Hypertension pulmonaire sévère du groupe 3‎ : une étude observationnelle rétrospective multicentrique au sein du Centre de Compétence des Hypertensions Pulmonaires 76-27, de janvier 2014 à mai 2017

L’hypertension pulmonaire (HTP) des pathologies respiratoires chroniques (groupe 3) est la 2ème cause la plus fréquente d’HTP. Elle complique le plus souvent une bronchopneumopathie chronique obstructive (BPCO) et est modérée. L’HTP sévère du groupe 3 est une pathologie rare, concernant moins de 5% des patients BPCO, de pronostic sombre. Elle se caractérise par l’existence d’un « phénotype vasculaire ». La question de l’indication des traitements vasodilatateurs spécifiques de l’hypertension artérielle pulmonaire (HTAP) dans l’HTP notamment sévère du groupe 3 semble donc être légitime. L’objectif de cette étude est d’établir un état des lieux des pratiques cliniques et d’analyser l’évolution clinique, écho-cardiographique, hémodynamique et biologique des patients présentant une HTP sévère du groupe 3 suivis au sein du centre de Compétence des HTP 76-27. Matériels et Méthodes : Il s’agit d’une étude observationnelle descriptive rétrospective multicentrique s’intéressant aux 26 patients présentant une HTP sévère du groupe 3 documentée par cathétérisme cardiaque droit au CHU de Rouen (service de Pneumologie ou de Cardiologie) ou à l’hôpital Jacques Monod du Havre (service de Pneumologie) entre le 1er janvier 2014 et le 31 mai 2017. Les caractéristiques des patients (sexe, âge, indice de masse corporelle, date de décès, score de dyspnée NYHA, signes de décompensation cardiaque droite, signes droits électro-cardiographiques, antécédents de syncope, antécédents d’intérêt, tabagisme), de la pathologie respiratoire chronique sous-jacente (étiologie, sévérité évaluée aux épreuves fonctionnelles respiratoires (EFR), gaz du sang (GDS)), de l’HTP (date du diagnostic, sévérité selon les données écho-cardiographiques et hémodynamiques du cathétérisme cardiaque droit), le retentissement à l’exercice (test de marche de 6 minutes (TM6), exploration fonctionnelle à l’exercice (EFX)), les résultats des examens biologiques et d’imagerie pertinents ainsi que les modalités thérapeutiques (mesures générales et traitements spécifiques) ont été recueillis à l’inclusion (baseline), à 4-6 mois d’évolution (M4-6), à 12 mois (M12) et à 18 mois (M18). Les données qualitatives étaient exprimées en valeur absolue et en % de la population concernée. Les données quantitatives étaient décrites par leur médiane accompagnée de l’intervalle interquartile. Les courbes de survie ont été réalisées grâce à la méthode de Kaplan-Meier. Résultats : 26 patients ont été inclus. Il s’agissait principalement d’hommes (92%), fumeurs (85%), en surpoids, d’âge médian égal à 71.3 ans, présentant une dyspnée invalidante NYHA III (77%). La pathologie respiratoire chronique la plus fréquente était une BPCO post-tabagique (50% des cas) avec un trouble ventilatoire obstructif modéré (Tiffeneau médian = 53% ; VEMS médian = 51% de la théorique, intervalle interquartile = 34-57%) au stade de l’insuffisance respiratoire chronique Gold IV (69% des cas). 23% des patients étaient porteurs d’un syndrome emphysème-fibrose (SEF), 12% d’une pneumopathie interstitielle diffuse (PID) et 15% d’une atteinte respiratoire autre. Une altération sévère de la capacité de diffusion du monoxyde de carbone était mise en évidence aux EFR ainsi qu’une hypoxémie marquée aux GDS sans hypercapnie associée, quelque soit l’étiologie de la pathologie respiratoire chronique sous-jacente. Le cathétérisme cardiaque droit retrouvait un profil d’HTP sévère (PAPm médiane = 44mmHg, intervalle interquartile = 38-49mmHg), avec critères de gravité (IC médian = 2.8L/min/m², POD médiane = 11mmHg), confirmé par l’ETT qui retrouvait une VmaxIT médiane augmentée égale à 3.6m/s. L’intolérance à l’exercice était marquée : diminution de la distance médiane parcourue au TM6, désaturation significative dans la majorité des cas. N = 19 patients ont bénéficié d’un traitement vasodilatateur spécifique de l’HTAP. Pour l’étude du suivi, n = 22 patients ont été inclus à M4-6, 19 à M12 et 14 à M18. Au cours du suivi, la dyspnée avait tendance à s’améliorer. La tolérance à l’effort tendait à s’améliorer initialement (amélioration de la distance médiane parcourue au TM6 entre la baseline et M4-6) puis se dégradait. Parmi le sous-groupe des patients traités par vasodilatateur(s) spécifique(s) dont la majorité ont été réévalués par cathétérisme cardiaque droit au cours du suivi, on observait sur le plan hémodynamique les tendances suivantes : stabilisation de la PAPm et de l’IC, diminution des RVP, majoration initiale puis stabilisation de la POD. Il n’y avait pas de dégradation significative du rapport PaO2/FiO2 parmi les patients traités, ce qui correspondait à une stabilisation de l’hypoxémie. 14 patients (soit 54% de la population totale) étaient décédés à la fin de l’étude, dont 10 (38%) des suites de leur HTP. La médiane de survie globale de la population totale était de 1 an et 10 mois. La médiane de survie globale des sujets traités par vasodilatateur(s) spécifique(s) était de 2 ans et 11 mois et demi. On observait une tendance à une meilleure probabilité de survie chez les patients BPCO en comparaison avec les patients porteurs d’un SEF, d’une PID ou d’une autre pathologie respiratoire chronique.Conclusion : L’HTP sévère du groupe 3 est une pathologie rare, grave, caractérisée par une atteinte vasculaire pulmonaire à part entière. Il n’existe à ce jour aucune recommandation quant à l’indication d’un traitement par vasodilatateur spécifique de l’HTAP. Il pourrait cependant sembler licite de le proposer à certains patients : jeunes, BPCO post-tabagiques avec un VEMS modérément altéré, porteurs d’une HTP sévère avec retentissement fonctionnel majeur. L’indication d’un tel traitement devrait être discutée de façon collégiale au sein d’un Centre de Compétence, en prenant en compte les facteurs pronostics actuellement utilisés dans l’HTAP

