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Interferons – they’re there to help

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some human interferon looks something like this, according to someone

When I first heard of interferon (singular), I thought it was a drug, some sort of miracle drug being touted as a cure-all. I had no idea. Recently I’ve heard that it, or they, are part of our innate immune system, which is different from our adaptive immune system, though what the differences are I have no idea. Again. So, it’s learning time.

Wikipedia vastly increases my knowledge with its first sentence on interferons (duh, I wonder why people don’t use it more):

Interferons … are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

Host cells are the cells of larger organisms (such as ourselves) that ‘host’, willingly or not, viruses and other bugs, or organelles, whatever. Signalling proteins are explained, somewhat, in the second quoted sentence.

Anyway, interferons belong to the larger class of proteins known as cytokines, which I’ve heard of in relation to the ‘cytokine storm’, a reaction or over-reaction to viruses such as SARS-Cov2, but they do more than just signal, they interfere, as the name suggests. In fact they have multiple functions, such as ‘upregulating antigen presentation’. An antigen, as I almost recall, is a molecular structure, part of a pathogen that can be bound by an antigen-specific antibody. Antigen presentation is – well it’s too complex to explain here, though I feel I need to arm myself with as much immunological knowledge as possible against the misinformation out there.

So IFNs, as they’re known, come in 3 types, alpha, beta and gamma, based on the receptors through which they signal. They form part of the innate immune system, generally speaking, but there are in fact complex interactions between the innate and adaptive immune systems which immunologists are still trying to work out. I should point out here that my first understanding of interferon was no doubt based on a breakthrough in the eighties when interferons were created in the lab to treat certain types of cancer, and later in the treatment of hepatitis, multiple sclerosis and other conditions, though many of these interferon medications have been superseded by newer treatments with fewer side-effects.

My question arose through watching a Medcram video – update 128 – ‘innate immunity, interferon and Covid-19 in children’. I’ve used these updates in the past to reduce my general ignorance of immunology, virology and the like, but I’ve not watched any for a while. So, having just perused the Wikipedia article on IFNs and finding it way too complex for my small brain, I’ll base the rest of this piece on Dr Seheult’s Medcram presentation.

So, the innate and adaptive immune systems are presented pictorially. The innate system starts with a myeloid progenitor cell. These cells are described in ScienceDirect as ‘the precursors of red blood cells, platelets, granulocytes…’ and a bunch of other cells. In the Medcram pictorial, arrows from the myeloid progenitor cell lead to five other cell types – mast cells, basophils, neutrophils, monocytes and eosinophils. Arrows from the monocytes then lead to macrophages and dendritic cells. What do these have to with IFNs? I’m trying to find out.

Mast cells are types of granulocyte, and they contain granules ‘rich in histamine [which induces inflammation] and heparin [which prevents blood clotting]’. They play an important protective role in the immune and neuroimmune systems.

Basophils are also granulocytes, and a type of white blood cell (leukocyte). They’re the rarest and largest type of granulocyte, and are an inflammatory agent.

A neutrophil is ‘a type of immune cell that is one of the first cell types to travel to the site of an infection. Neutrophils help fight infection by ingesting microorganisms and releasing enzymes that kill the microorganisms. A neutrophil is a type of white blood cell, a type of granulocyte, and a type of phagocyte’ (National Cancer Institute – USA).

Eusinophils ‘are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates’ (Wikipedia).

A monocyte is ‘a type of immune cell that is made in the bone marrow and travels through the blood to tissues in the body where it becomes a macrophage or a dendritic cell. Macrophages surround and kill microorganisms, ingest foreign material, remove dead cells, and boost immune responses. During inflammation, dendritic cells boost immune responses by showing antigens on their surface to other cells of the immune system. A monocyte is a type of white blood cell and a type of phagocyte’ (National Cancer Institute).

Now to return to the Medcram video, which tells me that the innate immune system includes macrophages and killer T cells (which are also part of the adaptive immune system). These combine to phagocytise, or ingest, viral or pathogenic material. This innate immune system is generally very strong in childhood and gets weaker with age. Interferon is a product of this innate system. Dr Seheult cites a recent article from Nature Biotechnology with the revealing title ‘Pre-activated antiviral innate immunity in the upper airways controls early SARS-Cov2 infection in children’. I’m fascinated with the idea of ‘pre-activated’ immunity here. As far as I know vaccines pre-activate immunity to viruses or pathogens by presenting the immune system with a part of that pathogen, or a protein unique to it. But with children, how is their immune system pre-activated? In any case, the article explains that ‘children displayed higher basal expression of relevant pattern recognition receptors [involving interferons] in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-Cov2 infection than in adults’. This finding highlights the importance of interferons and of perhaps trying to maintain their prevalence in older subjects. The article described children presenting in emergency with severe Covid19 as having an impaired IFN response, though the molecular mechanisms for this, and for the protective effects on those children with mild or no symptoms, were unknown.

