Posts Tagged ‘Covid-19’
Is/was the Covid 19 pandemic overblown?
Jacinta: So clearly Covid-19 fatigue is becoming a worldwide phenomenon, and I’m not talking about long Covid. Mask-wearing here in Australia has reduced almost to pre-Pandemic levels, and I’m beginning to hear more claims that it was never really that much worse than the flu, and that the world has suffered more from lock-downs and other restrictions than from the virus itself. This is a bit shocking, so it’s time to evaluate these claims, for what they’re worth.
Canto: Well we haven’t been keeping tabs on this lately, but in the first year of the pandemic we regularly visited the Johns Hopkins and Worldometer sites to keep track of the global and nation-by-nation statistics on SARS CoV-2. Returning now, I find that Worldometer provides an overall death toll so far of a little over 6.7 million. The Johns Hopkins Coronavirus Resource Center has almost exactly the same figures…
Jacinta: And how does this compare to flu figures? Someone asked.
Canto: Actually, this is not a simple question. For a start, people may die with a particular illness or infection but not necessarily of it. And death certificates can often be ambiguous on this matter. This also allows ‘Covid skeptics’ – and there have long been plenty of them – to distort the figures any way they can. Death certificates are used by the UK’s Office for National Statistics:
The ONS uses data from death certificates to count deaths from Covid-19 and all other causes. This is distinct from public health measures, which include deaths within 28 days of a positive Covid-19 test. We use the term ‘due to Covid-19’ when referring only to deaths with an underlying cause of death of Covid-19. When taking into account all of the deaths that had Covid-19 mentioned anywhere on the death certificate, whether as an underlying cause or not, we use the term ‘involving Covid-19’. This is also the same for flu and pneumonia.
Jacinta: Yes, this is good policy, as it puts Covid-19 and flu etc on the same footing. But mightn’t it be the case that, due to the prevalence and greater public face of Covid-19 in these times, medical authorities would be more likely to attribute cause of death to Covid-19 than to anything else, just because the patient tested positive? I mean, why test for anything else when they’re sick and Covid-positive?
Canto: Hmmm, well why indeed – if they’re sick and have the symptoms of Covid, trying to reduce those symptoms would be the medico’s first duty. After all, Covid-19 is a far more deadly disease than flu.
Jacinta: But not everyone agrees, apparently.
Canto: Yeah, and not everyone agrees that the Earth is an oblate spheroid – so what? You asked about deaths from Covid v flu. Looking at the data from the UK is a good idea, because both the flu and pneumonia are more prevalent there than in Australia.
Jacinta: And yet interestingly the relaxed restrictions and reduced mask-wearing that occurred from mid-22 resulted in our worst – most deadly – flu season in five years. Influenza was considerably reduced in Australia in the winters of 2020 and 2021, obviously due to those restrictions.
Canto: Well we’ve asked, by someone sceptical of the fuss and perhaps the over-reaction to this pandemic, to look into it more deeply, though this is probably a task way beyond our powers. We’ve been given a reference to start us off, an essay by John Ioannidis, a professor of medicine, epidemiology and population health at Stanford – at least he was at the time of writing the essay, back in March 2020, only 2 months into the pandemic.
Jacinta: Yes I remember there was something of a furore around this essay, a lot of blowback as the Yanks say. I never read it, but we did do a lot of reading and listening vis-a-vis SARS-CoV2 in the first months of 2020.
Canto: That’s right – the Medcram coronavirus updates, delivered by Dr Roger Seheult and designed, as the name suggests, for medical students, were always our first port of call. I watched over a hundred of them on YouTube, and educated myself pretty well on the structure of the virus, its method of action within the body, from the lungs into the epithelial tissue and the bloodstream, the ensuing cytokine storm, and of course the method of transmission from person to person. It was quite an education.
Jacinta: When Ioannidis wrote his piece there were 68 recorded deaths from Covid-19 – according to his own figures.
