COVID-19 – a bit of perspective: update

An update

According to ONS, in the week up to Sept 11th, there were 9,215 deaths from all causes in England. Of these, COVID-19 accounted for 97 deaths – that is about 1% of the total. Of course, we would expect that figure to rise as the number of cases increases. For the whole period of the epidemic (up to Sept 11), COVID deaths (52,482) account for about 12% of the total number of deaths (434,618) in England and Wales..

If we assume a case fatality rate (the number of deaths as a percentage of the number of cases) of 1%, this means that just under 9% of the population have been infected.  But we don’t know the case fatality rate for sure; I have seen estimates that put it as low as 0.3%. If that is true, then the number who have been infected (England and Wales) would be as high as 17.5 million, or 29% of the population.  That would mean, given the highly uneven spread of cases, that there would be some areas that would, at some point during the ‘second wave’, approach the level required for herd immunity to kick in (usually taken as about 60%).

Jeremy Dale 25/9/20

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

Moonshine Project

Is it a good idea to regularly test the whole population for infection with SARS-CoV-2?

Superficially, you might well say the answer is ‘Yes, obviously’. But I want to look at it in more depth.

First of all, obviously, there are the practical considerations. The current system, fragmented as it is (some would say deliberately fragmented between the private and public sector), is proving to be quite unable to cope with testing those who really need it. And the tracing aspect is even worse. Remember when you hear the figures quoted, e.g., 70% of infections are detected, and 70% of contacts are traced – that is 70% of 70%, or 49%. So even with the Government’s claims, only about half of potential contacts are traced. And it is far too slow – several days to get the test result, and several more days (often longer) to reach the contacts, who thus may have been spreading the disease for days before being told to isolate,

Secondly, it depends on technology that doesn’t yet exist. There is much talk about rapid tests that are being introduced. These are antibody tests, which only tell you whether someone has been infected at some time in the past, not whether they are currently infected, Antibody tests don’t give a positive result until the infection is, in most cases, over.

Leaving the practicality aside, let’s assume that somehow we do have a test that can be easily and rapidly done for vast numbers of people. Would it be a good idea then, to screen the whole population?

To answer that question, we need to look at some concepts related to the test. I should clarify that what I mean by ‘test’ is what happens in the laboratory with the sample you have provided. The other parts of the process – taking the sample, transmitting it to the lab, and reporting the results – all have their problems, but I’m not considering those.

No laboratory diagnostic test is perfect. Biological systems are very complex, and all sorts of things can lead to a ‘wrong’ result. This can mean that someone who is infected gives a negative result (a ‘false negative’). For example, there might be something in the sample that interferes with the test process. The ability of the test to detect real positives is referred to as the sensitivity, which is defined as the number of positives detected divided by the number of true positives.

The other side of the coin is the specificity, which roughly means the ability of the test to correctly identify someone who is not infected. This is defined as the number correctly identified as negative divided by the number who are really not infected. This gives us a measure of how often we would get a false positive – i.e., a positive test result for someone who does not have the disease.

Now we can look at what this means in reality. Let’s assume we have a test that is 99% sensitive and 99% specific. That would be regarded as a really good test. And let’s assume we have a prevalence of 1 in 1,000. So, in a population of 100,000, there would be 100 cases, and the test would detect 99 of them. That’s not bad. The crunch comes with the specificity. In this situation, the test would return a positive result for 999 people who do not have the disease (false positives). In other words, there would be about 10 false positives for every correctly identified positive. If we scale that up to 60 million people, there would be nearly 600,000 people who would be told they were infected when they weren’t. Would they all have to isolate themselves? And even thinking about contact tracing on that scale gives me a headache.

These considerations apply to all occasions when you are screening random samples for some relatively rare event, whether it’s screening donated blood for an infectious agent such as HIV, or mass screening for cancer. The standard way of dealing with it is to use two independent tests. So, you take all the samples that gave a positive result in the first test and re-test them, with a different test. (It has to be a different test as the reason for the ‘wrong; result might be inherent in the sample). If you did that, with the above example, then after re-testing all the positives from the first test, you would find that fewer than 10% of the positives would now be false positives.

In effect this is what happens when you use a test to confirm a clinical diagnosis, or if you are applying a COVID-19 test to people who have symptoms. The clinical picture is the first test, giving a group of people who are much more likely to have the disease than the general population is.

Is a two-step procedure feasible? It could be argued that the first step could use the hitherto unknown and entirely conjectural rapid test, and the positive samples submitted to the existing PCR-based test – but only if this hypothetical new test was something entirely different. And it would still demand adding an additional 600,000 samples to the existing testing workload. Since that system is currently unable to meet the present demands, this seems unlikely.

If you would like to see the calculations I have used, and play around with them, send me an email and I’ll send you the spreadsheet.

Jeremy Dale

20 Sept 2020

COVID-19 – a bit of perspective

An update

According to ONS, in the week up to Sept 11th, there were 9,215 deaths from all causes in England. Of these, COVID-19 accounted for 97 deaths – that is about 1% of the total. Of course, we would expect that figure to rise as the number of cases increases. For the whole period of the epidemic (up to Sept 11), COVID deaths (52,482) account for about 12% of the total number of deaths (434,618) in England and Wales..

If we assume a case fatality rate (the number of deaths as a percentage of the number of cases) of 1%, this means that just under 9% of the population have been infected.  But we don’t know the case fatality rate for sure; I have seen estimates that put it as low as 0.3%. If that is true, then the number who have been infected (England and Wales) would be as high as 17.5 million, or 29% of the population.  That would mean, given the highly uneven spread of cases, that there would be some areas that would, at some point during the ‘second wave’, approach the level required for herd immunity to kick in (usually taken as about 60%).

Jeremy Dale 25/9/20

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 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