So the article explains that higher levels of genes coding for RIG-1, MDA5 and LGP2 in the epithelial cells of the upper airways were found in children, but not in adults. RIG-1 is a pattern recognition receptor (PRR) of the innate immune system, responsible for type 1 interferon responses. MDA5 and LGP2 are members of the same family of PRRs. The key being more innate immune cells in that region in children, exhibiting strong antiviral action against SARS-Cov2. This is apparently what is meant by ‘pre-activated’, because these primed cells were already in the upper airways (i.e the nose) of children. However, there appears to be a narrow window of opportunity before viral reproduction, which is especially intense with SARS-Cov2, shuts down this innate immune response. The paradox, it seems here, is that SARS-Cov2’s proteins  can effectively shut down interferon production, but at the same time the virus is highly sensitive to interferon. Anyway, it seems that if we can step up IFN production, assisting the body’s innate immune system, this may enable us to resist the virus (along with vaccination, effective mask wearing and physical distancing of course). One way to do this is by raising the core temperature of the body (inducing hyperthermia). At a core temp of 39 degrees celsius, the amount of IFN released from lymphocytes after mitogen stimulation (i.e inducing mitosis) increases ten-fold from just a degree or so below, at least in vitro. This may sound crazy, but the benefits of induced fever have been proven in various treatments for various infections, including viral infections, in the past, along with other ways of boosting the immune system (vitamin D, zinc and selenium) mentioned previously by Dr Seheult and other experts.

Science science science science science science. Don’t use social media to find out about SARS-Covid19 and its treatment. Never never never never. There are dozens of reputable scientific sites that will inform you, in the USA and in every other country – at least the WEIRD ones. Knowledge is power. Get informed.

References

https://en.wikipedia.org/wiki/Interferon

https://www.webmd.com/drug-medication/interferons-guide#1

Innate Immunity, Interferon, and COVID 19 in Children: Update 128 (video)

https://www.sciencedirect.com/topics/immunology-and-microbiology/myeloid-progenitor-cell

https://en.wikipedia.org/wiki/Mast_cell

https://www.healthline.com/health/basophils

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neutrophil

https://en.wikipedia.org/wiki/Eosinophil

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/monocyte

https://en.wikipedia.org/wiki/RIG-I

https://en.wikipedia.org/wiki/MDA5

https://en.wikipedia.org/wiki/Mitogen

 

Written by stewart henderson

September 6, 2021 at 10:12 pm

A coronavirus update: new variants

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Everyone wearing a mask in this Tokyo airport, but still there are lots of problems, and lots of travellers

So there’s much concern about new variants of the SARS-CoV2 virus, one from the UK, now known as the Kent variant, and one from South Africa. My main source of info on this will be the SGU podcast 809, from January 6.
The Kent strain is more infectious than the original, by 50-60%, though not more deadly. However its infectiousness is fast making it the more dominant strain. The South African variant, though, is causing most concern, as virologists are uncertain about its response to the vaccines now available. It has some of the same mutations that are in the Kent variant, making it also more infectious, but it also has mutations that allow it to evade antibodies targeting previous variants. This won’t make the variant immune to the vaccine, but it will make the vaccine less effective, though exactly how much less effective is the big question currently.
Another major concern is that this new variant can infect people who’ve already contracted and recovered from the virus. As Dr Steven Novella and others on the podcast argue (and this quote is ‘tidied up’ from direct speech):

This is the result of allowing a pandemic to simmer along over time. Mutations are inevitable, though different viruses mutate at different rates. SARS-CoV2 has error-correction mechanisms when it replicates, so that’s why it mutates more slowly. But if an infection in an individual, or an epidemic, lingers long enough, you’ll still get mutations. Part of the problem is that, with so many people infected, for so long, there are a great number of opportunities for new variants to arise. There are thousands of roughly equivalent variants, which are neutral or inconsequential in effect, but now we have two variants that are more mutated, and more consequential. They have a suite of mutations that seem to have developed much faster than the background mutation rate of the virus. It’s thought that this is because in individual patients who’d had the infection for months and were being treated during that time, the increased selective pressure on the virus may have caused this suite of mutations to be formed. This kind of mutation rate has been shown in the lab with respect to antibiotic resistance in bacteria. 

The point here for the future is to get to a level of herd immunity through vaccination. Considering that new strains arise regularly, as with the flu (and we don’t yet know how regularly this will happen with SARS-CoV-2), it may be that the vaccine will have to be tweaked regularly to cover these new strains. Time will tell, and of course we don’t yet know how effective the new vaccines will be against these current major variants. In fact we don’t know for sure how long the vaccines, or the antibodies they create, will be effective, regardless of these variants. But mRNA vaccines can apparently be produced, and tweaked, quite quickly, once the variant’s RNA is sequenced.

All of this tells us that the science is generally on top of this. The major problem is political, and social. Trying to get people to do the right thing, to wear a mask, physically distance, avoid large indoor gatherings and to get vaccinated when the vaccine becomes available. This is easier in some regions of the world than in others, and the problems ranges from distrust or ignorance of modern science, to conspiratorial thinking, to rights over responsibilities, to cultures of compliance and non-compliance. Humans are delightfully diverse, or just a mess, and the WHO warns us that this may not be ‘the big one’ in pandemic terms. The year 2021 will not see the end of all this – far from it. 

