Simon O'Neill's update on Coronavirus (July 2020)

Tony from the DUK group in Brighton hosted a zoom meeting last week with great success. The session featured a talk from Simon O’Neill who is Director of Health Intelligence and Professional Liaison at Diabetes UK. He talked about Covid-19 and diabetes, followed by a Q&A where he was able to help bust some of the myths around the topic. Below is copy of Simon’s more detailed report for anyone interested.
 

Simon O’Neill – Health Intelligence

July 2020

Update on Coronavirus

We are all very aware of severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the disease it causes – COVID-19, which has had such a huge global impact. At the time of writing 10,890,511 people have been diagnosed (which will be a huge underestimate of the people who have been infected, as many will not have been tested for the virus) and 521,694 people have died (again, an underestimate as this figure does not include those who have died without being tested).

We are probably also all aware of the fact that people with diabetes seem to have a worse response to the disease, with around a third of all deaths being in people with diabetes. In this report I want to bring together some of the more recent research and to highlight some of the challenges that SARS-CoV-2 is bringing for people with diabetes.

Early research
There is some evidence to suggest that people with diabetes, if particularly poorly controlled, may be more susceptible to infection due to the impact of hyperglycaemia on the immune system. This may well be true in the case of coronavirus, though this has not been proved, but of more concern is that people with diabetes tend to have worse outcomes from such viruses. This was seen in the earlier outbreaks of SARS and MERS (other coronaviruses), where people with diabetes were more commonly hospitalised and died.

Much of the research on coronavirus has been based on those who have developed COVID-19 and been hospitalised so gives a somewhat skewed overview of how the virus actually affects the
majority of people with diabetes who contract it. Some studies suggest that up to 86% of all people infected show no symptoms. We are aware of people with diabetes who have contracted the virus, had only mild symptoms and fully recovered and this is likely to be true for the majority, particularly for younger people. The early research was also largely based on retrospective observational studies on groups of patients and most of the research published has not been peer reviewed. Early studies seemed to show a larger number of people with diabetes being admitted to hospital than would be expected. For example, one study in New York looking at 4,103 people diagnosed with COVID-19 showed that nearly half of them ended up in hospital. 15% of the 4,103 had diabetes (compared with a general prevalence of 10.5% in the US) but 80% of those ended up being hospitalised. Most early studies seem to show that about 20-30% of people admitted to hospital with COVID-19 had diabetes. What the studies don’t clarify though is whether they were hospitalised because of COVID-19 symptoms or because of diabetes related issues such as DKA or HHS. 

Other factors may also play a part. The large percentage of people with diabetes being admitted to hospital may actually reflect several issues, particularly the high rates of diabetes in some countries and some specific populations (prevalence in China is up to 14.7% of the population and, in the US, diabetes affects about 22% of the American Hispanic population). It may also reflect that there are more people with diabetes in the lowest socioeconomic groups, where COVID-19 seems to be having a greater impact. 

Another suggestion is that people with diabetes may respond differently initially to SARS-CoV-2 infection. It is known that people with diabetes are more likely to have ‘silent’ CVD with 1 in 3 having no obvious symptoms (compared with 1 in 5 of people without diabetes) and nearly 20% of heart attacks being symptomless. The theory in COVID-19 is that people with diabetes may initially have milder symptoms which then mask the severity of the infection. In one study people with diabetes were less likely to experience fever (59.5% vs 83.2%), chills (56.8% vs 71.5%), chest tightness (13.5% vs 29.2%), and shortness of breath (13.5% vs 27%). The suggestion is that this lack of symptoms may cause a life-threatening delay in providing the needed care, finally resulting in poorer prognosis.

