Risk factors of long term symptoms and outcomes among patients discharged after covid-19: prospective, multicentre observational study

Objective To investigate risk factors and subphenotypes associated with long term symptoms and outcomes after hospital admission for covid-19. Design Prospective, multicentre observational study. Setting 93 hospitals in France. Participants Data from 2187 adults admitted to hospital with covid-19 in France between 1 February 2020 and 30 June 2021. Main outcome measures Primary endpoint was the total number of persistent symptoms at six months after hospital admission that were not present before admission. Outcomes examined at six months were persistent symptoms, Hospital Anxiety and Depression Scale, six minute walk test distances, 36-Item Short Form Health Survey scores, and ability to resume previous professional activities and self-care. Secondary endpoints included vital status at six months, and results of standardised quality-of-life scores. Additionally, an unsupervised consensus clustering algorithm was used to identify subphenotypes based on the severity of hospital course received by patients. Results 1109 (50.7%) of 2187 participants had at least one persistent symptom. Factors associated with an increased number of persistent symptoms were in-hospital supplemental oxygen (odds ratio 1.12, 95% confidence interval 1 to 1.24), no intensive care unit admission (1.15, 1.01 to 1.32), female sex (1.33, 1.22 to 1.45), gastrointestinal haemorrhage (1.51, 1.02 to 2.23), a thromboembolic event (1.66, 1.17 to 2.34), and congestive heart failure (1.76, 1.27 to 2.43). Three subphenotypes were identified: including patients with the least severe hospital course (based on ventilatory support requirements). Although Hospital Anxiety and Depression Scale scores were within normal values for all groups, patients of intermediate severity and more comorbidities had a higher median Hospital Anxiety and Depression Scale score than did the other subphenotypes. Patients in the subphenotype with most severe hospital course had worse short form-36 scores and were less able to resume their professional activity or care for themselves as before compared with other subphenotypes. Conclusions Persistent symptoms after hospital admission were frequent, regardless of acute covid-19 severity. However, patients in more severe subphenotypes had a significantly worse functional status and were less likely to resume their professional activity or able to take care of themselves as before. Trial registration NCT04262921.

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.

Association of COVID-19 Acute Respiratory Distress Syndrome With Symptoms of Posttraumatic Stress Disorder in Family Members After ICU Discharge.

IMPORTANCE: Persistent physical and mental disorders are frequent in survivors of COVID-19-related acute respiratory distress syndrome (ARDS). However, data on these disorders among family members are scarce. OBJECTIVE: To determine the association between patient hospitalization for COVID-19 ARDS vs ARDS from other causes and the risk of posttraumatic stress disorder (PTSD)-related symptoms in family members. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study in 23 intensive care units (ICUs) in France (January 2020 to June 2020 with final follow-up ending in October 2020). ARDS survivors and family members (1 family member per patient) were enrolled. EXPOSURES: Family members of patients hospitalized for ARDS due to COVID-19 vs ARDS due to other causes. MAIN OUTCOMES AND MEASURES: The primary outcome was family member symptoms of PTSD at 90 days after ICU discharge, measured by the Impact of Events Scale-Revised (score range, 0 [best] to 88 [worst]; presence of PTSD symptoms defined by score >22). Secondary outcomes were family member symptoms of anxiety and depression at 90 days assessed by the Hospital Anxiety and Depression Scale (score range, 0 [best] to 42 [worst]; presence of anxiety or depression symptoms defined by subscale scores ≥7). Multivariable logistic regression models were used to determine the association between COVID-19 status and outcomes. RESULTS: Among 602 family members and 307 patients prospectively enrolled, 517 (86%) family members (median [IQR] age, 51 [40-63] years; 72% women; 48% spouses; 26% bereaved because of the study patient's death; 303 [50%] family members of COVID-19 patients) and 273 (89%) patients (median [IQR] age, 61 [50-69] years; 34% women; 181 [59%] with COVID-19) completed the day-90 assessment. Compared with non-COVID-19 ARDS, family members of patients with COVID-19 ARDS had a significantly higher prevalence of symptoms of PTSD (35% [103/293] vs 19% [40/211]; difference, 16% [95% CI, 8%-24%]; P < .001), symptoms of anxiety (41% [121/294] vs 34% [70/207]; difference, 8% [95% CI, 0%-16%]; P= .05), and symptoms of depression (31% [91/291] vs 18% [37/209]; difference, 13% [95% CI, 6%-21%]; P< .001). In multivariable models adjusting for age, sex, and level of social support, COVID-19 ARDS was significantly associated with increased risk of PTSD-related symptoms in family members (odds ratio, 2.05 [95% CI, 1.30 to 3.23]). CONCLUSIONS AND RELEVANCE: Among family members of patients hospitalized in the ICU with ARDS, COVID-19 disease, as compared with other causes of ARDS, was significantly associated with increased risk of symptoms of PTSD at 90 days after ICU discharge. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04341519.

