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COVID-19 – a bit of perspective

COVID-19 – a bit of perspective

Every death is a tragedy for those affected. Especially so for COVID, where someone may die in isolation, unable to see, or be seen by,  their loved ones.

In no sense do I want to diminish that – and if you have been affected by the virus you may not want to read on.

But in the midst of all the publicity about COVID, I feel it is necessary to try to put it into perspective.

First of all, let’s look at the data for COVID deaths. This is very confusing. The Government dashboard (1 August) puts it at 46,193 in the UK. This is the number who have died having had a positive test result. This has been much criticised, as it would seem to mean that even if you get run over by the proverbial bus, having been tested positive months ago, you are still counted as a COVID-related death. On the other hand, if you die from COVID but have never been tested (or the test didn’t work), you wouldn’t be counted.

If you look at the data from the Office of National Statistics (ONS), you get a different figure,  50.800, in England and Wales only. This comes from death certificates, and is the number of times COVID was mentioned (even if other causes such as pneumonia were also mentioned). I’ll stick with the ONS figure, mainly because I want to compare it with other data from ONS.

So, 50,000 deaths. That’s a lot of tragedies. But death is a part of life. During the period of the epidemic, 245,000 people have died from all causes – so that’s getting on for 200,000 people have died from something other than COVID. And during each of the last five weeks, more people have died from what is recorded as Influenza/pneumonia than from COVID.

Another way of looking at the impact of COVID is to consider the excess deaths – that is the number of people who have died from any cause, compared to the average number who died in the same period over the last five years. This shows that since the epidemic started there have been over 53,000 excess deaths. That measure includes the possible indirect effects of COVID, e.g., people who didn’t get appropriate treatment in time. If we look at the weekly breakdown of excess deaths, we see that during the last five weeks it has been negative – that is, fewer people are dying than expected. The likely reason for this is that one effect of COVID has been to cause the death of some people who would otherwise have died soon anyway.

Historical comparisons

The current crisis has highlighted the fact that we are no longer used to people dying in large numbers from infective diseases. Medical advances, including antibiotics and vaccines, coupled with improvements in nutrition, housing, public health and other environmental issues, have in general made such diseases of historic interest only, at least in countries like the UK. (This is not of course true for most of the world, where diseases such as malaria and tuberculosis are causing death and suffering on a large scale – in low income countries, communicable diseases represent 5 of the top 10 causes of death).

A look at the death statistics (from ONS) for 100 years ago (1915) illustrates the point. In that year, there were 66k deaths from pneumonia/bronchitis and 39k deaths from tuberculosis. We can add others – 13k deaths from measles. 5k each from diphtheria and flu (not an epidemic year), 4k from whooping cough and nearly 2k from scarlet fever.

In the more distant past, there are numerous examples of devastating infections. The Black Death (1381) is thought to have killed a third of the population. In the nineteenth century, there were repeated epidemics of cholera, with tens of thousands of deaths, and tuberculosis was rampant (at its height, causing a third of all deaths).

In more recent times, the best comparison is with pandemics of influenza. (Technical note: Influenza viruses are classified by their H and A antigens, the most common type being H1N1. Various H1N1 strains are similar but not identical in both, so you get a degree of cross-immunity, while another type say H2N2 differs in both and there is no cross-immunity between them. Major pandemics usually occur with a virus that has ‘shifted’ to different H and N types)

In 1957-58 there was a pandemic of so-called ‘Asian flu’ (H2N2), which caused some 20-30k deaths in the UK. Then in 1968-69, we had an H3N2 strain (labelled ‘Hong Kong’ flu) for which the estimates of the number of UK deaths go up to 80k. In neither case was the official response anything like what we are currently seeing with COVID-19. And the media managed to find plenty of other news to cover.

More recently, there was some concern about ‘swine flu’ (2009). The incidence rose to about 110k cases per week in July, before dropping off, and then re-emerging in the autumn to about 84k cases per week in October. However, mortality was low (<1,000 deaths in UK), probably because this was an H1N1 strain, and older people had already encountered H1N1 strains and so had significant immunity to it.

Why all the fuss?

Why is it that fifty years ago we could face a disease that caused up to 80k deaths, not exactly with equanimity but at least without the massive sacrifices that we are currently making for a disease of (apparently) similar magnitude? Of course, we have to recognise that without the control measures it might have been much worse. Based on what was known about the disease, the initial assessment was that, if left unchecked, the disease would spread until Herd Immunity was achieved, and that would happen when about 60% of the population had been infected. Assuming a case fatality rate of 1%, that implied something like 350,000 deaths, which was deemed unacceptable. Of course we will never know if that would have happened, but a comparison with other countries is interesting. We hear a lot about the numbers of deaths in the USA and Brazil, but if we look at the numbers of deaths per million population, we are still some way ahead of either of them (UK 680, USA 477, Brazil 440) – although I am well aware of the dangers of reading too much into such comparisons, given the different methods and reliability of reporting deaths. But superficially, it could mean that our lockdown didn’t have much effect, and the original estimate of 350,000 deaths was over the top.

I’m not saying that we should all ignore the advice, and go out and party. But let’s keep a sense of perspective. At the individual level, unless you are in an extremely vulnerable category, there are plenty of other ways of dying that we don’t bother too much about. But collectively, we still have a duty to try to limit transmission so as to protect those who are more vulnerable. Above all, don’t panic!

Jeremy Dale

2 August 2020

 

COVID-19: Airborne transmission?

COVID-19: Airborne transmission?

Some of you may have been as confused as I was by the recent reports suggesting that the possibility of airborne transmission of SARS-CoV2 has been neglected. You would be forgiven for thinking that the airborne route is what we’ve been talking about all along, and that it is the main route of transmission. That’s what masks and distancing are all about. This is an attempt to straighten out the issues.

Basic principles

When we cough or sneeze, or, to a lesser extent, talk or even just breathe, we eject small droplets of saliva and mucus. A sneeze may produce thousands of these, while a cough may yield only a few hundred. For talking, or singing, it will depend on the consonants – f, b, p, t and s are especially good at producing droplets (I am indebted to Cedric Mims in The Pathogenesis of Infectious Disease for the observation that most abusive words in English start with one of these consonants!). If we are infected with a respiratory tract pathogen, such as SARS-CoV2, then some of these droplets may contain virus particles. I’ll come back to that later.