Canto: yes, here’s a quote from the essay:
Some worry that the 68 deaths from Covid-19 in the U.S. as of March 16 will increase exponentially to 680, 6,800, 68,000, 680,000 … along with similar catastrophic patterns around the globe. Is that a realistic scenario, or bad science fiction? How can we tell at what point such a curve might stop?The most valuable piece of information for answering those questions would be to know the current prevalence of the infection in a random sample of a population and to repeat this exercise at regular time intervals to estimate the incidence of new infections. Sadly, that’s information we don’t have.
Jacinta: And Johns Hopkins puts the total number of US deaths from Covid-19 at 1,097, 660, as of January 10 2023 – far worse than Ioannidis’ most catastrophic scenario. And yet, Ioannidis has never backed down from the claim that the world is over-reacting. One has to wonder how many people would have to die before he changed his mind.
Canto: Maybe he wants to argue that many of these people didn’t ‘really’ die of Covid-19 – that they would’ve died anyway. Now that’s a hard thing to prove. We all die, after all.
Jacinta: And interestingly, the USA’s death toll is about 16% of the global toll, though the USA has only about 4% of the world’s population. Does this mean the USA’s response has been a big failure, or are they attributing more deaths to Covid-19?
Canto: The USA has suffered way more deaths from Covid-19 than any other country, and it jumped to the lead very early on. In that period there was huge criticism about how the Trump administration had gutted the CDC and the FDA, and of course Trump’s response to the outbreak was to mock mask-wearing and to compare it to the flu – ‘it’ll be gone in weeks’. That’s when his approval rating – already much lower than his disapproval rating – really tanked, and he started talking – in April – about the November election being rigged, but only if he lost!
Jacinta: Well some thugocracies like Russia and China can’t be trusted on their figures, but getting back to Ioannidis, in his March 2020 essay, he seemed to be concerned more about the under-estimation of figures rather than the opposite:
Given the limited testing to date, some deaths and probably the vast majority of infections due to SARS-CoV-2 are being missed. We don’t know if we are failing to capture infections by a factor of three or 300. Three months after the outbreak emerged, most countries, including the U.S., lack the ability to test a large number of people and no countries have reliable data on the prevalence of the virus in a representative random sample of the general population.
Canto: Yes, and the ability to test clearly improved in most developed countries over time, but Ioannidis still wasn’t satisfied. And how do you measure a country’s ‘ability to test’? Clearly you can’t force everyone to be tested – not even the Chinese Testosterone Party can do that – because they’ve allowed too many people to exist. Even a ‘no child policy’ would take too long to improve the situation, they need another Mao-style ‘great leap forward’ to do the job. But that only killed 70 million at most, a mere drop in the bucket…
Jacinta: Yeah well, back to the topic. Ioannidis talks about an ‘evidence fiasco’, but surely he’s being unrealistic – we could never expect to test everyone, and so of course plenty of unsymptomatic carriers, especially the young, would pass through the net and unsuspectingly pass on the virus. That’s why physical distancing and mask-wearing became a high priority as we learned how the virus was being transmitted.
Canto: Of course it must be remembered that Ioannidis wrote this essay (referenced below) at the very outset of the pandemic. Even so, his predictions were way off. He projected case fatality rates from the Diamond Princess outbreak onto the general (US) population:
Projecting the Diamond Princess mortality rate onto the age structure of the U.S. population, the death rate among people infected with Covid-19 would be 0.125%. But since this estimate is based on extremely thin data — there were just seven deaths among the 700 infected passengers and crew — the real death rate could stretch from five times lower (0.025%) to five times higher (0.625%).
Please note that Ioannidis’ projected worst-case scenario, adjusting for the higher age range of the Diamond Princess crew, was 0.625%. According to the latest figures from Johns Hopkins and the WHO, the USA’s current case fatality rate is about 1.1%, almost twice Ioannidis’ worst case projection. Of course, Ioannidis can’t be blamed for his under-estimation in the early stages of the pandemic, but it’s rather surprising that he hasn’t modified his views in line with ongoing evidence. So, unfortunately, he has become a beacon for contrarian views about the impact of and response to Covid-19. Even the highly-regarded Scientific American magazine defended Ioannidis in a brief November 2020 article that it later apologised for as an ‘opinion piece’ containing a series of factual errors.