Stop press – a new variant has just been found in Japan in four travellers from Brazil, the Sydney Morning Herald reports. Twelve mutations have been identified, one of which is shared by the UK and South African strains, suggesting a higher infection rate. The travellers are in quarantine in Tokyo airport. Due to a steep rise in cases, a state of emergency has been declared for Tokyo and surrounding prefectures. And so it goes.

Reference

https://www.theskepticsguide.org/podcasts

Written by stewart henderson

January 11, 2021 at 10:47 am

more on rapid antigen testing, and the vaccine race

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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.

Written by stewart henderson

December 9, 2020 at 5:44 pm

the rapid testing system that went begging

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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)

 

Written by stewart henderson

December 5, 2020 at 10:06 pm

covid19 – the European CDC shows the way

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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.opendemocracy.net/en/democraciaabierta/political-tirals-electoral-bans-battle-ecuador-democracy/

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31955-3/fulltext

https://www.bbc.com/news/world-europe-54478320

Written by stewart henderson

October 11, 2020 at 1:50 pm

stuff on covid19 and immunology

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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

Written by stewart henderson

October 8, 2020 at 11:55 pm

covid-19 – on civil liberties and death in the USA

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Canto: So, in the USA, according to today’s Worldometer figures – and it’s not unreasonable to say that these figures are only as reliable as the reporting agencies, and are probably understated – there have been slightly more than 203,000 deaths from covid19 – that’s almost 250 times the number of deaths in Australia, which has one thirteenth of the US population. This is a stark illustration of the USA’s failure to protect itself against this virus, in comparison to some other countries. Maybe this is an unfair comparison, though I honestly don’t see why it would be, but we can make an even more stark comparison. The liberal democracy that is Taiwan, the world’s gold standard in terms of response to covid19, with its population only slightly smaller than Australia’s, has experienced seven deaths so far. So, to compare with the USA, that’s a fourteenth of the population, but the USA has suffered almost 30,000 times more deaths from the virus. Such are the almost unfathomably various degrees of success in dealing with this pandemic. I’ve chosen these more or less opposite ends of the spectrum – and, to be fair, the USA isn’t the shit standard (in comparison to gold), as Brazil’s performance is even worse – in order to reflect on how best to save lives, which is surely what we want to do above all else, as a matter of common humanity.

Jacinta: And our discussion will be based on a statement made by the US Attorney-General, William Barr, who described the current lockdown in the USA as the greatest erosion of civil liberties in the country since slavery. But maybe, as an outstanding humanist, and a follower of the meek and mild Jesus, a supporter of the downtrodden, who told his followers that it is easier for a camel to pass through the eye of a needle than for a rich man to enter the kingdom of God (Matthew 19: 23-26), Barr was speaking positively about the lockdown as a sacrifice that must be made to save lives – especially those of the poor, with whom he so strongly identifies as a follower of the aforementioned Jesus.

Canto: Well, that’s an interesting interpretation, but I think the more straightforward one is that he thinks people should be free to mix and mingle, in spite of the pandemic. In any case I’ve not heard of him wanting to impose any restrictions of any kind, in spite of the covid19 death rate in the country. It would be interesting to know what he makes of the fact that covid19 is disproportionately affecting the poor as well as African-American and Latino communities. He himself is a multi-millionaire, unlike Jesus, and Euro-American, also unlike Jesus. Yet he calls himself a Christian and believes that Judeo-Christian values, whatever they may be, are the basis of civilisation, at least in the USA. I’m not sure if he’s ever sampled any other society. 

Jacinta: Which brings us to Taiwan. What is it that has made Taiwan the gold standard in dealing with this pandemic? Is it Christianity, of a different kind from that which the multi-millionaire Barr espouses, in spite of Jesus’ teachings? Or is it a very different, but equally, or more, effective tradition? Did Taiwan even experience a lockdown, of the type that Barr seems to have such strong feelings about?

Canto: So let’s explore Taiwan. in fact it has had a complex and very turbulent history, especially over the past century or so, one that, I’d say, would have made its citizens value their hard-won freedom rather more than those of most nations, including the US. I can’t imagine that these people, who’ve undertaken rebellion after rebellion, would allow their government to take away their ‘civil liberties’ without good reason. They just wouldn’t stand for it.

Jacinta: Could it be that they’re just more educated than ‘Americans’, as to their national interest? And even as to what’s required in dealing with a pandemic? It certainly seems that way.

Canto: In fact last month the US federal health secretary (I didn’t know they had one) was over in Taiwan praising the country’s covid19 response. That was a good thing to see. 

