Trajectories of the evolution of post-COVID-19 condition, up to two years after symptoms onset.

OBJECTIVES: We aimed to identify trajectories of the evolution of post-COVID-19 condition, up to 2 years after symptom onset. METHODS: The ComPaRe long COVID e-cohort is a prospective cohort of patients with symptoms lasting at least 2 months after SARS-CoV2 infection. We used trajectory modeling to identify different trajectories in the evolution of post-COVID-19 condition, based on symptoms collected every 60 days using the long COVID Symptom Tool. RESULTS: A total of 2197 patients were enrolled in the cohort between December 2020 and July 2022 when the Omicron variant was not dominant. Three trajectories of the evolution of post-COVID-19 condition were identified: "high persistent symptoms" (4%), "rapidly decreasing symptoms" (5%), and "slowly decreasing symptoms" (91%). Participants with highly persistent symptoms were older and more likely to report a history of systemic diseases. They often reported tachycardia, bradycardia, palpitations, and arrhythmia. Participants with rapidly decreasing symptoms were younger and more likely to report a confirmed infection. They often reported diarrhea and back pain. Participants with slowly decreasing symptoms were more likely to have a history of functional diseases. CONCLUSION: Most patients with post-COVID-19 condition improve slowly over time, while 5% have rapid improvement in the 2 years after symptom onset and 4% have a persistent condition.

Pandemic lockdown, isolation, and exit policies based on machine learning predictions.

The widespread lockdowns imposed in many countries at the beginning of the COVID-19 pandemic elevated the importance of research on pandemic management when medical solutions such as vaccines are unavailable. We present a framework that combines a standard epidemiological SEIR (susceptible-exposed-infected-removed) model with an equally standard machine learning classification model for clinical severity risk, defined as an individual's risk of needing intensive care unit (ICU) treatment if infected. Using COVID-19-related data and estimates for France as of spring 2020, we then simulate isolation and exit policies. Our simulations show that policies considering clinical risk predictions could relax isolation restrictions for millions of the lowest risk population months earlier while consistently abiding by ICU capacity restrictions. Exit policies without risk predictions, meanwhile, would considerably exceed ICU capacity or require the isolation of a substantial portion of population for over a year in order to not overwhelm the medical system. Sensitivity analyses further decompose the impact of various elements of our models on the observed effects. Our work indicates that predictive modeling based on machine learning and artificial intelligence could bring significant value to managing pandemics. Such a strategy, however, requires governments to develop policies and invest in infrastructure to operationalize personalized isolation and exit policies based on risk predictions at scale. This includes health data policies to train predictive models and apply them to all residents, as well as policies for targeted resource allocation to maintain strict isolation for high-risk individuals.

Strategies to safely rule out pulmonary embolism in COVID-19 outpatients: a multicenter retrospective study.