What happens to those droplets? That depends on their size. The largest ones (1mm or more) will fall to the ground (or some other surface) within a few metres or less. With the smaller ones, because they have a large surface area relative to their volume, the water content will evaporate rapidly, resulting in tiny particles (‘droplet nuclei’) less than 5 micrometres in size (a micrometre is a millionth of a metre, or a thousandth of a millimetre). These can remain airborne virtually indefinitely. It is the potential of these particles to transmit the disease that is the focus of the current discussion. This is sometimes referred to as ‘aerosol transmission’ to distinguish it from transmission by large droplets.

Some unanswered questions

In order to assess the significance of the potential risk posed by these tiny particles, we need to consider the following factors:

– the likelihood that they carry the virus

– how many virus particles they carry

– how long will the virus remain able to establish infection

– how are they distributed in the air

– How many virus particles are needed to cause an infection (the infective dose).

Most of these are unknown; we’re just guessing, partly based on experience with other viruses. Let’s fill in some details.

Will the particles contain virus particles, and how many?

This depends on another unknown, the viral load, or more specifically the number of virus particles shed by someone infected. One of the main factors limiting our knowledge here, and elsewhere, is that almost exclusively the assays are based on detection of viral RNA rather than viable virus particles (which are much more difficult to measure).

Leaving that question on one side, it is intuitively obvious (and probably true) that the larger droplets are more likely to contain virus particles than smaller ones, and similarly are likely to have more virus in them. That’s just on a statistical basis. You should also consider the size of the virus. A single coronavirus, including the spikes, is about 130 nanometres (nm) in diameter (one nanometre being a thousandth of a micrometre). So if you put 7 or so viruses side by side, that would span the diameter of a one micrometre droplet. Without doing the detailed calculation, it can be estimated that the maximum capacity of the largest of these persistent airborne droplets (say 5 micrometres) might be of the order of 100 virus particles, if they can be tightly packed. And many of the droplets will be much smaller, containing no more than a few viruses. This will be relevant when we look at the infectious dose later.

How long does the virus remain infectious in small droplets?

Another unknown, and here the RNA assay is of no help at all. RNA will remain long after the virus itself is ‘dead’. But it is likely that it will be of limited duration due to drying – and, especially in the open air, the effect of UV light.

How are the droplets distributed?

This is a bit easier to answer. For the larger droplets, which are essentially transmitted directly from the source to the subject, the likelihood is dependent on the distance separating them, and more or less to the square of that distance (as it can go to either side of you). If the smaller droplets are distributed throughout the air-space, it will be related to the size of the room you are in. If you have a lot of people in a small, low ceilinged, room, then the risk may be considerable. If the room is larger it will be much less so, especially if the room is well ventilated. And of course if you are outside, the risk virtually disappears.

How likely are you to be infected?

This depends on the biggest unknown of them all, the infectious dose (i.e., how many virus particles do you need to inhale in order to catch the disease?). This varies a lot from one disease to another, from a few hundred up to millions. Because we have a variety of non-specific mechanisms protecting us against invading microbes, very few diseases have infectious doses less than a few hundred – it is often said that tuberculosis can arise from a single bacterium penetrating as far as the lungs, but that is exceptional (and a bit dubious!). For the original SARS virus, the infectious dose has been estimated as a few hundred (although this is not much more than a guess, and it may be higher), so it is often assumed that this will apply to SARS-CoV2 as well. If we combine that estimate with the previous discussion, recognising that each of these tiny droplets is likely to contain only a small number of virus particles, we would have to inhale dozens or hundreds of such particles. Potentially, this could happen in a small, ill-ventilated room if there was someone shedding large numbers of virus, but my conclusion is that this is likely to have a comparatively small effect on the overall transmission of the virus, compared to the risk of more direct transmission by larger droplets.

Jeremy Dale

10 July 2020

World-beating?

World-beating?

Johnson likes to talk up the UK performance in dealing with COVID-19. But strangely he doesn’t consider one statistic that shows the UK competing strongly for the ‘world-beating’ title. If we ignore San Marino, that title goes to Belgium, but with the UK in second place (here I ignore Andorra, with my apologies to both countries) – and closing.

We hear a lot about the numbers of deaths in various countries, and how USA and Brazil are leading the field- but to get a true picture we need to relate this to the population size, as deaths per million inhabitants, a parameter known to epidemiologists as the ‘death rate’. Let’s look at some data (as at 13 June).

Belgium has recorded 841 deaths per million. For the UK the figure is 621.

Spain and Italy are close behind (581, 566 respectively).

Some others for comparison: Sweden 482, France 452, Ireland 354, USA 352, Brazil 204, Germany 106. Of these, USA and Brazil are both likely to move up the list.

I should add that all of these figures are somewhat suspect, some more so than others, as practices vary between countries, for example in whether they are COVID-confirmed or merely suspected, and how assiduous they are in ascertaining COVID-related deaths in the community.

How did we get to the unenviable position of being (almost) world-beating?

The UK Government has done a lot of things wrong (or failed to do the right things). I’m not going to attempt a complete list, but a few examples will suffice.

It starts several years ago. There were warnings from at least two ‘exercises’ that we were ill-prepared for a pandemic – notably, but not solely, in the inadequacy of the stockpiles of PPE. These warnings were not acted upon. I suspect that the government was influenced by the ‘just in time’ business model, which holds that stockpiles are inefficient. This model failed spectacularly as it doesn’t deal with a situation when circumstances change suddenly (as supermarkets also found out).

Other problems arose from the repeated reorganisation of the infection control systems. At one time, each hospital had its own diagnostic lab, and each local authority had well-organised arrangements for monitoring and dealing with outbreaks of infectious diseases, including experienced teams of contact tracers. Much of this was dismantled and centralised, and what was left has been largely ignored by the government. Hence people having to travel considerable distances to be tested and it taking several days to get the results back.

Then we come to the lack of action at the early stages of the pandemic. Warnings were there in January, becoming more serious in February. The government did nothing until well into March. No controls on passengers coming to the UK, not even temperature checks. Now we hear that there were at least 1300 separate introductions of the virus to the UK.

