Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034). Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Brain 18F-FDG PET imaging in outpatients with post-COVID-19 conditions: findings and associations with clinical characteristics.

BACKGROUND: Brain 18F-FDG PET imaging has the potential to provide an objective assessment of brain involvement in post-COVID-19 conditions but previous studies of heterogeneous patient series yield inconsistent results. The current study aimed to investigate brain 18F-FDG PET findings in a homogeneous series of outpatients with post-COVID-19 conditions and to identify associations with clinical patient characteristics. METHODS: We retrospectively included 28 consecutive outpatients who presented with post-COVID-19 conditions between September 2020 and May 2022 and who satisfied the WHO definition, and had a brain 18F-FDG PET for suspected brain involvement but had not been hospitalized for COVID-19. A voxel-based group comparison with 28 age- and sex-matched healthy controls was performed (p-voxel at 0.005 uncorrected, p-cluster at 0.05 FWE corrected) and identified clusters were correlated with clinical characteristics. RESULTS: Outpatients with post-COVID-19 conditions exhibited diffuse hypometabolism predominantly involving right frontal and temporal lobes including the orbito-frontal cortex and internal temporal areas. Metabolism in these clusters was inversely correlated with the number of symptoms during the initial infection (r = - 0.44, p = 0.02) and with the duration of symptoms (r = - 0.39, p = 0.04). Asthenia and cardiovascular, digestive, and neurological disorders during the acute phase and asthenia and language disorders during the chronic phase (p ≤ 0.04) were associated with these hypometabolic clusters. CONCLUSION: Outpatients with post-COVID-19 conditions exhibited extensive hypometabolic right fronto-temporal clusters. Patients with more numerous symptoms during the initial phase and with a longer duration of symptoms were at higher risk of persistent brain involvement.

Prevalence of post-acute coronavirus disease 2019 symptoms twelve months after hospitalization in participants retained in follow-up: analyses stratified by gender from a large prospective cohort.

OBJECTIVES: Persistent post-acute coronavirus disease 2019 (COVID-19) symptoms (PACSs) have been reported up to 6 months after hospital discharge. Herein we assessed the symptoms that persisted 12 months (M12) after admission for COVID-19 in the longitudinal prospective national French coronavirus disease cohort. METHODS: Hospitalized patients with a confirmed virological diagnosis of COVID-19 were enrolled. Follow-up was planned until M12 after admission. Associations between persistence of ≥3 PACSs at M12 and clinical characteristics at admission were assessed through logistic regression according to gender. RESULTS: We focused on participants enrolled between 24 January 2020 and 15 July 2020, to allow M12 follow-up. The M12 data were available for 737 participants. Median age was 61 years, 475 (64%) were men and 242/647 (37%) were admitted to intensive care units during the acute phase. At M12, 27% (194/710) of the participants had ≥3 persistent PACS, mostly fatigue, dyspnoea and joint pain. Among those who had a professional occupation before the acute phase, 91 out of 339 (27%) were still on sick leave at M12. Presence of ≥3 persistent PACS was associated with female gender, both anxiety and depression, impaired health-related quality of life and Medical Muscle Research Council Scale <57. Compared with men, women more often reported presence of ≥3 persistent PACSs (98/253, 39% vs. 96/457, 21%), depression and anxiety (18/152, 12% vs. 17/268, 6% and 33/156, 21% vs. 26/264, 10%, respectively), impaired physical health-related quality of life (76/141, 54% vs. 120/261, 46%). Women had less often returned to work than men (77/116, 66% vs. 171/223, 77%). CONCLUSIONS: One fourth of the individuals admitted to hospital for COVID-19 still had ≥3 persistent PACSs at M12 post-discharge. Women reported more often ≥3 persistent PACSs, suffered more from anxiety and depression and had less often returned to work than men.

Remdesivir for Patients Hospitalized with COVID-19 Severe Pneumonia: A National Cohort Study (Remdeco-19).

