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By Christian Hoffmann &
Bernd S. Kamps
23 May
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Summary
First, continue following the antiviral saga. You’ll finally read the ‘preliminary report’ of a study that randomized 1,063 COVID-19 patients to receive remdesivir or placebo. (Remember: the data were pre-announced three weeks ago during a hastily arranged press conference in the wake of the publication of a study by Wang and collaborators who found no clinical benefit for remdesivir in a randomised, double-blind, placebo-controlled, multicentre trial (The Lancet: Wang 2020)). The preliminary report, now published in the New England Journal of Medicine, suggests that remdesivir may shorten the time to recovery in hospitalized adults by a few days. Mortality was somewhat but not significantly lower in patients who received remdesivir.
Afterwards, simulate three transmission modes including close contact, respiratory droplets and aerosol routes in naive h ACE2 mice; publish the cryo-electron microscopic structure of the SARS-CoV-2 RdRp in its active form; evaluate different DNA vaccine candidates expressing different forms of the spike protein in 35 rhesus macaques in regard to neutralizing antibody titers; discuss with your colleagues the administration of thymosin alpha 1 (subcutaneous injections of 10 mg) to 76 patients with severe COVID-19; describe clinical characteristics, imaging findings, and outcomes among 24 patients who presented with acute hypoxemic respiratory failure; explore why immunity passports are a bad idea; present clinical data from 20,133 patients, admitted to (or diagnosed in) 208 acute care hospitals in the UK until April 19, and discuss overall mortality (26%) and mortality of patients admitted to high-dependency or intensive care units (32%) and of those who received mechanical ventilation (37%).
Finally, investigate viral and host factors related to the clinical outcome of COVID-19. You’ll find that up to now, different viral clades did not exhibit significant difference in clinical features, mutation rate or transmissibility. However, lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts, was predictive of disease progression. High levels of IL-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age, lymphocytopenia, and its associated cytokine storm.
Epidemiology
Kofler N, Baylis F. Ten reasons why immunity passports are a bad idea. Nature 2020, 581, 379-381. Full-text: https://doi.org/10.1038/d41586-020-01451-0
Forget the COVID pass! During the past weeks, we have shared several reasons why immunity passports are a bad idea. This commentary provides 10 more reasons. Restricting liberty on the basis of biology threatens freedom, fairness and public health.
Haushofer J, Metcalf JE. Which interventions work best in a pandemic? Science 21 May 2020: eabb6144. Full-text: https://doi.org/10.1126/science.abb6144
Randomized controlled trials can be used for non-pharmaceutical interventions. Surprisingly they have received little attention in the current pandemic, despite a long history in epidemiology and social science. In this interesting commentary, authors describe how RCTs can be practically and ethically implemented in a pandemic, how compartmental models from infectious disease epidemiology can be used to minimize measurement requirements, and how to control for spillover effects and harness their benefits.
Virology
Hillen HS, Kokic G, Farnung L et al. Structure of replicating SARS-CoV-2 polymerase. Nature 2020. Full-text: https://doi.org/10.1038/s41586-020-2368-8.
The cryo-electron microscopic structure of the SARS-CoV-2 RdRp in its active form, mimicking the replicating enzyme. Long helical extensions in nsp8 protrude along exiting RNA, forming positively charged ‘sliding poles’. These sliding poles can account for the known processivity of the RdRp that is required for replicating the long coronavirus genome. A nice video provides an animation of the replication machine.
Zhang X, Tan Y, Ling Y, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature (2020). Full-text: https://doi.org/10.1038/s41586-020-2355-0
Viral variants do not affect outcome. This important study on 326 cases found at least two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Patients infected with these different clades did not exhibit significant difference in clinical features, mutation rate or transmissibility. Lymphocytopenia, especially a reduced CD4+ and CD8+ T cell counts upon admission, was predictive of disease progression. High levels of IL-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age, lymphocytopenia, and its associated cytokine storm.