Jacinta: Yes and many prominent nations are warming in their relations with Taiwan, not before time, and it’s annoying the Chinese government no end. But on covid19, I suspect many ‘Americans’ will dismiss Taiwan’s success as typical of Asian nations and their collective, ‘sheep-like’ mentality. Clearly, collective pro-community action trumps selfish individualism when it comes to pandemics, but I’m sure Taiwan’s success can’t be explained in such simplistic terms, as the Taiwanese have fought long and hard, against the communists, the Japanese and the Kuomintang, suffering massacre after massacre, to achieve multi-party democracy. So the idea that this is about tough-minded, risk-taking ‘sovereign citizens’ who won’t be pushed around by so-called health experts versus namby-pamby obedient puppets of the state who’re prepared to sacrifice their freedom just for the sake of their lives – well, this is surely a furphy. 

Canto: So what do we make of this Barr character? He attacks ‘lock-downs’ – which are simply a needed response to the refusal by so many to wear masks and to practice physical distancing. Sometimes authorities need to clamp down, when so many lives are being lost. Every government, regardless of their place on the political spectrum, has done something to try to reduce the spread of this virus. As would be expected. And this has necessarily impinged on ‘civil liberties’, because there are obviously other priorities. So, again, what point is Barr trying to make?

Jacinta: I can’t honestly say, but it does appear that he’s opposed to lock-downs, so presumably he has other ideas for saving the lives of ‘Americans’, but I’ve no idea what they may be. He’s also said recently that ‘scientists aren’t seers’ and that ‘free people make their decisions through their elected representatives’, which is a little incoherent, because when it comes to epidemics, sensible people should obviously listen to the advice of epidemiologists, especially those who are expert in the disease, virus or pathogen in question, rather than to politicians. You don’t even have to be an adult to realise that.

Canto: Yes, people are free to decide on their own science by popular vote, but if they did, we’d still be living in caves and believing that the earth is flat. Such are the limits of democracy.

Jacinta: So in times like these, the politicians should work with the experts, which is exactly what’s happening in all those countries that have handled covid19 most successfully. It’s notable that when he talks about these freedoms and civil liberties he makes no mention of all the suffering and the deaths in the USA. It somehow doesn’t seem to be relevant to him. What a bizarre, creepy character. 

Canto: Well, as a multi-millionaire – and I didn’t realise that politics was such a lucrative business – he very likely lives in one of those gated communities (with the emphasis on the gate rather than the community). Covid19 is disproportionately affecting African-Americans, Latinos, the poor, factory workers, prisons, aged-care facilities. Not really the sort of people you associate with gated communities. So I can only suppose he’s out of touch with much of the suffering. Lock-downs affect people universally – though obviously in different ways, depending on whether you’re in a mansion or a hovel – but the financial elites naturally don’t feel equal to the poor, and their ‘inequality’ is a matter of great pride to them. Barr is being a spokesperson for these types, I think. They’re having to suffer lock-downs because the less privileged are dying. It’s just not fair. 

Jacinta: And I just want to add something here about scientists. I’ve met a few of them, and I wish I was one of their number. They don’t pretend to be seers – my experience is that they tend to be nerdy, self-effacing types, not power junkies as many politicians tend to be. They generally tend not to display all the knowledge they have – it often has to be dragged out of them, whereas the worst politicians often claim knowledge they don’t have and like to belittle the knowledge or understanding of their rivals. In this respect, Barr is very much the politician, and little else.

Canto: Yes, and meanwhile the deaths keep piling up in the USA, and at the federal level the scientists are being sidelined by the politicians, the CDC is being stifled, and the world watches on with alarm, disgust and sometimes a smug sense of superiority. It isn’t of course the end of US ascendancy – the states with the most massive weaponry will always be the most powerful – but as to moral authority, that’s fast disappearing. If you leave aside the many non-democracies, which nation is less worthy of respect and emulation than the USA? I can’t think of too many.

Canto: Well, on a more hopeful note, there’s an election coming, and the country may start to redeem itself. But it will take far more than an election to do that, IMHO.

Written by stewart henderson

September 21, 2020 at 10:47 pm

reading matters 11 – encephalitis lethargica. Will it return?

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Asleep, by Molly C Crosby, 2010

Canto: This was one of the saddest books I’ve read in a long time. It’s about a disease that arose, and was recognised, at around the time of the ‘Spanish flu’ of 1918, though it was more sporadic and long-lasting, and rather more mysterious. It’s also a kind of cautionary tale for those among us who downplay the impact of diseases and their effects, which are so often long-term and horrifically devastating. It’s humbling to realise that we just don’t know all the answers to the pathogens that strike us down. 

Jacinta: And could revisit us, in mutated and perhaps even more deadly form, some time in the future. This book is about encephalitis lethargica, a disease that was personal to the author, as it infected her grandmother, whose entire life, though she lived to a goodly age, was clearly stunted by it. She was struck down at the age of 16, and slept for 180 days, and though she lived almost 70 years afterwards, she was robbed by this brain-blasting illness of the life of the mind, the rising above ourselves and grasping of the world that we’re attempting in this blog. Through sheer bad luck. 

Canto: And as Crosby points out, her grandmother was far from being the worst-affected victim of this disease. People died of course, but others were disastrously transformed.

