Time to treat the climate and nature crisis as one indivisible Global Health Emergency

@#Over 200 health journals call on the United Nations, political leaders, and health professionals to recognise that climate change and biodiversity loss are one indivisible crisis and must be tackled together to preserve health and avoid catastrophe. This overall environmental crisis is now so severe as to be a global health emergency.

Cohort Profile: The Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 vaccines (ENFORCE)

PurposeThe ENFORCE cohort is a national Danish prospective cohort of adults who received a Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as part of the Danish National SARS-CoV-2 vaccination program. It was designed to investigate the long-term effectiveness, safety and durability of SARS-CoV-2 vaccines used in Denmark. ParticipantsA total of 6943 adults scheduled to receive a SARS-CoV-2 vaccine in the Danish COVID-19 Vaccination Program were enrolled in the study prior to their first vaccination. Participants will be followed for a total of two years with five predetermined follow-up visits and additional visits in relation to any booster vaccination. Serology measurements are performed after each study visit. T-cell immunity is evaluated at each study visit for a subgroup of 699 participants. Safety information is collected from participants at visits following each vaccination. Data on hospital admissions, diagnoses, deaths and SARS-CoV-2 polymerase chain reaction (PCR) results are collected from national registries throughout the study period. The median age of participants was 64 years (IQR 53-75), 56.6% were females and 23% were individuals with an increased risk of a serious course of COVID-19. A total of 340 (4.9%) participants tested positive for SARS-CoV-2 spike IgG at baseline. Findings to dateResults have been published on risk factors for humoral hyporesponsiveness and non-durable response to SARS-CoV-2 vaccination, the risk of breakthrough infections at different levels of SARS-CoV-2 spike IgG by viral variant, and on the antibody neutralizing capacity against different SARS-CoV-2 variants following primary and booster vaccinations. Future plansThe ENFORCE cohort will continuously generate studies investigating immunological response, effectiveness, safety and durability of the SARS-CoV-2 vaccines. Registrationclinicaltrials.gov identifier: NCT04760132. Strengths and limitations- The ENFORCE study combines repeated detailed SARS-CoV-2 specific immunological measurements prior to, and throughout the course of SARS-CoV-2 vaccination, with register-based follow-up of safety data and microbiological test results. - The ENFORCE cohort includes a large proportion of elderly participants and participants with concomitant diseases. - The three vaccine groups display a high degree of variation in demographic factors and distribution across risk groups, due to the prioritization of specific vaccines to risk groups during the primary roll out of the SARS-CoV-2 vaccination program.

Testing Denmark: A Danish nationwide surveillance study of COVID-19

BackgroundNational data on the spread of SARS-CoV-2 infection and knowledge on associated risk factors are important for understanding the course of the pandemic. "Testing Denmark" is a national large-scale epidemiological surveillance study of SARS-CoV-2 in the Danish population. MethodsBetween September and October 2020, approximately 1.3 million of 5.8 million Danish citizens (age > 15 years) were randomly invited to fill in an electronic questionnaire covering COVID-19 exposures and symptoms. The prevalence of SARS-CoV-2 antibodies was determined by Point-of Care rapid Test (POCT) distributed to participants home addresses. FindingsIn total 318,552 participants (24.5% invitees) completed the questionnaire and provided the result of the POCT. Of these, 2,519 (0.79%) were seropositive (median age 55 years) and women were more often seropositive than men, interquartile range (IQR) 42-64, 40.2% males. Of participants with a prior positive Polymerase Chain Reaction (PCR) test (n=1,828), 29.1% were seropositive in the POCT. Seropositivity increased with age irrespective of sex. Elderly participants (>61 years) reported less symptoms and had less frequently been tested for SARS-CoV-2 compared to younger participants. Seropositivity was associated with physical contact with SARS-CoV-2 infected individuals (Risk ratio (RR) 7.43, 95% CI: 6.57-8.41) and in particular household members (RR 17.70, 95% CI: 15.60-20.10). Home care workers had a higher risk of seropositivity (RR 2.09 (95% CI: 1.58-2.78) as compared to office workers. Geographic population density was not associated to seropositivity. A high degree of compliance with national preventive recommendations was reported (e.g., > 80% use of face masks), but no difference was found between seropositive and seronegative participants. InterpretationThis study provides insight into the immunity of the Danish population seven to eight months after the first COVID-19 case in Denmark. The seroprevalence was lower than expected probably due to a low sensitivity of the POCT used or due to challenges relating to the reading of test results. Occupation or exposure in local communities were major routes of infection. As elderly participants were more often seropositive despite fewer symptoms and less PCR tests performed, more emphasis should be placed on testing this age group.

Clinical validation of point-of-care SARS-COV-2 BD Veritor antigen test by a single throat swab for rapid COVID-19 status on hospital patients predominantly without overt COVID symptoms

BACKGROUNDFast identification of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infected individuals is a strategically vital task to ensure correct management and quarantine. Rapid antigen test could be a supplement to the standard-of-care Nucleic Acid Amplification Test (NAAT). The aim of this study was to determine the accuracy of the BD Veritor SARS-CoV-2 antigen test as a screening instrument in a hospital setting. METHODSA cohort of prospective samples were collected from hospital staff and patients at the Emergency, Infectious Diseases and Pediatrics and Adolescent Medicine departments at Hvidovre Hospital. All samples were collected using oropharyngeal swabs, and BD Veritor Antigen test results were paired with routine NAAT test results. Sensitivity, specificity, positive and negative predictive values of the antigen test were calculated using NAAT as reference. RESULTSOverall, 809 samples from 674 individuals were included (average age 45 years, range 0-98 years). Among all samples, 8% were SARS-CoV-2 positive by NAAT testing and 5.3% by BD Veritor. The sensitivity of the antigen test was 63.1% and specificity 99.7%. The positive predictive value was 95.3%. False-positive rate was 4%. The cycle threshold value was significantly higher among individuals with false negative antigen tests compared to true positives. CONCLUSIONThe sensitivity, specificity and positive predictive values show that the BD Veritor antigen test from oropharyngeal collected specimens performs well. Antigen testing may be a supplement, but not substitute, to NAAT testing as the primary diagnostic modality in hospital settings where fast turnaround test results may assist in decisions regarding isolation and quarantine.

