“Unprecedented” appears to be the term of the moment, its frequency of use by citizens, governments, health authorities and businesses, probably itself being unprecedented.

Whether through the presence of a new virus, or, through our reaction to it, the situation the world faces is indeed unprecedented, as countries across the globe go into lockdown to prevent further spread of Covid-19 and reduce deaths. Stringent measures were announced in the UK by Prime Minister Boris Johnson on Monday night, while Indian Prime Minister Narendra imposed a nationwide total lockdown yesterday.

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In France already draconian measures have been tightened even further with those who ‘break the rules’ subject to penalties. In Switzerland mobile phone data will be used to track individual’s movements to decide whether further restrictions are required.

Following on from last week’s science update, the ANH team has continued to monitor, assess, digest and analyse multiple streams of scientific and other information so we can bring you the most up-to date, relevant and accurate information on the current situation. Access to full scientific papers has been made easier by the decision of two of the largest publishers of peer-reviewed journals Springer and Elsevier to allow free access to articles relating to the pandemic.

One thing is clear, the situation is fast-paced and highly changeable, as different factions of society try to come to grips with the situation we find ourselves in, whether it’s linked to our own health risks or those of our loved ones, or the impacts the lockdowns and prevailing uncertainty have on our livelihoods and futures.   

Covid-19 symptoms

A question mark continues to sit over the proportion of people who might be asymptomatic or who have had such minor symptoms they've neither been tested nor have their symptoms been recorded by a medical doctor. The ongoing case analyses of confirmed cases by the World Health Organization (WHO) confirms that common symptoms of SARS-CoV-2 infection are a sore throat, high fever, headache, tiredness, dry cough, shortness of breath and breathing difficulty. Many patients are experiencing aches and pains as with any bad flu and some diarrhoea as well. These symptoms range in severity and are sometimes mild. Many people are recovering at home without the need for any specialist treatment. It's hard to say for sure, but it would seem that approximately 1 in 5 people become more seriously ill and require medical attention.

Diarrhoea is now being described as an early symptom of infection in a new paper published in the American Journal of Gastroenterology.

Losing sense of taste and smell (anosmia) can be another indicator of infection by the new coronavirus. In some cases this appears to be the only noticeable symptom of infection. The number of such ‘hidden’ carriers remains unknown and has been among the reasons being used to justify lockdowns. As with other respiratory viruses known to cause anosmia, the condition may persist long after infection has been eliminated.

A new app has been launched by UK-based Kings College London and Guy’s and St Thomas’ Biomedical Research Team to collect data allowing researchers to track the spread of COVID-19 and assess those most at risk. The app encourages users to share data whether you are well or ill. It will be available in the US from the 26^th March.

‘Test, test, test’* *(recall Dr Tedros Adhanom Ghebreyesus' statement, 16 March 2020)

High levels of testing in Iceland and the Italian city of Vò have shown that a high proportion of those tested showed no symptoms (asymptomatic), but were still carriers with the potential to infect others. A new modelling study from researchers at the University of Oxford suggests as much as 50% of the UK population has already been infected presenting a very different scenario to that of government advisors. Based on a ‘susceptibility-infected-recovered-model’ the researchers used data from the UK and Italy to build their model. The results of the study mean the UK population has already acquired substantial herd immunity through the unrecognised spread of the disease via asymptomatic carriers. This would also indicate the UK is experiencing peak infection now so potentially restrictions could be lifted far earlier than previously thought. Giving evidence to the UK's select committee on Science and Technology this week, Imperial College's Neil Ferguson revised predictions of 500,000 UK deaths from the virus to 20,000 given current restrictions on citizen's movements.

Given the possibility that a much higher proportion of the population have been asymptomatic and have acquired immunity (but not been tested), the currently widely reported fatality rates may be much higher than the real percentage. A new study of the Wuhan outbreak estimates the death rate was nearer 1.4%, which is substantially lower than previously thought.

The choice of denominator (the total number of cases of infection into which the fatalities are divided) is the key factor here. Even in the case of the influenza A pandemic of 2009 (‘swine flu’), subsequent analyses of published estimates of case rate fatalities varied hugely – from less than 1 to more than 10,000 deaths per 100,000 cases or infections. This denominator may be comprised only of laboratory-confirmed cases, it may or may not include cases diagnosed by symptoms, and it usually avoids including estimates for the number likely to be asymptomatic.

Once antibody testing becomes widely available, we will begin to have a much better idea of the extent of unknown, unconfirmed and asymptomatic cases.

Different ways of looking at the same thing

Following are grabs from two of the most commonly used portals used to track the pandemic, from the WHO and Johns Hopkins, respectively.

Source: WHO Situation Report 65, 25 March 2020

Source: Johns Hopkins Coronavirus Resource Center, 25 March 2020

It’s becoming increasingly clear to us that the graphical representations being used by the WHO (and used as a key authoritative source of information for the media) is grossly inadequate as any country simply gets marked with one large bubble. This way, cases in countries like the USA, Italy, Germany, Spain and China are all marked by the same sized bubble. The Johns Hopkins data, by contrast, shows in much greater granular detail the geographic location of embryonic loci of infection. Based on the location and extent of these in the USA, as well as the intrinsic susceptibility of the US population (e.g. age, underlying conditions, ACE-inhibitor usage), the US could easily become the country in the world in which the impact of COVID-19 is felt most severely. In this context, it will be interesting to see if Donald Trump’s ‘back to work’ plan is rolled out as quickly as the President would like.

