved to an initial combination therapy reducing the overall morbi-mortality of the patients. Therefore, early therapy appears to be a priority in PAH underlying the need for increasing the global knowledge around PAH. © 2019 Revue Medicale de Liege. All Rights Reserved

A Blood Exosomal miRNA Signature in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a diffuse, acute, inflammatory lung disease characterized by a severe respiratory failure. Recognizing and promptly treating ARDS is critical to combat the high mortality associated with the disease. Despite a significant progress in the treatment of ARDS, our ability to identify early patients and predict outcomes remains limited. The development of novel biomarkers is crucial. In this study, we profiled microRNA (miRNA) expression of plasma-derived exosomes in ARDS disease by small RNA sequencing. Sequencing of 8 ARDS patients and 10 healthy subjects (HSs) allowed to identify 12 differentially expressed exosomal miRNAs (adjusted p 0.8) (miR-130a-3p, miR-221-3p, miR-24-3p, miR-98-3p, Let-7d-3p, miR-1273a, and miR-193a-5p). These findings highlight exosomal miRNA dysregulation in the plasma of ARDS patients which provide promising diagnostic biomarkers and open new perspectives for the development of therapeutics

Acute respiratory distress syndrome

peer reviewedSince its first description in 1967, a lot of progress has been made in understanding the pathophysiology, diagnosis and management of acute respiratory distress syndrome (ARDS). This nosological entity is based on the appearance of a diffuse alveolar damage associating pulmonary epithelial barrier disruption with an alveolar filling, both responsible of profound hypoxemia and important morbi-mortality. Nowadays, ARDS remains a frequent syndrome, associated with various etiologies. Diagnosis is based on the occurrence of acute hypoxic respiratory failure not explained by cardiac insufficiency or volume overload, within 7 days after a recognized risk factor, and in the presence of bilateral pulmonary opacities not fully explained by effusions, atelectasis or nodules on the chest radiography. Survivors present an increased risk of developing cognitive decline, depression, post-traumatic stress, and typical ICU related side-effects such as polyneuropathy and sarcopenia. In this context and not withstanding significant recent progress in the field of mechanical ventilation and extra-corporeal respiratory assistance, early diagnosis remains essential to identify patients with ARDS in order to offer them the most appropriate therapy

Comparison of Covid-19 patient management and outcome in a tertiary care center during the first and second waves of the pandemic.

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