Prognostic and predictive biomarkers in patients with COVID-19 treated with tocilizumab in a randomised controlled trial

BackgroundRetrospective observational studies suggest that interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, lymphocytes, monocytes, neutrophils, D-dimer, and platelets are associated with disease progression, treatment outcomes, or both, in patients with COVID-19 pneumonia. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti-IL-6 receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 pneumonia. MethodsCandidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomisation) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. FindingsModelling in the placebo arm showed all candidate biomarkers except LDH and D-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modelling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction p=0.03), mechanical ventilation (predictive interaction p=0.01), and clinical status (predictive interaction p=0.02) compared with placebo. InterpretationMultiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28. RESEARCH IN CONTEXT Evidence before this studyThe efficacy and safety of the anti-interleukin-6 receptor antibody tocilizumab in the treatment of patients hospitalised with COVID-19 pneumonia was investigated in COVACTA, a double-blind, randomised, placebo-controlled trial. The primary endpoint of improved clinical status on a seven-category ordinal scale (1, discharged/ready for discharge; 7, death) at day 28 was not met in this trial. Among the secondary endpoints, no difference in mortality at day 28 was observed, but time to hospital discharge was shorter in the tocilizumab group. Subgroup analysis suggested there might be a treatment benefit in patients grouped according to their ordinal scale category at baseline. We searched PubMed on September 14, 2020, using the terms "tocilizumab AND (COVID-19 OR coronavirus) AND biomarker" with no language or date restrictions. The search retrieved 18 articles, four of which identified laboratory measures as potential biomarkers in patients who received tocilizumab for the treatment of COVID-19 pneumonia. The biomarkers reported in these studies include interleukin-6, C-reactive protein, ferritin, fibrinogen, liver transaminases, lymphocytes, platelets, and D-dimer. However, these previous studies were single-centre, retrospective, observational studies. Larger, prospective, controlled trials are needed to investigate potential prognostic and predictive biomarkers to assess the outcomes and response to treatments for COVID-19. Added value of this studyThis exploratory analysis of data from COVACTA demonstrated interleukin-6, C-reactive protein, ferritin, neutrophils (percentage and absolute count), neutrophil-to-lymphocyte ratio, lymphocytes (percentage and absolute count), monocytes (percentage), and platelets as strong prognostic biomarkers in patients hospitalised with severe COVID-19 pneumonia. More important, ferritin showed predictive value for tocilizumab treatment effects on day 28 clinical outcomes of mortality, mechanical ventilation (among the subgroup of patients not receiving mechanical ventilation at randomisation), and clinical status compared with placebo. Implications of all the available evidenceIn patients with elevated levels of ferritin at baseline, tocilizumab decreased the probability of death, mechanical ventilation, and worsening clinical status at day 28 compared with placebo, suggesting that ferritin might be useful as a predictive biomarker of efficacy outcomes for tocilizumab in patients with severe COVID-19 pneumonia.

Low vitamin K status predicts mortality in a cohort of 138 hospitalized patients with COVID-19

It has recently been hypothesised that Vitamin K could play a role in COVID-19. We aimed to test the hypothesis that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls; and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 140 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional Vitamin K status in peripheral tissue. Fourty-three patients died within 90-days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low Vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.50, 95% CI: 1.03; 2.18). In conclusion, we found that low Vitamin K status predicted mortality in patients with COVID-19 supporting a potential role of Vitamin K in COVID-19.

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We conducted a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine was 1.11 (95% CI: 1.02, 1.20; I2=0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I2=0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine was associated with increased mortality in COVID-19 patients, and there was no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Evaluation of commercially available immuno-magnetic agglutination and enzyme-linked immunosorbent assays for rapid point-of-care diagnostics of COVID-19

IntroductionCoronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory coronavirus-2 (SARS-CoV-2). Fast, accurate and simple blood-based assays for quantification of anti-SARS-CoV-2 antibodies are urgently needed to identify infected individuals and keep track of the spread of disease. MethodsThe study included 35 plasma samples from 22 individuals with confirmed COVID-19 by real time reverse-transcriptase-polymerase-chain-reaction and 40 non-COVID-19 plasma samples. Anti-SARS-CoV-2 IgM/lgA or IgG antibodies were detected by a microfluidic quantitative immunomagnetic assay (IMA) (ViroTrack Sero COVID IgM+lgA /IgG Ab, Blusense Diagnostics, Denmark) and by enzyme-linked immunosorbent assay ((ELISA) (Eurolmmun Medizinische Labordiagnostika, Germany). ResultsOf the 35 plasma samples from the COVID-19 patients, 29 (82.9%) were positive for IgA/IgM or IgG by IMA and 29 samples (82.9%) were positive by ELISA. Sensitivity for only one sample per patient was 68% for IgA+IgM and 73% IgG by IMA and 73% by ELISA. For samples collected 14 days after symptom onset, the sensitivity of both IMA and ELISA was around 90%. Specificity of the IMA reached 100% compared to 95% for ELISA IgA and 97.5% for ELISA IgG. ConclusionIMA for COVID-19 is a rapid simple-to-use point of care test with sensitivity and specificity similar to a commercial ELISA.