A COVID-19 READER

Emerging Infectious Diseases (EIDs) trigger a scramble for new scientific insights to exploit in a co-ordinated public health response. The approach we have used for over a decade is to develop a systematic argument for causation, that links the proposed biological agent of infection with its effects and corresponding countermeasures. Building an argument for cause, effect and countermeasure is an iterative process of argumentation based on a series of four questions about key attributes:

  1. congruence: the point of convergence of molecular and cell biology, clinical features and community impact
  2. consistency: the degree of repetition of the congruent features in subsequent case clusters
  3. cumulative dissonance: a mechanistic understanding of how the biological agent and its effects escalate through increasing layers of biological organisation from the molecular level to the global community
  4. curtailment: demonstration of effective countermeasures at every stage of targeted intervention from diagnosis, through treatment to control and prevention

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For a keynote summary on COVID-19 click here.

Week ending 5th April, 2020.

CONSISTENCY (case clusters, modelling). Gilbert M., et al. Preparedness and vulnerability of African countries against importations of COVID-19: a modelling study.  Lancet. 2020 Mar 14;395(10227):871-877. doi: 10.1016/S0140-6736(20)30411-6. This study identified  countries with variable capacity to respond and high vulnerability. Several clusters of African countries were found to be at risk of imported COVID-19 from Guangdong, Fujian and Beijing.

CUMULATIVE DISSONANCE (disease progression). Chen W, et al. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity. Emerg Microbes Infect. 2020 Feb 26;9(1):469-473. doi: 10.1080/22221751.2020.1732837. In a small series, SARS-CoV-2 was found in blood from 6/57 and in anal swans from 11/28 patients. All those with coronavirus RNA detected in blood and 8/11 with positive anal swabs progressed to more severe disease.

COUNTERMEASURES. Shen C. et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Mar 27. doi: 10.1001/jama.2020.4783. This small trial of convalescent plasma treatment of severe COVID-19 used plasma with antibody binding tires of more than 1:1000 at 10-22 days after patient admission. Acute Respiratory Distress Syndrome resolved in 4/5  at 12 days after their transfusions, while three were weaned off their ventilators within two weeks. These preliminary observations need confirmation in prospective trials.

Week ending 29th March, 2020.

Before we pick up the EID causality lens, let’s take a look at key questions that should drive operational research efforts in the coming months [Yuen K-S et al. SARS-CoV-2 and COVID-19: The most important research questions. Cell & Biosci 2020 10:40]

  1. How SARS-CoV-2 is transmitted currently in the epicenter of Wuhan
  2. How transmissible and pathogenic is SARS-CoV-2 in tertiary and quaternary spreading within humans.
  3. The importance of aymptomatic and presymptomatic virus shedding in SARS-CoV-2 transmission
  4. The importance of fecal-oral route in SARS-CoV-2 transmission.
  5. How COVID-19 should be diagnosed and what reagents should be made available.
  6. How COVID-19 should be treated and what treatment options should be made available.
  7. Whether inactivated vaccines are a viable option for SARS-CoV-2.
  8. The origins of SARS-CoV-2 and COVID-19.
  9. Why SARS-CoV-2 is less pathogenic.

We should bear these in mind as we pick through the recent literature.

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Principia aetiologica.

Logic in a time of coronavirus.

CONGRUENCE (molecular biology). Rehman SU et al. Evolutionary trajectory for the emergence of novel coronavirus SARS-CoV-2. Pathogens 2020, 9 (3) pii: E240. This study used whole genome sequencing to show how SARS-CoV-2 is the likely descendant of bat SARS viruses, and uses mutation and recombination events in parts of the viral genome to change envelope, membrane, nucleocapsid and spike glycoproteins to become a novel infectious agent. Multiple recombinations in the S gene were detected. These are thought to improve survival and adapt to a human host.

CONSISTENCY (case clusters). Chan JF et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020; 395: 514-23. This a key case-cluster report from Wuhan in the early stages of the pandemic, and therefore a good place to start assessing the consistency of clinico-pathological and epidemiological features in subsequent clusters.

CUMULATIVE DISSONANCE (mechanism of pathogenesis). Hoffmann M et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Mar 4. pii: S0092-8674(20)30229-4. Entry of SARS-CoV-2 relies on binding of viral spike proteins to cell surface receptors and subsequent priming by enzymes called proteases. This could help identify possible future treatments. This study showed that SARS-CoV-2 uses an ACE2 receptor to enter mammalian cells and then primes its spike protein with a protease. The study also showed that serum from convalescent patients neutralised SARS-2-S-driven cell entry.

CURTAILMENT (targeted countermeasures). Peto J. COVID-19 mass testing facilities could end the epidemic rapidly. BMJ 2020; 368: m1163. This is an interesting proposition that mass screening, performed on more than one occasion could be used to bring the UK’s national COVID-19 epidemic to an end more quickly and cheaply than a vaccine. The argument revolves around using RT-PCR assays as the key enabler for mass rapid diagnosis and subsequent control.