an autodidact meets a dilettante…

‘Rise above yourself and grasp the world’ Archimedes – attribution

Archive for the ‘covid19’ Category

covid19 – the European CDC shows the way

leave a comment »

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…


Coronavirus Pandemic Update 109: New Data From Europe As COVID 19 Infections Rise

Written by stewart henderson

October 11, 2020 at 1:50 pm

stuff on covid19 and immunology

leave a comment »


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. 


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

leave a comment »

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?

leave a comment »

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

leave a comment »

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

leave a comment »

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…


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

Written by stewart henderson

September 14, 2020 at 12:21 pm

covid19: autopsy analyses, biomarkers, von Willebrand factor

leave a comment »

von Willibrand factor, a multimeric blood protein which plays a central role in blood clotting

Canto: So we’re working hard to get through what has been reported on medcram update 95, even though it’s taking us further behind the times in terms of what’s happening in the fight against this virus – there’s been some controversy on convalescent plasma recently for example – because it’s important to get the most out of every report before going onto the next one.

Jacinta: Yes, which means we need to work harder and faster. So in this study of a number of fatal cases of covid19 they found ‘no endothelial abnormalities on microscopic review, in alignment with previous studies’, which suggests that evidence of endothelial damage just doesn’t seem to be there, but they couldn’t rule out pro-coagulant endothelial dysfunction in the absence of ‘histopathological evidence of cell activation or erosion’, and they referred to another autopsy study with specialised equipment which ‘demonstrated ultrastructural endothelial damage’. So it seems they’re struggling with causes.

Canto: What they call the precise aetiology of the disease. 

Jacinta: Yes that’s what we’re after. So they do mention elevated troponin in covid19, which appears to be found regularly. Troponins are ‘a group of proteins found in skeletal and cardiac muscle fibres that regulate muscular contraction’. As the update tells us, troponin tests measure cardiac-specific troponin in the blood as a sign of heart injury. This Australian site tells us more:

For patients who are hospitalised with COVID-19, mild elevation of troponin is common (19.7%) and frequently correlates with disease severity, acting as a marker for cardiac injury. The cause of troponin elevation in serious infection is multifactorial.

In the study under discussion, they consider that the elevated troponin has to do with ‘thrombosis of the microvasculature and cardiac veins’. This cardiac vein finding is apparently important – they found, they believe for the first time, that thrombosis of a cardiac vein can cause myocardial infarction. They also write about renal findings in their subjects, to ‘shed light on the pathogenesis of acute kidney injury in covid19’. They found virions in proximal tubular cells. A virion is essentially a full, active molecule of a virus (there’s still some disagreement about these definitions, it seems). The proximal tubules are components of nephrons, the most important functional units of kidneys. They found acute tubular necrosis and other damage, and noted that this was common to other covid19 autopsy findings, perhaps unsurprisingly as these tubular cells present ACE2, the receptor for the virus. Dr Seheult then goes on to another study from Switzerland. This study looked at 639 critically ill covid10 patients, to determine which factors were most associated with survival or otherwise. So in general they found that this group suffered a ‘moderate’ mortality rate of 24%. To understand the findings will require quite a bit of medico-immunological knowledge, but here goes: they found that ‘PCT and IL-6 levels remained similar in ICU survivors and non-survivors throughout the ICU stay’. PCT is procalcitonin. According to Medscape:

Procalcitonin (PCT) is a biomarker that exhibits greater specificity than other proinflammatory markers (eg, cytokines) in identifying sepsis and can be used in the diagnosis of bacterial infections. Procalcitonin is also produced by the neuroendocrine cells of the lung and intestine and is released as an acute-phase reactant in response to inflammatory stimuli, especially those of bacterial origin. This raised procalcitonin level during inflammation is associated with bacterial endotoxin and inflammatory cytokines.

IL-6 is interleukin-6. An opinion article in Frontiers in Microbiology  entitled ‘The Role of Interleukin-6 During Viral Infections’ describes IL-6:

IL-6 is a pleiotropic cytokine produced in response to tissue damage and infections…  Multiple cell types including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells are associated with the production of this cytokine….

