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From The New England Journal of Medicine
Therapeutic anticoagulation with heparin in critically ill patients with COVID-19: “The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio < 1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. Conclusions: In critically ill patients with COVID-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis.”
Therapeutic anticoagulation with heparin in non-critically ill patients with COVID-19: “The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high D-dimer cohort, 92.9% in the low D-dimer cohort, and 97.3% in the unknown D-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. Conclusions: In noncritically ill patients with COVID-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.
Subcutaneous REGEN-COV antibody combination to prevent COVID-19: “Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV (a combination of the monoclonal antibodies casirivimab and imdevimab) group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P < 0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. Conclusions: Subcutaneous REGEN-COV prevented symptomatic COVID-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load.”
Tofacitinib in patients hospitalized with COVID-19 pneumonia: “A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. Conclusions: Among patients hospitalized with COVID-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo.”
From The Lancet
Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): “The trial began enrolment on April 2, 2020, with randomisation to budesonide from November 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n = 1073), usual care alone (n = 1988), or other treatments (n = 1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2.94 days (95% Bayesian credible interval [BCI] 1.19 to 5.12) in the budesonide group versus the usual care group (11.8 days [95% BCI 10.0 to 14.1] vs 14.7 days [12.3 to 18.0]; hazard ratio 1.21 [95% BCI 1.08 to 1.36]), with a probability of superiority greater than 0.999, meeting the prespecified superiority threshold of 0.99. For the hospital admission or death outcome, the estimated rate was 6.8% (95% BCI 4.1 to 10.2) in the budesonide group versus 8.8% (5.5 to 12.7) in the usual care group (estimated absolute difference 2.0% [95% BCI –0.2 to 4.5]; odds ratio 0.75 [95% BCI 0.55 to 1.03]), with a probability of superiority 0.963, below the prespecified superiority threshold of 0.975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). Interpretation: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications.”
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): “Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57.8 years (SD 4.7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9.2 (one-sided 97.5% CI 7.5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0.51 (one-sided 97.5% CI 0.43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.”
Cerebral venous thrombosis after vaccination against COVID-19 in the UK: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32–55) was lower than in the non-VITT group (57 years; 41–62; P = 0.0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2–4) than non-VITT patients (two, 2–3; P = 0.041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; P = 0.0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; P = 0.0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; P = 0.0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; P = 0.022). Interpretation: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate.”
Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: “86 742 patients with COVID-19 were included in the SCCS study, and 348 481 matched control individuals were also included in the matched cohort study. When day of exposure was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 2.89 (95% CI 1.51–5.55) for the first week, 2.53 (1.29–4.94) for the second week, and 1.60 (0.84–3.04) in weeks 3 and 4 following COVID-19. When day of exposure was included in the risk period, IRR was 8.44 (5.45–13.08) for the first week, 2.56 (1.31–5.01) for the second week, and 1.62 (0.85–3.09) for weeks 3 and 4 following COVID-19. The corresponding IRRs for ischaemic stroke when day of exposure was excluded from the risk period were 2.97 (1.71–5.15) in the first week, 2.80 (1.60–4.88) in the second week, and 2.10 (1.33–3.32) in weeks 3 and 4 following COVID-19; when day of exposure was included in the risk period, the IRRs were 6.18 (4.06–9.42) for the first week, 2.85 (1.64–4.97) for the second week, and 2.14 (1.36–3.38) for weeks 3 and 4 following COVID-19. In the matched cohort analysis excluding day 0, the odds ratio (OR) for acute myocardial infarction was 3.41 (1.58–7.36) and for stroke was 3.63 (1.69–7.80) in the 2 weeks following COVID-19. When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 6.61 (3.56–12.20) and for ischaemic stroke was 6.74 (3.71–12.20) in the 2 weeks following COVID-19. Interpretation: Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. This indicates that acute myocardial infarction and ischaemic stroke represent a part of the clinical picture of COVID-19, and highlights the need for vaccination against COVID-19.”
