Publications by authors named "Francis Couturaud"

141 Publications

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

Ann Intern Med 2021 Nov 23. Epub 2021 Nov 23.

Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (A.P., P.P., P.W., M.C.).

Background: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown.

Objective: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation.

Design: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818).

Setting: Eighteen sites between February 2011 and February 2021.

Patients: Patients with isolated subsegmental pulmonary embolism.

Intervention: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy.

Measurements: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period.

Results: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism.

Limitation: The study was restricted to patients with low-risk subsegmental pulmonary embolism.

Conclusion: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism.

Primary Funding Source: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.
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http://dx.doi.org/10.7326/M21-2981DOI Listing
November 2021

Nebulised liposomal-amphotericin-B as maintenance therapy in ABPA: a randomised, multicentre, trial.

Eur Respir J 2021 Nov 11. Epub 2021 Nov 11.

Service de Pneumologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bichat, Paris, France.

Background: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission.

Methods: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after a 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal-amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time-to-first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters.

Results: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) of 65 patients in nebulised liposomal-amphotericin-B group and 38 (51.3%) of 74 in placebo group (absolute difference -0.6%, 95% CI -16.8% to +15.6%, odds ratio 0.98, 95% CI 0.50 to 1.90; p=0.95). The median time-to-first severe clinical exacerbation was longer in liposomal-amphotericin-B group, 337 days (IQR, 168 to 476) 177 (64 to 288). At the end of maintenance therapy, total immunoglobulin-E and precipitins were significantly decreased in nebulised liposomal-amphotericin-B group.

Conclusions: In ABPA, maintenance therapy using nebulised liposomal-amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.
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http://dx.doi.org/10.1183/13993003.02218-2021DOI Listing
November 2021

Long-term risk of major bleeding after discontinuing anticoagulation for unprovoked venous thromboembolism: a systematic review and meta-analysis.

Thromb Haemost 2021 Nov 9. Epub 2021 Nov 9.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.

Background: The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain.

Objectives: To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE.

Methods: We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked VTE who had completed ≥3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies.

Results: Of 1123 records identified by the search, 20 studies (17 RCTs) and 8740 patients were included in the analysis. During 13 011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n=41) and fatal bleeding (n=7) per 100 person-years was 0.35 (95% confidence interval [CI], 0.20-0.54) and 0.09 (95% CI, 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI, 0.4%-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI, 10.6%-31.1%).

Conclusions: Patients with a first unprovoked VTE have a non-trivial risk of major bleeding once anticoagulants are discontinued. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.
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http://dx.doi.org/10.1055/a-1690-8728DOI Listing
November 2021

Management of patients with pulmonary mycobacteriosis in France: a multicenter retrospective cohort study.

BMC Pulm Med 2021 Oct 26;21(1):333. Epub 2021 Oct 26.

Department of Bacteriology, CHU Montpellier, Montpellier, France.

Background: Recent studies report very low adherence of practitioners to ATS/IDSA recommendations for the treatment of nontuberculous mycobacteria pulmonary disease (NTM-PD), as well as a great variability of practices. Type of management could impact prognosis.

Methods: To evaluate management and prognosis of patients with NTM-PD cases with respect to ATS recommendations, we conducted a multicenter retrospective cohort study (18 sentinel sites distributed throughout France), over a period of six years. We collected clinical, radiological, microbiological characteristics, management and outcome of the patients (especially death or not).

Results: 477 patients with NTM-PD were included. Respiratory comorbidities were found in 68% of cases, tuberculosis sequelae in 31.4% of patients, and immunosuppression in 16.8% of cases. The three most common NTM species were Mycobacterium avium complex (60%), M. xenopi (20%) and M. kansasii (5.7%). Smear-positive was found in one third of NTM-PD. Nodulobronchiectatic forms were observed in 54.3% of cases, and cavitary forms in 19.1% of patients. Sixty-three percent of patients were treated, 72.4% of patients with smear-positive samples, and 57.5% of patients with smear-negative samples. Treatment was in adequacy with ATS guidelines in 73.5%. The 2-year mortality was 14.4%. In the Cox regression, treatment (HR = 0.51), age (HR = 1.02), and M. abscessus (3.19) appeared as the 3 significant independent prognostic factors.

Conclusion: These findings highlight the adequacy between French practices and the ATS/IDSA guidelines. Treatment was associated with a better survival.
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http://dx.doi.org/10.1186/s12890-021-01701-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549171PMC
October 2021

Apixaban and rivaroxaban in obese patients treated for venous thromboembolism: Drug levels and clinical outcomes.

Thromb Res 2021 Oct 15;208:39-44. Epub 2021 Oct 15.

Univ Rennes, Rennes University Hospital, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, France; Hematology Laboratory, Rennes University Hospital, Rennes, France. Electronic address:

Background: Direct oral anticoagulants (DOAC) use remains challenging in obese patients treated for Venous-Thrombo-Embolism (VTE) due to the paucity of prospective and dedicated studies.

Objective: To assess rivaroxaban and apixaban concentrations at different time-points after intake, in obese patients followed at a thrombosis center and treated for VTE; to define factors associated with DOAC levels outside the on-therapy ranges; and to evaluate bleeding and thrombosis rates during follow-up.

Methods: Observational prospective study in two French University hospitals. Apixaban or rivaroxaban concentrations were measured after the first visit, regardless of last intake in obese patients receiving DOAC for VTE. Concentrations were compared to published reference values for non-obese patients. Demographic, clinical, biological and therapeutic data were collected. Univariate and multivariate analyses were performed to identify factors associated to DOAC concentrations outside the on-therapy ranges.

