COVID-19 is 2019’s unwanted legacy. Its trail of destruction has left governments and their public health machinery with a cloud of acronyms. The most notorious of these are SARS-CoV-2 and its disease manifestation, COVID-19.
A frenzy of acronyms
The three-letter acronym (TLA) is the lower-order entry point to a mature bureaucracy. You know you’re part of the in crowd when you can pepper your workplace conversation with TLAs. The higher you rise in the organisation, the longer the acronyms get. There is a linguistic efficiency in the use of these short forms. Call it laziness if you want to, but hard-pressed functionaries wield acronyms in verbal briefs and everyday conversation, as if their lives depend on it.
How long is a string?
The machinations behind the emergence, spread and diverse forms of disease we have come to know as COVID-19 are replete with a rich vocabulary of virological, pathophysiological, clinical and epidemiological terms that have been quickly reduced to their respective acronominal versions. Here we’ll resist the temptation to come up with an -al singing, -al dancing acronym that goes from virus to epidemic and back.
If we unwrap COVID-19, we recognise a form of disease, a type of virus and the year of origin all packed into one new alphanumeric string. The number hanging onto the end of COVID-19 is a bit sinister. It implies there might, conceivably, be another such disease at a currently undefined point in the future. Plausible, going from two other members of this disease family; SARS and MERS, which passed the entry level TLA 17 years ago.
Not counting the -19 suffix, the pandemic disease entity has gone even further and matured into a T2F (Type II FLA, or five letter acronym’). This raises an interesting linguistic question: how long can an alphanumeric string be before it ceases to function as a verbal short form? There must be a culminating point where brevity and rhythm of utterance are lost. Is the TLA the sweet spot? Does a four letter acronym (T1F) serve as well if it forms a single syllable?
The viral TLA
Which brings us to the virus itself: THE virus; the one everybody and their fur babies are talking about. That’s the novel coronavirus responsible for the COVID-19 pandemic. It’s hardly surprising that the general usage is ‘coronavirus’. It has a ring to it, and not just because it’s surrounded by a ring or corona of nasty adhesive spike proteins. Coronavirus is a proper word that trips off the tongue smoothly, without too much spatter or bioaerosol, unless you need to roll your Rs.
But SARS-CoV-2, the agreed virus designation, is a clumsy concatenation of short forms designed primarily for scientific accuracy; not for linguistic survival under intense worldwide use. Even if you get used to pronouncing the SARS component in its monosyllabic version, those two hyphens denote short pauses. This articulated ELA (yes, eight, not counting hyphens) has too many moving parts. Clunk-y.
Which is why those who deal with THE virus daily don’t use SARS-CoV-2 in normal speech. Its survival in the evolutionary bottleneck of contemporary language depends on its utility for written reports. Even that is in doubt. SARS-CoV-2 can be neatly reduced to a conventional TLA that captures all the information wrapped up in the scientifically correct eight-letter version.
That neat little TLA is “SC2”.
In the interests of brevity, the name of the virus responsible for COVID-19 should be reduced to a three letter acronym like SC2.
BLUF: there is growing interest in vitamin D supplements as a low risk intervention for COVID-19
Vitamin D and respiratory infection.
There is a long-standing interest in the value of vitamin D supplements in management of infectious diseases, particularly in influenza and other acute viral respiratory infections. Just over a decade ago, as the world learned to cope with pandemic influenza A/H1N1/09, a meta-analysis concluded that these claims were worth investigating in properly designed trials . More recent analysis of multiple studies supports the association between vitamin D deficiency and acute respiratory infection , and the use of vitamin D supplements to prevent acute respiratory infection .
Occurrence of COVID-19.
