Posts Tagged ‘covid19’
stuff about Omicron
testing queue in New York, early December
Canto: So we seem to be getting good news about Omicron from the researchers, even if it’s been rather muted by the media, the intermediaries between the research and the public. Of course, since there’s still something out there that’s highly transmissible and generally treated as SARS-CoV2, the deadly virus that’s killed almost 5.5 million people (according to data that’s only as reliable as its sources, which would be highly variable…
Jacinta: We’re using the worldometer covid-19 statistics, which has a very slightly higher death toll than the WHO. The Johns Hopkins death toll stats are also very similar, slotting between WHO and worldometer.
Canto: … and since we’ve been living with this deadly virus for almost two years now, everybody’s pretty spooked about new variants, as well as exhausted by all the lifestyle disruption – which for some is the least of their worries.
Jacinta: Yes, they might be mourning the death of loved ones or living with the after-effects of infection. But here in Australia we’re very low in the number of cases – 82nd in the world – and even lower in per capita death rate, at 168th. Currently we have just over 115,000 active cases, but just over 0.1% are described as serious or critical.
Canto: Well that massive gap between case numbers and serious, hospitalised covid-19 sufferers seems to be a story of Omicron.
Jacinta: Yes, looking at yet another data source, Our World in Data (all these sites can be easily googled), we can see graphic proof of Omicron’s rapid spread.
Canto: Yes, this scenario has been more or less duplicated in South Africa, the UK, just about everywhere that Omicron has taken hold. But it’s a very different beast from previous variants, and this post is an attempt to comprehend that more fully.
Jacinta: You jokingly referred to it at first hearing as the Omygod variant, but we’re thinking about it very differently now. But before we get into amateur microbiology, there are other stats to mention. As of 4 days ago, December 27, over 77% of Australia’s covid19 cases were Omicron, compared to 13% two weeks before, on December 13. It will surely be over 80% now. It is displacing the Delta variant, and the importance of this development can hardly be understated.
Canto: So we need to understand Omicron fully, or as fully as we can given our General Ignorance and the fact that research is obviously ongoing.
Jacinta: So this variant, which appears to have first sprung to viral life in Botswana, has mutated much further away from the original or most thoroughly spread early strain of SARS-CoV2, and this appears to be to our advantage. We’ve been following Dr John Campbell’s own analysis of data coming from South African research…
Canto: As well as watching the Medcram series of videos, designed, as the title suggests, for medical students of epidemiology, virology and such, but in terms even we General Ignoramuses can understand. Dr Roger Seheult has made over 130 of these videos, and we’ve watched over 100 of them, so hopefully it’s all in our heads somewhere.
Jacinta: Omicron appears to be so different from previous variants that it’s like a different disease, or perhaps we might say, a different condition. Obviously it’s spreading very fast, with an r number of between 3 and 5, but that number may already be out of date. And the rapid spread appears to be due to the way it affects the upper bronchi. Here’s the low-down from the University of Hong Kong’s faculty of medicine.
The researchers found that Omicron SARS-CoV-2 infects and multiplies 70 times faster than the Delta variant and original SARS-CoV-2 in human bronchus, which may explain why Omicron may transmit faster between humans than previous variants. Their study also showed that the Omicron infection in the lung is significantly lower than the original SARS-CoV-2, which may be an indicator of lower disease severity.
Canto: Yes, that indicates that this variant is very different. Geneticists have long been analysing differences in the variants, especially changes to the spike protein, but apparently the Omicron variant has about 20 mutations outside the spike gene, which may have a variety of impacts on our immunity. Researchers are scrambling to study all the mutations to see how they reinforce or counteract other mutations.
Jacinta: There’s been a focus for some time now on a viral protein called ORF9b, which is a mitochondria-targeting immunosuppressant. Clearly we’ll be in over our heads if we’re not careful here, but having read the abstracts of various research articles, what I’ve found is that ORF9b ‘immediately accumulates and antagonizes the antiviral type I IFN [interferon] response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells’, to quote from one article.
Canto: But Omicron, I’ve read, isn’t so much getting to those alveolar epithelial cells. Faster in airways, slower in lungs is the populist version. Or to be more ‘precise’, 70 times faster in upper airways, 10 times slower in lungs.
Jacinta: Well, slower doesn’t mean never. And this variant may well vary… none of this is predictable, which is why I tend to be more sympathetic than many to public health spokespeople and politicians as they try to give the best advice and develop the best policies for public safety.
Canto: The way it works in the airways helps to explain Omicron’s extreme transmissibility – we’re breathing and coughing it out all the time when we’re infected. They say we’re all going to get it, so the choice might be permissibility – let it spread and get it over with – or caution – flatten the curve with a tightening of mask-wearing, with better masks, and physical distancing, and boosters.
Jacinta: I don’t think too many governments will go the permissive way – everybody’s too spooked by this pandemic. And I notice that most media outlets are almost delightedly reporting on the huge spike in covid cases, without too much nuance. And of course there are people with comorbidities and weakened immune systems that would be put at risk.
Canto: But the spruiking of vaccines and boosters, and the lack of advice on prevention and general health, is striking. Pharmaceutical companies are making huge amounts of money in this period. The Biden administration is paying Pfizer $5 billion for their new covid pill, for example. I haven’t forgotten my reading of Ben Goldacre’s Bad Pharma. I wonder what he’s thinking of all this.
Jacinta: To be fair, the pharmaceutical companies and the research virologists have been amazing in what they’ve come up with to meet the crisis. Surely it’s the so-called ‘vaccine hesitant’ sector, the numbers of which have grown so alarmingly, that’s the biggest headache at the moment. Who’d of thunk that a virus that’s killed five and a half million and counting, and which has produced record-breaking responses in life-saving immunological technology, would lead to an outbreak of anti-science fanaticism?
Canto: Mmmm. Having met people in the teaching profession who’re convinced that the moon landings were a hoax, and that the September 11 attacks were an inside job, I have to wonder. It doesn’t seem to be a lack of basic education. There’s a strange willingness to think in contrarian terms, for some. It doesn’t seem to be group-think either, and yet… they couldn’t have come up with these notions themselves, they must have been somehow captured, ideas-wise.