Results: Out of the 146 patients included, 22 (15%) had DOAC concentrations outside the on-therapy ranges, mainly in the rivaroxaban group (n = 17). Age ≤ 63 years, use of rivaroxaban and time since last intake ≤8 h were associated with DOAC concentrations outside the on-therapy ranges, in multivariable analysis. During the median follow-up of 16 months, two (1%) patients receiving apixaban had recurrent VTE. No patient had major bleeding, 11 (8%) patients had minor bleeding.

Conclusion: In this specific prospective bi-centric study dedicated to VTE obese patients, use of DOACs at fixed doses led to concentrations similar to those of non-obese patients in a high proportion of patients, without any effect of the BMI, and with risk-benefit profile comparable to non-obese patients.
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http://dx.doi.org/10.1016/j.thromres.2021.10.009DOI Listing
October 2021

Diuretic vs. placebo in intermediate-risk acute pulmonary embolism: a randomized clinical trial.

Eur Heart J Acute Cardiovasc Care 2021 Oct 11. Epub 2021 Oct 11.

Université Paris Est Creteil, INSERM, IMRB, Creteil F-94010, France.

Aims: The role of diuretics in patients with intermediate-risk pulmonary embolism (PE) is controversial. In this multicentre, double-blind trial, we randomly assigned normotensive patients with intermediate-risk PE to receive either a single 80 mg bolus of furosemide or a placebo.

Methods And Results: Eligible patients had at least a simplified PE Severity Index (sPESI) ≥1 with right ventricular dysfunction. The primary efficacy endpoint assessed 24 h after randomization included (i) absence of oligo-anuria and (ii) normalization of all sPESI items. Safety outcomes were worsening renal function and major adverse outcomes at 48 hours defined by death, cardiac arrest, mechanical ventilation, or need of catecholamine. A total of 276 patients underwent randomization; 135 were assigned to receive the diuretic, and 141 to receive the placebo. The primary outcome occurred in 68/132 patients (51.5%) in the diuretic and in 49/132 (37.1%) in the placebo group (relative risk = 1.30, 95% confidence interval 1.04-1.61; P = 0.021). Major adverse outcome at 48 h occurred in 1 (0.8%) patients in the diuretic group and 4 patients (2.9%) in the placebo group (P = 0.19). Increase in serum creatinine level was greater in diuretic than placebo group [+4 µM/L (-2; 14) vs. -1 µM/L (-11; 6), P < 0.001].

Conclusion: In normotensive patients with intermediate-risk PE, a single bolus of furosemide improved the primary efficacy outcome at 24 h and maintained stable renal function. In the furosemide group, urine output increased, without a demonstrable improvement in heart rate, systolic blood pressure, or arterial oxygenation.ClinicalTrials.gov identifier NCT02268903.
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http://dx.doi.org/10.1093/ehjacc/zuab082DOI Listing
October 2021

Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial.

Chest 2021 Oct 8. Epub 2021 Oct 8.

F-CRIN INNOVTE Network, Saint-Etienne, France; Service de Médecine Vasculaire et Thérapeutique, CHU Saint-Etienne, Hôpital Nord, Saint-Etienne, France.

Background: Direct oral anticoagulants (DOACs) are an alternative to low-molecular-weight heparin for treating cancer-associated VTE.

Research Question: Is rivaroxaban as efficient and safe as dalteparin to treat patients with cancer-associated VTE?

Study Design And Methods: In a randomized open-label noninferiority trial, patients with active cancer who had proximal DVT, pulmonary embolism (PE), or both were assigned randomly to therapeutic doses of rivaroxaban or dalteparin for 3 months. The primary outcome was the cumulative incidence of recurrent VTE, a composite of symptomatic or incidental DVT or PE, and worsening of pulmonary vascular or venous obstruction at 3 months.

Results: Of 158 randomized patients, 74 and 84 patients were assigned to receive rivaroxaban and dalteparin, respectively. Mean age was 69.4 years, and 115 patients (76.2%) had metastatic disease. The primary outcome occurred in 4 and 6 patients in the rivaroxaban and dalteparin groups, respectively (both the intention-to-treat and per-protocol populations: cumulative incidence, 6.4% vs 10.1%; subdistribution hazard ratio [SHR], 0.75; 95% CI, 0.21-2.66). Major bleeding occurred in 1 and 3 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 1.4% vs 3.7%; SHR, 0.36; 95% CI, 0.04-3.43). Major or clinically relevant nonmajor bleeding occurred in 9 and 8 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 12.2% vs 9.8%; SHR, 1.27; 95% CI, 0.49-3.26). Overall, 19 patients (25.7%) and 20 patients (23.8%) died in the rivaroxaban and dalteparin groups, respectively (hazard ratio, 1.05; 95% CI, 0.56-1.97).

Interpretation: In this trial comparing rivaroxaban and dalteparin in the treatment of cancer-associated VTE, the number of patients was insufficient to reach the predefined criteria for noninferiority, but efficacy and safety results were consistent with those previously reported with DOACs. An updated meta-analysis of randomized trials comparing DOACs with low-molecular-weight heparin in patients with cancer-associated VTE is provided.

Trial Registry: ClinicalTrials.gov; No.: NCT02746185; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.09.037DOI Listing
October 2021

Cardiovascular Mortality after Venous Thromboembolism: A Meta-Analysis of Prospective Cohort Studies.