Yu , Tostanoski LH, Peter L, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 20 May 2020. Full-text: https://doi.org/10.1126/science.abc6284
A series of different DNA vaccine candidates expressing different forms of the spike protein were evaluated in 35 rhesus macaques. Vaccinated animals (especially those receiving a vaccine encoding the full-length spike protein) developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans. Protection was likely not sterilizing but instead appeared to be mediated by rapid immunologic control following challenge.
Transmission
Bao L, Gao H, Deng W, et al. Transmission of SARS-CoV-2 via close contact and respiratory droplets among hACE2 mice. J Inf Dis 2020, May 23. Full-text: https://doi.org/10.1093/infdis/jiaa281
Using ACE2 mice, authors simulated different transmission modes. Close contact and droplets worked better than aerosol exposition. Animals could not be experimentally infected via aerosol inoculation until continuous exposition for up to 25 min even with high virus concentrations.
Clinical
Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020 May 22. Full-text: https://doi.org/10.1136/bmj.m1985
Clinical data from 20,133 patients, admitted to (or diagnosed in) 208 acute care hospitals in the UK until April 19. Median age was 73 years (interquartile range 58-82) and 60% were men. Comorbidities were common, namely chronic cardiac disease (31%), diabetes (21%), non-asthmatic chronic pulmonary disease (18%). Overall, 41% of patients were discharged alive, 26% died, and 34% continued to receive care. 17% required admission to high dependency or intensive care units; of these, 28% were discharged alive, 32% died, and 41% continued to receive care. Of those receiving mechanical ventilation, 17% were discharged alive, 37% died, and 46% remained in hospital. Increasing age, male sex, and comorbidities including chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease and obesity were associated with higher mortality in hospital.
Severe COVID-19
Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in Critically Ill Patients in the Seattle Region — Case Series. N Engl J Med 2020, May 21; 382:2012-2022. Full-text: https://doi.org/10.1056/NEJMoa2004500
This report describes clinical characteristics, imaging findings, and outcomes among 24 critically ill COVID-19 patients who presented with acute hypoxemic respiratory failure in the Seattle metropolitan area. Mortality was high (at least 50%, three patients still intubated at last follow-up).
Treatment
Beigel JH. Tomashek KM, Dodd LE. Remdesivir for the Treatment of Covid-19 — Preliminary Report. NEJM 2020, May 22. Full-text: https://doi.org/10.1056/NEJMoa2007764
It took almost a month to publish this eagerly awaited paper: does remdesivir work? Yes, in some patients. The conclusion of this double-blinded study that randomized 1,063 COVID-19 patients throughout the world to the drug or to placebo, was remarkably short: “Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection”. Median recovery time was 11 versus 15 days. The benefit was most apparent in patients with a baseline ordinal score of 5 (requiring oxygen but no high-flow oxygen). In patients requiring mechanical ventilation or ECMO, there was no effect at all (although the numbers were low). Gender, ethnicity, age or symptom duration had no impact. The Kaplan-Meier estimates of mortality at 14 days were 7.1% and somewhat (not significantly) lower with remdesivir compared to 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). This is, however, preliminary. The full analysis of the entire trial population will occur soon, although more comparative data may be hard to find as all patients were rolled over to the active agent at this point in the study.”
Liu Y, Pang Y, Hu Z, et al. Thymosin alpha 1 (Tα1) reduces the mortality of severe COVID-19 by restoration of lymphocytopenia and reversion of exhausted T cells. Clinical Infectious Diseases 2020, May 22. Full-text: https://doi.org/10.1093/cid/ciaa630
In this study of 76 patients with severe COVID-19, Tα1 supplement (subcutaneous injections of 10 mg) appeared to reduce mortality, especially in those with low CD4 and CD8 cell counts. This immunomodulating thymic peptide reversed T cell exhaustion and recovers immune reconstitution through promoting thymus output during SARS-CoV-2 infection. However, this is uncontrolled retrospective data and results should be interpreted with caution.