From JAMA
Factors associated with use of and satisfaction with telehealth by adults in rural Virginia during the COVID-19 pandemic: “The 253 participants (183 women [77.87%]) had a mean (SD) age, of 52.41 (16.12) years; 135 participants (57.69%) were non-Hispanic White and 157 (70.72%) lived in rural areas. After March 2020, 102 participants (41.00%) reported telehealth use. Eighty participants (78.00%) were comfortable communicating with clinicians using telehealth, and 81 (79.00%) said they would use telehealth again. Some participants (69 participants [68.00%]) agreed that telehealth is an acceptable mode for health care delivery. Satisfaction among the 102 participants who used telehealth was associated with regular access to the internet (χ21 = 4.58; P = 0.03) and higher health literacy (χ21 = 5.02; P = 0.03) compared with those who were not satisfied. Factors significantly associated with higher odds of telehealth use included high health literacy (odds ratio, 2.93; 95% CI, 1.42–6.04) and perceived stress (adjusted odds ratio, 1.17; 95% CI, 1.05–1.31). No demographic differences were associated with telehealth satisfaction or use. Discussion: Utilization of and satisfaction with telehealth services in this sample were associated with regular internet access, higher health literacy, and greater perceived stress. Demographic variables were not significantly associated with use of telehealth. Limitation of this study are that the convenience sample has implications for generalizability, we did not differentiate between modalities of telehealth use, and health literacy was measured with a 1-item screener; however, this screener has been shown to reliably differentiate high vs low health literacy.6 Implementation of telehealth will continue after the pandemic, and our work highlights key considerations for rural residents to ensure that existing technology barriers are not exacerbated.”
SARS-CoV-2 antibody responses in infection-naive or previously infected individuals after 1 and 2 doses of the BNT162b2 (Pfizer/BioNTech) vaccine: “Among 59 participants, 29 (49%) were white individuals and 43 (73%) were female individuals. The mean (SD) age was 42 (12) years. Infection-naive participants (n = 30) had mean SARS-CoV-2 spike-RBD IgG levels at baseline of 4.03 AU/mL (95% CI, 1.92-6.13 AU/mL) and increasing to 1822 AU/mL (95% CI, 1266-2377 AU/mL) after 1 vaccine dose and to 15 005 AU/mL (95% CI, 12 533-17 476 AU/mL) after 2 vaccine doses. Previously infected individual’s (n = 29) mean IgG levels increased from 621.3 AU/mL (95% CI, 388.90–853.70 AU/mL) at baseline to 30 173 AU/mL (95% CI, 15 571–44 775 AU/mL) after 1 dose and 36 600 AU/mL (95% CI, 19 563–53 637 AU/mL) after 2 doses. Mean (standard error of the mean [SEM]) differences between second and first doses were 13 183 (1218) AU/mL (P < 0.001) in infection-naive participants. Mean (SEM) IgG differences were 6427 (10 876) AU/mL (P = 0.56) between second and first doses in previously infected individuals. Four previously infected participants reported a previous positive PCR but did not develop antibodies. Vaccine responses in these 4 participants resembled infection-naive individuals. Mean (SEM) antibody differences after 2 vaccine doses in infection-naive individuals compared with 1 and 2 vaccine doses in previously infected individuals were 15 168 (6963) AU/mL (P = 0.03) and 21 595 (7927) AU/mL (P = 0.009), respectively. Discussion: We observed higher SARS-CoV-2 antibody levels in previously infected individuals after 1 dose of BNT162b2 compared with infection-naive individuals after 2 doses. Importantly, in previously infected individuals with positive SARS-CoV-2 spike IgG levels, the second dose did not significantly increase IgG levels compared with the first dose, suggesting that 1 dose may be acceptable in this group. However, it is important to note that a positive PCR diagnosis alone was not enough to discount the need for a second vaccine dose. In 4 participants who reported a positive PCR, but did not develop S-protein antibodies, the response to the first vaccine dose was more similar to that of the infection-naive group. Furthermore, these results highlight that even in previously infected individuals, baseline serological testing should be performed prior to deciding whether to forego a second vaccine dose. This study highlights the potential for recommending a single dose for previously infected individuals and may be useful for discussions surrounding vaccination strategy.”