Semin Thromb Hemost 2021 Oct 8. Epub 2021 Oct 8.

Department of Vascular Medicine, Brest Teaching Hospital, Brest, France.

Many studies from current literature show that cardiovascular diseases in patients with venous thromboembolism (VTE) are more frequent than in the general population without VTE. However, data summarizing the impact of cardiovascular diseases on mortality of patients with VTE are lacking. In this systematic review and meta-analysis, we aimed to determine the frequency and incidence rate of cardiovascular death in patients with VTE. MEDLINE and EMBASE were searched from January 1, 2000 to February 28, 2021. Eligible studies were observational prospective cohort studies including patients with VTE and reporting all causes of death. Cardiovascular death was defined as deaths that result from new or recurrent pulmonary embolism, death due to acute myocardial infarction, sudden cardiac death or heart failure, death due to stroke, death due to cardiovascular procedures or hemorrhage, death due to ruptured aortic aneurysm or aortic dissection and death due to other cardiovascular causes. Random-effect models meta-analysis served to determine all pooled effect size of interest with their 95% confidence interval (CI). Thirteen observational studies enrolling 22,251 patients were identified and included. The mean/median age varied between 49 and 75 years. The proportion of men ranged from 38.3 to 53.2%. The overall pooled frequency of cardiovascular death in patients with VTE was 3.9% (95% CI: 2.5-5.6%), while the overall pooled frequency of all-cause mortality was 12.0% (95% CI: 9.1-15.4%). The pooled proportion of cardiovascular death among all causes of deaths in patients with VTE was 35.2% (95% CI: 22.2-49.3%). The pooled incidence rate of cardiovascular death was 1.92 per 100 patient-years (95% CI: 0-4.1). The frequency of cardiovascular death in patients with VTE was significantly higher than in patients without VTE (risk ratio: 3.85, 95% CI: 2.75-5.39). Based on this updated meta-analysis from 13 prospective cohort studies, cardiovascular death in patients with VTE is more frequent than in the general population without VTE.
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http://dx.doi.org/10.1055/s-0041-1733923DOI Listing
October 2021

Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD Exacerbation: A Randomized Clinical Trial.

JAMA 2021 10;326(13):1277-1285

CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain.

Importance: Active search for pulmonary embolism (PE) may improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD).

Objective: To compare usual care plus an active strategy for diagnosing PE with usual care alone in patients hospitalized for COPD exacerbation.

Design, Setting, And Participants: Randomized clinical trial conducted across 18 hospitals in Spain. A total of 746 patients were randomized from September 2014 to July 2020 (final follow-up was November 2020).

Interventions: Usual care plus an active strategy for diagnosing PE (D-dimer testing and, if positive, computed tomography pulmonary angiogram) (n = 370) vs usual care (n = 367).

Main Outcomes And Measures: The primary outcome was a composite of nonfatal symptomatic venous thromboembolism (VTE), readmission for COPD, or death within 90 days after randomization. There were 4 secondary outcomes, including nonfatal new or recurrent VTE, readmission for COPD, and death from any cause within 90 days. Adverse events were also collected.

Results: Among the 746 patients who were randomized, 737 (98.8%) completed the trial (mean age, 70 years; 195 [26%] women). The primary outcome occurred in 110 patients (29.7%) in the intervention group and 107 patients (29.2%) in the control group (absolute risk difference, 0.5% [95% CI, -6.2% to 7.3%]; relative risk, 1.02 [95% CI, 0.82-1.28]; P = .86). Nonfatal new or recurrent VTE was not significantly different in the 2 groups (0.5% vs 2.5%; risk difference, -2.0% [95% CI, -4.3% to 0.1%]). By day 90, a total of 94 patients (25.4%) in the intervention group and 84 (22.9%) in the control group had been readmitted for exacerbation of COPD (risk difference, 2.5% [95% CI, -3.9% to 8.9%]). Death from any cause occurred in 23 patients (6.2%) in the intervention group and 29 (7.9%) in the control group (risk difference, -1.7% [95% CI, -5.7% to 2.3%]). Major bleeding occurred in 3 patients (0.8%) in the intervention group and 3 patients (0.8%) in the control group (risk difference, 0% [95% CI, -1.9% to 1.8%]; P = .99).

Conclusions And Relevance: Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome.

Trial Registration: ClinicalTrials.gov Identifier: NCT02238639.
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http://dx.doi.org/10.1001/jama.2021.14846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493436PMC
October 2021

The prognostic value of respiratory symptoms and performance status in ambulatory cancer patients and unsuspected pulmonary embolism; analysis of an international, prospective, observational cohort study.

J Thromb Haemost 2021 11 16;19(11):2791-2800. Epub 2021 Sep 16.

Department of Medicine and Ageing Sciences, University G. D'Annunzio, Chieti, Italy.

Background: Optimal risk stratification of unsuspected pulmonary embolism (UPE) in ambulatory cancer patients (ACPs) remains unclear. Existing clinical predictive rules (CPRs) are derived from retrospective databases and have limitations. The UPE registry is a prospective international registry with pre-specified characteristics of ACPs with a recent UPE. The aim of this study was to assess the utility of risk factors captured in the UPE registry in predicting proximate (30-, 90- and 180-day) mortality and how they performed when applied to an existing CPR.

Objectives: To evaluate risk factors for proximate mortality, overall survival, recurrent venous thromboembolism and major bleeding, in the patients enrolled in the UPE registry cohort.