Jacinta: Anyway, I think we’re in an interesting phase of the pandemic. Optimists are calling it the beginning of the end, while others are cautiously watching the relationship between cases and hospitalisations and deaths over the next few weeks. Currently, the figures are totally confusing. Australia has seen a massive spike in cases, and a small increase in deaths over the past few days. In Russia – and I don’t much trust figures out of Russia, obviously – there have been about half as many cases over the same period, but more than a hundred times as many deaths! Presumably they’re still dealing with the Delta variant, but who knows – it’s hard to find figures connected to variants.
Canto: We’re having problems with outbreaks in remote indigenous communities, with low immunisation rates and probably low rates of previous covid infections. It makes me think, probably too dramatically, of how smallpox hit the indigenous community here when it was brought over by Europeans a couple of centuries ago. The Europeans had some immunity, but it was new to the Aborigines, otherwise noted for their health and fitness. About 70% of the indigenous population that was exposed died, in horrific circumstances.
Jacinta: Yes, that’s a bit dramatic, but an important lesson about the dangers of exotic pathogens. Our immune system can’t be prepared for everything that’s out there.
Canto: Omicron also seems to be infecting young children much more than any previous variant, partly because they haven’t been vaccinated as much, but there might be more to the story. In any case, it seems that, though there is ‘immunity escape’ with Omicron, vaccines appear to offer greater protection than previous infection, so again it’s the unvaccinated that will be hardest hit. And I’m at last getting my booster tomorrow. Yay!
more on rapid antigen testing, and the vaccine race
So to continue with this issue of rapid at-home testing, there are/were many tests of a more simple and potentially cheaper type being manufactured, but they were all diagnostic tests (i.e tests that require expert interpretation as part of a diagnosis), and even if they’d been scaled up fairly rapidly they wouldn’t meet the kind of demand Dr Mina was envisaging. That’s to say, not doubling the tests available but multiplying those tests by a hundred or more, for nationwide availability in the US.
I want to get clear here, for myself, about the difference between an antigen test and a PCR test. An antigen test detects viral proteins. The paper strip test Dr Mina refers to contains antibodies that will bind to the antigens, or proteins, if those antigens are present in sufficient numbers. The presence of those antigens, or viral proteins, indicates that the virus is active – it is producing the antigens via the ribosomes of host cells. The PCR test detects viral RNA, whether or not the RNA is active. And so the antigen test reveals infectivity. The PCR test more often than not finds inactive viral fragments, since this RNA remains in the cell for some time after the period of infectivity, the upswing, which is relatively short.
Dr Mina has this to say about the sensitivity of the two test types. The PCR test will pick up virus from a few days to six weeks (or more) after infection, but the subject may be infective, that is, able to spread the virus, for the first two weeks (or less) after acquiring it. So its sensitivity to detecting an infective subject is not so great as its sensitivity to the virus itself (living and reproducing, or dead, or disabled). An antigen will be testing negative, both in the very early phase of infection, when the virus isn’t yet producing enough viral protein to show up on the test, and in the long phase when the virus, or parts of it, are still present but no longer replicating and infecting. So it is actually more sensitive to infectivity, which is exactly what’s required. And this essentially has to do with the frequency with which the antigen test can be used, because the PCR test has this lag time built into it.
It’s hard to believe that it’s this simple and straightforward, and that supposedly smart regulators aren’t jumping on this and getting these tests out there. Could I be missing something? I note that Dr Mina uses transmissible rather than infective, by the way.
So why aren’t such tests available? In the USA, it’s because it sounds a lot like a diagnostic, which requires approval or licensing from an organisation called CLIA – but that’s for them to work out. As to the situation here in Australia, which hasn’t had to deal with anything like the mess they’ve made for themselves in the USA, such a testing system would still help to detect spreaders, providing there was blanket use, and this would mean fewer lock-downs and less economic impact. As would be the case globally. An ABC article from late October features an interview with Prof. Deborah Williamson, director of clinical microbiology at Melbourne’s Doherty Institute, who recognises the value of rapid antigen testing, but feels that we need ‘to better understand their effectiveness as a screening tool in different epidemiological contexts’. This is understandably cautious, but then there isn’t the urgency in Australia that there so obviously is in the USA. But the USA has another major problem, which is almost incomprehensible considering the disaster that has unfolded there – and that is lack of compliance. Even if rapid antigen testing – cheap and in such supply that it could be utilised on a daily basis by the whole population – even if this was made available, there’s surely a major question as to whether most people would use the test any time they looked a bit peely-wally [under the weather], let alone when they were completely asymptomatic. So you could say that Americans are paying the price for their ‘rights without responsibility’ ideology – not shared by all Americans of course, but apparently shared by too many for them to escape from this, or any other pandemic, lightly.
Anyway, if we imagine a world, or a country, of largely compliant, responsible individuals, and widely available, cheap or free antigen testing, there would be no need for the quite onerous contact tracing mechanisms that we now have – signing in by phone or by hand at restaurants, pubs and the like – because those testing positive at home wouldn’t be attending those places until they tested negative again. Businesses could run, schools, airlines, etc. Economies could function almost as normal.
Of course now we have the vaccine, or almost. So far though it’s the Pfizer/BioNTech two-shot vaccine, which needs to be kept at way below zero (celsius) temperature, so, difficult to scale up and make available to those without proper facilities. No sign of that one coming to Australia for a while. I read an article yesterday, ‘The Amazing Vaccine Race’, in Cosmos mag. It outlines some of the contenders – the companies and the vaccine types. It points out that some companies are trying to play the long game, to try not for the first vaccine, or one of the first, but the best. The problem though, says, Nicolai Petrovsky, whose company Vaxine is based here in Adelaide, is that ‘the first runners end up getting all the resources’. And it may take quite a while to work out the best, and if the early runners turn out to be good enough, we may never find out which would’ve been the best. Vaxine is currently trialling a covid19 vaccine which combines the virus’s spike protein with an adjuvant (a treatment which enhances the immune response of the vaccine) based on a plant polysaccharide. And there are some 160 other contenders, according to the article. One in Sydney is combining the spike protein with bacillus Calmette-Guerin (BCG) which has been shown to reduce mortality from a range of viral respiratory infections. And there are others, just sticking with Australia, some with a degree of complexity that defeats me, for now. However, there are scant resources for local production here.