They also failed at that stage to ramp up the provision for testing and contact tracing, so that it quickly became overwhelmed when the outbreak started in earnest, and had to be abandoned. It could have made a vital difference at that stage.

They were very slow to stop large gatherings of people – including the rugby international at Twickenham (7 March), the Cheltenham Races (10-13 March) and the Atletico Madrid match at Anfield (11 March). They maintain that the scientific advice was that these events were low risk – and it could be that while people were sitting in the stands watching, the risk was less than for people in a crowded pub. But what about travel to get there? What about the bars at the event? And in the pubs afterwards?

Even after those events, with the warnings becoming clearer and clearer, it took them another two weeks to impose a lockdown.

A large part of the blame must lie with Johnson himself – first of all his refusal to engage with the issue during January and February, and then, well I can’t blame him for being ill, but he seems to have established a cabinet without anyone able to take charge in his absence. And to cap it all, his failure to deal with Cummings after his flagrant flouting of the lockdown has created a situation where large sections of the populace no longer have the respect for the advice that is necessary for maintaining control during the easing of the lockdown.

I could go on – the refusal to co-operate with the EU over the supply of PPE and ventilators (was this a dogmatic antagonism to anything ‘European’?), the hesitation and vacillation over any changes, and then imposing them suddenly without warning, and without consultation with those who would be most affected – notably the fiasco over the re-opening of the schools, plus the multitude of ever-changing ‘guidance notes’, and the proposal to change the distancing rules – will they, won’t they? Who knows? But enough is enough.

 

Jeremy Dale

15/6/20

 

Am I a Racist?

Am I a Racist?

The killing of George Floyd, and the world-wide reaction to it, has brought the issue of racism to the fore once again. So this is a good time to think a bit about what we mean by ‘racism.’

The dictionary definition starts with “belief in the superiority of a particular race”. Leaving on one side the absence of any scientific meaning to the term ‘race’ in this context, this definition is rather an extreme position; we really need something broader. The second definition in my dictionary – “antagonism towards other races” –gets nearer to the current issues, but I maintain is still inadequate. I would certainly not admit to being a racist on either of those definitions.

Basically I don’t like the terms ‘racist’ and ‘racism’. I would prefer to redefine my starting  question as ‘Am I racially prejudiced?’ To which, if I am honest, the answer must be ‘Yes’. That needs some explanation.

I think, as a white person living in a society such as Britain that is historically ‘white’, (and still remains dominantly white, politically, economically and culturally), a degree of racial prejudice is inescapable. I say nothing about how someone from another ethnic background would feel; how could I possibly know? The challenge that we face is to recognise, and try to deal with, that prejudice.

One example. I’m walking along a street and I see ahead of me a group of people largely blocking the pavement. Do I a) continue and hope they make way for me to pass. b) step out into the road to pass them, or c) cross over to the other side of the street. I know that my instinctive reaction would be different if they were black. I know nothing else about them; I have no reason behind my reaction. I am pre-judging the situation – which is prejudice. You can extend this scenario to other forms of prejudice – contrast my likely behaviour if they were young males as opposed to elderly women.

Another, real, situation. When I was a University lecturer, many years ago, students had to put their names on the front of their exam papers. Some of us thought this was not good practice, and we argued (eventually successfully) for anonymous marking. There was opposition to this – some of my colleagues were actually offended by the implication that their marking might be affected by knowing who the student was. They said they weren’t prejudiced. I knew I could be, and so I always tried not to look at the cover page. But after I had given a mark, I sometimes thought, when I did see who the student was, ‘That can’t be right. She’s done much better than I expected.’ And I was tempted to go back and re-mark it.

So, yes, I admit to prejudice. And I come from a Quaker family background, with deep roots opposed to all forms of prejudice. Hence my contention that all (or at least all white people in a society such as ours) must also be prejudiced. The people who worry me are those who deny their prejudice. Until you recognise it, you cannot deal with it.

On a larger scale, this applies to organisations and institutions as well. To refer to an organisation as ‘institutionally racist’ does not mean, as it is often taken to mean, that every individual in that organisation is overtly racist. Rather it means that the organisation has failed to recognise the possibility of racial prejudice inherent in its practices and procedures, and by failing to recognise them it has failed to deal with them.

How does this relate to the killing of George Floyd – and very many other similar incidents, in this country as well as the USA and elsewhere? I have to resort to the rather hackneyed comparison with an iceberg. The tip of an iceberg showing above water only exists because of the very much larger mass of ice out of sight beneath the water. If you tried to cut the tip off, the iceberg would float higher in the water. In other words, it is not sufficient simply to campaign against such incidents of racial violence. Nor is adequate to tackle the inequalities in society. These actions are necessary, but incomplete. To banish ‘racism’ we have to work to eliminate all forms of racial prejudice – in our institutions and organisations, and in ourselves. This requires all of us to recognise the existence of our prejudices, and take appropriate action to counter them..

Jeremy Dale

6 June 2020.

 

 

Stay alert – a guide

Stay alert – a guide

As the ‘English’ government seems to be unable to explain clearly what the new regulations mean, for those who live in England, I thought I would help them out a bit. This is not based on scientific advice, or anything else.

Stay alert.  Obvious, but difficult to do. I find myself nodding off by the end of the day, and eventually I confess I have to give up and go to bed. I hope nobody reading this shops me. I don’t want the police coming round in the middle of the night and asking complicated questions to test how alert I am.

Visiting family and friends. You can now do this, as long as they don’t live in Wales or Scotland. Except they changed their minds; Johnson now says it’s only ‘one on one’.  But there’s two of us, so if we visit family we can only visit one member each. After a while, we can swap over. And it has to be in a public place (not in their garden*).  If, while I’m talking to one friend (A), another friend (B) comes by, I can start talking to B only if A backs off. If we all stay 4 metres apart then that’s OK.

*If you live in Chatsworth, your garden is public. so that’s OK. I’m thinking of declaring my garden a “public space” so I could have friends visiting me.

Travel. You can now travel as far as you like, as long as you don’t stray over the border. But everything will be shut when you get there, so take your own food – but if you end up in Wales, you would have to eat it standing up because otherwise it would be a picnic, which is not allowed. And take a sunhat, and cover yourself up well, otherwise you would be accused of sunbathing.