Methods: Data from the 695 ACPs in this registry were subjected to multivariate logistic regression analyses to identify predictors independently associated with proximate mortality and overall survival. The most consistent predictors were applied to the Hull CPR, an existing 5-point prediction rule.

Results: The most consistent predictors of mortality were patient-reported respiratory symptoms within 14 days before, and ECOG performance status at the time of UPE. These predictors applied to the Hull-CPR produced a consistent correlation with proximate mortality and overall survival (area under the curve [AUC] = 0.70 [95% CI 0.63, 077], AUC = 0.65 [95% CI 0.60, 070], AUC = 0.64 [95% CI 0.59, 068], and AUC = 0.61, 95% CI 0.57, 0.65, respectively).

Conclusion: In ACPs with UPE, ECOG performance status logged contemporaneously to the UPE diagnosis and respiratory symptoms prior to UPE diagnosis can stratify mortality risk. When applied to the HULL-CPR these risk predictors confirmed the risk stratification clusters of low-intermediate and high-risk for proximate mortality as seen in the original derivation cohort.
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http://dx.doi.org/10.1111/jth.15489DOI Listing
November 2021

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

Ann Intern Med 2021 10 14;174(10):1420-1429. Epub 2021 Sep 14.

Bayer, Wuppertal, Germany (A.W.L., M.G.).

Background: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain.

Purpose: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups.

Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021.

Study Selection: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment.

Data Extraction: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies.

Data Synthesis: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs.

Limitation: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs.

Conclusion: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE.

Primary Funding Source: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).
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http://dx.doi.org/10.7326/M21-1094DOI Listing
October 2021

Screening for COPD in primary care, involving dentists, pharmacists, physiotherapists, nurses and general practitioners (the UNANIME pilot study).

Respir Med Res 2021 Aug 2;80:100853. Epub 2021 Aug 2.

Département de Médecine Vasculaire, Interne et Pneumologie, Groupe D'Etude de la Thrombose de Bretagne Occidentale, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest EA3878, France; Centre d'Investigation Clinique, INSERM, Brest 1412, France.

Background: COPD is underdiagnosed and is projected to be the third cause of death in 2030. However, recent reviews do not recommend screening for COPD in the general population.

Methods: We conducted a prospective study to assess the feasibility of implementing COPD screening in a high-risk COPD population, with the help of various healthcare professionals (General practitioners, pharmacists, dentists, physiotherapists, and nurses). Participants filled out a questionnaire, performed a spirometry (COPD6™) and counselling was performed, including smoking cessation and chest physician referral. Participants were contacted at two months to evaluate the effect of the intervention.

Results: Between April 7th, 2017 and July 30th, 2018, 157 participants filled out the questionnaires, performed spirometry and were contacted at two months. Thirty-five out of 157 (22% [95% CI, 15.8-28.8]) participants were detected with an airflow obstruction (FEV1/FEV6 < 0.7), using COPD6™ device. At the two-month-contact, 68 participants (43%, [95%CI 35.5-51.1]) were engaged in a smoking cessation program and 22 (14% [95 % CI, 8.6-19.4]) reported having quit smoking.

Conclusion: This pilot study suggested that a predefined screening of COPD by different healthcare professionals could be implemented in primary care and might be part of counselling for smoking cessation (NCT03104348 on ClinicalTrials.gov).
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http://dx.doi.org/10.1016/j.resmer.2021.100853DOI Listing
August 2021

Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis.

J Thromb Haemost 2021 11 22;19(11):2801-2813. Epub 2021 Aug 22.

Bayer AG, Wuppertal, Germany.

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain.

Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE.

Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results.

Results: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%).

Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.
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http://dx.doi.org/10.1111/jth.15491DOI Listing
November 2021

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

Lancet Haematol 2021 Sep 4;8(9):e627-e636. Epub 2021 Aug 4.

Internal and Subintensive Medicine Department, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe.

Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555).

Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran.

Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation.

Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S2352-3026(21)00203-9DOI Listing
September 2021

Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: the HOME-PE randomized trial.

Eur Heart J 2021 08;42(33):3146-3157

F-CRIN, INNOVTE, Saint-Etienne, France.

Aims: The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment.

Methods And Results: Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm.

Conclusions: For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.
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http://dx.doi.org/10.1093/eurheartj/ehab373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408662PMC
August 2021

Quality of life in patients with pulmonary embolism treated with edoxaban versus warfarin.

Res Pract Thromb Haemost 2021 Jul 14;5(5):e12566. Epub 2021 Jul 14.

Daiichi Sankyo Pharma Development Basking Ridge NJ USA.

Background: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin.

Methods: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire.

Results: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score.

Conclusion: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time.
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http://dx.doi.org/10.1002/rth2.12566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279124PMC
July 2021

Risk Factors of Arterial Events in Patients with Venous Thromboembolism: A Systematic Review and Meta-Analysis.

Thromb Haemost 2021 Jul 11. Epub 2021 Jul 11.

EA3878 (GETBO), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Brest University, Brest, France.

Background:  If recent studies suggested that arterial ischemic events in patients with venous thromboembolism (VTE) are more frequent than in the general population without VTE, whether patients with VTE have different risk factors of arterial events than classic known cardiovascular risk factors remain undefined. Through this systematic review and meta-analysis, we aimed to identify risk factors of arterial ischemic events in patients with VTE.