 Jacinta: So let’s go to a modern website, a department of the USA’s NIH, the National Institute of Neurological Disorders and Stroke, for a definition:

Encephalitis lethargica is a disease characterized by high fever, headache, double vision, delayed physical and mental response, and lethargy. In acute cases, patients may enter coma. Patients may also experience abnormal eye movements, upper body weakness, muscular pains, tremors, neck rigidity, and behavioral changes including psychosis. The cause of encephalitis lethargica is unknown. Between 1917 to 1928, an epidemic of encephalitis lethargica spread throughout the world, but no recurrence of the epidemic has since been reported. Postencephalitic Parkinson’s disease may develop after a bout of encephalitis-sometimes as long as a year after the illness.

Canto: Yes, and having read Crosby’s book and knowing about the worst symptoms and a few heart-rending cases, the sentence that most strikes me here is, ‘The cause.. is unknown’. Apparently Oliver Sacks’ book Awakenings, which we haven’t read, is all about patients who have ‘awakened’, permanently damaged, from this bizarre disease, and that’s a book we now must read, though of course it will provide us with no solutions.   

Jacinta: And no arms against its future devastation, should it return – and why wouldn’t it? Crosby and others have suggested that ‘fairy stories’ like Sleeping Beauty and Rip van Winkle may have been inspired by outbreaks of the disease. Of course this is conjecture, and only if the disease returns will we be able to attack it with the technology we’ve developed in the intervening century. As the neurologist Robert Sapolsky points out in his mammoth book Behave, (so mammoth that I can’t find the quote), the number of papers published on the brain, its activity and functions, in the 21st century, has grown exponentially. We might just be ready to counteract the long term horrors of encephalitis lethargica next time round, if it comes around. 

Canto: Crosby’s book is organised into case histories, featuring people who fell into this bizarre torpid state for long periods, and when aroused, often behaved in anti-social and self-destructive ways that in no way resembled depression, between bouts of a ‘normality’ that was never quite normal. And one of the saddest features of these case histories, richly described in the notes of famous figures in early neuropsychology, such as Constantin von Economo, Smith Ely Jellife and Frederick Tilney, is that the victims disappeared into the void  once it became clear that no known treatment could save them.

Jacinta: Yes, some may have died soon afterward, others may have lived on in a limbo, locked-in state for decades. In fact the symptoms of this disease were bewilderingly varied -various tics, hiccupping, catatonia, salivation, schizoid episodes… Encephalitis literally means swelling of the brain, and it doesn’t take a medical degree to realise this could cause a variety of effects depending on which area of the most complex organism known to humanity is most affected. 

Canto: Encephalitis is usually caused by viruses, and of course viruses hadn’t been fully conceptualised when von Economo wrote his 1917 paper on what was to become known as encephalitis lethargica, as the role of DNA and RNA was unknown. However, von Economo was the first to recognise the vital role of a tiny, almond-shaped section near the base of the brain, the hypothalamus, in the distorted sleep patterns of these patients. He also wondered if there was a connection between the so-called Spanish flu and this sleeping sickness.

Jacinta: Yes, and this brings to mind the current nightmare pandemic. People, including of course epidemiologists, are wondering about the long-term effects of this virus, especially in those who seem to have recovered from a serious infection. Crosby writes of the situation a hundred years ago:

The war had provided the first opportunity encephalitis lethargica had to crawl across the world with little notice from the medical community. And by 1918, the pandemic flu had given it the second opportunity, stealing worldwide attention, infecting and killing millions. Epidemic encephalitis moved with the flu, almost like a parasite to a host, often attacking many of the same victims, receiving very little notice at all. 

Of course there has been no sign of a return of encephalitis lethargica – as yet – from a medical community that is somewhat forewarned, but it’s clear that inflammation can have very diverse effects, especially when it involves the brain. 

Canto:  But it’s like an undefeated enemy that has gone into hiding. We’ve defeated smallpox; tuberculosis and polio are in heavy retreat; leprosy seems as remote to us as the Bible, but this sleeping sickness, some of the victims of which have died within our lifetimes, has tantalised us with its bizarre and devastating effects, but has never really given us a chance to fight it.

Jacinta: Yes fighting is what it’s all about. The anti-vaxxers and the natural health crowd seem to want to leave everything to our immune system, to let diseases take their course, killing and maiming a substantial percentage of the herd to let the remainder grow stronger. If they were to read some of these case studies, to witness the lives of young Rosie, Adam and Ruth, they would surely think differently, if they had a modicum of humanity. 

Written by stewart henderson

September 18, 2020 at 11:01 pm

covid19: sensible testing, mostly

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Canto: So we’re looking at medcram coronavirus update 98 now, and it’s a fascinating one entitled ‘Rapid COVID 19 Antigen Testing at Home – A Possible Breakthrough’, though it comes with the clear proviso – this would require co-ordinated political action, and that won’t happen in the USA, not just under Trump, but at any time.