As the world began to recognise the gravity of COVID-19, a case was made for vitamin D supplementation as a potential antiviral intervention . The hypothesis that vitamin D deficiency might explain epidemiological features of the COVID-19 pandemic, was explored in detail. Grant and colleagues listed a series of reasons for their hypothesis:
the occurrence of the epidemic during the Northern Hemisphere’s winter when natural vitamin D synthesis is at its lowest
the lower number of cases in the Southern Hemisphere, then in summer
the association of vitamin D deficiency with acute respiratory distress syndrome
an increased case-fatality rate in the elderly and chronically diseased who are also prone to vitamin D deficiency
Vitamin D deficiency in Europe during COVID-19
Interest in using vitamin D to prevent progression from mild to severe COVID-19 has been raised further by discussion about the recent publication of the Irish Longitudinal Study into Ageing (TILDA) which specifically addresses COVID-19 . Finding that 13% adults over 55 years of age are deficient in vitamin D all year-round, they note that vitamin D supplements could be used for the at-risk elderly, particularly those being coccooned for their own protection. As the Irish population already has a low exposure to sunlight for much of the year, it is a logical recommendation. The authors note Finland’s elimination of vitamin D deficiency through an effective national policy. At the time of writing there have been 174 deaths and 5,364 COVID-19 cases reported from Eire (popn.; 4.9 million), compared to 28 deaths and 2,176 COVID-19 cases in Finland (popn.; 5.5 million). In an unreviewed pre-publication report, there was an interesting correlation between a population’s mean vitamin D levels, the number of cases and fatal COVID-19 infections . This preliminary data does not prove a causal association between vitamin D deficiency and infection, severe or otherwise. However, this observation merits closer study as the COVID-19 pandemic runs its course.
And where the sun does shine?
In sunnier climates, the benefit of vitamin D supplementation might not be so obvious. However, the high-risk elderly who are being coccooned indoors may not have sufficient sunlight exposure to sustain higher blood levels of vitamin D. In Australasia, where there are many of Anglo-Celtic and other northern European heritage, the not-quite-so-elderly may also choose to retreat indoors during the summer months to reduce their skin cancer risk. Now, with restrictions on outdoor movement and the autumn well under way, it is possible that there will be an unintended consequence of reduced natural vitamin D synthesis in the winter months if COVID-19 persists until then.
So, how might vitamin D supplementation help counter the COVID-19 threat? The benefit of vitamin D supplements against influenza and other viral respiratory infections appears to be quite widely supported, but evidence has yet to be presented for clinical benefit in COVID-19. It remains to be seen what can be prevented of disease, progression, complications and mortality. Any advance would be noteworthy.
In view of our current lack of approved, effective anti-coronavirus drugs with evidence-based indications, known dose-effect profile and proven efficacy, claims for low risk preventive and immunomodulatory interventions need close examination. The jury might still be out, but surely there is a good case for carefully designed clinical trials of vitamin D supplements for the over 60s and others at risk of high level exposure such as first responders, emergency department and intensive care unit staff during this time of COVID-19.
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 . 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 .
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 . 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 . 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 . 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.
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.
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.
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.
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
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.
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:
congruence: the point of convergence of molecular and cell biology, clinical features and community impact
consistency: the degree of repetition of the congruent features in subsequent case clusters
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
curtailment: demonstration of effective countermeasures at every stage of targeted intervention from diagnosis, through treatment to control and prevention
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.
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.
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.
an infectious disease attributed to the SARS-CoV-2 RNA virus
transmitted via droplets of respiratory secretions directly to close contacts, or indirectly via hands and subsequent facial contact, and possibly via contact with contaminated inanimate surfaces
most clinically apparent disease is limited to upper respiratory tract infections, but a minority will develop a potentially fatal lower respiratory infection
those most vulnerable to COVID-19 are the elderly, those with chronic cardiac or respiratory disease and diabetes
as no vaccine or specific antiviral treatment has been approved for use yet, preventive measures including rigorous hand hygiene, personal protective equipment, physical distancing and effective quarantine are the mainstay of the public health response
There’s something very sinister about a potentially fatal virus that doesn’t declare its presence with a decent set of symptoms until a week or more after contact. The thought that this virus might be lurking undetected while a serious infection is brewing gets in the way of practical conversations about when we need to do about it.
Now that we’re beginning to understand the immediate consequences of having no effective treatment or vaccine, people are starting to ask what we should do until that elusive vaccine puts a stop to this pandemic personification of SARS-CoV-2. It really doesn’t help that this virus can transform your close friends and family into a clear and present danger to your own health.
Submerged munitions. This coronavirus has adapted it genetic code to exploit every opportunity to improve its chances of spread among the human population before detection, just like mines submerged out of sight beneath the waves. No question of icebergs here; the virus is completely undetectable when it matters most. Straying into a minefield is not something you choose to do, but that is exactly what we risk doing if we blunder back to pre-pandemic normal without more permanent measures to inactivate the viruses we detect. It doesn’t seem that smart to wait for a second wave of cases, or even a steady trickle of sporadic cases before we act, as that looks like a step back to the reactive phase of the pandemic.