BACKGROUND: Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies. Evidence suggested the potential utility of remdesivir in the framework of an early access program. REMDECO-19 is a multicenter national cohort study assessing the ability of remdesivir to improve the outcome of patients hospitalized with COVID-19. METHODS: We conducted a retrospective real-life study that included all patients from the early access program of remdesivir in France. The primary endpoint was the clinical course evolution of critically ill and hospitalized COVID-19 patients treated with remdesivir. Secondary endpoints were the SOFA score evolution within 29 days following the admission and mortality at 29 and 90 days. RESULTS: Eighty-five patients were enrolled in 22 sites from January to April 2020. The median WHO and SOFA scores were respectively reduced by two and six points between days 1 and 29. Improvement in the WHO-CPS and the SOFA score were observed in 83.5% and 79.3% of patients, respectively, from day 10. However, there was no effect of remdesivir on the 90-day survival based on the control cohort for hospitalized COVID-19 patients with invasive ventilation. CONCLUSIONS: SOFA score appeared to be an attractive approach to assess remdesivir efficacy and stratify its utilization or not in critically ill patients with COVID-19. This study brings a new clinical benchmark for therapeutic decision making and supports the use of remdesivir for some hospitalized COVID-19 patients.

Prevalence of post-acute COVID-19 symptoms twelve months after hospitalisation in participants retained in follow-up: analyses stratified by gender from a large prospective cohort

Objectives Persistent post-acute COVID-19 symptom (PACS) have been reported up to 6-months (M6) after hospital discharge. Here we assessed, in the longitudinal prospective national French COVID cohort, symptoms that persisted 12-months (M12) after admission for COVID-19. Methods Hospitalized patients with a virologically-confirmed COVID-19 were enrolled. Follow-up was planned until M12 post-admission. Associations between persistence of ≥3 PACS at M12 and clinical characteristics at admission were assessed through logistic regression according to gender. Results We focused on participants enrolled between January 24th and July 15th 2020, in order to allow M12 follow-up. M12 data were available for 737 participants. Median age was 61 years, 475 (64%) were men and 242/647 (37%) were admitted to ICU during the acute phase. At M12, 194/710 (27%) of participants had ≥3 persistent PACS, mostly fatigue, dyspnea and joint pain. Among those who had a professional occupation before the acute phase 91/339 (27%) were still on sick leave at M12. Presence of ≥3 persistent PACS was associated with female gender, both anxiety and depression, impaired health-related quality of life (HRQL) and mMRC scale <57. Compared to men, women more often reported presence of >3 persistent PACS (98/253, 39% vs 96/457, 21%), depression and anxiety (18/152, 12% vs 17/268, 6% and 33/156, 21% vs 26/264, 10%, respectively), impaired physical HRQL (76/141, 54% vs 120/261, 46%). Women had less often returned to work than men (77/116, 66% vs 171/223, 77%). Conclusions A fourth of individuals admitted to hospital for COVID-19 still had ≥3 persistent PACS at M12 post-discharge. Women reported more often ≥3 persistent PACS, suffered more from anxiety and depression, and had less often returned to work than men.

Anti-spike IgG antibody kinetics following the second and third doses of BNT162b2 vaccine in nursing home residents.