More recent UK based research

More recently some large studies have been published based on the UK population. Although not peer reviewed, they have used large datasets.
One study (Docherty, AB et al.) looking at 16,749 people in hospitals in England, Wales and Scotland, with diagnosed COVID-19, found that 33% of the whole cohort died during the period of the study. The main factors associated with in-hospital death were age once adjusted for comorbidity (median age was 80) and existence of comorbidities (88% had a comorbidity). Those who were admitted to ICU had worse outcomes – with 45% having died following admission. For those who needed mechanical ventilation 53% died – though interestingly these were a younger cohort (median age of 61) which may suggest that clinical decisions were being made regarding the elderly frail and the benefit of ventilation vs the risk and likely outcome.
Only 2% of this group were under the age of 18, highlighting that this is a disease which disproportionately affects the older population. Older age decreased the chance of survival, after adjusting for comorbidities. Compared with someone aged 50 or less, those aged 50-69 had a four times greater risk of dying, a 9.5 times greater risk if 70-79 and a 13.5 times greater risk if over 80.
Another study (Barron, E. et al) looked at a population of 61,414,470 individuals in England of whom 263,830 (0∙4%) had a recorded diagnosis of type 1 diabetes, 2,864,670 (4∙7%) of type 2 diabetes and 41,750 had other types of diabetes (0∙1%). Within this population there were 23,804 COVID-19 related deaths in hospital settings. One third occurred in people with diabetes: 7,466 (31∙4%) with type 2 and 365 (1∙5%) with type 1 diabetes. Other types of diabetes accounted for 69 (0∙3%).

After adjusting for age, sex, ethnicity, socioeconomic deprivation and region, people with type 1 diabetes were at three and a half times the risk of in-hospital death with COVID-19, while people with type 2 diabetes had double the risk, compared to people without a diagnosis of diabetes. Further adjustment for diagnosed cardiovascular comorbidities attenuated these risks slightly but after adjustment, there was still an additional risk of 186% for people with type 1 diabetes and 81% for those with type 2 diabetes compared to people without diabetes.

However, age was still the dominant risk factor for in-hospital death with COVID-19 and had a much greater influence on risk than diabetes status, sex, ethnicity or socioeconomic deprivation. Even with the additional risk associated with type 1 diabetes or type 2 diabetes, people under the age of 40 years with either type of diabetes were at very low absolute risk of in-hospital death with COVID-19 and there is a 700-fold difference in risk between those aged under 40 compared to those over 80.

The most relevant research in terms of diabetes was a paper specifically looking at outcomes for people with diabetes who caught the virus. The paper looked at an overall population of 265,090 people with Type 1 diabetes and 2,889,210 people with Type 2 diabetes living in England covered by the National Diabetes Audit and included ethnicity, diabetes control (HbA1c), age, deprivation, renal function and previous hospital stay for stroke or heart failure. As this used data from death certificates, it included all deaths from COVID-19, where this was included on the death certificate but was not limited to deaths in hospitals.
There were 418 deaths in people with type 1 and 9,377 deaths in people with type 2. Because this doesn’t use comparator data, it can’t tell us how much more likely someone with diabetes is to die than someone without diabetes but it can identify those at highest risk of death in both type 1 and type 2 diabetes. Using this baseline, it suggested that about 0.15% of all people with type 1 and about 0.32% of all people with type 2 had died as a result of coronavirus.

Age was the main factor, with 39.7% of deaths in type 1 being in people aged over 80 and this rising to 55.7% in type 2. In people under 40 years of age, the number of deaths was less than 0.2%.
In both types of diabetes, about a third of deaths were in women, showing that men were at higher risk. Also social deprivation appeared to play a part with almost three times more deaths in the most deprived compared with the least in type 1 and twice as many deaths in type 2.

People from Asian and Black backgrounds with type 1 diabetes were 68% and 79% more likely to die, though this is less the case in type 2 diabetes, where there appears to be an increased risk of death mainly in Black people (63% increased risk) whereas the increased risk is only 9% in Asian people.

A quarter of the deaths in type 1 occurred in people with an HbA1c less than 58mmol/mol (7.5%) but deaths rose as HbA1c increased, though this was less marked in type 2. People with type 1 and an HbA1c over 85mmol/mol (10%) were twice as likely to die as those with good control and for type 2 there was a 62% increased risk. Those people who also had renal impairment, heart failure or stroke were also more likely to die.

A different paper also noted an increased risk in people who had been hospitalised with DKA or hypoglycaemia in the past 5 years as well as in those with retinopathy whether referable or not.
Because most of these papers are looking at people who die as a result of COVID-19, there is little positive data to reassure people with diabetes, other than the fact that the actual numbers of deaths is relatively small. However, a paper from France4, although very similar in outcomes to the UK papers, did highlight one positive result.

Of 1,317 people with diabetes hospitalised with COVID-19, although 140 had died within 7 days of admission, 237 had been discharged from hospital which shows that hospital admission with COVID-19 isn’t necessarily a death sentence.