Pleiotropic cytokines – a cytokine is a type of small protein – affect the activity of multiple cell types. The complex pleiotropic nature of IL-6 unsurprisingly implicates it in both pro-inflammatory and anti-inflammatory effects. So, PCT and Il-6 levels remained similar for these study subjects, but ‘CRP, creatinine, troponin, D-dimer, lactate, neutrophil count, P/F diverged within the first seven days.’  Okay, C-reactive protein (CRP) is produced in the liver, from which it enters the bloodstream, and its levels ‘start to increase very soon after any inflammation or infection affects the body’, according to Australia’s healthdirect website. Creatinine is a waste product found in everyone’s bloodstream, and it’s produced by muscle metabolism. It’s generally filtered out by the kidneys. Too much blood creatinine may be a sign of kidney dysfunction. D-Dimer, the fibrin degradation product, always contains ‘two D fragments of the fibrin product joined by a cross-link’. I won’t try to explain much further at present. Neutrophils, remember, are infection-fighting white blood cells, and P/F ratio, aka PaO2/FiO2 ratio, is, briefly, an assessment of lung function. So with that, and some more, the study looked at levels of different markers most associated with mortality. To quote from the study: 

In contrast to risk factors in hospitalised patients reported in other studies, the main mortality predictors in these critically ill patients were markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. Elevated risk of bloodstream infections underscores the need to exercise caution with off-label therapies. 

Canto: That last point seems important- it’s all about the blood. Or mostly..?

Jacinta: They presented a number of graphs which Dr Seheult interprets for us, but basically they are all likely to mark higher levels of microthrombi in the patients who died, and this seemed more clearly so in the D-dimer levels. High lactate levels are a sign of anaerobic metabolism, a problem with oxygenation. Ischemic heart disease was also measured, and this has to do with narrowing of the arteries. So blood oxygenation, or lack thereof, and coagulation, which can happen just about anywhere, seems to be happening early, leading to a wide range of symptoms, especially in patients with comorbidities, some of them previously undetected. 

Canto: So we’re moving on to update 96, which starts again with thrombosis due to endothelial damage causing increased production or release of von Willibrand factor (VWF).

Jacinta: Yes, and they’re apparently finding that different blood groups or types – and that’s a topic we could spend a lot of time on – affect the level and activity of VWF. As do other factors, according to Russian researcher Anna Aksenova:

The level and activity of VWF in the blood in people can be different. The lowest values are associated with von Willebrand disease. It is a hereditary blood disease that is characterized by spontaneous bleeding. Additionally, it differs markedly among healthy people. For example, it is higher among: African Americans than among Europeans; in men than in women; in adults than in children; and in the elderly than in middle-aged people. Also, academic papers have described the VWF and blood group relationship—its level is lower among people with blood group 0, and is higher among those with blood group A. The different amount and activity of VWF in people with different blood groups has a very interesting explanation: this protein is modified by oligosaccharide chains of antigenic determinants of the AB0 system (one of the blood group systems), and this affects its stability and activity.

She points out that ‘to date, the way in which the level of VWF is regulated in the blood has not yet been fully studied’, and then she describes some of what we do know, that it’s stored in special organelles (Weibel-Palade bodies) from where it’s secreted in multimeric form. She argues that, in order to determine the level of involvement of VWF in the progress of covid19, ‘large scale and comprehensive research’ needs to be carried out. Another article which is looking at emergency covid19 treatment has the title ‘targeting raised VWF levels and macrophage activation in severe covid19: consider low volume plasma exchange and low dose steroid’. It points out that VWF is such a large protein that it can only really be removed from the body through plasma exchange. This may be a way to reduce thrombosis in serious cases. Another interesting commentary piece is titled ‘microthrombotic complications of covid19 are likely due to embolism of circulating endothelial-derived ultralarge von Willebrand Factor (eULVWF) decorated-platelet strings’. 

Canto: An embolism being a blockage, caused by an embolus. That embolus could be a blood clot (a thrombus) or a fat globule or an air or gas bubble. 