Jacinta: Well, but especially under Trump. But the issue is one of trying to get much more testing done, with far less emphasis on the sensitivity of the test, because rapid-fire, fast turnaround testing is far more useful than expensive, hard-to-evaluate slow-turnaround testing, which puts a premium on sensitivity. But before we get to all that, Dr Seheult looks at a paper on viral loads vis-à-vis covid19 patients. They looked at nasal and throat swabs, and then checked the Ct values over time. 

Canto: The Ct values are a measure of viral load and it works inversely – a 3.32 reduction in Ct value means a ten-fold-increase in viral load. 

Jacinta: Yes, so a low Ct value means a high viral load, and of course viral replication works exponentially, at least during the early infection period, so your viral load can be massively different from one day to the next – think about that for testing, and delayed results. 

Canto: A Ct value of 40 is close to undetectable, depending of course on the sensitivity of the test. And the value can go down as low as 5, all approximately of course. The course of the virus is generally, exponential growth, then a tapering off of the growth rate, reaching a peak, then a descent to finally a remnant population of largely disabled viral scraps, with of course mortality intervening along the way in the worst cases. 

Jacinta: Far from the majority of cases, thankfully. So the ‘gold standard’ test is the reverse transcriptase polymerase chain reaction (rt-PCR) test – also called real-time PCR, I’ve just found out. It’s relatively expensive at around $US100, with turnaround times – and this might depend on demand and other factors – of between 3 and 9 days. There aren’t enough of these tests to go round, but they are very sensitive, detecting the virus reliably from a Ct value of about 35, or maybe even 40 (for argument’s sake, Seheult says). But there are other, cheaper, less sensitive tests, called paper tests, that can be rolled out more easily to the general public. The paper is coated with monoclonal antibodies that can detect antigens – substances that evoke an immune response. These paper tests cost at most a couple of dollars each, and would be sensitive to a viral load measured at a Ct value of around 32. These figures aren’t exact but this would make the test around 50-55% sensitive. 

Canto: But there’s this issue called the ‘threshold of transmissibility’, which is important in all this, and a virologist, Dr Michael Mina, shown speaking on this update, explains:

So people who are transmitting probably have Ct values that are below 30 and the vast majority probably have them below 25 or so.

As Seheult explains, people may be testing positive at that range above 30 (i.e. low viral load) but not transmitting the virus. This is especially so if they’re on the downward trajectory, as described above, and what the rt-PCR test (or assay) is detecting are those remaining viral fragments. And as Dr Mina points out, it’s the downward trajectory that’s being picked up for the most part, because the initial upward trajectory is exponential. Here’s what he says:

A lot of people are saying, ‘we need the really sensitive tests to be able to detect people early on in their infection’, but almost all the time that people spend with this virus near the limit of detection of PCR is on the tail end of their infection. This is a virus that, once it hits PCR positivity levels, it’s growing well in its exponential phase and it’s probably a matter of hours, not days, before it passes the threshold to be detected on some of these slightly lower sensitivity assays. And then it may persist for weeks or possibly months even in some cases at very low RNA levels. So it’s after people are well beyond their transmissible period that we’re actually seeing the loss in sensitivity of these assays. It’s very rare that you actually detect somebody with a Ct value 0f 39 in that window on their way up, because they’re only sitting there for a few hours before they get down to a 33, so if you’re missing Ct values of 39… it’s really not that important..

Jacinta: Not that important, but the point Dr Mina is making is really important – if the threshold of transmissibility is at 33 or below vis-à-vis Ct values, then a high-sensitivity test may even be a barrier to focussing on getting at the most transmissible subjects. 

Canto: Yes, especially when you have an alternative test that can be applied much more regularly with a quick turnaround – results on these paper tests take ten minutes! And being cheap, you can test as often as you feel you need to. If you’re positive, you quarantine yourself for a while, keep testing, find yourself negative, wait for a few more days, considering the low sensitivity of the test, keep testing in case there’s a recurrence, and when it’s still ok after a few days you can resume your life, go back to work or school, whatever, being pretty sure you’re past the infectious phase. 

Jacinta: Yes, as Dr Mina says, 9 out of 10 people go undiagnosed with the virus in the USA, according to the CDC – indicating the inadequacy of testing. And he goes on to say, of the other one out of ten, those that are caught, are mostly post-infectious, at the ‘tail end’. The point is that, because of the woeful lack of testing and the long turnarounds, they’re catching far fewer of the transmissible cases, the ones they want and need to catch, than the pitiful few that they actually find testing positive. 

Canto: The bottom line being that if they tested with a far less sensitive, but cheap and readily available quick-result assay, they would capture far more of the transmissible cases, and save lives. 