An as yet unpublished paper from Scotland5 has also shown that out of a total population of 319,352 with diabetes in the SCI-DC database, 1,943 people had had a positive test for SARS-CoV-2. There were a further 240 people with diabetes with COVID-19 mentioned on their death certificate. Thus, overall 0.7% (7 in a 1,000) of those with diabetes had any detected SARS-CoV-2 (although presumably they had shown symptoms and had gained access to a test. More people may have been infected but never became ill enough to be tested). Altogether, there have been 744 COVID-19 deaths; (27 in type 1 diabetes, 700 in type 2, with 17 deaths being in other or type unknown diabetes) which is about 2 in 1,000 people with diabetes. This suggests that the majority of people with diabetes who test positive for SARS-CoV-2 will survive the infection.

Theories about why it affects people with diabetes

So far this isn’t clear why people with diabetes seem to fare so badly, but various theories have been proposed. Further research will need to be done to see whether these are correct.
One fairly widespread early theory was that people on ACE inhibitors and ARBs (both common medicines to treat blood pressure) might have been more at risk. Many people with diabetes will be on these as blood pressure control is important in diabetes and ACE inhibitors are also used to protect the kidneys in early stage renal failure.

It is understood that the SARS-CoV-2 virus binds to the cells they target through angiotensin-converting enzyme 2 (ACE2), which is found particularly in cells in the lung, intestine, kidney, pancreas and blood vessels. People who are treated with ACE inhibitors and ARBs make more ACE2 as do people treated with TZDs (a drug used in diabetes) and ibuprofen. The theory therefore went that, because they are producing more ACE2s, this could increase the risk of COVID-19 taking hold more strongly, as there are more cells to target.

However, more recent research seems to refute this theory. Several papers from China have examined the severity of infection and mortality in people with hypertension and COIVD-19. Although hypertension itself appears to be a risk factor, there was no difference in either severity of infection or death rates in those taking ACEi or ARB compared with those on no blood pressure medication or other types of anti-hypertensives. More recent and larger studies from the US and Italy also support the supposition that these medications can be taken safely even with COVID-19 which appears to support the recommendations of most major cardiovascular societies to remain on these drugs. In fact some studies have even suggested that the opposite may be true and those on ACEi and ARB may have better survival rates.
Another theory, based on experience with influenza infection, has suggested that COVID-19 might lead to an inflammatory cytokine storm in people with diabetes leading to rapid deterioration in COVID-19. As our Research team described it - cytokines are small proteins which carry messages to our immune system, either telling it to ramp up and help fight infections and invaders, or to wind down. If levels of cytokines which raise our immune systems’ defences become too high it can cause the immune system to go into overdrive. Instead of just tackling an infection, this storm can damage healthy tissue and lead to people becoming really ill. One small study suggested that people with diabetes were at higher risk for severe pneumonia, release of tissue injury-related enzymes, excessive uncontrolled inflammation responses and a greater tendency for the blood to clot, all of which combined to give worse outcomes.

Another study has proposed that COVID-19 may also directly attack the pancreatic beta cells, causing blood glucose levels to rise as less insulin can be produced in relation to the stress of infection, when it is needed. They noted that 29.2% of the people with diabetes who were already taking insulin before had to increase the dose of insulin after admission, and 37.5% who took oral medicine before admission had to start on insulin after admission, which meant that patients had poor glycaemic control during hospitalization. The reason they think COVID-19 could be attacking the islets comes from studies after the SARS epidemic where high levels of ACE2 were found in the islets but not the rest of the pancreas – linking back to the previous paragraph on ACE inhibition.

One simpler suggestion is linked to the fact that COVID-19 tends to cause serious disease in older people and older people are more likely to have diabetes. The IDF Atlas (2019) showed that around 1 in 5 people over the age of 69 has diabetes (predominantly type 2). Furthermore, diabetes in older age is associated with cardiovascular disease, which in itself could help to explain the association with fatal outcomes of COVID-19.

COVID-19 causing diabetes

One impact of COVID-19 infection is new cases of diabetes, often presenting in ketosis. Although the exact numbers affected aren’t yet know, in one small study from China, of 42 people presenting with COVID-19 and ketosis, 65% had no previous diagnosis of diabetes.