Although phase 3 trials of the current front-runners tested for safety among many thousands, it’s unlikely that scaling up to the millions will be without casualties, however minimal. And there’s the question of long-term immunity, which can’t really be tested for in this rushed situation. So it will be very interesting to see which of the current contenders wins out in the ultra-long run, or if something we’ve barely heard of yet finally proves the best option.
References
Rapid Coronavirus Testing – At HOME (COVID-19 Antigen Tests) with Dr. Michael Mina (video)
https://www.abc.net.au/news/health/2020-10-24/rapid-antigen-tests-for-coronavirus-screening/12808176
Dyani Lewis, ‘The Amazing Vaccine Race’, in Cosmos: the science of everything, issue 88, September-December 2020.
the rapid testing system that went begging
this is a screen shot taken from the video – the Ct values are inversely proportional to the viral load, and are plotted on a logarithmic scale (not drawn to scale though!). the x-axis is the infection time scale. viral particles can remain in the host for some time
For something completely different, I want to return to the matter of this pandemic, which in the past 24 hours has claimed more reported deaths in the USA since it began – a disaster of mismanagement, neglect, and of course the selfish civil disregard so typical of that country.
But of course that’s a generalisation, there are plenty of productive, socially concerned, often frustrated individuals trying to buck the trend, and Dr Michael Mina is one of them. He’s been advocating for a type of cheap, home-based, fast turnaround test for this virus (actually for the proteins that the virus produces via the host’s own ribosomes) which would vastly reduce spread, eliminate the need for contact tracing, and help the economy. Had this type of monoclonal antibody testing been scaled up at the outset, and made available worldwide, it’s likely that countless lives would have been saved. And it may well be generalised for other outbreaks.
So I’m writing this based on a video I watched, called ‘Rapid Coronavirus Testing – At HOME (COVID-19 Antigen Tests) with Dr. Michael Mina’. The video was produced in late July, and of course no progress has been made, and in the US the case numbers and the death numbers have jumped to the highest so far recorded, and rising.
So Dr Mina is a well-qualified immunologist whose impressive bio is detailed in the video. His ideas on this topic are published in a paper entitled ‘Test sensitivity is secondary to frequency and turnaround time for Covid-19 surveillance’, which has eight co-authors. The title captures the whole argument really, but I want to clarify to myself and others these issues of sensitivity and frequency. The video begins with a point-by-point comparison of the ‘paper antigen testing’ Dr Mina advocates, and RT-PCR (reverse transcriptase – polymerised chain reaction) tests, which are currently considered the gold standard. Firstly, the antigen tests are potentially much cheaper, once scaled up, and can be made for $1 to $2 per test. The PCR tests currently cost between $35 and $100 each. Secondly, the result of the antigen test can be known in 15 minutes, while the PCR test takes a minimum of 3 days, sometimes 7 days or longer. Third, the antigen test can be self-administered at home, while the PCR cannot. Fourth, the antigen test can be used daily, or three times a week, or with as much regularity as can be wished for or afforded, whereas this isn’t really viable for the expensive PCR test. Fifth, the simple antigen test can easily be mass-produced, but the lab processing involved in the PCR test would make this difficult. The sixth comparison favours PCR, which has a high sensitivity at over 90%, meaning that if there’s any virus present, it is over 90% likely to detect it, whereas the antigen test has a likelihood of around 55%. However, the antigen test will be able to pick up the majority of infectious cases, which is the key requirement. This will be explained later.
As Dr Mina points out, the rapid antigen test is a public health measure, unlike vaccines and therapeutics, which are medical interventions. The vital point he is making is that much investment is being put into the medical interventions, which, if successful, will bring solid returns on those investments. And so that is why so many private firms are competing for producing these ‘quick’ and hopefully effective, fixes, whereas there’s no return on investment for a public health measure such as a rapid, effective testing regime, even though this would be the best thing for keeping an economy running during a pandemic. It would require effective, good faith governance – something in short supply, particularly in the US.
So there’s a lack of financial incentive to scale up this rapid testing system, and according to Dr Mina, there’s also a regulatory problem. There’s no technical problem to scaling up, but as Mina says, there is a grey zone for this kind of testing which means it doesn’t quite fall under FDA’s guidelines, and there seems to be no governmental will (given that the USA currently has no federal government, and hasn’t really had one for four years) to provide a regulatory pathway for this kind of unique public health tool. FDA or other authorised approval is essential for mass-manufacture, and this isn’t forthcoming. As Mina says, this isn’t a diagnostic test, and isn’t meant to compete as a diagnostic test, it’s meant as a public health measure to prevent spread. So it’s a human and political problem, and this period in the USA is obviously bad for that sort of thing.
So the regulators appear obsessed with high-sensitivity testing, which tends to be expensive. If PCR testing could be done cheaply, at home, with rapid turnaround, that would be ideal, bit it isn’t going to happen, for a variety of reasons. This sensitivity issue needs to be looked at more closely, in the context of a rapidly multiplying virus, within a particular host. The rapid antigen tests may be a thousand times less sensitive than PCR, which sounds useless but not if you understand the virus and its action. It starts with a tiny number of parts per millilitre, and when it gets to a larger number, the PCR test will pick it up, and then when it gets much larger still, the androgen test will pick it up. But even then, the viral load will not be enough to effect transmission (and this will vary between individuals). And the whole aim is to prevent transmission, rather than the virus itself. The antigen test will tell you that you are transmitting (more later), and is effective in stopping or breaking that transmission chain. Testing frequency becomes more important than sensitivity. PCR tests conducted weeks apart could miss a whole infection cycle.
The FDA at the time had a news release entitled ‘FDA posts new template for at-home and over-the-counter diagnostic tests for use in non-lab settings, such as homes, offices and schools’, which sounds like just what the doctor ordered, but Mina points out that, though the regulators are showing willingness to relinquish testing power to members of the public to some degree, they’re clearly not willing to swap what is in essence a lab-based, PCR-type test, with all its super-sensitivity, for a rapid antigen test. So, no real possibility of rapid turnaround, and they require reporting of all positive and negative tests to the relevant lab or the Department of Health, rather than at-home monitoring. Among other things that means more work and more expenses for the monitoring company. Most results would obviously be negative, so a great deal of logistics to cover every negative result, which people probably wouldn’t comply in reporting anyway. So, not very viable. Dr Mina compared it to cheap instant coffee compared to those super-expensive Nespresso coffee machines that presumably the elites buy. The instant coffee version does the job without the bells and whistles, and he believes it’s the best intervention possible, short of a vaccine.