Ioannidis doubled down on his claims of an over-reaction to the pandemic, appearing on various news networks throughout 2020 to express caution and to question the measures taken to prevent spread, but he was arguing against a growing consensus. The Washington Post put it this way in December 2020, after a terrible year in the USA:
… as the pandemic enters its deadliest phase, Ioannidis is losing the argument over how to combat covid-19. Among epidemiologists, consensus now exists that it was inaction, not overreaction, that helped create the worst public health crisis in a century. The uncontrolled spread of the virus has led to overrun ICUs in South Dakota and makeshift morgues in Texas. States and countries are locking down in a bid to preserve lives as vaccines start to roll out. Even Sweden, which resisted tough restrictions through the spring, is now reversing course to avert catastrophe.
So, of course we can’t compare what happened with restrictions, lockdowns and mandatory mask-wearing with what might have happened had we continued with business as usual and relied on herd immunity (that’s to say, the development of natural immunity without vaccines), but it’s surely worth listening to those who work in the field of virology and immunology. And within those circles there appears to be broad agreement. Here’s what the Mayo Clinic has to say:
There are some major problems with relying on community infection to create herd immunity to the virus that causes COVID-19:
- Reinfection. It’s estimated that getting COVID-19 results in a low risk of another infection with a similar variant for at least six months. However, even if you have antibodies, you could get COVID-19 again. Because reinfection can cause severe medical complications, it’s recommended that people who have already had COVID-19 get a COVID-19 vaccine.
- Health impact. Infection with the COVID-19 virus could lead to serious complications and millions of deaths, especially among older people and those who have existing health conditions. The health care system could quickly become overwhelmed.
Vaccines
Herd immunity also can be reached when enough people have been vaccinated against a disease and have developed protective antibodies against future infection. Unlike the natural infection method, vaccines create immunity without causing illness or resulting complications. Using the concept of herd immunity, vaccines have successfully controlled contagious diseases such as smallpox, polio, diphtheria, rubella and many others.
I should also add that the pandemic, for all the suffering caused, has led to a marked improvement in the time-frame for effective vaccine production, and of course a breakthrough in the form of mRNA vaccines, which has been something of a revolution in immunology.
I’ve not properly answered the question – are there more deaths from flu than from covid? A 2021 article from the British Medical Journal answers precisely that question, again quoting the ONS:
Data from the Office for National Statistics show that in England and Wales the number of deaths from influenza was 1598 in 2018 and 1223 in 2019. This is way below the annual deaths from covid-19, which at the current rate of around 800 deaths a week in England and Wales equates to more than 40 000 a year.
That’s a huge difference, despite all the caveats mentioned above and repeated in the BMJ article. But unfortunately people will believe what they want to believe.
References
A fiasco in the making? As the coronavirus pandemic takes hold, we are making decisions without reliable data
https://www.washingtonpost.com/dc-md-va/2020/12/16/john-ioannidis-coronavirus-lockdowns-fox-news/
https://www.bmj.com/content/375/bmj.n2514
Americans who turn to the White House for coronavirus news tend to think the media’s pandemic coverage is overblown
catching up on SARS-CoV-2
Canto: So, having largely ignored COVID-19 in the last few months, since having my fourth vaccine, which came before or after having tested positive (a RAT test) for the virus, with minimal symptoms – and I suppose it may have been a false positive – I hear that it’s still causing serious problems two years on. And I’m still encountering people who make light of the virus, and are ‘on the fence’ about ‘the whole vaccine thing’, so I think we should explore the situation anew – variants, comorbidities, actions to be taken, long covid etc etc.