Jacinta: Yes, and VWF can come in these long strings of platelets. In fact the platelets adhere to the strings. Anyway, that’ll do for now. We’ll go on about ivermectin and the Moderna vaccine trials next time. 


Coronavirus Pandemic Update 95: Widespread Clotting on Autopsy; New COVID-19 Prognostic Data

Coronavirus Pandemic Update 96: RNA Vaccine; Ivermectin; von Willebrand Factor and COVID-19,to%20help%20detect%20heart%20injury.,a%20marker%20for%20cardiac%20injury.&text=The%20cause%20of%20troponin%20elevation%20in%20serious%20infection%20is%20multifactorial.

Written by stewart henderson

September 6, 2020 at 1:44 pm

covid 19: health in Kazakhstan, megakaryocytes, the endothelial hypothesis

leave a comment »

two megakaryocytes in the bone marrow, arrowed


Jacinta: So just to point out, from our last post, that Dr Seheult described long-term inhaled corticosteroid as sometimes having serious side-effects, such as cataracts, osteoporosis and pneumonia. He also presented contradictory rat studies on using NAC as a supplement, highlighting the need for more systematic RCTs in humans.

Canto: And what do we make of the Chinese embassy in Kazakhstan warning of a pneumonia outbreak there, which they claim is deadlier than covid19? Can we trust this?

Jacinta: Well, the Kazakhstan government has denied that the pneumonia problem was new and unknown, but it is clearly a problem, and sadly I can’t find any news about it that’s less than a month old, at about the time the news broke internationally. Some Chinese health officials are claiming that the pneumonia outbreak is related to covid19, but there’s no clear evidence about that, and this pneumonia problem in Kazakhstan is well over a year old, though it has become more of a problem with the advent of covid19. More research and information required.

Canto: Update 95 is dated July 14, and starts with conditions in Dr Seheult’s own county in California, where as we know the cases numbers have risen almost catastrophically. Some parts of the  county’s hospitals have been newly transformed into ICUs. He presents a graph showing the recent increase in covid19 patients, but also a diminution in the number of suspected cases, indicating an improvement in diagnosis. And then he looks at a paper about ‘megakaryocytes and platelet fibrin thrombi [which] characterise multi-organ thrombosis at autopsy in covid19’..

Jacinta: Yes it looks at some autopsies and finds these megakaryocytes, which are precursors to platelets – they’re large as the name suggests, and they’re produced in the bone marrow, and are normally relatively rare, constituting 1 in 10,000 bone marrow cells, but can rapidly increase in response to some infections – they found these cells throughout the body. So how did they get to these multiple organs? Thrombosis was a feature of multiple organs regardless of anticoagulation treatment, suggesting that this thrombosis process started early in the infection cycle. The paper presents some fairly graphic images of large-scale thrombosis in the pulmonary artery and thickening of alveolar walls, with diffuse alveolar damage (DAD) preventing effective oxygenation, and also megakaryocytes in the kidneys. Other sites, such as the heart epicardium, feature large numbers of white blood cells and megakaryocytes. We also see ECGs apparently during myocardial infarction (heart attack) but I don’t know how to read those. The conclusion of the paper finds that the many thrombi found throughout the microvasculature of principal organs occurred in situ and before death. This was confirmed by ‘lines of Zahn’, visible layering which reveals clot formation while the blood is flowing, pumped by a beating heart. Now, this is very complex but important stuff, so I’m going to quote from the paper and try to make sense of it:

The extensive nature of platelet-fibrin thrombi in the alveolar capillaries in our patients may explain the observation that oxygenation is disrupted in an exaggerated fashion early in the disease course of patients with covid19, as this suggests evidence of ventilation-perfusion mismatch unrelated to hyaline membrane formation. Our patients’ lungs all had histopathologic findings of DAD, which has been the most frequently reported finding in covid19 autopsies thus far. 