And that was in July, and the current death rate and case rate are breaking all records, but of course a vaccine is round the corner – maybe. So the moment has probably gone, but the lessons still need to be learned, by a more responsible administration. I will keep on this topic for the next couple of posts.
Reference
Rapid Coronavirus Testing – At HOME (COVID-19 Antigen Tests) with Dr. Michael Mina (video)
covid19 – the European CDC shows the way
poverty and crowding in Peru – BBC picture
Canto: The US response to the pandemic continues to be massively hampered by political muzzling of and interference with the science, especially at the federal level, but the Medcram updates continue to inform us, and to be, or pretend to be, indifferent to this political interference.
Jacinta: Yes, and update 109 has introduced us to the European CDC’s website, which provides us with a wealth of information, on the progress of the pandemic itself in European countries, but also in the political response to it, and how those two things interact.
Canto: The country overview page, and it’s currently updated to week 39 of the pandemic, is as data-rich as anyone can imagine, a statistician’s wet dream, but interpretation of the data needs to be handled carefully.
Jacinta: Dr Seheult does some interpretation of some of the data in his medcram update 109, but there’s so much more in there, and so much more to say. So let’s take a European country at random – Denmark – and look closely at the stats.
Canto: But before that, let’s look at some general European trends they report. It’s fascinating:
By the end of week 39 (27 September 2020), the 14-day case notification rate for the EU/EEA and the UK, based on data collected by ECDC from official national sources, was 113.6 (country range: 9.9–319.9) per 100 000 population. The rate has been increasing for 70 days.
So the EU is the European Union and the EEA is the European Economic Area. I’m not sure what is meant by ’14-day’ but I presume the case notification rate is simply the case rate, as far as they can ascertain from the data supplied to them – the cases they’ve been notified about. It’s good that they make that distinction, shifting the onus on the notifiers. So it’s 113.6 cases per 100,000 population over the whole region, and has been rising for over two months – a second wave.
Jacinta: I think ’14 day’ just means the rate over the previous 14 days. They report every seven days for the previous 14 days, so there’s a 7-day overlap. That data is not only dependent on the reliability of particular reporting countries, it’s also dependent on testing levels, obviously. So in the general trends they tell us which countries are doing the most testing. Highest is Denmark, followed by Luxembourg, Iceland, Malta and Cyprus. Small countries, unsurprisingly.
Canto: With all this, it’s interesting from Dr Seheult’s analysis of the data that the death rate isn’t mapping with the case rate, thankfully, and that the age of people contracting the virus in the second wave is much lower, which seems weird.
Jacinta: Probably explained by an increase in testing since the early days. Now they’re catching milder and asymptomatic cases. It suggests, of course, that the case rate was much higher during the first wave, when the testing regime was still being put together. So let’s look at Denmark, and now we have data for week 40. There are four graphs, and in the first we see the case notification rate experiencing a big bump peaking in April with the death notification rate mapping pretty closely with that bump. Then there’s a gradual falling away in both figures, until August when the case rate starts to rise again, but not the death rate. Then in September that case rate rises very sharply, rising well above the April bump, though in the last week it seems to have leveled off at this high level. But the death rate has stayed pretty well level and quite low. Now that raises questions that the other graphs might help to answer. The second graph looks at the testing rate – tests per 100,000. The testing rate was pretty flat and low from February into April, but after the April rise in cases the testing began to rise from late April into May. It flattened and even dipped a bit into June. It stayed fairly steady through the northern winter, but of course at a high level compared to the earliest period, then it started to rise in August, presumably in anticipation of a rise in cases as the colder weather arrived. That rise in testing peaked at a very high level in late September, but has dropped quite sharply in the the last week or so.
Canto: Interesting, so that does strongly suggest a sharp rise in mild cases being ‘caught’, and presumably dealt with, as the death rate hasn’t spiked at all.
Jacinta: Yes, though we don’t know how well those cases have been dealt with – people are talking about ‘long covid’, people possibly having long-term issues. The two graphs don’t really give us granular detail – hospitalisation rates for example. So the third graph breaks the notified case numbers into age groups, and the results are fascinating. The first wave bump shows that most of the cases recorded were in the older age groups, particular those at 80 or over. There were cases in all age groups, but very few under 15. However, in the second wave, the cases found were predominantly in the young. In fact the 15-24 age group was way out in front, followed by the 25-49 group. Even the under 15s were well above the oldest age groups. So what does this mean? It seems to suggest that the older, and perhaps wiser, are recognising the dangers, especially to their age group, and taking fewer risks, and that the younger are still not very sick but can be carriers of the virus and more than ever a danger to the older generation.
Canto: I wonder is Denmark ‘typical’ in this regard?
Jacinta: There are variations of course, but the general trend is much the same. The fourth graph shows test positivity – the percentage of people who tested positive. There was a massive spike in positive test results in March, up to around 16 -17%, but this dropped as sharply at it rose, due presumably to the rapid rise in testing from that period. By May it was around 1% and it has remained much the same since, as the number of tests administered has never been higher, in spite of the recent drop I mentioned. It’s still much higher than it was pre-September.
Canto: But there are more than four graphs as we’ve found. We’ve looked at the data for notification rates and testing, there are other graphs which look at ICU and hospitalisation rates, public health response measures, and which break the nation down into specific regions.
Jacinta: Yes, it’s particularly important to look at public health measures – restrictions on mass gatherings, closures or partial closures of public spaces, workplaces and schools, the mandating or recommendations around face masks, and map them against notification rates, hospitalisations and so forth. The picture that emerges is generally pretty clear, though sadly some countries, such as the USA and Brazil, aren’t paying heed to the fact that public health measures save lives as well as a lot of suffering.