Jacinta: Okay, another interminable conversation perhaps. Where do we start? According to a graph (see below) on the situation in South Australia, case numbers have spiked a few times in the last year, but the graphic gives no indication of severity of symptoms. The reporting on new cases seems to be more sporadic at the moment, which explains the gap between the lines, which are getting disturbingly longer. We’ve noticed of course, that mask-wearing and other precaution-taking has slackened off during the year, and government-enforced mandates were lifted months ago….
Canto: And few people seem to be concerned about crowded settings any more… The ABC has a state-by state report, referenced below, which gives weekly stats. It shows that in every single state and territory the case numbers for the last week were higher than those of the week before. Their site presents a rather alarming graphic of case numbers over the last four months, which speaks for itself:
Jacinta: And yet, as you say, covid fatigue, or rather covid restrictions fatigue, has set in, and governments are no doubt reluctant to get tough again, unless things get even worse. What I’m hearing, from people much younger than me, is that it’s no big deal for the young and healthy, only elderly people or those with comorbidities need to worry – and of course it’s all a bit overblown. I hesitate to ask if they’ve been fully vaxed – they’ve obviously never heard of Typhoid Mary.
Canto: And that was 100 years ago – the germ theory of disease wasn’t fully accepted then, but now information is easily available.
Jacinta: And so is misinformation. Anyway, the ‘fourth wave’ is now underway, according to the media. According to Dr Nancy Baxter in an ABC interview, our vaccine immunity has declined over time and most covid restrictions are gone, so numbers are increasing again, and hospitalisations are rising.
Canto: My sympathies go to all the medicos, nurses and other such workers out there. What about death rates – and what about variants, where are we with those?
Jacinta: So just over a month ago the federal government’s Chief Medical Officer made this public statement:
We are seeing an increase in COVID-19 case numbers in Australia, reflecting community transmission of the Omicron variant XBB. We are also closely monitoring the overseas transmission of a second Omicron variant – BQ.1. While evidence is still emerging, the experience to date with these two variants overseas is that they do not appear to pose a greater risk of severe illness and death – and that the COVID-19 vaccines provide good protection against these outcomes. All indications are that this is the start of a new COVID-19 wave in Australia. This was to be expected and will be part of living with COVID-19 into the future. The overseas experience is that these new variants have driven increases in case numbers – and hospitalisations at a rate proportionate to these increases – because of their ability to evade the immunity provided by prior infection and vaccination.
So, not more deadly, but each new variant that comes to our attention does so because it has varied sufficiently to evade the immunity provided by previous infections and the vaccines created to target those earlier forms of the virus. So this could be an ongoing problem, as the CMO says.
Canto: So doesn’t this remind you of the antibiotics dilemma? Rapid reproduction means rapid variation, and we can’t keep up, with antibiotics or vaccines. We’re all doomed!
Jacinta: Well, the panic seems to be over – though panic is the wrong word, to be sure – but case numbers continue to be high, though they appear to go in waves, as every new more successful variant comes along. And death rates, which of course lag case rates and are complicated by comorbidity and age factors, are still higher than we’d like them to be. It’s a weird situation we’re in now, with so many people being in denial or just switched off, perhaps because they’ve made it okay thus far. But of course we’re not doomed – we just need to keep informed about our local area, keep up the vaccines as required, and take precautions as necessary. Remember it’s a largely airborne virus, and it loves crowds of people in enclosed spaces.
Canto: Well we might be keeping up with the vaccines, but are the vaccines keeping up with the variants?
Jacinta: Well this week the CDC in the USA came out with an advisory about updated (bivalent) boosters for adults and children – though the adult one came out on September 2, so not so recent…
Canto: What’s a bivalent booster?