Myocarditis and pericarditis after vaccination for COVID-19: “Among 2 000 287 individuals receiving at least 1 COVID-19 vaccination, 58.9% were women, the median age was 57 years (interquartile range [IQR], 40–70 years), 76.5% received more than 1 dose, 52.6% received the BNT162b2 vaccine (Pfizer/BioNTech), 44.1% received the mRNA-1273 vaccine (Moderna), and 3.1% received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson). Twenty individuals had vaccine-related myocarditis (1.0 [95% CI, 0.61–1.54] per 100 000) and 37 had pericarditis (1.8 [95% CI, 1.30–2.55] per 100 000). Myocarditis occurred a median of 3.5 days (IQR, 3.0–10.8 days) after vaccination (mRNA-1273 vaccine, 11 cases [55%]; BNT162b2 vaccine, 9 cases [45%]). Fifteen individuals (75%; 95% CI, 53%–89%) were male, and the median age was 36 years (IQR, 26–48 years). Four persons (20%; 95% CI, 8%–42%) developed symptoms after the first vaccination and 16 (80%; 95% CI, 58%–92%) developed symptoms after the second. Nineteen patients (95%; 95% CI, 76%–99%) were admitted to the hospital. All were discharged after a median of 2 days (IQR, 2–3 days). There were no readmissions or deaths. Two patients received a second vaccination after onset of myocarditis; neither had worsening of symptoms. At last available follow-up (median, 23.5 days [IQR, 4.8–41.3 days] after symptom onset), 13 patients (65%; 95% CI, 43%–82%) had symptom resolution and 7 (35%; 95% CI, 18%–57%) were improving. Pericarditis developed after the first immunization in 15 cases (40.5%; 95% CI, 26%–57%) and after the second immunization in 22 cases (59.5%; 95% CI, 44%–74%) (mRNA-1273 vaccine, 12 cases [32%]; BNT162b2 vaccine, 23 cases [62%]; Ad26.COV2.S vaccine, 2 cases [5%]). Median onset was 20 days (IQR, 6.0–41.0 days) after the most recent vaccination. Twenty-seven individuals (73%; 95% CI, 57%–85%) were male, and the median age was 59 years (IQR, 46–69 years). Thirteen (35%; 95% CI, 22%–51%) were admitted to the hospital, none to intensive care. Median stay was 1 day (IQR, 1–2 days). Seven patients with pericarditis received a second vaccination. No patient died. At last available follow-up (median, 28 days; IQR, 7–53 days), 7 patients (19%; 95% CI, 9%–34%) had resolved symptoms and 23 (62%; 95% CI, 46%–76%) were improving. The mean monthly number of cases of myocarditis or myopericarditis during the prevaccine period was 16.9 (95% CI, 15.3–18.6) vs 27.3 (95% CI, 22.4–32.9) during the vaccine period (P < 0.001). The mean numbers of pericarditis cases during the same periods were 49.1 (95% CI, 46.4–51.9) and 78.8 (95% CI, 70.3–87.9), respectively (P < 0.001).”
From The BMJ
Diagnostic accuracy of rapid antigen tests in asymptomatic and presymptomatic close contacts of individuals with confirmed SARS-CoV-2 infection: “Of 2678 participants tested with Veritor, 233 (8.7%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 149 were also detected by the rapid antigen test (sensitivity 63.9%, 95% confidence interval 57.4% to 70.1%). Of 1596 participants tested with Biosensor, 132 (8.3%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 83 were detected by the rapid antigen test (sensitivity 62.9%, 54.0% to 71.1%). In those who were still asymptomatic at the time of sampling, sensitivity was 58.7% (51.1% to 66.0%) for Veritor (n = 2317) and 59.4% (49.2% to 69.1%) for Biosensor (n = 1414), and in those who developed symptoms were 84.2% (68.7% to 94.0%; n = 219) for Veritor and 73.3% (54.1% to 87.7%; n = 158) for Biosensor. When a viral load cut-off was applied for infectiouness (≥ 5.2 log10 SARS-CoV-2 E gene copies/mL), the overall sensitivity was 90.1% (84.2% to 94.4%) for Veritor and 86.8% (78.1% to 93.0%) for Biosensor, and 88.1% (80.5% to 93.5%) for Veritor and 85.1% (74.3% to 92.6%) for Biosensor, among those who remained asymptomatic throughout. Specificities were > 99%, and positive and negative predictive values were > 90% and > 95%, for both rapid antigen tests in all analyses. Conclusions: The sensitivities of both rapid antigen tests in asymptomatic and presymptomatic close contacts tested on day 5 onwards after close contact with an index case were more than 60%, increasing to more than 85% after a viral load cut-off was applied as a proxy for infectiousness.”
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