Canto: Well we should be talking about the governments rather than the countries, when we’re talking about public health measures. So I’ve assumed that the CDC in the USA has been hobbled by the Trump debacle, so I’ve gone to the Johns Hopkins site to see what detailed info they provide. Indeed they do have a lot of useful data both for the USA and other countries, though little on the effect of public health measures. An interesting graph they present on mortality shows that, in terms of deaths per 100,000 persons – and they show only the top 20 nations – Peru is on top, followed by Brazil, Ecuador, Spain, Mexico, the USA and the UK, in that order.
Jacinta: Well we know about the macho governments of Brazil, the UK and the USA – not that government is always entirely to blame, but it’s a key indicator – so what about the national governments of those other countries?
Canto: Well other key indicators would be the country’s wealth, or lack thereof, and its healthcare infrastructure, but as to government, Peru had a federal election in January this year – it’s a multi-multi-multi-party system with the most popular party getting only 10% of the vote. The result was that Martin Vizcarra retained the presidency. He appears to be a genuine reformist who has tried to implement stay-at-home orders, but widespread poverty and overcrowding are major problems there. Brazil we already know about. Ecuador’s current President is Lenin Moreno, a right-wing figure who has slashed government funding and seems obsessed with destroying political opponents. He has a popularity rating of 8%, according to an article in Open Democracy, and his mishandling of the pandemic has been extreme. Spain is a ‘parliamentary monarchy’, and its current Prime Minister is Pedro Sanchez, leader of a leftist coalition. Currently there’s a battle with right-wing local authorities, especially in Madrid, to enforce lockdowns as a second wave hits the country. So it’s the usual problem there of non-compliance, it seems. And Mexico is, as is I think well known, a country with a lot of poverty and a lot of problems. Its governmental system has long been a minefield – in fact I’d love to learn more about its chequered history. Currently the President is Andrés Manuel López Obrador, a veteran politician who has been a member of various parties and is essentially a political centrist. So again it’s about lack of political control, poverty, lack of services, overcrowding and so forth. As to the UK, years of conservative government have gutted the NIH, there has been a ton of mixed messaging from the top… I’m getting sick of all this. I want to go to Taiwan.
Jacinta: Hmm. How’s your Chinese? Things are pretty covid-safe here in South Australia. Here’s hoping a safe and effective vaccine is ready by next year, and some big improvements are made in certain countries, with a return to justice and human decency…
References
Coronavirus Pandemic Update 109: New Data From Europe As COVID 19 Infections Rise
https://www.ecdc.europa.eu/en/covid-19/country-overviews
https://coronavirus.jhu.edu/us-map
https://www.bbc.com/news/world-latin-america-53150808
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31955-3/fulltext
stuff on covid19 and immunology
Canto: Well it’s a great time to be living in quiet South Australia, with a global pandemic raging in many places elsewhere..
Jacinta: Particularly the US, which we’ve long been focussing on, maybe in a schadenfreude kind of way.
Canto: Yes or maybe in a lazy way, because we’re so inundated by American media, social media, cable news, the NYT, the WaPo, the Atlantic, Politico, the Medcram lecture series, it just seems easier to plug into US info these days. Which makes me wonder…
Jacinta: And all hell’s breaking loose with Trump having come down with covid19 and the misinformation machine starting to overheat. Currently – October 5 – according to the Worldometer figures, which we’ve been using since the start of the pandemic – the USA has suffered 214,611 deaths, more than a fifth of the world’s deaths by that database’s figures.
Canto: Yes, we’ve noticed that the US media always has figures a little below ours – I presume because they’re using the Johns Hopkins figures, which seem to have a time lag. We can’t say which is more reliable of course. Complete reliability for all sources is unlikely.
Jacinta: In any case the USA has spectacularly failed to get on top of this virus, and is still experiencing high case-rates and death-rates, though the variations between states are constantly changing, and tell their own complex story. Overall, though, unless something drastic happens, the US is on track to have suffered 250,000 to 300,000 deaths by the end of the year – and I haven’t accounted for the winter season.
Canto: Yes and that’s no outlier prediction, that’s just a very simple forward projection.
Jacinta: I’m half-wondering when the Trump administration will try to throw cold water – or bleach perhaps – at the covid figures, as they’ve tried to misinform with everything else to do with the virus, including Trump’s condition and the timeline of his infection. But I want to look at what we’re hearing from the Walter Reed medicos about his treatment, and more generally about immunology and the virus’ progress. From the figures, it doesn’t seem as if anything is working very effectively, but Trump will be getting treatment that isn’t widely available to anyone else in that country, and we’re getting no clear answers as to how he’s faring.
Canto: The treatment everyone’s reporting on currently is the ‘antibody cocktail’ produced by the drug company Regeneron. This was made available through an emergency use authorisation, and unsurprisingly there’s now demand pressure on the product. He’s also on the antiviral remdesivir, and the steroid dexamethasone, and it seems he’s been given oxygen, though medical and other experts have had to read between the lines of public announcements to work out what exactly is going on.
Jacinta: Yes, many experts suspect he’s been sicker than he’s been prepared to admit, and of course the Democrats and health officials are all wishing him well and ‘praying for him’ in their American way. Frankly, I hope he dies, for the simple reason that his death will likely save thousands of lives, as it will stem the flow of misinformation, and scare even his dumbest followers into wearing masks, physically distancing and generally starting to act sensibly and humanely. It will have been the best thing he’s ever done with his life. But enough controversy, let’s look at immunology and treatment. According to the NYT, Trump has also been taking Vitamin D, zinc, the hormone melatonin, and famotidine, an anti-heartburn medication.
Canto: So he’s fit as a fiddle, then?
Jacinta: Hmm. As we know, Dr Seheult on Medcram has spoken of the benefits of zinc and vitamin D, as well as remdesivir and dexamethasone, but none of these treatments have been subjected to rigorous clinical trials in relation to SARS-CoV2 as yet. It’s my guess that Trump himself is pushing the envelope to be treated with these drugs, though it could also be that he’s actually quite sick, as I’ve said. And unless he actually dies, it could be that we’ll never know.
Canto: He won’t die. Anyway, what about Regeneron, and these monoclonal antibodies?
