Logic in the time of coronavirus

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This insight editorial in the Journal of Medical Microbiology examines COVID-19 through the prism of the priobe hypothesis, and uses an argument for causality as a means of identifying key research and development priorities in the campaign against SARS coronavirus 2 (SC2).

The article follows the fours steps in the priobe arguments:

  • congruence
  • consistency
  • cumulative dissonance
  • curtailment

Evidence can be found in the biomedical literature to support each of these stages in the priobe argument.

Additional commentary on SC2 and it’s disease; COVID-19, can be found at these links:

 

 

COVID-19 and SARS-CoV-2 viral load

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COVID-19 and SARS-CoV-2 viral load

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There has been a bit of discussion recently about the importance of viral load in the transmission and pathogenesis of COVID-19. Until the infectious dose of the SARS-CoV-2 virus has been determined, our understanding of the contribution of viral load to disease dynamics will be speculative.

Methods of measuring the amount of virus in patients are relatively crude. Nevertheless, there has been a small study of viral dynamics in mild and severe COVID-19 that support increasing viral load as infection progresses [1]. Higher figures were recorded in severe infections. But note; the measurement was based on SARS-CoV-2 viral RNA detection in a small cases series. Other studies have failed to demonstrate a correlation between viral load and severity, so the jury is still out on the issue. In another recent study, higher viral loads were found in the nose than in the throat and peaked around 10 days [2].

The reason viral load has come under scrutiny is that higher amounts of some other viruses that cause respiratory infection are known to increase the risk of transmission and increase disease severity [3]. Infectivity and severity are two different issues. Once established, the consequences of viral infection do not necessarily depend on the amount of virus involved at the initial encounter.

Disease severity in COVID-19 spans an extreme range from death due to acute respiratory distress syndrome, thrugh mild illness, to a complete lack of symptoms. In patients who recover from a mild illness, acquired immunity takes over control of the infection to help restore normality, while patients with more severe disease do not engage their acquired immunity until after their innate immunity goes into overdrive to cause a bystander effect [4]. Opinion is divided on whether this process is mainly due to viral features or to specific patient characteristics. Either way, the contribution of viral load is unclear.

From the limited evidence available, and experience with other coronaviruses, patients with severe disease need to be considered a high risk to those close to them, whether household contacts, carers or healthcare workers. But if high viral loads can be detected in asymptomatic infection, we may need to reconsider the load/severity concept [5]. Other aspects of encounter with SARS-CoV-2 have to be taken into account before we can develop a fuller concept of infectivity that goes beyond detectability.

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See also COVID-19, a reader, COVID 5 facts

References

  1. Liu Y, Yan LM, Wan L, Xiang TX, Le A, et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020 Mar 19. pii: S1473-3099(20)30232-2. doi: 10.1016/S1473-3099(20)30232-2.
  2. Zou L, Ruan F, Huang M, Liang L, Huang H, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med. 2020 Mar 19; 382(12):1177-1179. doi: 10.1056/NEJMc2001737.
  3. Granados A, Peci A, McGeer A, Gubbay JB. Influenza and rhinovirus viral load and disease severity in upper respiratory tract infections. J Clin Virol. 2017 Jan; 86:14-19. doi: 10.1016/j.jcv.2016.11.008.
  4. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017 Jul;39(5):529-539. doi: 10.1007/s00281-017-0629-x
  5. Kim ES, Chin BS, Kang CK, Kim NJ, Kang YM, et al.; Korea National Committee for Clinical Management of COVID-19. Clinical Course and Outcomes of Patients with Severe Acute Respiratory Syndrome Coronavirus 2 Infection: a Preliminary Report of the First 28 Patients from the Korean Cohort Study on COVID-19. J Korean Med Sci. 2020 Apr 6; 35(13):e142. doi: 10.3346/jkms.2020.35.e142.

A COVID-19 READER

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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.