Sweeping the coronavirus minefield. The line the World Health Organisation took early in the pandemic emphasised the importance of high throughput testing to generate the data disease control specialists use to target their countermeasures. Wherever SARS-CoV-2 tests have been actively deployed, including adaptive testing of asymptomatic people, there have been disease control benefits. Admitted, physical distancing, barrier controls and disinfection are currently the sum total of our effective coronavirus countermeasures, but there is a limit to how long coronaviruses can last in a hostile inanimate environment without another unsuspecting victim. Clearance from human populations after the end of local transmission requires patience. In the absence of the minesweeping effect of antiviral treatment, we’re going to need a large measure of forbearance.
How long will this last? Spoiler alert: we’re going to be at this physical distancing and enhanced hygiene deal well beyond the next few months. Patience is a quality admired in others, but one we’ll hurry past in a dash to the finish. In a recent disease forecasting study, the most likely COVID-19 scenarios were explored on the assumption that effective antiviral therapy or vaccines won’t be widely available in the near future. While some nations have either dodged the worst of it, or put a brake on the initial wave of pandemic infection, a flatter curve is not the same as COVID-19 elimination. We’ll be hearing ‘Are we nearly there?’ from the back of the car for some time yet.
Making the journey a bit less dangerous. It’s becoming crystal clear that there’s no direct, through route to the post-COVID-19 uplands. For some, the worst dangers are past, but the way to an effective vaccine is unlikely be plain sailing. We’re going to learn a lot about this virus, how to live with it, and what needs adapting from the pre-pandemic normal. A previous analysis came up with an adversary profile that emphasised this unseen passenger that exploits the weakness of human behaviour and health administration. It follows that on the route out of the pandemic we will develop a finely tuned awareness of this disease, strongly founded on diagnostic test results, and guidance from disease control. It has been heartening to see what can be achieved when public health and their laboratory services co-ordinate their work. This is not a minesweeper competition to detonate as many mines as possible no matter what the collateral damage. Mine clearance needs a light touch, determination and patience.
It may not be the beginning of the end, but in parts of the world that are detecting fewer cases of COVID-19, it is starting to look like the end of the beginning. Maritime metaphors are in heavy demand. Maybe it’s the thought of returning to the beach, as some have already done. The storms that have just battered southern Australia are a rough reminder that nature is unpredictable. These events can come without warning, and may return in waves. You may have noticed talk of a second wave of COVID-19, after a calm interval.
Ebb tide or false dawn?
If a change is made to test criteria during the shift from response to pandemic recovery, it will affect the bottom line. The ebbing of COVID-19 cases is a real thing only as long as the basis of COVID diagnosis remains constant. But if case selection for laboratory tests change, it can introduce a bias that increases or reduces the odds in favour of detection. It sounds obvious when plainly stated: test everyone with symptoms and you should detect more positive cases than if you only test the sickest patients when admitted to hospital. Clearly, a higher percentage of hospitalised COVID-19 patients are likely to be positive than people who are well enough to stay at home. At the other extreme, inclusion of individuals who are positive without symptoms will add to the total while reducing the apparent mortality rate. This is why other figures can be much more instructive at this stage in the pandemic, as can be seen from metrics such as the effective reproduction number, the gradient of the epidemic curve and the number of days post-epidemic without cases. Experienced epidemiologists look at the whole data set from different angles, and identify trends with caution to avoid over-interpreting the data. No matter how much pressure to put a positive spin on the figures, we don’t want a false dawn.
Catastrophising is a national pastime
Too much time in lockdown fuels introspection and worst case scenario building in which the doomsayer’s prediction of oncoming disaster has the upper hand. The end of life as we know it has not, to the author’s knowledge, happened yet. Some would go so far as to say that the clear and present national threat has thrown us and our leaders together in ways you wouldn’t have picked four months ago. Yes, it is the responsible thing to plan for similar problems over the event horizon. Yes, even in Australia, that may include a second wave of COVID-19 going from the rate of SARS-CoV-2 mutation. But no, a potential second wave does not necessarily have to be a tsunami after the initial wave ebbs. The example so often stated is the 1918-19 influenza pandemic which was followed by a disastrous second wave of infections. Influenza belongs to a different virus family from the coronaviruses. In 1918 Europe was still embroiled in industrial scale warfare at the expense of the health and welfare of the civil population. And health care fell well short of the standards available today. SARS and MERS are much better precedents, though COVID-19 has its own unique features.