Anesthesiology

Despite expanding use, knowledge on extracorporeal membrane oxygenation support during the COVID-19 pandemic remains limited. The objective was to report characteristics, management, and outcomes of patients receiving extracorporeal membrane oxygenation with a diagnosis of COVID-19 in France and to identify pre-extracorporeal membrane oxygenation factors associated with in-hospital mortality. A hypothesis of similar mortality rates and risk factors for COVID-19 and non-COVID-19 patients on venovenous extracorporeal membrane oxygenation was made. The Extracorporeal Membrane Oxygenation for Respiratory Failure and/or Heart failure related to Severe Acute Respiratory Syndrome-Coronavirus 2 (ECMOSARS) registry included COVID-19 patients supported by extracorporeal membrane oxygenation in France. This study analyzed patients included in this registry up to October 25, 2020, and supported by venovenous extracorporeal membrane oxygenation for respiratory failure with a minimum follow-up of 28 days after cannulation. The primary outcome was in-hospital mortality. Risk factors for in-hospital mortality were analyzed. Among 494 extracorporeal membrane oxygenation patients included in the registry, 429 were initially supported by venovenous extracorporeal membrane oxygenation and followed for at least 28 days. The median (interquartile range) age was 54 yr (46 to 60 yr), and 338 of 429 (79%) were men. Management before extracorporeal membrane oxygenation cannulation included prone positioning for 411 of 429 (96%), neuromuscular blockage for 419 of 427 (98%), and NO for 161 of 401 (40%). A total of 192 of 429 (45%) patients were cannulated by a mobile extracorporeal membrane oxygenation unit. In-hospital mortality was 219 of 429 (51%), with a median follow-up of 49 days (33 to 70 days). Among pre-extracorporeal membrane oxygenation modifiable exposure variables, neuromuscular blockage use (hazard ratio, 0.286; 95% CI, 0.101 to 0.81) and duration of ventilation (more than 7 days compared to less than 2 days; hazard ratio, 1.74; 95% CI, 1.07 to 2.83) were independently associated with in-hospital mortality. Both age (per 10-yr increase; hazard ratio, 1.27; 95% CI, 1.07 to 1.50) and total bilirubin at cannulation (6.0 mg/dl or more compared to less than 1.2 mg/dl; hazard ratio, 2.65; 95% CI, 1.09 to 6.5) were confounders significantly associated with in-hospital mortality. In-hospital mortality was higher than recently reported, but nearly half of the patients survived. A high proportion of patients were cannulated by a mobile extracorporeal membrane oxygenation unit. Several factors associated with mortality were identified. Venovenous extracorporeal membrane oxygenation support should be considered early within the first week of mechanical ventilation initiation