Quarantine. If you enter the UK (or do they mean England?) by air, you will have to go into quarantine for 14 days. No, that’s changed. Now it applies however you arrive. No, that’s changed too – it doesn’t apply to entry from Ireland or France. If you come from anywhere else, you have to go to France first and then come to England.

(At the risk of sounding serious, why do this now – when we have more cases than most other countries in Europe – and not 3 months ago when we had few cases. And why 14 days? The median time between infection and symptoms is 5-6 days.)

Garden centres. Your best bet is to find one in Wales, close to the border, and go there. Technically, you’re not allowed to drive far in Wales, but if it’s close to the border the police might not notice.

Other cross-border activities. Take care (be alert!) when doing anything close to the border in case you stray across. This includes walking in the Cheviots or the Black Mountains. It also includes any golf courses that cross the border, where you can only play those holes that are in England. If your tee shot is wayward, you will lose the ball.

Face covering. Recommended to be used in enclosed spaces, but not proper face masks which are needed elsewhere. Niqab is suitable but beware of being mistaken for a letterbox. (Strange that some countries ban face covering but also make it mandatory!)

Swimming is allowed, outdoors. So rivers are fine, but be careful in parts of rivers like the Tweed and Wye. If you stray too far across the river, you will find yourself in Scotland or Wales. which is not allowed. See Cross-border activities.

Jeremy Dale

12 May 2020

 

COVID-19: Contact tracing

COVID-19: will contact tracing work?

It’s widely said that testing and contact tracing (using a smartphone app) is the key to the control of COVID-19. But it is not necessarily that simple; there are several unknowns that are worth thinking about.

The textbook example that underpins much of the thinking about this issue is the eradication of smallpox. The later stages of that campaign relied on the early detection of cases and the vaccination of “contacts” (in this case, everyone within a certain area). There are several factors underlying the success of that strategy.

The most obvious is the availability of an effective vaccine. We don’t have that (yet?) for COVID-19.

Secondly, the symptoms of smallpox were obvious and distinctive. There was no need for a complex and time-consuming test to identify a case. In the final stage, in remote areas of Ethiopia, one person in each village was trained to spot, and report, cases, so the vaccination team could respond quickly.

A third important factor is that smallpox is not infective until symptoms appear. Here there is considerable uncertainty in the comparison with COVID-19. There is circumstantial evidence that transmission may occur from pre-symptomatic individuals (i.e., those who subsequently develop symptoms) and possibly also from asymptomatic people (who never develop recognisable symptoms) – although probably to a lesser extent than from those who have symptoms. But we don’t really know, and if it happens to a significant extent it could reduce the effectiveness of a contact tracing strategy. On the other hand, if R is less than one for pre-symptomatic/asymptomatic individuals, then it might not matter.

The comparison with smallpox does have one favourable factor. Both diseases have a relatively low R0 value (2-4)*. This is a marked contrast with another textbook example – measles, where the R0 value is much higher (15-20 is often quoted). Measles also provides another contrast, in that the initial disease is an inconspicuous respiratory tract infection. This is the infectious stage. The typical symptoms come later (they are an immunological response to the virus), and by that stage the patient is not infectious. The high R0 value would make a contact tracing strategy extremely difficult; infectivity before detection makes it effectively impossible.

*A digression to clear up a point that often causes confusion. For epidemics in general, R0 (the basic reproduction rate) is the value of R at the start of a new epidemic, when everyone is susceptible. As the epidemic progresses, and the number who have had the disease (and become immune) increases, the value of R (the actual reproduction rate) declines. For COVID-19, we are largely looking at the effect of control measures rather than the number of those who have become immune; nevertheless it is simpler to refer to this as an effect on R rather than R0.

Before getting back to the point – will contact tracing work in enabling a relaxation of the lockdown while still keeping R below 1? – we need a more subtle interpretation of R. It is an average value across the whole population. If R is very low for some people and much higher for others, you could still get an average value of R <1 even if there is a subpopulation that is spreading the virus quite effectively. If this is geographical (a rural-urban distinction for example) it will show up quite readily (and already does). But if it applies to different groups within say a major city, it is not so easy to see.

Furthermore, although a value of R<1 is (rightly) regarded as a significant point in predicting a decline in the epidemic, it is not an absolute objective. The further it can be reduced, the quicker the epidemic will die out (as well as countering the possibility of a sub-population of spreaders.

Now we can think more clearly about contact tracing. Firstly it depends on the relationship between infectivity and symptoms. Assuming, for the moment, we will not be undertaking massive random testing of the whole population, the contact tracing app will largely apply only to those who are symptomatic. We would have to hope that for those without symptoms, R is already quite low – i.e., there may be a possibility of transmission, but at a low frequency.

Secondly, there is the time factor. Once someone develops symptoms, how soon would they become aware of that and report it? One day? Two days? Then the app needs to notify the identified contacts, who are expected to self-isolate. The crucial factor here is whether those contacts will self-isolate quickly enough, before any of them have become infectious. If the original person is infectious for two days before reporting it, and if the identified contacts don’t act quickly, they may well have been infectious themselves for a day or so before they self-isolate.

The third factor is the degree of uptake of the app. The government originally predicted 80% but have backtracked on that to a figure of 50%. Many people regard that as optimistic – some predictions put it as low as 20%. (Bear in mind that only 79% of adults have a smartphone; for those over 65, it is 40%). Concerns over privacy could have a major impact – I can think of several examples of people who wouldn’t want to disclose who they have been in contact with, however much they are told the data is anonymised!

Then we come to the question of numbers. Suppose we have 10,000 cases per day. (Yesterday, 6 May, there were just over 6k positive tests in the UK, from 57,000 people tested, so the actual number of cases is probably much higher than this). And suppose each case had 5 contacts. That makes 50,000 people per day told to self-isolate for a week – giving a total of 350,000 people self-isolating at any one time. The vast majority will not develop symptoms and may regard the exercise as a waste of time. Is this sustainable?

Of course, if distancing works, there shouldn’t be any contacts, but a lot depends on what the app considers as a ‘contact’. How close do you have to be, and for how long?

You may notice that I’ve said very little about testing. Despite all the publicity about the number of tests being done, and how important it is to do much more, it is far from clear how this would contribute towards a contact tracing strategy. If the identified contacts were tested, would this discriminate between those who had been infected and those who hadn’t? If it did, you could release some from isolation. But there is some doubt as to how early in infection the test result becomes positive, and with the current delays in getting the result back to the subject, they would be half-way through their isolation before they were told the result.