BACKGROUND: Duration of post-vaccination protection against COVID-19 in nursing home (NH) residents is a critical issue. The objective of this study was to estimate the duration of the IgG(S) response to the mRNA BNT162b2 vaccine in NH residents with (COV-Yes) or without (COV-No) history of SARS-CoV-2 infection. METHODS: A 574 COV-Yes and COV-No NH residents were included in 2 cohorts: Main (n = 115, median age 87 years) or Confirmatory (n = 459, median age 89 years). IgG(S) quantification was carried out at three different time points following the BNT162b2 vaccine: three (1st) and seven (2nd) months after the 2nd dose, and 1 month after the 3rd dose (3rd quantification) in the Main cohort, and twice (2nd and 3rd) in the Confirmatory cohort. The seroneutralization capacity according to COVID-19 history was also measured in a subgroup of patients. RESULTS: Neutralization capacity was strongly correlated with IgG(S) levels (R2 :76%) without any difference between COV-Yes and COV-No groups for the same levels of IgG(S). After the 2nd dose, duration of the assumed robust protection (IgG(S) >264 BAU/ml) was two-fold higher in the COV-Yes vs. COV-No group: 12.60 (10.69-14.44) versus 5.76 (3.91-8.64) months, with this advantage mainly due to the higher IgG(S) titers after the 2nd dose and secondary to a slower decay over time. After the 3rd dose, duration of robust protection was estimated at 11.87 (9.88-14.87) (COV-Yes) and 8.95 (6.85-11.04) (COV-No) months. These results were similar in both cohorts. CONCLUSIONS AND RELEVANCE: In old subjects living in NH, history of SARS-CoV-2 infection provides a clear advantage in the magnitude and duration of high IgG(S) titers following the 2nd dose. Importantly, the 3rd dose induces a much more pronounced IgG(S) response than the 2nd dose in COV-No subjects, the effect of which should be able to ensure a prolonged protection against severe forms of COVID-19 in these subjects.

Long-Lasting Myocardial and Skeletal Muscle Damage Evidenced by Serial CMR During the First Year in COVID-19 Patients From the First Wave.

Introduction: This observational CMR study aims to characterize left-ventricular (LV) damage, which may be specifically attributed to COVID-19 and is distant in time from the acute phase, through serial CMR performed during the first year in patients with no prior cardiac disease. Methods: This study included consecutive patients without any prior history of cardiac disease but with a peak troponin-Ic > 50 ng/ml at the time of the first COVID-wave. All had a CMR in the first months after the acute phase, and some had an additional CMR at the end of the first year to monitor LV function, remodeling, and abnormalities evocative of myositis and myocarditis - i.e., increased T1/T2 relaxation times, increased extracellular volume (ECV), and delayed contrast enhancement. Results: Nineteen consecutively admitted COVID-19 patients (17 men, median age 66 [57-71] years) were included. Eight (42%) had hypertension, six (32%) were obese, and 16 (84%) had suffered an acute respiratory distress syndrome. The 1st CMR, recorded at a median 3.2 [interquartile range: 2.6-3.9] months from the troponin peak, showed (1) LV concentric remodeling in 12 patients (63%), (2) myocardial tissue abnormalities in 11 (58%), including 9 increased myocardial ECVs, and (3) 14 (74%) increased ECVs from shoulder skeletal muscles. The 2nd CMR, obtained at 11.1 [11.0-11.7] months from the troponin peak in 13 patients, showed unchanged LV function and remodeling but a return to normal or below the normal range for all ECVs of the myocardium and skeletal muscles. Conclusion: Many patients with no history of cardiac disease but for whom an increase in blood troponin-Ic ascertained COVID-19 induced myocardial damage exhibited signs of persistent extracellular edema at a median 3-months from the troponin peak, affecting the myocardium and skeletal muscles, which resolved within a one-year time frame. Associations with long-COVID symptoms need to be investigated on a larger scale now. Clinical Trial Registration: NCT04753762 on the ClinicalTrials.gov site.

Visual interpretation of brain hypometabolism related to neurological long COVID: a French multicentric experience.

BACKGROUND: This multicentre study aimed to provide a qualitative and consensual description of brain hypometabolism observed through the visual analysis of 18F-FDG PET images of patients with suspected neurological long COVID, regarding the previously reported long-COVID hypometabolic pattern involving hypometabolism in the olfactory bulbs and other limbic/paralimbic regions, as well as in the brainstem and cerebellum. METHODS: From the beginning of August 2021 to the end of October 2021, the brain 18F-FDG PET scans of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology tests for SARS-CoV-2 infection were retrospectively reviewed in three French nuclear medicine departments (143 patients; 47.4 years old ± 13.6; 98 women). Experienced nuclear physicians from each department classified brain 18F-FDG PET scans according to the same visual interpretation analysis as being normal, mildly to moderately (or incompletely) affected, or otherwise severely affected within the previously reported long-COVID hypometabolic pattern. RESULTS: On the 143 brain 18F-FDG PET scans performed during this 3-month period, 53% of the scans were visually interpreted as normal, 21% as mildly to moderately or incompletely affected, and 26% as severely affected according to the COVID hypometabolic pattern. On average, PET scans were performed at 10.9 months from symptom onset (± 4.8). Importantly, this specific hypometabolic pattern was similarly identified in the three nuclear medicine departments. Typical illustrative examples are provided to help nuclear physicians interpret long-COVID profiles. CONCLUSION: The proposed PET metabolic pattern is easily identified upon visual interpretation in clinical routine for approximately one half of patients with suspected neurological long COVID, requiring special consideration for frontobasal paramedian regions, the brainstem and the cerebellum, and certainly further adapted follow-up and medical care, while the second half of patients have normal brain PET metabolism on average 10.9 months from symptom onset.