The cautious observer will stick to the firm sand between the high and low water marks. COVID-19 may well return in weeks to months, and might even return periodically as a result of continued virus mutation. But the apocalypse tomorrow scenario that came on the back of the northern hemisphere portion of the pandemic lacks plausibility. What we now need is decent mapping of COVID-19’s tidal reach, including the high water mark using properly validated laboratory tests, carefully planned survey methods and robust epidemiological analysis. There are plenty of anecdotal reports and small studies appearing in the rush to publish. Now that the early stages of the pandemic have passed, it should be possible to conduct studies that address some of the big questions about diagnosis, treatment, prevention and surveillance.
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:
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:
“If you know the enemy and know yourself, you need not fear the result of a hundred battles..” Sun Tzu
We need to know our enemy. In order to plan our return to normality, we need to consider the SARS coronavirus’s key attributes, and what makes up its centre of gravity.
COVID-19 is a disease caused by a new infectious agent; the SARS-CoV-2 coronavirus, for the sake of convenience shortened here to SC2. The disease, COVID-19, is the personified version of SC2, which is able to hijack its victims and turn them into coronavirus factories.
CENTRE OF GRAVITY
A key to understanding the connection between SC2, COVID-19 and all its human consequences is its prodigious transmissibility.
The word ‘transmission’ is made up of ‘trans-‘ (across) and ‘-mission’ (purpose, intent, expeditionary group). This combination signifies a dynamic process across space and time boundaries to recruit new individuals, communities, populations and even other species. Addition of ‘-ability’ denotes a notable feature of SC2, resulting in doubling of new cases in as little three days. This is SC2’s centre of gravity, summarised here as TRANS.
Key: CoG, centre of gravity; CCs, critical capabilities; CVs, critical vulnerabilities.
SC2 achieves its centre of gravity through a series of critical capabilities:
STEALTH. SC2’s capacity for undetected spread by people with asymptomatic infection, such as during the pre-symptomatic, and convalescent periods. Estimates of asymptomatic infection vary between 30 and 60% of SC2 test-positive people. A notable contributor is SC2’s ability to cause mild symptoms that may seem trivial to the index case, cand an interval of several days until more severe symptoms set in.
PASSENGER. A second key attribute of SC2 is its ability to exploit and target normal human behaviour including close personal contact, prolonged proximity, social aggregation, and easing of hygiene practices in familiar company. SC2 is not self-propelled.
3-D. SC2 exposes weaknesses in the organisation of healthcare delivery, including diagnostic, therapeutic, preventive, long term residential and surveillance services. As a consequence, SC2 exploits the slow rhythms of peacetime bureaucracy that place a dead hand on lean thinking. This attribute is highlighted where health services are stretched to their limits by high service demand, at great distance for long duration in our most vulnerable remote communities. These three dimensions of logistics give COVID-19 its freedom of action.
COVID-19 is vulnerable to countermeasures that target these critical capabilities.
INTELLIGENCE. STEALTH dictates that COVID-19 can be countered by early detection. This demands increased molecular diagnostic tests, a broadening of indications for testing to include people without any symptoms, and deployment of test capability closer to regional and remote communities. Early detection enables better targeting of control and containment efforts through laboratory evidence.
DISPERSAL. PASSENGER demands an increase in interpersonal distance among social, work and recreational groups. This requires a reduction in people density to individual level for extended periods to achieve a circuit-breaker effect.
LIGHTBULB. 3-D requires organisational agility, a scything elimination of bureaucratic complexity and adoption of lean thinking. SC’s freedom of action is vulnerable to just-in-time decisions that trigger actions within COVID-19’s three day doubling time. Timely solutions will do much for the most vulnerable remote communities.
In the current reactive stage of the COVID-19 response the current paradigm is largely one of containment. The main effort is about delay, denial, disconnection, disruption and defeat. Accepting that effective treatments and vaccines are at least months away, a comprehensive defeat of SC2 will have to be achieved by other means. The key priorities that come out of COVID-19’s centre of gravity assessment are:
increased SC2 test availability, throughput, geographic reach and repetition for the duration of the pandemic
increased interpersonal distance, reduced population density, interposition of multiple layers of personal hygiene and protective physical barriers
adaptive decision-making, supported by streamlined administrative support and just-in-time operational research