Or, if we did random testing of the population, that would identify a lot of people who were infected but asymptomatic. They could be told to self-isolate, and report it to the app, resulting in a large increase in the number of contacts who would in turn need to self-isolate. But if someone who is asymptomatic transmits the disease only occasionally, this does not have much of an effect.

It would be nice if those advocating a large increase in testing would be more explicit about why it is important. I should emphasise that I’m thinking in terms of control strategy in the general population, and not staff and patients in hospitals and care homes, and similar situations, which is a very different matter, and the need for testing there is quite clear.

The final assessment is that potentially it could work, but it will require a very effective publicity campaign, first to convince people to use the app, and then to take notice of the requirement to self-isolate if they have had a reported contact.

 

COVID-19 vaccines

COVID-19 vaccines

There is no doubt that an effective vaccine against COVID-19 would be a game-changer. So it is not surprising that there are over 100 different vaccine candidates at various stages of development. It might be helpful if I review some of the ways in which vaccines can be developed, starting with the approaches that have been used historically. Whatever approach is used, the goal is to produce a protective immune response, without causing any harm to the subject.

1. Inactivated vaccine. This is conceptually the simplest approach. You grow the virus in the lab and inactivate it, e.g., by heat or chemical treatment, so that it is incapable of causing disease but is still immunogenic. The Salk polio vaccine (the one given by injection, not the ‘sugar-lump ‘one) is an example. Although conceptually simple, very few of the COVID vaccine teams are using this approach. One possible reason is that it requires the production of large amounts of active virus, which is not easy and very hazardous. It also requires meticulous testing to ensure that it is completely inactivated.

2. Live attenuated virus. This requires the virus to be genetically altered in some way so that it is unable to cause disease, but is still viable (so you can still grow it in the lab). If the virus is fully attenuated, this is a safe approach, but achieving attenuation is time-consuming – although these days, rather than trying a variety of random mutants, you can specifically knock out key genes (if you know enough about the biology of the virus). The other polio vaccine (Sabin vaccine) is an example of this type. Again, there are only a few potential COVID vaccines in this category.

3. Toxoids. The third historic approach, exemplified by tetanus and diphtheria vaccines, is to purify and inactivate the bacterial toxin responsible. This is not relevant here (I include it merely for the sake of completeness).

We then come to approaches that rely on recombinant DNA technology (‘genetic engineering’).

4. Recombinant proteins. This involves cloning one of the viral genes (typically coding for a spike protein), and putting it into a bacterial cell (or some other convenient cell) and getting that cell to make quantities of the protein (or a specific part of the protein). The host cell can be grown in large quantities and the desired protein purified for use as a vaccine. Since there is no actual virus involved, this is safe to produce and use, at least from the point of view of infection. Many of the vaccine candidates are of this type (although there may be differences in the details). Since this approach is already used for some existing vaccines, there are already large-scale production facilities available.

5. Viral vectors. In this approach, instead of expressing the protein in a bacterial cell, the gene is inserted into the genome of a harmless virus, so you use the recombinant virus as the vaccine; when it infects a human cell, the required protein will be produced. There are several well-characterised vectors available, which have been developed (and in some cases used) either for other vaccines or for gene therapy. Several of the candidate vaccines that have started clinical trials are of this type.

6. Nucleic acid vaccines. Here the vaccine consists, essentially, of just the RNA of the virus (or a DNA copy of it). The RNA or DNA is taken up by a human cell which uses the information to produce the relevant viral protein. There are also several candidate vaccines of this type in early stage clinical trials.

Testing your vaccine.

The obvious questions are Is it safe? and Does it work?

Ideally, you would start with several different lab animals to see if it is safe to use. You could test the immune response created, but that does not necessarily mean the same thing as efficacy, unless you have an animal model that mimics the human disease, so you can do challenge studies – i.e., you deliberately infect a group of vaccinated animals and see if they survive. You obviously cannot do that with humans!

You would then move, cautiously, to human studies, starting with a very limited number of healthy young volunteers (phase I), mainly to assess any possible side-effects. Again, you can monitor antibody production but you cannot assume that this equates to protection.

Phase II would consist of an extension to a larger panel of subjects, representative of the population, still mainly concerned with safety, but also possibly investigating other factors such as size of dose and route of administration.

Only in phase III would you start in earnest to get data about efficacy. This involves a much larger group of people (often thousands) in a randomised, controlled, double-blind study. They are assigned, randomly, to one of two groups. One group gets the vaccine, and the others something else (in one case, a meningitis vaccine is being used for the control group).  The subjects don’t know which group they are in, nor do those administering the vaccine or assessing the results. The key is held by an independent person who monitors the results as you go along, and may call a halt if anything is obviously going wrong, e.g., there are side effects associated with the use of the vaccine. The trial may also be halted prematurely if things are going very well; if the vaccine clearly works, it is unethical to continue giving a placebo to the control group.

That’s, more or less, the text-book description. With the COVID-19 candidate vaccines, short cuts are being used, partly because of the urgency of the situation, and partly because many of the vaccines involve the use of existing tried and tested technology. So while many vaccines are described as being in clinical trials at phase I, in practice these seem to be hybrid phase I/II trials with an element of phase III in them – e.g, using several hundred volunteers in a randomised controlled trial aimed at assessing efficacy as well as safety.

Jeremy Dale

27 April 2020

 

 

 

COVID-19 tests

COVID-19 tests

There has been a lot of talk about tests for COVID-19 (or the virus that causes it,  SARS-CoV-2). The purpose of this piece is to try to clarify the nature of the tests that are usually referred to, and some other possible tests.

In general, most diagnostic tests for an infectious disease fall under the following headings:

1.Tests for the presence of the whole (‘live’) pathogen

2. Tests for the presence of some part of the pathogen. These can be divided into

a) tests for the nucleic acid of the pathogen (RNA in this case).

b) tests for an antigen of the pathogen

3. Tests for antibodies produced by the body in response to the presence of the pathogen.

1. Live pathogen tests.

For most bacterial diseases, this is the ‘gold standard’. Bacterial pathogens can (mostly) be grown easily in the lab, so this is a good way of detecting them.