Severity of self-reported symptoms and psychological burden 6-months after hospital admission for COVID-19: a prospective cohort study.

OBJECTIVES: Few studies have reported clinical COVID-19 sequelae six months (M6) after hospital discharge, but none has studied symptom severity. METHODS: Prevalence and severity of 7 symptoms were estimated until M6 using the self-administered influenza severity scale in COVID-19 hospitalized patients enrolled in the French COVID cohort. Factors associated with severity were assessed by logistic regression. Anxiety, depression and health-related quality of life (HRQL) were also assessed. RESULTS: At M6, among the 324 patients (median age 61 years, 63% men, 19% admitted to intensive care during the acute phase), 187/324 (58%) reported at least one symptom, mostly fatigue (47%) and myalgia (23%). Symptom severity was scored, at most, mild in 125 (67%), moderate in 44 (23%) and severe in 18 (10%). Female gender was the sole factor associated with moderate/severe symptom reporting (OR = 1.98, 95%CI=1.13-3.47). Among the 225 patients with psychological assessment, 24 (11%) had anxiety, 18 (8%) depressive symptoms, and their physical HRQL was significantly poorer than the general population (p=0.0005). CONCLUSION: Even if 58% of patients reported ≥1 symptom at M6, less than 7% rated any symptom as severe. Assessing symptoms severity could be helpful to identify patients requiring appropriate medical care. Women may require special attention.

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-ß-1a and hydroxychloroquine in hospitalized patients with COVID-19.

OBJECTIVES: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-ß-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. METHODS: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. RESULTS: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-ß-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-ß-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. CONCLUSION: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Corticosteroids in patients hospitalized for COVID-19 pneumonia who require oxygen: observational comparative study using routine care data.

OBJECTIVE: To assess the effectiveness of corticosteroids on outcomes of patients with coronavirus disease 2019 (COVID-19) pneumonia requiring oxygen without mechanical ventilation. METHODS: We used routine care data from 51 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.8 mg/kg/day eq. prednisone (CTC group) versus standard of care (no-CTC group) among adults 18-80 years old with confirmed COVID-19 pneumonia requiring oxygen without mechanical ventilation. The primary outcome was intubation or death by day 28. In our main analysis, characteristics of patients at baseline (i.e. time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting. RESULTS: Among the 891 patients included in the analysis, 203 were assigned to the CTC group. Use of corticosteroids was not significantly associated with risk of intubation or death by day 28 (weighted hazard ratio (wHR) 0.92, 95%CI 0.61-1.39) nor cumulative death rate (wHR 1.03, 95%CI 0.54-1.98). However, use of corticosteroids was associated with reduced risk of intubation or death by day 28 in the prespecified subgroups of patients requiring oxygen ≥3 L/min (wHR 0.50, 95%CI 0.30-0.85) or C-reactive protein level ≥100 mg/L (wHR 0.44, 95%CI 0.23-0.85). The number of hyperglycaemia events was higher for patients with corticosteroids than for those without, but the number of infections was similar. CONCLUSIONS: We found no association between the use of corticosteroids and intubation or death in the broad population of patients 18-80 years old, with COVID-19, hospitalized in settings non intensive care units. However, the treatment was associated with a reduced risk of intubation or death for patients with ≥3 L/min oxygen or C-reactive protein level ≥100 mg/L at baseline. Further research is needed to confirm the right timing for corticosteroids in patients with COVID-19 requiring oxygen only.