Methods:  We searched PubMed, EMBASE, and Cochrane databases to identify cohort studies published between January 1, 2000, and December 31, 2020, reporting risk factors of arterials ischemic events in patients with VTE. Random-effect models meta-analysis served to get the pooled hazard ratio (HR) and 95% confidence interval (CI) of each risk factor identified.

Results:  We screened 1,467 records of which 18 were finally included in systematic review and 10 in meta-analyses. Adjusted HR for 9 factors were included in meta-analysis. Male gender (HR: 1.38; 95% CI: 1.28-1.49), diabetes (HR: 1.65; 95% CI: 1.28-2.12), hypertension (HR: 1.38; 95% CI: 1.04-1.84), previous atherothrombotic event (HR: 3.22; 95% CI: 1.12-9.23), chronic kidney disease (HR: 1.41; 95% CI: 1.05-1.88), cancer (HR: 1.72; 95% CI: 1.41-2.09), and unprovoked VTE (HR: 1.88; 95% CI: 1.37-2.57) were the identified risk factors of arterial events in VTE population after meta-analysis.

Conclusion:  Risk factors of arterial events in patients with VTE include usual cardiovascular risk factors and other risk factors that are related to VTE such as cancer and unprovoked VTE.
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http://dx.doi.org/10.1055/s-0041-1732300DOI Listing
July 2021

Risk of recurrent venous thromboembolism and bleeding in patients with interstitial lung disease: a cohort study.

J Thromb Thrombolysis 2021 Jul 7. Epub 2021 Jul 7.

EA 3878, CIC INSERM 1412, FCRIN INNOVTE, Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest, France.

Interstitial lung disease (ILD) encompasses various parenchymal lung disorders, which has the potential to increase the risk of venous thromboembolism (VTE). To evaluate, in patients with ILD and VTE, the risk of recurrent VTE during follow-up after stopping anticoagulation. This was a cohort of patients with a first VTE recruited between 1997 and 2015. The primary outcome was adjudicated fatal or nonfatal recurrent VTE after stopping anticoagulation. Main secondary outcomes were major or clinically relevant non-major bleeding under anticoagulation. Among 4314 patients with VTE, 50 had ILD diagnosed before VTE. Of these, anticoagulation was stopped in 30 patients after a median duration of 180 days and continued indefinitely in 20 patients. During a median follow-up of 27.8 months after anticoagulation discontinuation, recurrent VTE occurred in 15 on 30 patients (annual incidence of 19.2 events per 100-person-years [95%CI 12.0-29.3], case-fatality rate of 6.7% [95%CI 1.21-29.8]). The risk of recurrence was threefold higher when VTE was unprovoked and case-fatality rate of recurrence was increased by 3 when VTE index was PE. During the anticoagulant period, (median duration of 8.6 months), 6 patients had a major or clinically relevant bleeding (annual incidence of 7.3 events per 100-person-years [95%CI 3.4-15.1], case-fatality rate of 16.7% [95%CI 3.0-56.4]). In patients with ILD, the risk of recurrent VTE after stopping anticoagulation and the risk of bleeding under anticoagulation were very high. Our results suggest that anticoagulation should not be prolonged beyond 3-6 months of anticoagulation in most of cases.
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http://dx.doi.org/10.1007/s11239-021-02518-zDOI Listing
July 2021

Moving forward for incidental pulmonary embolism in cancer patients.

Eur Respir J 2021 07 1;58(1). Epub 2021 Jul 1.

Internal Medicine and Chest Diseases, Hopital de la Cavale Blanche, Brest, France.

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http://dx.doi.org/10.1183/13993003.04630-2020DOI Listing
July 2021

A case of acute pulmonary embolism with severe haemoptysis.

Thromb Res 2021 May 18. Epub 2021 May 18.

Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, CIC INSERM 1412, Brest, France; EA3878, Univ Brest, Brest, France. Electronic address:

Haemoptysis is a potentially life-threatening symptom, which require immediate management. Haemoptysis is a challenging situation because the potential numerous causes lead to strongly different therapeutic options (medical, surgical, systematic embolization). When haemoptysis occurred at the acute phase of pulmonary embolism, anticoagulation should be stopped and inferior vena cava filter is justified. Based on a case report of massive haemoptysis related to pulmonary infarction (i.e., no other causes) in a patient with a unprovoked intermediate high-risk pulmonary embolism, we describe the dilemma set in the paradox between the need for stopping anticoagulation and the need to treat the cause of haemoptysis which is also anticoagulation. If anticoagulation should be stopped, however, the optimal management regarding the use of specific reversal agents or prothrombotic plasma concentrates remains uncertain and weakly documented. After haemoptysis has been resolved, there is also uncertainty on restarting anticoagulation modalities. Regarding long-term management, the decision to stop at three months or to prolong indefinitely based on international recommendation is also challenging in the case of unprovoked severe pulmonary embolism. In this particularly high risk situation, multidisciplinary expertise is essential.
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http://dx.doi.org/10.1016/j.thromres.2021.05.011DOI Listing
May 2021

Frequency and incidence of arterial events in patients with venous thromboembolism compared to the general population: A systematic review and meta-analysis of cohort studies.

Thromb Res 2021 07 15;203:172-185. Epub 2021 May 15.

Vascular Medicine Department, Brest Teaching Hospital, Brest, France; EA3878 (GETBO), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Brest University, Brest, France.

Background: Recent literature hypothesized that patients with venous thromboembolism (VTE) are at increased risk of developing arterial ischemic events than general population without VTE. However, data summarizing the epidemiology of arterial events among VTE population compared to the general population are lacking.