It is not so easy for viruses. They don’t grow on their own – they have to get into a cell and use that cell to make more copies of the virus. (This makes it very debatable as to whether we consider a virus as ‘alive’; ‘viable’ is a better term). So you need to start with a culture of a human or other mammalian cell line that you can try to infect with the virus. There is a wide variety of such cell lines in common use in virology laboratories.

Viruses are often fussy – they will grow on some cell lines but not on others. Also, you want to be able to see the effect the virus has on the cells – a ‘cytopathic effect’. Fortunately, previous work with the related virus that caused SARS indicated which cell lines were most likely to be successful. So, quite soon after the first samples became available, several laboratories around the world had successfully cultivated SARS-CoV-2.

But this is not suitable as a diagnostic test. It is too slow (it takes several days or more) and needs high levels of containment. However, being able to grow the virus is important for several reasons, including:

– it is the only way of confirming that the virus is viable (and hence presumably infectious), which is necessary for investigating whether someone is shedding infectious virus, or for testing survival in the environment, for example.

– for lab-based testing of the effects of potential antiviral agents

– providing reasonably large amounts of the virus, especially for the development of some types of vaccines (especially those based on inactivated virus).

2. Tests for the presence of part of the virus.

This is the mainstay of current tests, using a technique known as RT-PCR (Reverse transcriptase-polymerase chain reaction). The RT part copies the viral RNA into DNA, and the PCR amplifies the DNA. It works through a series of cycles, each cycle doubling the amount of DNA. So after 10 cycles, you have 1,000 copies, after 20 cycles a million (106) copies, and after 30 cycles 109 copies. This can all be automated, so you put it into the machine which then tells you when you have a detectable product.

A key element in this process is that it requires the binding of specific ‘primers’ – short lengths of nucleic acid derived from the sequence of the DNA copy of the viral RNA. If the right DNA is present, the primers will bind and you get amplification. If it is not there, there’s no binding, and no amplification. So it is not only exquisitely sensitive, it is also highly specific.

You need to know the sequence of the viral RNA before you can do this. This sequence was made available very shortly after the virus was first identified.

It is important to remember that this test only detects the presence of viral RNA, not the whole virus. So a positive test does not necessarily mean that you are still infectious; it depends on how long the RNA remains after the virus has been inactivated by your immune response.

Some pathogens are detected or identified through the presence of other parts of their structure, mainly those that invoke an immune response – i.e., antigens. I have seen references to an ‘antigen test’ for this virus, but these are probably erroneous references to the RT-PCR test (to contrast it to the antibody tests, see below). There seems no point in an antigen test, which would be slower and less sensitive the RT-PCR.

3. Antibody tests.

These are highly controversial.

The principle is that during infection you produce antibodies (immunoglobulins) that are capable of reacting with a viral antigen (such as the proteins that form the ‘spikes’ on the surface of the virus). So you take a blood sample, mix it with a sample of the specific antigen, and the test detects the binding of the antibody to the antigen. So far, so good.

The problems are of two sorts. Firstly, sensitivity. During the early stages of infection, there may be only low levels of antibody. So you may not detect infection at that stage. Later on, after you have recovered, the antibody levels may drop off quite quickly – so it may not be a good test for immunity (see below).

Secondly, specificity. SARS-CoV-2 is closely related to the SARS virus, and (less closely) to a variety of other coronaviruses that cause a proportion of common colds. While it is easy to make the RT-PCR test specific (by choosing suitable primers), it is not so easy to get a highly specific antibody test.

These problems may be overcome in a lab setting, with experienced technicians, and larger samples of blood – and some laboratories are already conducting surveys using antibody tests. But we are not yet at the stage where you could reliably use a ‘pin-prick’ test in your own home.

This leads on to a related point. If a reliable antibody test says you have antibodies to the virus, what does that mean in practical terms? Especially, will you be resistant to further infection? I don’t want to get bogged down in the direct evidence, which is inconclusive – there are anecdotal reports of a second infection in individuals who have converted to RT-PCR negative (but there are other explanations for that), and on the other hand some animal experiments indicate that re-infection does not happen. The question I want to address is whether the detection of antibodies (assuming a reliable test) means you are now resistant to infection. A full answer, based on general concepts with other viruses, would be far too long and complex to be covered here -and I’m not an immunologist, so I’m not equipped to tackle it, but there are a few points worth making.

– With some viruses, you get ‘neutralising antibodies’ – i.e., binding of the antibodies to the virus is by itself enough to prevent the virus infecting cells (this can be detected in the lab). If that does not happen, the body has other ways of disposing of the virus-antibody complexes, including the activity of various cells such as macrophages and T cells. So in that case your resistance to the disease may depend on this cell-mediated immunity rather than, or as well as, the production of antibodies.

– As described above, antibody levels may fall off considerably after you recover from infection. But it’s worth noting that you can be effectively immune even if antibody levels are low – your immune system may ‘remember’ the previous exposure and produce antibodies very quickly in response to further exposure.

– Antibodies can be damaging as well as protective. The classic example is dengue, where a second infection, with a different strain, causes a much more serious disease – a phenomenon known as antibody-dependent enhancement. Although it is thought unlikely that this will happen with SARS-CoV-2, the prospect is enough to make the vaccine developers twitchy.

Jeremy Dale

24 April 2020

Sunbathing and suicide

Sunbathing and suicide

Some comments on lockdown and exit strategies

The purpose here is not to object to the general concept of a ‘lockdown’ It is a valid strategy for containing an infectious disease. But there are some elements of the strategy that are worth comment, because it is not clear how they contribute to reducing transmission and/or because they might be counter-productive. We will also, sooner or later, need an exit strategy, and I hope the government is already considering the options.

  1. Exercise in the country.

We have been told that we are allowed to have one form of exercise per day, but it must be close to home. That is fine for those of us who live on the edge of open country, but for those who live in cities it means they are confined to parks and other urban open spaces, which runs the risk of those places becoming crowded, and posing a much greater risk of transmission of the virus than if they took a short car ride into open country. Granted that we do not want large collections of people in popular beauty spots (just close the car parks?), nor is it desirable for people to travel hundreds of miles to get their exercise (although I’m not sure what the problem is there, but I’ll let that go). This looks like a London-based rule, that ignores the fact that in many Northern cities, open countryside is only a short way away.