OBJECTIVES: The objective was to define a safe strategy to exclude pulmonary embolism (PE) in COVID-19 outpatients, without performing CT pulmonary angiogram (CTPA). METHODS: COVID-19 outpatients from 15 university hospitals who underwent a CTPA were retrospectively evaluated. D-Dimers, variables of the revised Geneva and Wells scores, as well as laboratory findings and clinical characteristics related to COVID-19 pneumonia, were collected. CTPA reports were reviewed for the presence of PE and the extent of COVID-19 disease. PE rule-out strategies were based solely on D-Dimer tests using different thresholds, the revised Geneva and Wells scores, and a COVID-19 PE prediction model built on our dataset were compared. The area under the receiver operating characteristics curve (AUC), failure rate, and efficiency were calculated. RESULTS: In total, 1369 patients were included of whom 124 were PE positive (9.1%). Failure rate and efficiency of D-Dimer > 500 µg/l were 0.9% (95%CI, 0.2-4.8%) and 10.1% (8.5-11.9%), respectively, increasing to 1.0% (0.2-5.3%) and 16.4% (14.4-18.7%), respectively, for an age-adjusted D-Dimer level. D-dimer > 1000 µg/l led to an unacceptable failure rate to 8.1% (4.4-14.5%). The best performances of the revised Geneva and Wells scores were obtained using the age-adjusted D-Dimer level. They had the same failure rate of 1.0% (0.2-5.3%) for efficiency of 16.8% (14.7-19.1%), and 16.9% (14.8-19.2%) respectively. The developed COVID-19 PE prediction model had an AUC of 0.609 (0.594-0.623) with an efficiency of 20.5% (18.4-22.8%) when its failure was set to 0.8%. CONCLUSIONS: The strategy to safely exclude PE in COVID-19 outpatients should not differ from that used in non-COVID-19 patients. The added value of the COVID-19 PE prediction model is minor. KEY POINTS: • D-dimer level remains the most important predictor of pulmonary embolism in COVID-19 patients. • The AUCs of the revised Geneva and Wells scores using an age-adjusted D-dimer threshold were 0.587 (95%CI, 0.572 to 0.603) and 0.588 (95%CI, 0.572 to 0.603). • The AUC of COVID-19-specific strategy to rule out pulmonary embolism ranged from 0.513 (95%CI: 0.503 to 0.522) to 0.609 (95%CI: 0.594 to 0.623).

Platform trials.

For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities.

Effect of interleukin-6 receptor antagonists in critically ill adult patients with COVID-19 pneumonia: two randomised controlled trials of the CORIMUNO-19 Collaborative Group.

BACKGROUND: Our objective was to determine whether anti-interleukin (IL)-6 receptors improve outcomes of critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia. We report on two cohort-embedded, investigator-initiated, multicentre, open-label, Bayesian randomised controlled clinical trials. METHODS: Patients were randomly assigned to receive either usual care (UC) or UC+tocilizumab (TCZ) 8 mg·kg-1 (TOCI-2 trial) or UC or UC+sarilumab (SARI) 200 mg (SARI-2 trial), both intravenously on day 1 and, if clinically indicated, on day 3. RESULTS: Between 31 March and 20 April 2020, 97 patients were randomised in the TOCI-2 trial, to receive UC (n=46) or UC+TCZ (n=51). At day 14, numbers of patients who did not need noninvasive ventilation (NIV) or mechanical ventilation (MV) and were alive with TCZ or UC were similar (47% versus 42%; median posterior hazard ratio (HR) 1.19, 90% credible interval (CrI) 0.71-2.04), with a posterior probability of HR >1 of 71.4%. Between 27 March and 4 April 2020, 91 patients were randomised in the SARI-2 trial, to receive UC (n=41) or UC+SARI (n=50). At day 14, numbers of patients who did not need NIV or MV and were alive with SARI or UC were similar (38% versus 33%; median posterior HR 1.05, 90% CrI 0.55-2.07), with a posterior probability of HR >1 of 54.9%. Overall, the risk of death up to day 90 was: UC+TCZ 24% versus UC 30% (HR 0.67, 95% CI 0.30-1.49) and UC+SARI 29% versus UC 39% (HR 0.74, 95% CI 0.35-1.58). Both TCZ and SARI increased serious infectious events. CONCLUSION: In critically ill patients with COVID-19, anti-IL-6 receptors did not significantly increase the number of patients alive without any NIV or MV by day 14.

Les essais plateformes Plateform trials

Résumé Les essais plateformes connaissent depuis quelques années un essor important, amplifié récemment par la pandémie de coronavirus disease 2019 (COVID-19). La mise en œuvre d’un essai plateforme s’avère particulièrement utile dans certaines pathologies, notamment lorsqu’il y a un nombre important de candidats médicaments à évaluer, une évolution rapide du traitement de référence ou dans les situations de besoin urgent d’évaluation, au cours desquelles la mutualisation des protocoles et des infrastructures permet d’optimiser le nombre de patients à inclure, les coûts et les délais de réalisation de l’investigation. Toutefois, la spécificité des essais plateformes soulève des problématiques méthodologiques, éthiques et règlementaires, qui ont fait l’objet de la table ronde et qui sont exposées dans cet article. La table ronde a également été l’occasion d’aborder la complexité de la promotion et de la gestion des données liée à la multiplicité des partenaires, le financement et la gouvernance de ces essais, et le niveau d’acceptabilité de leurs résultats par les autorités compétentes.