Methods: We conducted a systematic review and meta-analysis from current literature. PubMed, EMBASE, and Cochrane databases were searched between Jan 1, 2000, and December 31, 2020. Eligible studies were observational cohort studies published in English on arterial ischemic events in patients with VTE. Pooled effect size estimates and their 95% confidence intervals were obtained through random-effect models meta-analysis.

Results: Twenty-eight observational studies enrolling 352,014 patients were identified and included. The pooled frequency of all arterial events was 6.1% (95% CI: 3.7-9.1) in patients with VTE and was significantly higher than the pooled frequency of 5.0% (95% CI: 3.1-7.2) found in controls, with a pooled risk ratio (RR) of 1.20 (95% CI: 1.01-1.44; p = 0.0422). The pooled incidence of all arterial events in patients with VTE was 11.3‰ per patient-year (95% CI: 4.6-18.0), and was significantly higher than the 9.2‰ per patient-year (95% CI: 2.0-16.4) obtained in controls (Incidence rate ratio, IRR: 1.32; 95% CI: 1.08-1.61; p = 0.0103). The pooled frequency and pooled incidence of arterial events were also higher in patients with unprovoked VTE than in patients with provoked VTE (RR: 2.12; 95% CI: 1.38-3.24; p = 0.0042; and IRR: 2.26, 95% CI: 1.45-3.49; p = 0.0032).

Conclusion: The frequency and incidence of arterial events in patients with VTE are considerably higher than in the general population, without VTE. Further studies are urgently needed to understand these differences and reduce the burden related to these diseases.

Funding: None.
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http://dx.doi.org/10.1016/j.thromres.2021.05.009DOI Listing
July 2021

Evaluation of beta-2 microglobulin, erythropoietin and tobacco use in polycythemic cases.

Int J Hematol 2021 Aug 22;114(2):222-227. Epub 2021 May 22.

EA3878 GETBO, Groupe D'Etude de La Thrombose en Bretagne Occidentale, Brest, France.

In the 2016 WHO classification, hemoglobin and hematocrit thresholds for diagnosing polycythemia vera (PV) have been lowered, increasing the number of consultations for polycythemia investigations. In PV, beta-2 microglobulin (B2m) levels are reportedly increased, whereas erythropoietin (EPO) levels are usually low. Most secondary polycythemia cases (SP) are caused by tobacco use. We decided to analyze the relevance of these three parameters in all patients seen for polycythemia investigations to help differentiate PV from SP cases. A cohort of 257 patients (123 PV; 134 SP) was identified. The median B2m level was higher for PV patients (3.16 vs 1.98 mg/l, p < 0.0001). Increased B2m levels were observed in 83.7% of PV patients (11.9% in SP). The median EPO level was lower in PV patients (4.4 vs 12.3 UI/l, p < 0.0001). Tobacco was used by 42.8% of SP patients (8% in PV, p < 0.0001). Increased B2m, low EPO and no tobacco exposure was predictive of PV (specificity and positive predictive value = 100%). Normal B2m, normal EPO and tobacco exposure was predictive of SP (positive predictive value = 100%). These simple and inexpensive parameters could be used to rapidly differentiate PV from SP cases, before prescribing time-consuming JAK2 V617F mutation analysis by specialists.
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http://dx.doi.org/10.1007/s12185-021-03164-0DOI Listing
August 2021

Pulmonary Embolism Prevalence Among Hospitalized Patients With COPD-Reply.

JAMA 2021 05;325(18):1903

Centre Hospitalo-Universitaire de Saint-Etienne, Université Jean Monnet, Saint-Etienne, France.

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http://dx.doi.org/10.1001/jama.2021.3247DOI Listing
May 2021

Effect of Local Anesthesia on Pain During Arterial Puncture: The GAEL Randomized Placebo-Controlled Trial.

Respir Care 2021 Jun 23;66(6):976-982. Epub 2021 Mar 23.

Department of Internal Medicine and Chest Diseases, EA3878 (GETBO) CIC INSERM 1412, University Hospital of Brest, European University of Occidental Brittany, Brest, France.

Background: Arterial puncture is often painful for patients. The aim of this study was to compare use of local anesthesia as a eutectic mixture of 2 local anesthetics, lidocaine and prilocaine, versus placebo.

Methods: We conducted a double-blind, randomized controlled trial. Subjects were eligible if arterial puncture was indicated. The primary outcome was an experienced pain > 2 on a numerical pain rating scale. As having had a previous experience of arterial puncture was expected to be predictive of the current response, we planned 3 comparisons between use of local anesthesia and placebo: in the whole sample, among subjects with a painful previous experience, and among subjects with a painless previous experience. Multiple testing was analyzed using the Bonferroni correction for the primary outcome. The secondary outcome was the numerical pain rating scale score itself. All analyses were performed on an intention-to-treat basis.

Results: A total of 136 subjects were included in this study. The primary outcome occurred in 20.9% in the active arm versus 37.7% in the placebo arm in the whole sample (relative risk 0.55; 95% CI when adjusting for multiple testing ranged was 0.28-1.09, = .10; 95% CI without adjustment was 0.32-0.97, = .038). No significant heterogeneity in the study treatment effect was found when considering previous painful or painless arterial puncture ( = .70). The numerical pain rating scale score was 1.55 ± 2.03 in active group versus 2.09 ± 2.15 in the placebo group ( = .13).