And now, predictably, we have some parks becoming sufficiently crowded that they are threatened with closure (and in some cases have been closed).

There has also been an element of ‘Eyam in reverse’ on some occasions. (Eyam, in case you don’t know, was the ‘plague village’ in Derbyshire which, when plague arrived there, decided to cut themselves off to prevent the spread of the disease to neighbouring villages.)  The comment from Derbyshire Police that some of the people visiting Curbar Edge came from Sheffield sounds rather like the reverse of Eyam’s action. So does the comment on the News tonight from a resident of the Lake District that visitors coming from Manchester were being selfish in that they might be bringing the virus with them. (But I do think that someone from Manchester has no need to go all that way when there are plenty of opportunities much nearer to home).

  1. Are we allowed to enjoy ourselves?

What is the problem with sunbathing, or having a picnic on a (deserted) beach? Provided of course that you keep your distance from everyone else. Yet we have seen police intervening to stop such activities. This looks like a rule that is designed to stop anyone from looking as though they might actually be enjoying themselves. I’ll come back later to the desirability of having fun.

  1. Do arbitrary and pointless rules matter?

At present, the vast majority of people seem to be going along with the rules (at least up to a point), but will it last? As the ancient proverb says “The tighter you screw the lid down, the sooner the boiler will burst”. (Actually, that’s not an ancient proverb; I just made it up. If anyone knows better, let me know!).

In an authoritarian culture, you would get away with it. But we’re not used to being told what to do in such depth, and if people start to think that the rules are unnecessary, it will be hard, if not impossible, to enforce them. Unfortunately, that might mean the sensible rules would be flouted as well as the pointless ones. This will become increasingly important once the peak of the epidemic has passed.

  1. Downsides of the lockdown.

The financial and social problems are sufficiently obvious that I don’t need to go over them. But there are other effects that are not well enough discussed publicly, mainly those associated with being cooped up all day in a small flat. We are starting to see evidence of an increase in domestic violence, mental illness, and apparently also in the number of suicides. There is not much public data yet, but the effects were predicted, so the small amount of evidence is credible.

A more subtle effect is the increased level of stress and anxiety in the population. Although a certain amount of anxiety is needed to ensure that the rules are kept, stress can also be counter-productive for attempts to control the epidemic. We know that factors like immune deficiency, respiratory problems, diabetes, obesity etc are risk factors for infection, and for the severity of the disease. It is less known that stress also reduces our resistance to infection. The precise mechanism of the interaction is imperfectly understood, but it has been shown in humans and in experimental animals, so it is a real effect.

This brings me back to point 3. If allowing people to have a bit of fun occasionally reduces their stress levels, it would go a long way to countering these negative effects of the lockdown.

So keep safe, but have some fun as well.

  1. An exit strategy.

Once the numbers start to come down in earnest, there will be increasing pressure to know when the brakes are coming off.  It will be essential to get this right. If we relax too soon, the epidemic could start off again. If it is delayed too long, apart from the unnecessary financial effects (both on industry and on the workers), there is the risk that people will start to take matters into their own hands.

Furthermore, it will have to be a staged exit. You can’t suddenly say ‘Tomorrow, we’re all back to normal’. The Glossop Labour Club will need to know in advance when we can start ordering beer, and our suppliers, in turn, will need to know when to start making it. Apply that over the whole country, and you can see that chaos will ensue unless the exit is managed carefully.

Am I being too sanguine in hoping that the government is already producing such a plan?

 

 

 

 

Coronavirus – some information

Coronavirus – some information

A The virus

  • COVID-19 is the name of the disease. The name of the virus is SARS-CoV-2. Not very snappy, but it identifies its relationship to the virus (SARS-CoV) that caused the SARS outbreak in 2002. The virus that caused the MERS outbreak in 2012 (MERS-CoV) was also a coronavirus, although a different type. (see below for more about these diseases).
  • It is a virus, not a bacterium. Therefore antibacterial disinfectants will (probably) not be effective. Alcohol (70%) and hypochlorite (bleach) will kill it.
  • Coronaviruses in general are not uncommon – for example, they are estimated to cause about 10% of colds.
  • The genetic material of coronaviruses is RNA, not DNA. This is significant because RNA genomes tend to mutate more rapidly.
  • The RNA is contained in an envelope, which is surrounded by an array of spikes. These are glycoproteins (proteins with sugar molecules attached). The spikes are necessary for attachment to human cells, by binding to specific receptors. The spikes are the likely target for an immune response,
  • After attachment of the virus, the RNA enters the host cell and uses the protein synthesis machinery of the cell to produce the proteins needed for copying the RNA and formation of new virus particles.
  • The cell then dies and releases the new virus particles which go on to infect other cells.

B. COVID-19 and other coronavirus diseases

  • When you cough or sneeze, or, to a lesser extent, speak or just breathe, you shed droplets of various sizes. If you are infected, these will contain virus particles, depending on their size. Bigger droplets are more likely to contain virus.
  • The larger droplets will fall quite quickly (and may contaminate surfaces); smaller ones may remain airborne for some time. These droplets are mainly water. Because of the large surface-volume ratio, the water evaporates readily, forming tiny ‘droplet nuclei’ which can consist of a virus particle and not much else. They may remain airborne for a long time.
  • Incidentally, those droplet nuclei are too small to be intercepted by a mask, so even a well-fitting mask will offer imperfect protection against infection. However, the particles emitted by an infected person are larger, and can be intercepted by a mask. So wearing a mask will reduce the infectivity of someone with the disease.
  • For most respiratory pathogens, it is these droplet nuclei that are the problem, as they are small enough to bypass the mechanical barriers in the respiratory tract and penetrate right into the lungs. SARS-CoV-2 seems to be unusual in that picking it up from contaminated surfaces seems to be more common, and also in that it can infect through the eyes. Hence the advice to decontaminate surfaces and wash your hands frequently
  • The vast majority of infected people show few if any symptoms. This may be due to a level of non-specific immunity to coronaviruses, from previous infections with other coronaviruses, and/or the body’s natural resistance to infection.
  • A small proportion develop severe disease, and some die. In part this it thought to be due to an over-reaction by the immune system. Most of those who die have some underlying health condition, including reduced immunity and pre-existing respiratory tract conditions.
  • There is uncertainty about the real mortality rate (primarily because of uncertainty about the actual number of infections), but the general consensus is that it is about 1%. The mortality rate increases with age, from 50 onwards. This could be due not to age itself but the higher prevalence of underlying conditions, especially the reduction in immunity as you get older.
  • SARS (Severe Acute Respiratory Disease) started in China in 2002. There were over 8000 cases, mainly in China and Hong Kong, plus a number in other countries in the region (e.g., Taiwan, Singapore, Vietnam.) Apart from an outbreak in Canada (257 cases, traced to a traveller from Hong Kong), there was only a sprinkling of cases in the rest of the world. The apparent mortality was quite high (about 10%).
  • MERS (Middle East Respiratory Syndrome). The first case was identified in Saudi Arabia in 2012. Most subsequent cases were in Saudi Arabia, plus smaller numbers in other middle-Eastern countries. There were few cases elsewhere in the world. The disease has reappeared repeatedly in Saudi Arabia, and there was an outbreak in South Korea in 2015 (traced to a man who had visited Saudi Arabia). MERS appears to be more severe, with mortality rates estimated as high as 40%.
  • Why have SARS and MERS (in contrast to COVID-19) not spread more widely? That is a very interesting question, and I wish I knew the answer!

