; for the CORIMUNO-19 Collaborative Group 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...

Aim The aim of this paper is to describe the clinical features of COVID‐19‐related encephalopathy and their metabolic correlates using brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission tomography (PET)/computed tomography (CT) imaging. Background and purpose A variety of neurological manifestations have been reported in association with COVID‐19. COVID‐19‐related encephalopathy has seldom been reported and studied. Methods We report four cases of COVID‐19‐related encephalopathy. The diagnosis was made in patients with confirmed COVID‐19 who presented with new‐onset cognitive disturbances, central focal neurological signs, or seizures. All patients underwent cognitive screening, brain magnetic resonance imaging (MRI), lumbar puncture, and brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission tomography (PET)/computed tomography (CT) (FDG‐PET/CT). Results The four patients were aged 60 years or older, and presented with various degrees of cognitive impairment, with predominant frontal lobe impairment. Two patients presented with cerebellar syndrome, one patient had myoclonus, one had psychiatric manifestations, and one had status epilepticus. The delay between first COVID‐19 symptoms and onset of neurological symptoms was between 0 and 12 days. None of the patients had MRI features of encephalitis nor significant cerebrospinal fluid (CSF) abnormalities. SARS‐CoV‐2 RT‐PCR in the CSF was negative for all patients. All patients presented with a consistent brain FDG‐PET/CT pattern of abnormalities, namely frontal hypometabolism and cerebellar hypermetabolism. All patients improved after immunotherapy. Conclusions Despite varied clinical presentations, all patients presented with a consistent FDG‐PET pattern, which may reflect an immune mechanism.

Background Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual. FindingsBetween April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2•5%, 90% credible interval [CrI] -17•1 to 12•0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61•2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54•5% (median posterior HR 0•97; 90% CrI 0•62 to 1•52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usu...

Purpose Little is known about the neuronal substrates of neuropsychiatric symptoms associated with COVID-19 and their evolution during the course of the disease. We aimed at describing the longitudinal brain metabolic pattern in COVID-19related encephalopathy using 18F-FDG-PET/CT. Methods Seven patients with variable clinical presentations of COVID-19-related encephalopathy were explored thrice with brain 18F-FDG-PET/CT, once in the acute phase, 1 month later and 6 months after COVID-19 onset. PET images were analysed with voxel-wise and regions-of-interest approaches in comparison with 32 healthy controls. Results Patients' neurological manifestations during acute encephalopathy were heterogeneous. However, all of them presented with predominant cognitive and behavioural frontal disorders. SARS-CoV-2 RT-PCR in the CSF was negative for all patients. MRI revealed no specific abnormalities for most of the subjects. All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities. Conclusion The implication of this widespread network could be the neural substrate of clinical features observed in patients with COVID-19, such as frontal lobe syndrome, emotional disturbances and deregulation of respiratory failure perception. This study suggests that this network remains mildly to severely impaired 6 months after disease onset.

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