So firstly, what are hyaline membranes? They’re a composite of fibrin (an insoluble protein used in blood clotting), cellular debris, including various blood cells or parts thereof, and other eosinophilic stuff – stuff that boosts inflammation and curbs infection, or tries to. So what’s being said here is that the ‘ventilation-perfusion mismatch’, the problems with oxygenation, may be more related to the platelet-fibrin thrombi than the hyaline membrane formation, found mostly in the lungs. So now I’m going to quote something even more technical – it’s all a learning process:

Thrombi were located in veins and in the pulmonary arteries and arterioles and in microvessels, but not in systemic arteries. Despite elevated fibrin degradation products, in only one case of a patient with cirrhosis did we observe glomerular thrombotic microangiopathy, arguing against disseminated intravascular coagulation, haemolytic-uremic syndrome, or thrombotic thrombocytopenic purpura as a predominant pathophysiological pathway. Schistocytes may suggest endothelial damage, but we found them only rarely. We found no endothelial abnormalities on microscopic review, in alignment with previous studies, but we cannot rule out increased exposure of tissue factor, erosion of the endothelial glycocalyx, or other mechanisms of endothelial dysfunction that could be pro-coagulant without showing histopathological evidence of activation or erosion. 

Canto: Scheisse! I can’t unpack too much of that, but I do note they ‘found no endothelial abnormalities… in alignment with previous studies’. I thought we were establishing that this is an endothelial disease, über alles? Are we being led up zie garden path?

Jacinta: Well let’s look more closely. The systemic arteries are those that carry oxygenated blood away from the heart to the other organs, and return deoxygenated blood to the heart. The pulmonary arteries, on the other hand, carry deoxygenated blood to the lungs. What this means in terms of thrombi I’m not sure. Fibrin degradation products (FDPs) (one sub-type of which are D-dimers, types of protein fragments) are produced by clot degeneration. Clotting creates a net of fibrin as part of the healing process, and after this process the net is broken down by an enzyme called plasmin, releasing protein fragments – FDPs. Now, they say that they observed ‘globular thrombotic microangiopathy’ in only one case of a patient with cirrhosis. Cirrhosis is essentially scar tissue of the liver, and it’s generally permanent – you can’t really unscar it, though you can of course prevent more damage being done. The scarring is a kind of self-repair of damage from a variety of sources – hepatitis, alcohol abuse and other liver diseases. As to glomerular thrombotic angiopathy, a glomerulus is a network of capillaries at the end of each nephron in the kidneys. Thrombotic microangiopathy is a rare but serious disease of those capillaries or microvessels, mostly in the kidney and the brain, obviously involving thrombosis.So the general lack of globular thrombotic microangiopathy – and remember they were only looking at at a handful of autopsy subjects – argued against these other pathologies as a pathway in the aetiology of covid19. But let’s look at them – disseminated intravascular coagulation (DIC) is as it sounds, blood clots forming throughout the body, often blocking small blood vessels…

Canto: But I thought that was just what was happening with covid19? That it was proving to be a a vascular, endothelial disease. 

Jacinta: Yes I’m a bit confused too. I just tell myself I’m only the messenger.. So haemolytic-uremic syndrome (HUS) is a group of blood disorders in which the red blood count goes down, platelets are also very low and the kidneys are failing. Very nasty symptoms. 

Canto: Right – that hasn’t been associated with covid19 before.

Jacinta: Not that I know of, FWIW. Finally, thrombotic thrombocytopenic purpura (TTP)  is another blood disorder with clots forming in small blood vessels throughout the body, and a drop in red blood cells and platelets. Its weird, but perhaps what is written next about schistocytes is key here. They didn’t find many schistocytes in these bodies. These are fragments of red blood cells, broken down, jagged pieces of cells that are characteristic by-products, I think, of the the above-mentioned diseases. So that’s something that marks off covid19. So they found no evidence of endothelial dysfunction, though they couldn’t rule out such things as ‘erosion of the endothelial glycocalyx’. This glycocalyx is a mesh of bound glycoproteins and such covering the lumen side of the endothelium. Anyway, all in all this seems a blow, though maybe only a minor one, to the endothelial hypothesis. 

Canto : Well, that was all very technical. Time for a rest….


Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?