C. Testing

  • The commonly used test is a molecular one technically known as RT-PCR (Reverse Transcriptase- Polymerase Chain Reaction). This copies the RNA into DNA and then amplifies it to an extent that it can be detected. It is very sensitive, but it detects the RNA and not the whole virus. So you may remain positive for a short while after the virus has been eliminated, and you are therefore no longer infectious. Conversely, it may not pick up the infection in the very early stages, when only a few cells are infected.
  • This test requires sophisticated materials and equipment, and skilled technicians. All of these are in short supply, which limits the number that can be done. Some countries were better prepared than others and/or were quicker to react and get everything in place.
  • How important is testing? It is useful for essential staff (esp NHS workers) to know whether or not they are infected, so they can continue to work. Widespread testing would be useful, as getting a better handle on the actual number of cases would inform policy decisions, but I’m sceptical as to how important this is. The traditional view, that finding cases enables the identification of contacts who can then be quarantined, becomes untenable with large number of cases, at least without a degree of surveillance that might well be unacceptable except under authoritarian rule.
  • A different test, that relies on the detection of specific antibodies, is much discussed. Such tests are being evaluated. However, they tell you whether someone has had the disease, not whether they are infected.

D. Interpreting the data

  • We are showered with statistics – numbers of cases or deaths, in various countries. These are a few points to consider when we look at those numbers, especially when comparing data from different countries.
  • Are the numbers adjusted for the population size? Very often they are not, or they don’t say one way or the other. Clearly, a large country would expect more cases than a small one.
  • Do they refer to the cumulative number (the total number of cases/deaths during the epidemic) or the number that day/week?
  • If considering the number of cases, the definition of a ‘case’ may vary between countries. In particular, consider the impact of testing. A country like Germany (which is doing a lot of testing) will identify a large number of cases with few if any symptoms that may not be counted by other countries – and hence will be expected to have a large number of ‘cases’.
  • The number of deaths is often regarded as a more reliable comparison, but this may also have problems. Does it include those who die outside hospital? And remember that many who die as a result (probably) of coronavirus infection actually die from e.g., pneumonia, heart failure, multiple organ failure, etc. How are these deaths recorded? Procedures may vary between countries.
  • To overcome these difficulties, it is best to look at the trends in different countries, i.e., the number of cases/deaths over time. This assumes that the practice in each country is consistent, which is not always true – the UK figure of deaths suddenly jumped today (3 April) after a change in reporting procedure.
  • Bear in mind that there is a delay between ‘cases’ and ‘deaths’ – so you might expect the death rate to continue to go up while the infection rate is levelling off.
  • The trend line will also show where the countries are on the epidemic curve. Italy for example had its first case earlier than Germany did, so comparing those two countries needs to take account of that, in effect looking at where Italy was a short while ago.
  • When considering deaths, it is important to remember that many deaths are among the very old or those who have other serious conditions. Trying not to be callous about this, we have to remember that some of them would be expected to die anyway in any given period. To get a true picture of the impact, we should look at excess deaths – i.e., the number of deaths above the number that would be expected to happen anyway. Bear in mind that there are normally about 0.5 million deaths per year (England and Wales).

E. In defence of ‘herd immunity’

  • The course of an epidemic is determined by a parameter known as R, the Reproduction Number, which is the number of people infected by a single case. At the outset, for COVID-19, R has been estimated as about 2.5.
  • R itself depends on a number of factors; I’ll just consider two of them. Firstly, the number of contacts a person has while they are infectious, and secondly how likely it is that those contacts are actually susceptible to the virus.
  • ‘Social distancing’ (or in extreme cases, isolation) is obviously a way of reducing the first of these.
  • The second factor comes into play when a significant number of people have had the disease (and are, we hope, immune to re-infection). This is the natural way in which an epidemic becomes self-limiting. As more people become infected, and hence immune, R falls. When it gets down to less than 1, the epidemic stops, even though there are a number (possibly a large number) of people still susceptible. This is ‘herd immunity’.
  • The point at which herd immunity kicks in (the Herd Immunity Threshold or HIT) is related to the initial value of R (Ro). Mathematically, the proportion still susceptible at the HIT is 1/Ro. So, if Ro is 2.5, we would get herd immunity with 40% still sensitive, or 60% having been infected. That’s a lot of people. But if we combine it with other measures, effectively reducing the value of Ro, say to 1.5, we get herd immunity after 33% have been infected. And if we reduce Ro still further, to 1, then we get herd immunity straightaway.
  • This is all a gross simplification! In particular, it assumes a homogeneous population, which is obviously not true. Someone living in London, especially if they still travel on public transport, will pass on the virus much more often than someone in the Highlands of Scotland. But it demonstrates the principle.

I hope this all makes sense. If you want to ask anything, or disagree with me, feel free to email me. You might also like to read my book Understanding Microbes which amplifies some of the basic issues (although not COVID-19 as it was published in 2013)