We know that diabetes is often precipitated by a stressful event, such as a severe infection. The natural stress response can raise blood glucose levels and, in people susceptible to diabetes, this can be the ‘last straw’. In those who are already producing less insulin or are very insulin resistant, they are unable to produce enough insulin to manage the hyperglycaemia and symptoms of diabetes may develop. So some of the new cases of diabetes may be in those who were going to develop diabetes at some point in time anyway – but others seem to be purely related to the COVID-19 infection. This phenomenon was also seen in SARS.
One possible explanation is that because SARS-CoV-2 binds to ACE2 receptors, which are expressed in key metabolic organs and tissues, the virus itself may cause changes in the way glucose is metabolised which could lead to new cases of diabetes. What is clear is that these COVID-19 related cases may experience DKA and HHS and require exceptionally high doses of insulin. They also have no previous history of diabetes and a normal HbA1c, suggesting rapid onset. These manifestations of diabetes pose challenges in clinical management and suggest a complex pathophysiology of COVID-19 related diabetes.

What isn’t clear is whether this diagnosis of COVID-19 related diabetes is transitory or whether it resolves when the person overcomes the infection. In some cases this is certainly the case, and insulin doses have to be dropped or stopped to avoid hypoglycaemia as the person recovers.

An international group of scientists have now set up a global registry to gather data on this new type of diabetes to answer a series of questions:
 How frequent is the phenomenon of new-onset diabetes?
 Is it classic type 1 or type 2 diabetes or a new type of diabetes?
 Do these people remain at higher risk for diabetes or diabetic ketoacidosis in the future?
The hope is that this will help decide on the best care for people with COVID-19 related diabetes (and indeed for those with pre-existing diabetes) and may also uncover novel mechanisms of disease.

Treatments

People with diabetes who develop any infection should follow the sick day rules and continue taking their normal medication. However, it is recommended that they should stop taking SGLT2 inhibitors (the ‘flozin’ tablets) if they become unwell, as these can increase the risk of developing DKA or HHS.

People with diabetes admitted to hospital will certainly have their SGLT2i stopped, as well as metformin initially, until lab results can show that it is safe to continue with this. Depending on blood glucose levels, people who normally manage their diabetes with tablets may be put on insulin. We also know that often very large amounts of insulin are needed to keep blood glucose under control, up to 20 units an hour in some cases.

In terms of managing COVID-19, the European Medicines Agency has just approved remdesivir for use in adults and adolescents from 12 years of age with COVID-19 induced pneumonia who require supplemental oxygen. This has been fast tracked, which is allowed when the benefit of a medicine’s immediate availability to people outweighs the risk inherent in not yet having all the data normally required.

Remdesivir is a broad spectrum anti-viral drug. In small trials, it was found that a five-day treatment course on top of standard care was more effective than standard care alone at achieving a significant improvement in symptoms in moderately-ill patients. However, it was announced this week that the USA have apparently bought up nearly all supplies of the drug so it is unlikely to be available in Europe for at least 3 months.
Dexamethasone is a corticosteroid which has been in use since the 1950s for a variety of conditions, such as rheumatic problems, skin diseases, severe allergies, asthma and chronic obstructive lung disease. A recent trial looking at its use in people with COVID-19 found that taking 6mg per day for 10 days reduced deaths by one-third in ventilated patients and by one fifth in other patients receiving oxygen only. There was no benefit among those people who did not require respiratory support.
The advantage of this is that it is a cheap, generic drug and should therefore be readily available. However, for people with diabetes, corticosteroids can cause insulin resistance and reduce insulin production and are the commonest cause of life threatening inpatient HHS in people with type 2 diabetes. Add that to the similar effects caused by COVID-19 itself, and there is a high risk for DKA and HHS. People who normally take sulphonylureas need to stop these and most people will need to be managed with insulin while taking dexamethasone. After the treatment is stopped, insulin requirements normally decrease.

The other drug people are very interested in is a potential vaccine to prevent SARS-CoV-2. More than 100 companies around the world are working on this as a matter of urgency. Two UK centres are currently working on vaccines. Oxford University, working with AstraZeneca, are currently in Phase 3 trials of their vaccine. Trials are taking place across the UK, South Africa and Brazil and they are planning to enter another 10,000 people in to the research. The second vaccine has been developed by Imperial College London and is in the earliest stages, with Phase 3 trials expected later in the year.