Veno-Arterial Extracorporeal Membrane Oxygenation for Circulatory Failure in COVID-19 Patients: Insights from the ECMOSARS Registry

International audienceObjectives: The clinical profile and outcomes of patients with Covid-19 who require veno-arterial or veno-venous-arterial extracorporeal membrane oxygenation (VA-ECMO - VAV-ECMO) are poorly understood. We aimed to describe the characteristics and outcomes of these patients and to identify predictors of both favorable and unfavorable outcomes.Methods: ECMOSARS is a multicenter, prospective, nationwide French registry enrolling patients who require VV/VA-ECMO in the context of Covid-19 infection (652 patients at 41 centers). We focused on 47 patients supported with VA- or VAV-ECMO for refractory cardiogenic shock.Results: Median age was 49. 14% of patients had a prior diagnosis of heart failure. The most common etiologies of cardiogenic shock were acute pulmonary embolism (30%), myocarditis (28%), and acute coronary syndrome (4%). E-CPR (Extracorporeal Cardiopulmonary Resuscitation) occurred in 38%. In-hospital survival was 28% in the whole cohort, and 43% when E-CPR patients were excluded. ECMO cannulation was associated with significant improvements in pH and FiO2 on day one, but non-survivors showed significantly more severe acidosis and higher FiO2 than survivors at this point (p = 0.030 and p = 0.006). Other factors associated with death were greater age (p = 0.02), higher BMI (p = 0.03), E-CPR (p = 0.001), non-myocarditis etiology (p = 0.02), higher serum lactates (p = 0.004), epinephrine (but not noradrenaline) use before initiation of ECMO (p = 0.003), hemorrhagic complications (p = 0.001), greater transfusion requirements (p = 0.001), and more severe SAVE and SAFE scores (p = 0.01 and p = 0.03).Conclusions: We report the largest focused analysis of VA- and VAV-ECMO recipients in Covid-19. Although relatively rare, the need for temporary mechanical circulatory support in these patients is associated with poor prognosis. However, VA-ECMO remains a viable solution to rescue carefully selected patients. We identified factors associated with poor prognosis and suggest that E-CPR is not a reasonable indication for VA-ECMO in this population

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia The ANTICOVID Randomized Clinical Trial

International audienceIMPORTANCE Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. OBJECTIVES To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. DESIGN, SETTINGS, AND PARTICIPANTS The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. INTERVENTIONS Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. MAIN OUTCOMES AND MEASURES A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). RESULTS Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95%CI, 39.9% to 54.8%] vs 52.7%[95%CI, 45.2%to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95%CI, 43.4%to 58.3%] vs 49.1% [95%CI, 41.7%to 56.6%]; P = .82) and TA compared with HD-PA (53.5%[95%CI 45.8% to 60.9%] vs 46.5% [95%CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2%thrombosis, 2.6%bleeding, 14.0% death), 16.4% receiving HD-PA (5.5%thrombosis, 3.6%bleeding, 11.8%death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7%death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95%CI -6.2 to -23.2] and -14.7 [95%CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95%CI -2.6 to -24.3). CONCLUSIONS AND RELEVANCE This randomized clinical trial found that compared with SD-PA, neither HD-PAnor TAuse improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemicCOVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis

High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure

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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old