Jacinta: Well we’ve talked about them before, but they’ve been mostly used in the past against cancer cells. In fact they’re finding uses in many medical fields but they’re tricky to manufacture, and would be expensive to roll out…
Canto: Actually I’ve heard some reports that it’s polyclonal antibodies they’re giving him. Is there a difference? I thought maybe because they were giving him a ‘cocktail’ of monoclonal antibodies, this amounted to polyclonal…?
Jacinta: Well, who knows what they’re actually giving him, but according to my reading, researchers have engineered (cloned) immune cells that produce specific antibodies – antibodies to a specific antigen, or more accurately, to the epitope, or binding site, of that antigen. That’s monoclonal antibodies. Polyclonal antibodies can bind to multiple epitopes, which sounds better but maybe they’re harder to manufacture in an effective form.
Canto: So these monoclonal or polyclonal antibodies are proteins, synthesised versions of proteins produced by the immune system. Is it that, due to the virus, the body is prevented from producing these antibody proteins naturally, or can’t produce enough of them, or what?
Jacinta: What I gather is that the response to the virus varies – some are producing antibodies, some aren’t. A report came out last week about Regeneron’s treatment, this ‘cocktail of two monoclonal antibodies’:
The company showed slides with detailed data from 275 infected people in a placebo-controlled trial that ultimately plans to enrol 2100 individuals who are asymptomatic or, at worst, moderately ill. The analysis divides patients into two groups: those who had detectable antibodies against SARS-CoV-2 at the trial’s start and those who did not, a so-called seronegative group. The monoclonal cocktail showed little effect on people who already had antibodies against the virus. But it appeared to help the seronegative patients, powerfully reducing the amount of virus found in nasopharyngeal swabs and alleviating symptoms more quickly.
So it appears to boost the immune system of those who haven’t, or haven’t yet produced antibodies to the virus. So, useful for those in the earliest phase of having contracted covid19. But all of this has to be more thoroughly tested – for example, would the treatment work as a general preventive?
Canto: There’s another company, Eli Lilly, which has been trialling a single monoclonal antibody treatment, with slightly different results – both companies have given low-dose and high-dose treatments, and Regeneron found no statistically significant difference, whereas Lilly found the high dose ineffective – which is good news as the lower dose will presumably be cheaper to manufacture, with fewer adverse effects, if any. The two companies have a slightly different approach to using their medications – though this might change in such a fluid situation. Regeneron is thinking of developing diagnostic tools to identify those most in need of the treatment, e.g those with the highest viral load, and those with low antibody levels (serology). Lily, on the other hand, are thinking that any covid19-positive people at higher risk – diabetics, overweight, or simply elderly – should be given the treatment, if possible.
Jacinta: In the meantime, the dangers of this virus are constantly being underplayed by this administration under pressure, clearly, from the Boy-King, while a large cluster of people who’ve had contact with him, either at the White House or on any of his jaunts around the country. Exactly who set off the cluster will probably never be known, because it sounds like they’re refusing, again under the orders of a clearly incompetent wee boy, to engage in contact tracing!
Canto: It’s a SNAFU to be sure. Apparently one of this number – 34 at last count – is gravely ill in hospital. It’s like we’re watching an episode of ‘Horrible Histories’ in real time. It’s good to see that the polls are predicting a landslide. That means if the actual numbers come in and it’s close, it may be to do with the dirty business Trump and the Republican ‘leadership’ appear to be trying on vis-à-vis voter suppression. And then all hell will break loose.
Jacinta: Hell will break loose no matter what happens. This next month or two will be a cracker for us non-Americans. We’re certainly living in interesting times. But seriously, my condolences to the American people.
References
https://www.sciencemag.org/news/2020/09/provocative-results-boost-hopes-antibody-treatment-covid-19
https://www.worldometers.info/coronavirus/country/us/
Coronavirus Pandemic Update 97: Vitamin D & COVID-19 Immunity, The Endothelium, & Deficiencies
Coronavirus Pandemic Update 77: Remdesivir Update; COVID-19 in Mexico
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released from UK
covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities
covid19: corticosteroids, male susceptibility, evaluating health, remdesivir, coagulation factors
from The Lancet, ‘the four horsemen of a viral apocalpse’
Canto: So short-course use of some steroids was being advocated in the medcram update 88, though without thorough RCT evidence.
Jacinta: Well, data was presented from the Oxford RCT on those on oxygen or on ventilators showing a statistically significant reduction of mortality from short-course (up to 10 days) low dosage of dexamethasone, a freely-available steroid medication. The study involved some 2000 patients, but only those severely afflicted were helped by the medication.
Canto: An interesting aside to the data is that in the study males outnumbered females by almost 2 to 1, and that accords with the overall ratio of male to female covid19 patients Dr Seheult is finding, which rather shocked me. Why would more males be coming down with the disease? Presumably that’s not the infection rate, but the rate at which they need to be hospitalised.
Jacinta: Yes, you’re right, according to this Australian site (unfortunately undated):
Reports continue to emerge that men are significantly more vulnerable to COVID-19 than women. The commonly held perception that more men smoke and this makes them more susceptible along with other lifestyle factors does not tell the whole picture. White House COVID-19 Task Force director Dr Deborah Birx highlighted a “concerning trend” that men in all age brackets were becoming seriously ill from the virus at a higher rate than women, including younger males.
They’re suggesting more research needs to be done on this gender difference, for health issues in general. Some are claiming that estrogen makes a difference. In any case I think cardiovascular problems are more common in males – but maybe not so much in younger males.
Canto: So update 89 is fairly short, and deals with US data about cases and deaths, most of it out of date now, and more on corticosteroids and the dangers of unsupervised use. Update 90 introduces us to a tool I’ve never heard of called ‘Discern’. Very useful for we autodidacts in helping us, for example, to enlighten our doctors as to our condition. Discern is a tool for evaluating internet health info, such as medcram’s updates on youtube, or anything else on youtube. The instrument asks you to evaluate the material according to 16 different criteria. Interestingly, this tool has been tested on covid19 material by a study out of Poland done in March. The results weren’t so good, especially for news channels.
Jacinta: Yes, physicians’ information did best – but of course we don’t go to news channels for health information, and we’d advise against anyone else doing so. The study evaluated the Discern tool itself and found it excellent, then used the tool to evaluate health information, specifically on youtube. Of course know that there’s ‘viral misinformation’ from various news outlets that gets posted on youtube. And good to see that the medcram updates were some of the most highly rated using the Discern tool.