Symptoms of Mental Health Disorders in Critical Care Physicians Facing the Second COVID-19 Wave: A Cross-Sectional Study.

BACKGROUND: Working in the ICU during the first COVID-19 wave was associated with high levels of mental health disorders. RESEARCH QUESTION: What are the mental health symptoms in health care providers (HCPs) facing the second wave? STUDY DESIGN AND METHODS: A cross-sectional study (October 30-December 1, 2020) was conducted in 16 ICUs during the second wave in France. HCPs completed the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised (for post-traumatic stress disorder), and the Maslach Burnout Inventory. RESULTS: Of 1,203 HCPs, 845 responded (70%) (66% nursing staff, 32% medical staff, 2% other professionals); 487 (57.6%) had treated more than 10 new patients with COVID-19 in the previous week. Insomnia affected 320 (37.9%), and 7.7% were taking a psychotropic drug daily. Symptoms of anxiety, depression, post-traumatic stress disorder, and burnout were reported in 60.0% (95% CI, 56.6%-63.3%), 36.1% (95% CI, 32.9%-39.5%), 28.4% (95% CI, 25.4%-31.6%), and 45.1% (95% CI, 41.7%-48.5%) of respondents, respectively. Independent predictors of such symptoms included respondent characteristics (sex, profession, experience, personality traits), work organization (ability to rest and to care for family), and self-perceptions (fear of becoming infected or of infecting family and friends, feeling pressure related to the surge, intention to leave the ICU, lassitude, working conditions, feeling they had a high-risk profession, and "missing the clapping"). The number of patients with COVID-19 treated in the first wave or over the last week was not associated with symptoms of mental health disorders. INTERPRETATION: The prevalence of symptoms of mental health disorders is high in ICU HCPs managing the second COVID-19 surge. The highest tiers of hospital management urgently need to provide psychological support, peer-support groups, and a communication structure that ensure the well-being of HCPs.

SARS-CoV-2 outbreak in immune-mediated inflammatory diseases: the Euro-COVIMID multicentre cross-sectional study.