Tocilizumab plus dexamethasone versus dexamethasone in patients with moderate-to-severe COVID-19 pneumonia: A randomised clinical trial from the CORIMUNO-19 study group.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.

Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort.

About 10% of people infected by severe acute respiratory syndrome coronavirus 2 experience post COVID-19 disease. We analysed data from 968 adult patients (5350 person-months) with a confirmed infection enroled in the ComPaRe long COVID cohort, a disease prevalent prospective e-cohort of such patients in France. Day-by-day prevalence of post COVID-19 symptoms was determined from patients' responses to the Long COVID Symptom Tool, a validated self-reported questionnaire assessing 53 symptoms. Among patients symptomatic after 2 months, 85% still reported symptoms one year after their symptom onset. Evolution of symptoms showed a decreasing prevalence over time for 27/53 symptoms (e.g., loss of taste/smell); a stable prevalence over time for 18/53 symptoms (e.g., dyspnoea), and an increasing prevalence over time for 8/53 symptoms (e.g., paraesthesia). The disease impact on patients' lives began increasing 6 months after onset. Our results are of importance to understand the natural history of post COVID-19 disease.

What level of D-dimers can safely exclude pulmonary embolism in COVID-19 patients presenting to the emergency department?

OBJECTIVES: To identify which level of D-dimer would allow the safe exclusion of pulmonary embolism (PE) in COVID-19 patients presenting to the emergency department (ED). METHODS: This retrospective study was conducted on the COVID database of Assistance Publique - Hôpitaux de Paris (AP-HP). COVID-19 patients who presented at the ED of AP-HP hospitals between March 1 and May 15, 2020, and had CTPA following D-dimer dosage within 48h of presentation were included. The D-dimer sensitivity, specificity, and positive and negative predictive values were calculated for different D-dimer thresholds, as well as the false-negative and failure rates, and the number of CTPAs potentially avoided. RESULTS: A total of 781 patients (mean age 62.0 years, 53.8% men) with positive RT-PCR for SARS-Cov-2 were included and 60 of them (7.7%) had CTPA-confirmed PE. Their median D-dimer level was significantly higher than that of patients without PE (4,013 vs 1,198 ng·mL-1, p < 0.001). Using 500 ng·mL-1, or an age-adjusted cut-off for patients > 50 years, the sensitivity and the NPV were above 90%. With these thresholds, 17.1% and 31.5% of CTPAs could have been avoided, respectively. Four of the 178 patients who had a D-dimer below the age-adjusted cutoff had PE, leading to an acceptable failure rate of 2.2%. Using higher D-dimer cut-offs could have avoided more CTPAs, but would have lowered the sensitivity and increased the failure rate. CONCLUSION: The same D-Dimer thresholds as those validated in non-COVID outpatients should be used to safely rule out PE. KEY POINTS: • The median D-dimer level was significantly higher in COVID-19 patients with PE as compared to those without PE (4,013 ng·mL-1 vs 1,198 ng·mL-1 respectively, p < 0.001). • Using 500 ng·mL-1, or an age-adjusted D-dimer cut-off to exclude pulmonary embolism, the sensitivity and negative predictive value were above 90%. • Higher cut-offs would lead to a reduction in the sensitivity below 85% and an increase in the failure rate, especially for patients under 50 years.

Surging bloodstream infections and antimicrobial resistance during the first wave of COVID-19: a study in a large multihospital institution in the Paris region.