Conclusions: We found that application of a eutectic mixture reduced the number of painful arterial punctures by 50% compared with placebo. However, this result was not statistically significant. (ClinicalTrials.gov registration NCT01964248.).
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http://dx.doi.org/10.4187/respcare.08328DOI Listing
June 2021

Whole exome sequencing, a hypothesis-free approach to investigate recurrent early miscarriage.

Reprod Biomed Online 2021 Apr 19;42(4):789-798. Epub 2021 Jan 19.

Université de Brest, EA 3878 (GETBO) Brest 29609, France. Electronic address:

Research Question: Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)?

Design: Thirty REM cases and 30 controls were selected with extreme phenotype among women from Eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live births, respectively. Peripheral blood was collected for DNA extraction at initial visit. The burden of low-frequency variants in the coding part of the genes was compared using whole exome sequencing (WES).

Results: Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and no miscarriages. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P = 0.68). The top five most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2 ± 32.1 versus 92.9 ± 34.3 pmol/l, respectively, P = 0.186). Five cases but no controls were below 50 pmol/l (P = 0.052).

Conclusions: This study highlights four new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). The study also confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.
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http://dx.doi.org/10.1016/j.rbmo.2021.01.008DOI Listing
April 2021

Henoch-Schönlein Purpura Associated with Lung Cancer: When Paraneoplastic Manifestations Impede Oncological Management.

Case Reports Immunol 2021 6;2021:8847017. Epub 2021 Feb 6.

Institut De Cancérologie, CHU Morvan, Brest 29200, France.

Background: Henoch-Schönlein purpura (HSP) is an uncommon syndrome that mostly occurs in children, in whom it is frequently triggered by infections. In contrast, HSP in adults is more frequently of neoplastic origin. . We report HSP associated with a locally advanced lung squamous cell carcinoma that was considered a paraneoplastic syndrome. Systemic corticosteroids were given because a kidney biopsy revealed active glomerulonephritis. Concomitant chemoradiotherapy achieved a partial response of the lung tumor. Consolidation immunotherapy (programmed death protein-1-ligand-1 (PD-L1) inhibitor) was cancelled because HSP is known to be an autoimmune vasculitis, and long-term corticosteroid therapy was pursued.

Conclusion: Further prospective studies are needed to evaluate the effect of anti-PD-(L) 1 immunotherapies on autoimmune manifestations.
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http://dx.doi.org/10.1155/2021/8847017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884136PMC
February 2021

The Extent of Aspergillosis in Critically Ill Patients With Severe Influenza Pneumonia: A Multicenter Cohort Study.

Crit Care Med 2021 06;49(6):934-942

Medical Intensive Care Unit, Centre Hospitalier et Universitaire de Brest, Université de Bretagne Occidentale, Brest, France.

Objectives: To determine the frequency and prognosis of invasive pulmonary aspergillosis in critically ill patients with severe influenza pneumonia.

Design: Retrospective multicenter cohort study.

Setting: Five French ICUs.

Patients: Patients with influenza admitted to ICU between 2009 and 2018.

Measurements And Main Results: Of the 524 patients admitted for severe influenza diagnosed with a positive airway reverse-transcriptase polymerase chain reaction test, 450 (86%) required mechanical ventilation. A lower respiratory tract sample yielded with Aspergillus (Asp+) in 28 patients (5.3%). Ten patients (1.9%) were diagnosed with putative or proven invasive pulmonary aspergillosis, based on the validated AspICU algorithm. A multivariate model was built to identify independent risk factors for Aspergillus-positive pulmonary culture. Factors independently associated with Aspergillus-positive culture were liver cirrhosis (odds ratio = 6.7 [2.1-19.4]; p < 0.01), hematologic malignancy (odds ratio = 3.3 [1.2-8.5]; p = 0.02), Influenza A(H1N1)pdm09 subtype (odds ratio = 3.9 [1.6-9.1]; p < 0.01), and vasopressor requirement (odds ratio = 4.1 [1.6-12.7]; p < 0.01). In-hospital mortality of Asp+ patients was 36% versus 21% in patients without Aspergillus-positive pulmonary culture (p = 0.09).

Conclusions: In this large retrospective multicenter cohort of critically ill patients, putative invasive pulmonary aspergillosis according to AspICU algorithm was a relatively rare complication of influenza. Patients at higher risk of Aspergillus pulmonary colonization included those with liver cirrhosis, hematologic malignancy, H1N1pdm09 influenza A virus, and requiring vasopressors. Our results provide additional data on the controversial association between severe influenza and invasive pulmonary aspergillosis. Reaching a consensual definition of invasive pulmonary aspergillosis becomes mandatory and confers further prospective research.
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http://dx.doi.org/10.1097/CCM.0000000000004861DOI Listing
June 2021

The Impact of Pulmonary Vascular Obstruction on the Risk of Recurrence of Pulmonary Embolism: A French Prospective Cohort.

Thromb Haemost 2021 Jul 14;121(7):955-963. Epub 2021 Jan 14.

Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, CIC INSERM, FCRIN INNOVTE, Brest, France.

Background:  We aimed to assess whether high pulmonary vascular obstruction index (PVOI) measured at the time of pulmonary embolism (PE) diagnosis is associated with an increased risk of recurrent venous thromboembolism (VTE).