Realistically, though, we are unlikely to have an effective vaccine in place within the next 12-18 months. Vaccine research normally takes time and the record for the fastest development of a vaccine currently stands at 4 years. However the researchers are certainly fast-tracking this.

Challenges for BAME

The UK is one of the first countries with widespread coronavirus cases that is ethnically diverse. What has become clear is that people from BAME backgrounds are more susceptible to developing serious COVID-19 than their white peers, with a third of people admitted to ICU being from a BAME background.
In terms of deaths, after adjusting for region, population density, socio-demographic and household characteristics, people of Black ethnic background of all ages had double the risk of death for males and 1.4 times greater for females compared with those of white ethnic background. South Asian males had a 1.6 greater risk of death while for South Asian women, the risk was the same as in white women.

For those with diabetes, their risk of dying was higher when compared with white people with diabetes, as previously mentioned.

The reason for the increased risk isn’t yet known and the NHS and Public Health England have committed to review the evidence on why ethnic minority populations seem to be disproportionately affected by COVID-19.

However, some potential reasons include:
 Differences in expression of ACE2
 Increased vitamin D deficiency which is more common in BAME people
 Increased systematic inflammation
 Higher prevalence of insulin resistance
 Higher prevalence of cardiovascular disease and type 2 diabetes, which are both linked to worse COVID-19 outcomes
 Other unknown genetic factors
 Socioeconomic disadvantages which could make social distancing more challenging, which includes a disproportionate level of employment in key worker roles, putting them into greater contact with the virus.

Diabetes Risk Calculator research

As the data earlier shows, we know that certain people with diabetes have far worse outcomes if they develop COVID-19 than others. What would therefore be helpful would be if there was a tool that could assess someone’s risk of worse outcomes, so that support and treatment could be targeted at them at the earliest opportunity. These people may also wish to follow stricter social distancing or even shield until the level of infection has greatly fallen or an effective vaccine is available.

The Public Health Scotland COVID-19 Health Protection Study Group and the Scottish Diabetes Research Network Epidemiology Group have started to do this. Telling someone their absolute risk (as is done with CVD) is impossible with COVID-19 as it will change depending on the stage of the pandemic and the current R number, showing the level of transmission of infection. Instead this group has developed a tool to predict the ‘COVID-19 age’ of a person with diabetes compared with someone without diabetes. The tool, called SHINY, is only to be used for illustrative purposes and relies heavily on socioeconomic factors and pre-existing conditions. Larger numbers will be needed to really emphasise the importance of individual diabetes factors, for example, the sample size was too small to give accurate assessment of the risk in type 1 diabetes, so this model lumps all people with diabetes together. The model will also need to be externally validated before it can be used for clinical purposes.
The model can be found here (https://diabepi.shinyapps.io/covidrisk/). The model gives a person with diabetes and a given set of risk factors the age at which a person without diabetes would be at the same level of risk. For example the model suggests that a 45 year old man with type 1 diabetes with a very good risk factor profile has a COVID-19 age of 52 whereas a 45 year old woman with type 2 diabetes and many risk factors present or elevated has a COVID-19 age of 76. The model only allows for evaluating COVID-19 age below age 70 as above this age risks of severe or fatal disease are mainly driven by whether you live in residential care.

Another risk tool is being developed in Oxford, with the support of NHS England and a wide range of other centres to support GPs and specialists to provide more targeted advice based on individual levels of risk. This risk engine uses the same methodology as QRisk, which is widely used to predict the risk of an individual developing cardiovascular disease over the next 10 years.

The team are currently analysing the anonymised health records of 8 million UK adults to identify factors that can be used to predict who will have the highest risk of serious illness or death from COVID-19, including age, sex, ethnicity, deprivation, smoking status, body mass index, pre-existing medical conditions and current medications. As well as enabling individuals to be risk assessed it will also help inform national public health policies in shielding and infection prevention, and could help determine who should be first in line for a potential vaccine. It isn’t yet clear when this tool will be made available.

Challenges for people with diabetes

As well as the threat of serious illness from COVID-19, we are aware of many challenges that people with diabetes have been facing. These include:

     Confusion over whether they should be shielded or not. Initial Government advice on 17 March suggested that all people who were offered free flu vaccinations, including people with diabetes, should be shielded. This was published in an article in Pulse but the advice was later altered to cover a much smaller number of people. This led to a great deal of confusion, including among HCPs.