BACKGROUND: The COVID-19 pandemic has raised numerous questions among patients with immune-mediated inflammatory diseases regarding potential reciprocal effects of COVID-19 and their underlying disease, and potential effects of immunomodulatory therapy on outcomes related to COVID-19. The seroprevalence of SARS-CoV-2 and factors associated with symptomatic COVID-19 in patients with immune-mediated inflammatory diseases are still unclear. The Euro-COVIMID study aimed to determine the serological and clinical prevalence of COVID-19 among patients with immune-mediated inflammatory diseases, as well as factors associated with COVID-19 occurrence and the impact of the pandemic in its management. METHODS: In this multicentre cross-sectional study, patients aged 18 years or older with a clinical diagnosis of rheumatoid arthritis, axial spondyloarthritis, systemic lupus erythematosus, Sjögren's syndrome, or giant cell arteritis were recruited from six tertiary referral centres in France, Germany, Italy, Portugal, Spain, and the UK. Demographics, comorbidities, treatments, and recent disease flares, as well as information on COVID-19 symptoms, were collected through a questionnaire completed by participants. SARS-CoV-2 serology was systematically tested. The main outcome was the serological and clinical prevalence of COVID-19. Factors associated with symptomatic COVID-19 were assessed by multivariable logistic regression, and incidence of recent disease flares, changes in treatments for underlying disease, and the reasons for treatment changes were also assessed. This study is registered with ClinicalTrials.gov, NCT04397237. FINDINGS: Between June 7 and Dec 8, 2020, 3136 patients with an immune-mediated inflammatory disease answered the questionnaire. 3028 patients (median age 58 years [IQR 46-67]; 2239 [73·9%] women and 789 [26·1%] men) with symptomatic COVID-19, serological data, or both were included in analyses. SARS-CoV-2 antibodies were detected in 166 (5·5% [95% CI 4·7-6·4]) of 3018 patients who had serology tests. Symptomatic COVID-19 occurred in 122 (4·0% [95% CI 3·4-4·8]) of 3028 patients, of whom 24 (19·7%) were admitted to hospital and four (3·3%) died. Factors associated with symptomatic COVID-19 were higher concentrations of C-reactive protein (odds ratio 1·18, 95% CI 1·05-1·33; p=0·0063), and higher numbers of recent disease flares (1·27, 1·02-1·58; p=0·030), whereas use of biological therapy was associated with reduced risk (0·51, 0·32-0·82; p=0·0057). At least one disease flare occurred in 654 (21·6%) of 3028 patients. Over the study period, 519 (20·6%) of 2514 patients had treatment changes, of which 125 (24·1%) were due to the pandemic. INTERPRETATION: This study provides key insights into the epidemiology and risk factors of COVID-19 among patients with immune-mediated inflammatory diseases. Overall, immunosuppressants do not seem to be deleterious in this scenario, and the control of inflammatory activity seems to be key when facing the pandemic. FUNDING: Pfizer, Sanofi, Amgen, Galapagos, and Lilly.

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.

Development of a multivariate prediction model of intensive care unit transfer or death: A French prospective cohort study of hospitalized COVID-19 patients.

Prognostic factors of coronavirus disease 2019 (COVID-19) patients among European population are lacking. Our objective was to identify early prognostic factors upon admission to optimize the management of COVID-19 patients hospitalized in a medical ward. This French single-center prospective cohort study evaluated 152 patients with positive severe acute respiratory syndrome coronavirus 2 real-time reverse transcriptase-polymerase chain reaction assay, hospitalized in the Internal Medicine and Clinical Immunology Department, at Pitié-Salpêtrière's Hospital, in Paris, France, a tertiary care university hospital. Predictive factors of intensive care unit (ICU) transfer or death at day 14 (D14), of being discharge alive and severe status at D14 (remaining with ventilation, or death) were evaluated in multivariable logistic regression models; models' performances, including discrimination and calibration, were assessed (C-index, calibration curve, R2, Brier score). A validation was performed on an external sample of 132 patients hospitalized in a French hospital close to Paris, in Aulnay-sous-Bois, Île-de-France. The probability of ICU transfer or death was 32% (47/147) (95% CI 25-40). Older age (OR 2.61, 95% CI 0.96-7.10), poorer respiratory presentation (OR 4.04 per 1-point increment on World Health Organization (WHO) clinical scale, 95% CI 1.76-9.25), higher CRP-level (OR 1.63 per 100mg/L increment, 95% CI 0.98-2.71) and lower lymphocytes count (OR 0.36 per 1000/mm3 increment, 95% CI 0.13-0.99) were associated with an increased risk of ICU requirement or death. A 9-point ordinal scale scoring system defined low (score 0-2), moderate (score 3-5), and high (score 6-8) risk patients, with predicted respectively 2%, 25% and 81% risk of ICU transfer or death at D14. Therefore, in this prospective cohort study of laboratory-confirmed COVID-19 patients hospitalized in a medical ward in France, a simplified scoring system at admission predicted the outcome at D14.