Study Design And Methods:  French prospective cohort of patients with a symptomatic episode of PE diagnosed with spiral computerized tomography pulmonary angiography (CTPA) or ventilation-perfusion (V/Q) lung scan and a follow-up of at least 6 months after anticoagulation discontinuation. PVOI was assessed based on the available diagnostic exam (V/Q lung scan or CTPA). All patients had standardized follow-up and independent clinicians adjudicated all deaths and recurrent VTE events. Main outcome was recurrent VTE after stopping anticoagulation.

Results:  A total of 418 patients with PE were included. During a median follow-up period of 3.6 (1.2-6.0) years, 109 recurrences occurred. In multivariate analysis, PVOI ≥ 40% was an independent risk factor for recurrence (hazard ratio 1.77, 95% confidence interval 1.20-2.62,  < 0.01), whether PE was provoked by a major transient risk factor or not. A threshold at 41% was identified as the best value associated with the risk of recurrence 6 months after stopping anticoagulation (area under curve = 0.64).

Conclusion:  PVOI ≥ 40% at PE diagnosis was an independent risk factor for recurrence VTE. Further prospective validation studies are needed.
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http://dx.doi.org/10.1055/s-0040-1722190DOI Listing
July 2021

A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant.

PLoS Genet 2021 01 19;17(1):e1009284. Epub 2021 Jan 19.

EA3878-GETBO, Univ Brest, Department of internal medicine and chest diseases, FCRIN_INNOVTE, CHU Brest, Brest, France.

Rare variants outside the classical coagulation cascade might cause inherited thrombosis. We aimed to identify the variant(s) causing venous thromboembolism (VTE) in a family with multiple relatives affected with unprovoked VTE and no thrombophilia defects. We identified by whole exome sequencing an extremely rare Arg to Gln variant (Arg89Gln) in the Microtubule Associated Serine/Threonine Kinase 2 (MAST2) gene that segregates with VTE in the family. Free-tissue factor pathway inhibitor (f-TFPI) plasma levels were significantly decreased in affected family members compared to healthy relatives. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in affected members than in healthy relatives. RNA sequencing analysis of RNA interference experimental data conducted in endothelial cells revealed that, of the 13,387 detected expressed genes, 2,354 have their level of expression modified by MAST2 knockdown, including SERPINE1 coding for PAI-1 and TFPI. In HEK293 cells overexpressing the MAST2 Gln89 variant, TFPI and SERPINE1 promoter activities were respectively lower and higher than in cells overexpressing the MAST2 wild type. This study identifies a novel thrombophilia-causing Arg89Gln variant in the MAST2 gene that is here proposed as a new molecular player in the etiology of VTE by interfering with hemostatic balance of endothelial cells.
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http://dx.doi.org/10.1371/journal.pgen.1009284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846112PMC
January 2021

Prevalence of Pulmonary Embolism Among Patients With COPD Hospitalized With Acutely Worsening Respiratory Symptoms.

JAMA 2021 Jan;325(1):59-68

Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Brest, France.

Importance: The prevalence of pulmonary embolism in patients with chronic obstructive pulmonary disease (COPD) and acutely worsening respiratory symptoms remains uncertain.

Objective: To determine the prevalence of pulmonary embolism in patients with COPD admitted to the hospital for acutely worsening respiratory symptoms.

Design, Setting, And Participants: Multicenter cross-sectional study with prospective follow-up conducted in 7 French hospitals. A predefined pulmonary embolism diagnostic algorithm based on Geneva score, D-dimer levels, and spiral computed tomographic pulmonary angiography plus leg compression ultrasound was applied within 48 hours of admission; all patients had 3-month follow-up. Patients were recruited from January 2014 to May 2017 and the final date of follow-up was August 22, 2017.

Exposures: Acutely worsening respiratory symptoms in patients with COPD.

Main Outcomes And Measures: The primary outcome was pulmonary embolism diagnosed within 48 hours of admission. Key secondary outcome was pulmonary embolism during a 3-month follow-up among patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulant treatment. Other outcomes were venous thromboembolism (pulmonary embolism and/or deep vein thrombosis) at admission and during follow-up, and 3-month mortality, whether venous thromboembolism was clinically suspected or not.

Results: Among 740 included patients (mean age, 68.2 years [SD, 10.9 years]; 274 women [37.0%]), pulmonary embolism was confirmed within 48 hours of admission in 44 patients (5.9%; 95% CI, 4.5%-7.9%). Among the 670 patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulation, pulmonary embolism occurred in 5 patients (0.7%; 95% CI, 0.3%-1.7%) during follow-up, including 3 deaths related to pulmonary embolism. The overall 3-month mortality rate was 6.8% (50 of 740; 95% CI, 5.2%-8.8%). The proportion of patients who died during follow-up was higher among those with venous thromboembolism at admission than the proportion of those without it at admission (14 [25.9%] of 54 patients vs 36 [5.2%] of 686; risk difference, 20.7%, 95% CI, 10.7%-33.8%; P < .001). The prevalence of venous thromboembolism was 11.7% (95% CI, 8.6%-15.9%) among patients in whom pulmonary embolism was suspected (n = 299) and was 4.3% (95% CI, 2.8%-6.6%) among those in whom pulmonary embolism was not suspected (n = 441).

Conclusions And Relevance: Among patients with chronic obstructive pulmonary disease admitted to the hospital with an acute worsening of respiratory symptoms, pulmonary embolism was detected in 5.9% of patients using a predefined diagnostic algorithm. Further research is needed to understand the possible role of systematic screening for pulmonary embolism in this patient population.
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http://dx.doi.org/10.1001/jama.2020.23567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786241PMC
January 2021
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