Canto: So we’re now into reporting from early July with update 91. It starts by looking at a ‘covid risk calculator’ in which you can type in your age, gender, BMI, underlying conditions, waist circumference, and other data which you might need a full medical checkup to find out about (and that’s overdue for me), including, for example, %FMD, a measure I’ve never heard of, but which has to do with endothelial function.
Jacinta: FMD stands for fibromuscular dysplasia. The Johns Hopkins medicine site describes it as a rare blood vessel disease in which the cells of some arteries become more stiff and fibrous and less flexible. This leads to weakness and damage. Not sure how it relates to covid19 but surely any pre-existing blood vessel damage is a danger for those contracting the virus.
Canto: Right, so it’s unlikely anyone will know offhand their percentage of FMD. I don’t even know my HDL and LDL levels, never mind my HbA1c or lipids. I’d love to be able to take measures of all these myself, without visiting a doctor.
Jacinta: Typical male control freak. So all of this is to measure your risk of covid19 hospitalisation, ICU admission or mortality. Fun times. So next the update looks at Gilead, the makers of the antiviral remdesivir, who donated all their supplies of the drug to the USA in early May. But of course they kept manufacturing the drug and have to recoup the money they spent researching, developing and trialling it etc. The Wall Street Journal reports that a typical course of the drug will cost over $3000 per patient. Interestingly the Trump administration is wanting the drug to stay in the USA as much as possible, rather than be available overseas, and is spending money to that effect.
Canto: Hmm. Is that protectionism?
Jacinta: Yes I suppose. It’s not surprising that a country wants to look after its own first, especially via a product produced within its own borders. But I suspect this government would’t be interested in helping any other country – unless there was a quid pro quo. And there’s another antiviral, favipiravir, currently being trialled in Japan and the USA (I mean as of early July), and a vaccine, developed in China, is being used on the Chinese military in what seems a rather rushed and somewhat secretive fashion – we don’t know if they got the soldiers’ permission on this seemingly untried vaccine. At least at the phase 3 level.
Canto: Very CCP.
Jacinta: So onto update 92, and we revisit the electron transport chain, with four successive electron transfers converting molecular oxygen into water. Problems within this chain can produce reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxy radicals, which are destructive in excess. We also look, yet again, at covid19’s impact on angiotensin and particularly the production of superoxide, which in turn causes endothelial dysfunction, increased von Willebrand factor activity, which leads to thrombosis. People were presenting as ‘happy hypoxics’, looking and feeling fine but with very low oxygen levels, and autopsies revealed ‘microthrombi in the interalveolar septa’ of victims’ lungs. All this leading to a paper published in The Lancet which looked at factors in this process of coagulation and thrombosis:
We assessed markers of endothelial cell and platelet activation, including VWF antigen, soluble thrombomodulin [a marker of endothelial cell activation], soluble P-selectin [a marker of endothelial cell and platelet activation], and soluble CD40 ligand [a marker of platelet and T-cell activation], as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.
So this was about getting to the bottom of the increased clotting. And the results were hardly surprising, but the final discussion section is worth quoting at length, as it seems to capture much that we know about covid19’s effects (at least short-term effects) at the moment:
We therefore propose that COVID-19-associated coagulopathy is an endotheliopathy that results in augmented VWF release, platelet activation, and hypercoagulability, leading to the clinical prothrombotic manifestations of COVID-19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis. The factors responsible for this endotheliopathy and platelet activation are uncertain but could include direct viral infection of endothelial cells, collateral damage to the tissue as a result of immune infiltration and activation, complement activation, or any number of inflammatory cytokines believed to play a role in COVID-19 disease.
They suggest anti-platelet therapy and endothelial cell modification treatments as well as anticoagulation treatments, and they suggest some agents ‘which might have therapeutic potential’.
Canto: Potential? You’d think they’d be onto all this by now.
Jacinta: Well there’s also potential for untried medications – at least untried in this context – to go terribly wrong. And it’s also likely that some hospitals are already onto using the safer forms of treatment. Dr Seheult speaks of the antioxidant N-acetylcysteine (NAC) in this context, as it has been shown to be a thrombolytic when used intravenously. There are studies pending on the effects of NAC in treating covid19 patients.
Canto: Now, I’ve just been watching something on monoclonal antibodies as perhaps the most promising treatment yet, short of a vaccine. Can you explain….
Jacinta: Yes I’ll try, maybe next time.
References
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released From UK
Coronavirus Pandemic Update 89: COVID 19 Infections Rising in Many States; Dexamethasone Cautions
Coronavirus Pandemic Update 90: Assess The Quality of COVID-19 Info With A Validated Research Tool
Coronavirus Pandemic Update 91: Remdesivir Pricing & Disparities in Drug Availability
Coronavirus Pandemic Update 92: Blood Clots & COVID-19 – New Research & Potential Role of NAC
amhf.org.au/covid_19
https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext
Covid 19: corticosteroids, inflammatory markers, comorbidities
Canto’s bronchiectasis – a relatively mild case, thank dog
Canto: So update 87, in late June, reflects a period when daily cases were just starting to rise, but deaths were apparently reducing – and various reasons were being given for this.
Jacinta: And interesting to note all the skepticism around Oxford University’s dexamethasone trial, which has led (the trial, not the skepticism) to a huge demand for the steroid. Dr Paul Sax of Harvard Medical School has expressed some dismay at the negativity, as this was a randomised controlled trial (RTC) of a widely available drug by a highly reputable, government-funded institution.