Symptoms of Anxiety, Depression, and Peritraumatic Dissociation in Critical Care Clinicians Managing Patients with COVID-19. A Cross-Sectional Study.

Rationale: Frontline healthcare providers (HCPs) during the coronavirus disease (COVID-19) pandemic are at high risk of mental morbidity.Objectives: To assess the prevalence of symptoms of anxiety, depression, and peritraumatic dissociation in HCPs.Methods: This was a cross-sectional study in 21 ICUs in France between April 20, 2020, and May 21, 2020. The Hospital Anxiety and Depression Scale and the Peritraumatic Dissociative Experience Questionnaire were used. Factors independently associated with reported symptoms of mental health disorders were identified.Measurements and Main Results: The response rate was 67%, with 1,058 respondents (median age 33 yr; 71% women; 68% nursing staff). The prevalence of symptoms of anxiety, depression, and peritraumatic dissociation was 50.4%, 30.4%, and 32%, respectively, with the highest rates in nurses. By multivariable analysis, male sex was independently associated with lower prevalence of symptoms of anxiety, depression, and peritraumatic dissociation (odds ratio of 0.58 [95% confidence interval, 0.42-0.79], 0.57 [95% confidence interval, 0.39-0.82], and 0.49 [95% confidence interval, 0.34-0.72], respectively). HCPs working in non-university-affiliated hospitals and nursing assistants were at high risk of symptoms of anxiety and peritraumatic dissociation. Importantly, we identified the following six modifiable determinants of symptoms of mental health disorders: fear of being infected, inability to rest, inability to care for family, struggling with difficult emotions, regret about the restrictions in visitation policies, and witnessing hasty end-of-life decisions.Conclusions: HCPs experience high levels of psychological burden during the COVID-19 pandemic. Hospitals, ICU directors, and ICU staff must devise strategies to overcome the modifiable determinants of adverse mental illness symptoms.

Randomized Controlled Study Evaluating Efficiency of Low Intensity Transcranial Direct Current Stimulation (tDCS) for Dyspnea Relief in Mechanically Ventilated COVID-19 Patients in ICU: The tDCS-DYSP-COVID Protocol.

The severe respiratory distress syndrome linked to the new coronavirus disease (COVID-19) includes unbearable dyspneic suffering which contributes to the deterioration of the prognosis of patients in intensive care unit (ICU). Patients are put on mechanical ventilation to reduce respiratory suffering and preserve life. Despite this mechanical ventilation, most patients continue to suffer from dyspnea. Dyspnea is a major source of suffering in intensive care and one of the main factors that affect the prognosis of patients. The development of innovative methods for its management, especially non-drug management is more than necessary. In recent years, numerous studies have shown that transcranial direct current stimulation (tDCS) could modulate the perception of acute or chronic pain. In the other hand, it has been shown that the brain zones activated during pain and dyspnea are close and/or superimposed, suggesting that brain structures involved in the integration of aversive emotional component are shared by these two complex sensory experiences. Therefore, it can be hypothesized that stimulation by tDCS with regard to the areas which, in the case of pain have activated one or more of these brain structures, may also have an effect on dyspnea. In addition, our team recently demonstrated that the application of tDCS on the primary cortical motor area can modulate the excitability of the respiratory neurological pathways. Indeed, tDCS in anodal or cathodal modality reduced the excitability of the diaphragmatic cortico-spinal pathways in healthy subjects. We therefore hypothesized that tDCS could relieve dyspnea in COVID-19 patients under mechanical ventilation in ICU. This study was designed to evaluate effects of two modalities of tDCS (anodal and cathodal) vs. placebo, on the relief of dyspnea in COVID-19 patients requiring mechanical ventilation in ICU. Trial Registration: This protocol is derived from the tDCS-DYSP-REA project registered on ClinicalTrials.gov NCT03640455. It will however be registered under its own NCT number.