Coronavirus Pandemic Update 95: Widespread Clotting on Autopsy; New COVID-19 Prognostic Data

Written by stewart henderson

September 2, 2020 at 6:29 pm

Posted in covid19

Tagged with , ,

covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities

with one comment

keeping it simple, for now


Jacinta: Let’s look at monoclonal antibodies briefly before we continue with those medcram updates. Francis Collins, the somewhat controversial but scientifically reliable directer of the NIH in the USA, recently described ‘monoclonals derived from people who’ve survived covid19’ as the best hope for treatment in the absence of a vaccine. So what are these monoclonals? There are lots of useful videos on youtube that provide detail. I’m picking one from the JAMA network. The technology for producing these types of antibodies was developed in the mid-seventies. It was called ‘murine hybridoma’ technology, murine meaning ‘mice’. I remember first reading about monoclonal antibodies in a Scientific American article in the early eighties. It went straight over my head of course, but now it’s time to get a grip on them. So mice were injected with an antigen, which in general terms is a pathogen that induces an immune response. In more specific terms an antigen is a molecule or structure, part of a larger pathogenic molecule, that can be bound to by an ‘antigen-specific antibody’ or B cell receptor. B cells are lymphocytes that secrete antibodies. So the researchers induced this response, then isolated B cells from the spleen of the mice, which they fused with myelomas (cancerous plasma cells). Cancer cells are notoriously long-lived – see ‘the Immortal Life of Henrietta Lacks’ – so these fused cells, called ‘hybridomas’, act like B cells in producing antibodies, and like tumour cells in their ability to replicate. So these hybridomas can be grown in culture and each one can produce a single antibody type, which targets a single antigen type. Hence monoclonal. They can clone themselves for a specific antigen. So, once you know your antigen, you can create a ‘monoclonal’ specifically for it, or two or three to choose from. And now, with covid19 and with technological development, we can isolate monoclonal antibodies not from mice but from recovered covid19 patients. So that’s a somewhat over-simplified account – for more detailed info on monoclonal antibodies, this zero to finals video is excellent, and there are doubtless others. The target for this work is generally the S-protein of the SARS-CoV2 virus, with various particular sites being looked at, and a number of teams working on the research. Some are pretty well ready to go, with specific antibodies or sets of antibodies. The argument is that they could be used for high-risk groups such as ICU workers and nursing home clients, as a kind of temporary vaccine. 

Canto: Okay, something else to keep track of. So update 93 discusses an article published in Nature Medicine – all the authors appear to be Chinese – which looks at 37 asymptomatic covid19-infected subjects and their antibodies, compared to those of 37 symptomatic subjects. 

Jacinta: So they looked at their immunoglubulin G (IgG) levels. These are the most common types of antibody, created and released by plasma B cells. They graphed the IgG during the acute and convalescent phases, and they defined the acute phase as that in which the viral RNA was detectable in a respiratory specimen, and the convalescent phase as from eight weeks post-release from hospital. What the graph shows is that the IgG levels decreased from acute to convalescent in both symptomatic and asymptomatic cases, but more in the symptomatic cases. They also looked at ‘neutralisation rates’, which presumably refers to the effect of antibody activity. A positive effect means more neutralising antibodies are produced. These seemed about the same between the phases for both groups, but another graphic shows that in the convalescent phase, the symptomatic group have substantially more neutralising antibodies. It seems from this admittedly small study that asymptomatic subjects are at risk of reinfection, after a period of time.

Canto: And even symptomatic subjects after recovery, as we have obviously no longitudinal studies on anti-viral IgG levels, as the study points out. 

Jacinta: Well that takes us to the next study, from Spain, which managed to round up almost 52000 participants. The study tells us between late April and mid-May the estimated seroprevalence (the percentage of inhabitants that had the virus) for the whole country was around 5%, depending on different test types and results, and with great variation between regions. Findings were that prevalence increased with increasing age. Looking at different jobs, those working in healthcare were clearly more at risk, and to a lesser but still significant degree, those working in nursing homes…

Canto: Which is still largely healthcare, but less trained, and often less prepared for this onslaught…

Jacinta: Point taken. And those living in the larger municipalities were more often infected than those in less densely populated regions. Interestingly, they found that the rapid (and cheap) fingerpoint test, which provides results within ten minutes, was pretty close to being as effective as an immunological assay, which is important as the delay in test results has been a major issue.