Jacinta: Dr Mina and many colleagues have written a paper on this, entitled ‘test sensitivity is secondary to frequency and turnaround time for covid19 surveillance’, and he points out that with this approach they would drive down the ‘r effective’ – the reproduction number – which is the number of people who can be infected by a carrier at any specific time – to well below 1. So if you were to give a significantly high proportion of people in in the worst affected areas these types of tests, you could bring the numbers down very rapidly, and this would eliminate the need for contact tracing. It would have an effect on schools, workplaces and so forth – because if you’re given one of these long-turnaround tests and your results eight days later turn out negative, that may be because you had just contracted the virus when the test was taken, but it didn’t show on the test – so you go back to school and infect people. With regular testing this problem would be eliminated. Hate to belabour the point, but – people are dying. 

Canto: It seems the CDC put a high priority on sensitivity, and so rejected these cheap paper tests, neglecting the obvious problem of turnaround more or less completely. The low sensitivity tests usually miss the subjects that are beyond infectivity. If they were on the upward trajectory they would likely be caught by the next test. It’s this upward trajectory that is the infective period. You would think regulatory organisations like the FDA or the CDC would twig to this, but not so much in the Trump era, when non-scientists are put in charge. Yet another failing of the individualist, anti-collaborative, egotistical destruction of all government agencies…

Jacinta: Or just the unwieldiness, the lack of finesse, of lumbering bureaucracies. Or a mix of both. 

Canto: Anyway, as things deepen and darken in the USA, we might have to skip a number of updates to keep up with the chaos, the failures, the resistance and everything else. It isn’t a great time to be living in the USA, but as outsiders we’re kind of ghoulishly fascinated by the mess they’re making of this pandemic, and much else besides.

Jacinta: But also genuinely sympathetic to those who are trying to make thing work in the teeth of all the craziness. 

Canto: Today, September 16, marks the day that 200,000+ deaths from covid19 have been recorded next to the name of the USA, according to Worldometer’s stats. Taiwan, a country that is separated from the so-called ‘China virus’ only by the narrow Formosa strait, has suffered only seven deaths in the nine months that this virus has raged. It has a population of about 24 million, slightly less than that of Australia, into which we find ourselves thrown. Australia has had 824 deaths thus far, and we’re regarded as something of a model!

Jacinta: Yes, several cheers for Tsai Ing-wen and for female leadership, sans egotism. And a special thanks to Audrey Tang, Taiwan’s digital minister – but she’s actually real, and a life-saver. We need more of her. 

Audrey Tang

Written by stewart henderson

September 17, 2020 at 12:03 am

Posted in covid19, Taiwan, USA

Tagged with , , ,

covid19: ivermectin, the Moderna vaccine, vitamin D

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Canto: So we were looking at the role of increased VWF and megakaryocytes in the blood, causing embolisms and clotting, and how to prevent or reduce such responses to the virus.

Jacinta: On the subject, Dr Seheult looks at a paper about the anti-malarial drug ivermectin and ‘CD147-mediated vascular occlusion’, CD147 being a protein attached to red blood cells (RBCs), which is apparently the entry pathway for malaria, and may also be a binding site for the S-protein of SARS-CoV2. However, binding to a CD147 protein on an RBC will not be a pathway for SARS-CoV2 as these blood cells don’t have nuclei, and so no mechanism for the virus to replicate. Still it’s possible, or likely, that this binding does take place, affecting the RBCs in such a way that they tend to aggregate. This is where ivermectin (IVM) comes in as a possible treatment:  

The potential for major dose-response gains is evaluated based upon studies indicating that IVM shields SARS-CoV2 spike protein and that this spike protein binds to the CD147 transmembrane receptor, as well as to ACE2. The abundant distribution of CD147 on RBCs suggests a possible ‘catch’ and ‘clump’ framework whereby virally-mediated bindings of RBCs to other RBCs, platelets, white blood cells and capillary walls impede blood flow, which in turn may underlie key morbidities of covid19. 

Now all of this is quite speculative as yet, and they quote an unpublished retrospective study with positive results from IVM treatment. Another study in Nature presents a systematic review of IVM use in covid19 and other infections – it’s apparently a medication which has ‘a good safety profile with low adverse effects when orally prescribed’. Clinical trials are necessary to appraise its use against covid19 however. 

Canto: Yes they point out that in vitro studies often involve higher dosages, and so results may not be replicable in vivo, where safety requires a lower dosage range. So now to the Moderna vaccine trials. Here’s the news from a July 14 article:

Moderna’s Covid-19 vaccine led patients to produce antibodies that can neutralize the novel coronavirus that causes the disease, though it caused minor side effects in many patients, according to the first published data from an early-stage trial of the experimental shot.

The data was published in the New England Journal of Medicine, as a preliminary report. As Seheult points out, this is a new type of vaccine, an mRNA vaccine, rather than a vaccine that introduces a protein into the body to stimulate the production of antibodies. In this vaccine the mRNA harnesses the mechanisms of the cells as the virus does, to produce the proteins that produce the immune response. Me think it mazing.   

Jacinta: Yes, this is reporting on dosage variation and response, and the data is pretty detailed, but the conclusions at this stage – and the vaccine is called the ‘mRNA-1273 vaccine’ – are that it ‘induced anti-SARS-CoV2 immune responses in all participants, and no trial-limiting safety concerns were identified’. So it’s steady as she goes at this stage. 