Underlying conditions and drug use increase risk

In our science update last week, we explained the way the SARS-CoV-2 virus binds to ACE2 binding sites in the lungs. Many of those who have developed severe/fatal respiratory failure are taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) to treat underlying health conditions such as cardiovascular disease, which increase the number of ACE2 receptors in the cardiopulmonary system. The increased numbers of ACE2 receptors created by such commonly prescribed medications have been found to put patients at far higher risk of becoming seriously ill following COVID-19 infection.

Healthcare pressure

Healthcare systems are being brought to their knees by the sudden spike of patients with Covid-19. With healthcare workers struggling under the onslaught of seriously ill patients compounded by a lack of suitable equipment.

As healthcare systems become overwhelmed scientists are turning their attention to repurposing drugs, rather than creating new compounds. The WHO has launched a global megatrial called SOLIDARITY to test the use of existing drugs already deployed against HIV and malaria plus a new antiviral created to combat Ebola. The drugs under investigation are remdesivir, chloroquine and hydroxychloroquine, ritonavir/lopinavir, ritonavir/lopinavir + interferon. The normal rules of randomised controlled trials will be suspended in favour of speed.

Some scientists have heralded the anti-malarial drug choroquine (and its analogue hydroxychloroquine) as a ‘breakthrough’, subsequently referred to as a ‘game-changer’ ‘with tremendous promise’ by President Trump, in the fight against Covid-19, leading many to pin their hopes on them to treat coronavirus patients following publication of a cluster of positive studies. Like so many ‘magic pills’ sadly there’s a sting in the tail. Globally many people suffer from an enzyme defect called G6PD, which can cause those given chloroquine to become seriously ill. Whilst chloroquine poisoning is commonplace in countries where malaria is endemic.

Hence the stark warnings from some scientists, their concerns arising from an evaluation of all the available evidence. It is clear that serious even lethal toxicity-related side effects could easily arise given the narrow margin between therapeutic and toxic dosages, and there is potential for compromising the all-important adaptive (cellular) immune response which leads to incomplete viral clearance.

Best defence is protection

Despite the apparent resolve by governments and health authorities to be almost mute on the subject, a robust immune system remains the best way we know to guard against serious illness following infection, while also providing immunity to the novel coronavirus. A new Chinese study uncovers further detail of the human immune response to SARS-CoV-2 as well as confirming the vital role a healthy immune system plays in combatting such viral infections.

Coming as the northern hemisphere emerges from the winter months when vitamin D levels among so many are at their lowest, immunity will be compromised. Vitamin D deficiency is a known risk factor in the development of acute respiratory distress syndrome (ARDS) as a result of viral infection. ARDS is also the condition that is most likely to kill Covid-19 patients with serious illness. In this condition, the person’s lungs fill with fluid and can no longer provide sufficient oxygen to the body’s vital organs so organ failure and death result.

Big Tech gets a corona halo

Big Tech companies are being praised for their efforts to counteract coronavirus ‘fake’ news and limit access to information deemed harmful. In a joint statement Facebook, Google, Twitter, Microsoft, YouTube and LinkedIn said, “We are working closely together on Covid-19 response efforts”. Sadly, even high quality, valuable information relating to immune support is being targeted and downgraded in social media posts. This has been our experience and a reason why it's so important that you share this and other information you value, even if it's by email, word of mouth or other methods.

A natural winner

With the lockdowns implemented to reduce the spread of the virus comes indirect and positive benefits for the environment. Reductions in pollution, most notably nitrogen dioxide levels, are being seen in China, Italy, the UK and the US. However, experts are warning that the effects are temporary and will go back to pre-virus levels unless major changes are made to maintain the reductions in emissions. If nothing else, the pandemic gives us a useful insight into how changes to our behaviour can affect global emissions and climate change. It’s also more than ironic that a health emergency has shown its potential to do more for the climate emergency than actions that were specifically targeting the climate emergency.

One thing is sure. Life as we know it has changed forever. Many lessons need to be learnt from the crisis. From how healthcare is delivered, to the long-term financial impacts.

More unknowns

There is so much we still don’t know, but may soon learn. Among these things is the medium- to longer-term impacts of social distancing, especially when we know social isolation may increase systemic inflammation (a risk factor for chronic diseases) and domestic violence. But, in contrast to these negative effects, there are also many positive social effects, including the huge upsurge in neighbourly and charitable behaviour.   

Perhaps the greatest concern in the minds of many will be the medium- to long-term impacts on the economy and livelihoods, as well as what this all means for democracy and individual freedom.

While in lockdown, it might be useful for us to contemplate the social, economic and health implications that emerge when we consider the latest graphic from GlobalData’s latest Executive Briefing Report on asset prices as measured by various internationally-recognised indices. The recession we could be heading towards, if things don’t change soon, could well make the financial crisis of 2009 look like a minor hiccup that would have indirect social and health impacts that could greatly exceed those caused directly by Covid-19.

Gotya Gøtzsche!

Finally, we leave you (not for the first time) with some words from Professor Peter C. Gøtzsche, the Danish physician and medical researcher that was wrongly expelled from Cochrane, the evidence-based medicine organisation he co-founded. Among his 'sins' was evidencing that prescription medicines were the third leading killer in society and that organised crime exists within the pharmaceutical industry.

He continues to argue that mass panic is unjustified.

In his blog, Gøtzsche says:

"No such draconian measures were applied during the 2009 influenza pandemic. Consider also, that it is always winter somewhere, and we cannot close down the whole world permanently. So why now? Well, obviously, no one will ever get in trouble for measures that are too draconian. The epidemic will likely die out not so far from now, and then there will be a queue of people wanting to take credit for it."