OBJECTIVES: This study measured the impact of the first wave of COVID-19 pandemic (COVID-19) (March-April 2020) on the incidence of bloodstream infections (BSIs) at Assistance Publique - Hôpitaux de Paris (APHP), the largest multisite public healthcare institution in France. METHODS: The number of patient admission blood cultures (BCs) collected, number of positive BCs, and antibiotic resistance and consumption were analysed retrospectively for the first quarter of 2020, and also for the first quarter of 2019 for comparison, in 25 APHP hospitals (ca. 14 000 beds). RESULTS: Up to a fourth of patients admitted in March-April 2020 in these hospitals had COVID-19. The BSI rate per 100 admissions increased overall by 24% in March 2020 and 115% in April 2020, and separately for the major pathogens (Escherichia coli, Klebsiella pneumoniae, enterococci, Staphylococcus aureus, Pseudomonas aeruginosa, yeasts). A sharp increase in the rate of BSIs caused by microorganisms resistant to third-generation cephalosporins (3GC) was also observed in March-April 2020, particularly in K. pneumoniae, enterobacterial species naturally producing inducible AmpC (Enterobacter cloacae...), and P. aeruginosa. A concomitant increase in 3GC consumption occurred. CONCLUSIONS: The COVID-19 pandemic had a strong impact on hospital management and also unfavourable effects on severe infections, antimicrobial resistance, and laboratory work diagnostics.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

Study of Thoracic CT in COVID-19: The STOIC Project.

Background There are conflicting data regarding the diagnostic performance of chest CT for COVID-19 pneumonia. Disease extent at CT has been reported to influence prognosis. Purpose To create a large publicly available data set and assess the diagnostic and prognostic value of CT in COVID-19 pneumonia. Materials and Methods This multicenter, observational, retrospective cohort study involved 20 French university hospitals. Eligible patients presented at the emergency departments of the hospitals involved between March 1 and April 30th, 2020, and underwent both thoracic CT and reverse transcription-polymerase chain reaction (RT-PCR) testing for suspected COVID-19 pneumonia. CT images were read blinded to initial reports, RT-PCR, demographic characteristics, clinical symptoms, and outcome. Readers classified CT scans as either positive or negative for COVID-19 based on criteria published by the French Society of Radiology. Multivariable logistic regression was used to develop a model predicting severe outcome (intubation or death) at 1-month follow-up in patients positive for both RT-PCR and CT, using clinical and radiologic features. Results Among 10 930 patients screened for eligibility, 10 735 (median age, 65 years; interquartile range, 51-77 years; 6147 men) were included and 6448 (60%) had a positive RT-PCR result. With RT-PCR as reference, the sensitivity and specificity of CT were 80.2% (95% CI: 79.3, 81.2) and 79.7% (95% CI: 78.5, 80.9), respectively, with strong agreement between junior and senior radiologists (Gwet AC1 coefficient, 0.79). Of all the variables analyzed, the extent of pneumonia at CT (odds ratio, 3.25; 95% CI: 2.71, 3.89) was the best predictor of severe outcome at 1 month. A score based solely on clinical variables predicted a severe outcome with an area under the curve of 0.64 (95% CI: 0.62, 0.66), improving to 0.69 (95% CI: 0.6, 0.71) when it also included the extent of pneumonia and coronary calcium score at CT. Conclusion Using predefined criteria, CT reading is not influenced by reader's experience and helps predict the outcome at 1 month. ClinicalTrials.gov identifier: NCT04355507 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Rubin in this issue.

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial.

Importance: Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19). Objective: To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia. Design, Setting, and Particpants: This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes. Interventions: Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants. Main Outcomes and Measures: Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events. Results: Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] -9.0%; 90% credible interval [CrI], -21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI -28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21). Conclusions and Relevance: In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results. Trial Registration: ClinicalTrials.gov Identifier: NCT04331808.