Canto: Quite exciting really – until someone gets really hurt. As you say, they tried different dosages, (25, 100 and 250 micrograms) and from the graphed results it seems fairly clear that they’ll go on in the next trial using the 100 microgram dose, which balances positive effects with negative effects in the most effective way, effectively. Effects seem to have been minor even in the highest dosage. 

Jacinta: And remember we’re almost two months behind the times here. Phase 3 trials were expected to begin in late July early August I think. That’s the real test, but even that won’t guarantee an entirely safe vaccine for everyone. Nothing can. 

Canto: Interesting that they required the subjects to have two injections each to get the best response. And as to side-effects, there were some severe ones at the 250μg dosage but very few at 100μg. 

Jacinta: There will inevitably be problems, I foresee that, and the anti-vaxxers will make a meal of any negative responses. In any case it’s unlikely that a virus will be available till next year. 

Canto: So now to update 97, which starts with a revisiting of vitamin D, which it seems a lot of health experts are raving about at the moment. 

Jacinta: So it’s a lipid-soluble vitamin, which means it retains its value in cooked foods, it’s stored in the liver, and when you’re exposed to ultraviolet light, it can transform cholesterol derivatives in the body to a form of this vitamin. Really sunlight exposure seems to be the best way of improving vitamin D levels. 

Canto: So this update looks at a paper published in early July, called ‘Vitamin D status and risk of all-cause and cause-specific mortality in a large cohort: results from the UK Biobank’. The results are a bit technical, but over a nine-year period for this cohort of older subjects, ‘higher 25(OH)D [that’s the active type of the vitamin] concentrations are non-linearly associated with lower-risk of all-cause, CVD [cardiovascular disease] and cancer mortality’. They recommend a particular threshold level of the vitamin as ‘an intervention target to reduce the overall risk of premature death’. 

Jacinta: Yes it certainly was a large cohort – over 365,000 subjects in a retrospective study. And Dr Seheult highlighted a comprehensive review article, ‘The immunological effects of vitamin D on human health and disease’, which I plan to read  in full, in order to live forever, but the key element for now is the effect of vitamin D on innate immunity. It ‘exhibits direct antiviral activities against many respiratory viruses by disrupting viral envelopes and altering viability of host target cells’. Further to this it has a section on ‘endothelial fuction and vascular permeability’. It’s pretty technical but the bottom line, they reckon, is that vitamin D3 is a helluva good product, in the correct form, for stabilising the endothelium, and Dr Seheult speculates that this is why it’s associated with a lower risk of mortality in covid19. It also appears to be associated, in the 1,25(OH2)D3 form, with increased endothelial production of nitric oxide. They make these interesting concluding remarks – ‘it is evident that vitamin D and its metabolites exert pleiotropic effects on the vascular endothelium that are protective against vascular dysfunction and tissue injury as a result of local and systematic inflammation’. Pleiotropic meaning multiple effects from a single gene. Vitamin D also has an effect on adaptive immunity – the helper and memory T cells, important as we don’t know whether these will develop a memory with respect to covid19.

Canto: The question of re-infection.

Jacinta: Indeed. But the review goes on and on about the positive effects of high vitamin D levels as a risk reducing factor in a range of conditions. And it goes specifically to covid19 which is, or starts as, an acute respiratory infection. Here are some fascinating results:

A prospective cohort study in healthy adults living in New England showed a two-fold reduction in the risk of developing acute respiratory tract infection (ARI) in those with serum 25(OH)D levels of 38ng/mL (95nmol/L) or more. A case-control study in children aged less than 2 years reported that children requiring hospitalisation for ARI had significantly 1.7 times higher odds of vitamin D deficiency as compared with those with mild ARI. This indicates the protective effects of sufficient vitamin D status against respiratory viral infection. 

And they go into the reasons why vitamin D might be protective, which I won’t detail here, but on covid19, they very reasonably claim that ‘one should maintain adequate vitamin D intake to achieve the desirable serum 25(OH)D level of 40-60ng/ml in order to minimise the risk and severity of covid19 infection’.    

Canto: Yes I notice they’re generally emphasising that 40ng/ml lower limit, which so many people are below. 

Jacinta: Yes, as they say, it’s been documented that about 60% of children and adults have circulating levels of less than 30ng/ml of 25(OH)D. So they reckon it reasonable that presenting covid19 patients will have insufficient vitamin D levels and so should be given supplementation on admission to hospital. However, overdosing on vitamin D can be an issue, so be very aware of dosage levels in consultation with your physician, if you’re self-medicating. 

Canto: Which I’m not sure if you should be doing.. please take my advice…

References

Coronavirus Pandemic Update 96: RNA Vaccine; Ivermectin; von Willebrand Factor and COVID-19

Coronavirus Pandemic Update 97: Vitamin D & COVID-19 Immunity, The Endothelium, & Deficiencies

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257661/

https://www.mdpi.com/2072-6643/12/7/2097

Written by stewart henderson

September 14, 2020 at 12:21 pm