Canto: Amazing. Why aren’t they using this all the time? Everywhere?

Jacinta: That’s another issue – maybe later. Anyway, much of this study confirms the many smaller studies that have been conducted. They found that healthcare workers comprised 24% of all confirmed cases. This may be partly because they had more access to testing. There is so much to glean from this study, I can only skim. But here are some very interesting remarks in their conclusion:

One in three infections seems to be asymptomatic, while a substantial number of symptomatic cases remained untested. Despite the high impact of covid19 in Spain, prevalence estimates remain low, and are clearly insufficient to provide herd immunity. This cannot be achieved without accepting the collateral damage of many deaths in the susceptible population and overburdening of health systems. In this situation, social distance methods and efforts to identify and isolate new cases are imperative for future epidemic control.

Canto: So there are no easy solutions, and even a vaccine is not necessarily going to be the magic bullet everyone’s hoping for. The proof of the pudding will be in the eating, and we haven’t eaten any vaccines yet. They won’t be on the menu for a while, and it’ll be a lot longer before we can gauge their nutritional value.

Jacinta: Yes, what you’re saying is, we don’t know how long antibodies to this virus will last. We’re still in unexplored terrain with respect to this very unusual and deadly virus. An article published on the Jama Network quite a while ago is still relevant now in its conclusions, as nothing we’ve so far found disconfirms it: 

… the immune response to covid19 is not yet fully understood and definitive data on post-infection immunity are lacking. Amidst the uncertainty of this public health crisis, thoughtful and rigorous science will be essential to inform public health policy, planning and practice. 

Canto: Frustrating to many. So with update 94 we’re getting towards mid-July and they’re noting that things are hotting up, as the weather is cooling down, in Australia, though of course it bears no comparison to the US tragedy. They were talking about things getting worse in their autumn, but summer hasn’t given them any sort of break. 

Jacinta: So update 94 first looks at inhaled corticosteroids, one of many medications being considered and perhaps used by health professionals, others being ivermectin (a broad-spectrum anti-parasitic drug) and nitric oxide, all without solid RCT-type evidence. Even so, case reports and other low-level studies show promise, and these are arguably desperate times. A study presented by Dr Seheult suggested that some corticosteroids showed positive immunological effects in case reports and in vitro. Interestingly, asthmatics have been prescribed corticosteroids quite regularly…

Canto: As have I, from time to time. At least I think it was corticosteroid…

Jacinta: Well, that’s interesting, I know you’re not asthmatic but with bronchiectasis you have asthma-like symptoms at times. And the good news for you, and generally interesting news for us all, is that ‘asthma patients with covid19 do not appear to have a higher rate of hospitalisation or mortality compared with other covid19 patients’. Indeed it may be the opposite, as data from Wuhan indicates that less than 1% of their hospitalised patients had asthma, compared to 5% in the general population. In New York, too, asthma wasn’t even in the top ten comorbidities, which is pretty striking for a virus that hits the lungs first. Similarly, COPD, which your ailment is surely associated with, comes in below diabetes, renal disease and a whole range of cardiovascular issues as a comorbidity factor. A possible reason for this is that the kind of chronic inflammation produced by asthma and COPD is associated with reduced ACE2 expression, meaning fewer receptors for the virus. So these conditions could actually be protective. And they might also be on corticosteroid inhalers, which may also be protective.

Canto: That sounds great. Let’s leave it there before I hear any bad news…


Coronavirus Pandemic Update 93: Antibodies, Immunity, & Prevalence of COVID-19 – New Data from Spain

Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?

How do monoclonal antibodies work? Rituximab, infliximab, adalimumab and others

Coronavirus Treatment and Prevention with Monoclonal Antibodies


covid19: corticosteroids, male susceptibility, evaluating health, remdesivir, coagulation factors

leave a comment »

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.


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