Signs of tracheobronchitis may constitute the principal finding on the lung SPECT/CT images of COVID-19 patients.

BACKGROUND: This study aimed to analyze the rates of tracheobronchitis signs observed on the ventilation scans of COVID-19 patients with shortness of breath, with comparisons to a non-COVID population. METHODS: Lung scintigraphy was collected in 10 such COVID patients, as well as from a non-COVID population investigated outside the epidemic wave period, on a CZT-SPECT/CT system, with ventilation images recorded with 99mTc-labeled Technegas® and perfusion images with 99mTc-labeled albumin macroaggregates. RESULTS: A diffuse tracheobronchial uptake was observed on the ventilation scans from 3 COVID patients (30%), whereas this rate was 3% (3/90) in the non-COVID group (P = 0.013). These 3 patients had no laryngeal extension of Technegas® uptake and limited parenchymal lung abnormalities. Follow-up scintigraphy demonstrated the withdrawal of tracheobronchitis signs in two cases, and the advent of a severe pulmonary embolism in one. CONCLUSION: Signs of tracheobronchitis may constitute the principal finding on lung SPECT/CT images of COVID-19 patients with shortness of breath.

Changes in characteristics and management among patients with ST-elevation myocardial infarction due to COVID-19 infection.

OBJECTIVES: To assess changes in characteristics and management among ST-elevation myocardial infarction (STEMI) patients with coronavirus disease (COVID-19) who underwent primary percutaneous coronary intervention. METHODS: Our prospective, monocentric study enrolled all STEMI patients who underwent PPCI during the COVID-19 outbreak (n = 83). This cohort was first compared with a previous cohort of STEMI patients (2008-2017, n = 1,552 patients) and was then dichotomized into a non-COVID-19 group (n = 72) and COVID-19 group (n = 11). RESULTS: In comparison with the pre-outbreak period, patients during the outbreak period were older (59.6 ± 12.9 vs. 62.6 ± 12.2, p = .03) with a delayed seek to care (mean delay first symptoms-balloon 3.8 ± 3 vs. .7.4 ± 7.7, p < .001) resulting in a two-fold higher in-hospital mortality (non COVID-19 4.3% vs. COVID-19 8.4%, p = .07). Among the 83 STEMI patients admitted during the outbreak period, 11 patients were infected by COVID-19. Higher biological markers of inflammation (C-reactive protein: 28 ± 39 vs. 98 ± 97 mg/L, p = .04), of fibrinolysis (D-dimer: 804 ± 1,500 vs. 3,128 ± 2,458 µg/L, p = .02), and antiphospholipid antibodies in four cases were observed in the COVID-19 group. In this group, angiographic data also differed: a thrombotic myocardial infarction nonatherosclerotic coronary occlusion (MINOCA) was observed in 11 cases (1.4% vs. 54.5%, p < .001) and associated with higher post-procedure distal embolization (30.6% vs. 72.7%, p = .007). The in hospital mortality was significantly higher in the COVID-19 group (5.6% vs. 27.3%, p = .016). CONCLUSION: The COVID-19 outbreak implies deep changes in the etiopathogenesis and therapeutic management of STEMI patients with COVID-19. The impact on early and long-term outcomes of systemic inflammation and hypercoagulability in this specific population is warranted.

Clinical recurrences of COVID-19 symptoms after recovery: Viral relapse, reinfection or inflammatory rebound?

For the first 3 months of COVID-19 pandemic, COVID-19 was expected to be an immunizing non-relapsing disease. We report a national case series of 11 virologically-confirmed COVID-19 patients having experienced a second clinically- and virologically-confirmed acute COVID-19 episode. According to the clinical history, we discuss either re-infection or reactivation hypothesis. Larger studies including further virological, immunological and epidemiologic data are needed to understand the mechanisms of these recurrences.