 Concerns over access to appropriate food, particularly hypo treatments. We received many calls, especially in the first weeks, when people couldn’t get online deliveries and items were either sold out or the number you could buy was limited in the shops. For those who were shielded because of other comorbidities, the quality of the food in the “Boris Boxes” was also seen as unhealthy and not particularly appropriate for people with diabetes.

 Concerns over work, with some people being told they had to go to work even though no social distancing or consideration of their needs had been put in place. From an online survey of over 5,000 people we found that 55% had issues with the workplace. Two thirds didn't feel safe at work and over half said that their employer was not making sure they could social distance at work.

 Concerns over access to routine care. Most regular appointments, such as retinal screening, have been cancelled and people have expressed concern about their ongoing health and whether they are safe if they are not being reviewed. On the other hand we have also had concerns from those who are being asked to attend hospital appointments and we know that the number of people not taking up ‘in person’ appointments, such as for ongoing eye or foot care, is large.

 Concerns over their individual level of risk. With newspaper headlines such as the Daily Mail’s - “Type 2 diabetics are TWICE as likely to die from COVID-19”, it is unsurprising that people with diabetes are scared and looking for reassurance. We have taken calls from people asking what level of HbA1c is safe, in light of research that shows people with higher blood glucose levels are more at risk.

In response to these, we have been actively responding to these concerns both on an individual level, through the Customer Care Centre and social media, but also by tailoring all our SARS-CoV-2 information to meet these needs. We are also campaigning both publicly and behind the scenes to try and shape NHS and others responses. For example, over 12,000 people have now signed our open letter to the Business Secretary and the devolved equivalent ministers about safety at work for people with diabetes.

Unresolved issues

A question that we cannot answer is if, when and how big a second wave might be, though, from the experiences of other countries, coming out of lockdown is likely to trigger an increase in cases, even if in limited geographies.

Various studies show that, when tested for SARS-CoV-2 antibodies, on average about 4% of the general population test positive, meaning that they have had the infection, whether they had symptoms or not. If this were true for the UK it would suggest that about 2.7M people would have been infected, compared with the 313,470 who have tested positive – suggesting that about 90% of people who have been infected have not been tested.

To ensure ‘herd immunity’, when enough of the population have some degree of immunity to infection, you need about 70% of the population to have been exposed to a virus and to have developed antibodies. It is very likely that we are very far off that target, so experts think that a second wave is very likely. Added to this, we don’t know how protective those antibodies will be or for how long. Because viruses mutate, you can catch a virus more than once, which is one of the reasons why we offer flu vaccinations every year to best match the likely strain of influenza present that year.

With SARS, antibodies seemed to be protective for about 2 years and with MERS perhaps up to 3 years in those who had more severe infection. However, whether such long-lasting antibodies can prevent reinfection or affect clinical outcome in SARS-CoV-2 has yet to be determined.

People with diabetes are encouraged to take up an influenza vaccine each year, as one of the high risk groups. In most years, only about 64% of people choose to do this but with potentially two widespread respiratory viruses in play in the flu season this year, people with diabetes should probably be encouraged to take up the offer of free vaccination, either through their GP or pharmacy.

A common trend after natural disasters, such as earthquakes or floods, is to see an increase in HbA1c and worse outcomes for people with diabetes. This obviously has little to do with the actual disaster itself but more to do with the impacts that fall out of that – such as worse access to food and healthcare. Although not a natural disaster in quite the same way, it is likely that the SARS-CoV-2 pandemic will impact on diabetes outcomes. Many people will have lost jobs and income security, which often means diabetes has to take a back seat while they are trying to cope with other aspects of their day to day lives. People from lower socioeconomic groups tend to have poorer diabetes outcomes.
Another impact has been on the health service, with many routine appointments being cancelled and a backlog of work building up. One consequence of this is that routine operations may be started up in private hospitals which won’t have access to an inpatient diabetes service. There is a fear that people with diabetes will therefore not be prioritised on waiting lists, because of the risk of undergoing surgery without specialist diabetes support.

The situation with SARS-CoV-2 and COVID-19 is changing daily, with new issues arising, new treatments being proposed and social changes being brought in. This, therefore, is a snapshot in time of where we are and what we know at this stage of the pandemic.