Canto: Yet it seems that the website on this trial has since been taken down, so maybe there are some issues…
Jacinta: Okay, so let’s move on. Dr Seheult talks about raised ‘inflammatory markers’ in patients he observes coming in with covid-19. He names them, and I want to do a shallow dive into what they are and what they mean: Ferritin, C-reactive protein (CRP), CPK (to do with muscle breakdown), erithrocyte sedimentation rate (ESR), and d-dimer levels. So, ferritin is an iron-containing protein. It stores the iron and releases it when needed. Ferritin is mostly concentrated in the liver cells (hepatocytes) and in the reticuloendothelial cells of the immune system. That endothelial word again. As for CRP, this abstract from a 2018 paper Frontiers in Immunology tells me that ‘C-reactive protein (CRP) is an acute inflammatory protein that increases up to 1,000-fold at sites of infection or inflammation….CRP is synthesized primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes’. Need I say/quote more? And on CPK, this from the Johns Hopkins Lupus Center:
Creatine phosphokinase (a.k.a., creatine kinase, CPK, or CK) is an enzyme (a protein that helps to elicit chemical changes in your body) found in your heart, brain, and skeletal muscles. When muscle tissue is damaged, CPK leaks into your blood. Therefore, high levels of CPK usually indicate some sort of stress or injury to your heart or other muscles.
And the US website medicineplus.gov has this to say on ESR:
An erythrocyte sedimentation rate (ESR) is a type of blood test that measures how quickly erythrocytes (red blood cells) settle at the bottom of a test tube that contains a blood sample. Normally, red blood cells settle relatively slowly. A faster-than-normal rate may indicate inflammation in the body.
So, a fast ESR is an inflammation marker. High levels of CPK in the blood are too, presumably, as are high levels of CRP, wherever. And ferritin. Lastly, d-dimer levels, which are also related to clotting. This Australian site, healthdirect, tells me that ‘D-dimer is a type of protein your body produces to break down the blood clot’. So, a d-dimer test is ‘a blood test usually used to help check for or monitor blood clotting problems. A positive test means the D-dimer level in your body is higher than normal and suggests you might have blood clots’.
Canto: With all that let’s continue with the update. In Seheult’s hospital they started using dexamethasone as soon as the Oxford results came out and they’ve seen a reduction in all these rising inflammation markers. He recognises issues here though. Is this just anecdotal? Is this just a drop in the markers without real-life effects? Could it be recall bias? We know how conveniently inaccurate memory can be.
Jacinta: My impression is that’s not going so well, though there’s no doubt still a varied use of dexamethasone and other corticosteroids throughout the USA. We’re at the point with the updates where they’re still thinking deaths in particular are reducing. We now know better. So the update next looks at a Chinese study from mid-June entitled ‘clinical and immunological assessment of asymptomatic SARS-CoV2 infections’. This small study looked at 37 asymptomatic patients and found that viral shedding (the release of virus from an infected person into the environment – the period of contagiousness) was 19 days, presumably on average. This compared with 14 days for symptomatics. A pretty significant finding. Immunoglobulin G (IgG) levels – essentially antibodies – were about six times higher in the symptomatic cases. That seems unsurprising I think, because it’s the antibodies that largely create the symptoms – the inflammation and clotting, the cytokine storm. Another finding was that, eight weeks after being discharged from hospital, the asymptomatic cases were 40% seronegative (having no antibodies) against SARS-CoV2, compared to 12.9% for the symptomatic cases. This suggests that neutralising antibodies may be ‘disappearing’ over time, though other immune cells, such as T cells may have a mitigating effect. Overall, though, the study advises extreme caution:
Together, these data might indicate the risks of using covid19 ‘immunity passports’ and support the prolongation of public health interventions, including social distancing, hygiene, isolation of high-risk groups and widespread testing.
Canto: Not suggestions the current Trump administration would be likely to pay attention to.
Jacinta: Well the question here is one of re-infection, and I don’t know if there are any clear answers to that. Anyway update 87 goes on to look again briefly at vitamin D, and research in the UK, where vitamin D deficiency is more of a problem, and is associated with viral chest infections and with covid19 outcomes, with people of colour being disproportionately affected. They’re looking to people to sign up with a study called ‘covidence UK’. Dr Seheult also looks at a ‘Research Letter’ from the JAMA network entitled ‘prone positioning in awake, non-intubated patients with covid19 hypoxemic respiratory failure’. Prone positioning – lying on your tummy – was highlighted in one of the earliest of these covid19 updates as improving the symptoms of patients with ARDS. The findings from this JAMA are instructive:
In this small, single-centre cohort study, we found that the use of the prone position for awake, spontaneously breathing patients with covid19 severe hypoxemic respiratory failure was associated with improved oxygenation. In addition, patients with an SPo2 [pulse oximetry, a measure of blood oxygen level] of 95% or greater after one hour of the prone position was associated with a greater rate of intubation.
So, though there’s a need for RCTs etc etc, Dr Seheult has found dramatic improvements in oxygenation in his own patients through prone positioning.
Canto: Who are we to argue? And this update 87 ends on a positive note due to these combined findings about treatment. Prone positioning, remdesivir, dexamethasone, vitamins D and C, zinc, and maybe convalescent plasma, which needs to be explored further..
Jacinta: That’s blood plasma from recovered covid19 patients, with of course the antibodies to go with it, and I’ve looked at the National Covid19 Convalescent Plasma Project website to see if there are recent studies on this, but there’s nothing since March – small studies from China, which seem promising.
Canto: Update 88 starts again with dexamethasone, the cheap and widely available steroid, which – and this is back in late June – the British government got behind after the Oxford study was published, authorising its use ‘for patients hospitalised with covid19 who required oxygen, including those on ventilators’. It’s interesting that clinical views have changed on corticosteroids for covid19 over time, and there are still concerns about dosage and time periods on the drugs.
Jacinta: Yes, short courses of corticosteroid treatment seem to be recommended, and not just dexamethasone. And many studies showed this before the release of the Oxford data.
Canto: So the Oxford data itself is fascinating, especially for comorbidities or previous conditions. Especially interesting to me as I have such a condition, one that fits under their heading ‘chronic lung disease’, in my case bronchiectasis. They’re finding that people with such conditions are ending up on ventilators far less than those with diabetes or heart disease. So that’s good news for me. The disease, as they’ve been finding, is that covid19 is essentially an inflammatory disease of the vascular system. However, it seems that Dr Seheult’s hopes, at the end of update 88, that the greater introduction of short-term corticosteroids, and the use of other medications that might be efficacious, would reduce the mortality rate, have been dashed. We’ll be interested to find out why in upcoming posts.
References
Coronavirus Pandemic Update 87: More on Dexamethasone; Do COVID-19 antibodies last?
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released From UK
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908901/