Jacinta: That’s a vaccine that confers immunity to two antigens, such as two versions of a virus, as is presumably the case here. So they’re able to tweak vaccines to cover new variants, methinks. Seems to be a bit of a race between antigens and prophylactics. As to keeping up, an article from the Nature website (referenced below) provides reassurance:
Booster shots against current SARS-CoV-2 variants can help the human immune system to fight variants that don’t exist yet. That’s the implication of two new studies analysing how a booster shot or breakthrough infection affects antibody-producing cells: some of these cells evolve over time to exclusively create new antibodies that target new strains, whereas others produce antibodies against both new and old strains.
Canto: So the message clearly seems to be to keep up the boosters, which I strongly suspect young healthy people aren’t doing, so they’re playing dice with their own health as well as threatening the health of others inadvertently, as more of less healthy carriers of the virus.
Jacinta: Yes, it’s really a difficult message to get through to the young, especially if they’re not in contact with serious sufferers or the mortality of loved ones.
Canto: Okay, so it’s an ongoing drama at present. I’m hoping that we can look at the long covid issue sometime soon, another complex problem, due to symptom variety, skepticism, and the whole issue of treatment.
Jacinta: Yes – whether the pandemic is over or not is a live issue. Sometimes I get the impression that it’s over just because people want it to be over. They want to return to ‘normality’ whatever the consequences. The virus may teach us otherwise. We need to keep an eye on it.
References
https://www.health.gov.au/news/new-covid-19-variant-leads-to-increase-in-cases
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bivalent-vaccine
covid19: sensible testing, mostly
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
covid 19: health in Kazakhstan, megakaryocytes, the endothelial hypothesis
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….
References
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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1915585/
https://en.wikipedia.org/wiki/Schistocyte
https://en.wikipedia.org/wiki/Thrombotic_thrombocytopenic_purpura
Covid-19: remdesivir, masks, vaccine trials, arrhythmias
So to Dr Seheult’s coronavirus update 77, where he looks again at the antiviral drug remdesivir. A preliminary report from the New England Journal of Medicine describes results from trials comparing remdesivir with placebo in covid-19 patients at various levels of treatment, i.e, those receiving oxygen, those not receiving oxygen, those receiving high-flow oxygen or ‘noninvasive mechanical ventilation’, and those receiving full mechanical ventilation or ECMO (extracorporeal membrane oxygenation), and the finding was that remdesivir only made a statistically significant difference in the oxygen-receiving patients, which is more or less an intermediate phase. This may be due to the larger sample size that fell into this category. There were apparently small benefits in the non-oxygen category, but nothing in the more serious patient categories. The report’s conclusion:
These preliminary findings support the use of remdesivir for patients who are hospitalised with Covid-19 and require supplemental oxygen therapy. However, given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient.
So remdesivir appears to be just one of many agents and therapeutics in the armamentarium of health authorities dealing with this pandemic, which over the past few months appear to have been utilised to reduce mortality and improve recovery times since the early phase of the outbreak in the USA, to judge from figures comparing, say, New York with Texas and Florida.
The update also discusses heat-treating the interior of police vehicles as a disinfectant, using a computer program. Basically a system has been devised to heat-treat unoccupied vehicles for 15 minutes to 133 degrees fahrenheit, long enough and hot enough to kill 99% of known pathogens, including SARS-CoV2, and it’s already being rolled out for police SUVs. Interesting, and obviously adaptive to other circumstances. The rest of the update discusses promising approaches as of the end of May, including convalescent plasma therapy, which I hope to look at later.
Update 78 starts with face masks. We here in South Australia have only suffered 459 cases in total, with 457 recovered and only 4 deaths. The majority of cases by far occurred in the early stages (March-April), and much has opened up since then, and the wearing of masks has always been optional here. However, the virus has had a resurgence in Australia’s more populated eastern states, so we’re on alert, and there’s been a partial closing down again. Still, most people I notice aren’t wearing masks. In the USA there seems to have been some prevarication from authorities like the CDC on mask-wearing, but with a further understanding, especially of asymptomatic and pre-symptomatic cases, they came out more strongly in favour of cloth masks ‘in public settings where other physical distancing measures are difficult to maintain (e.g. grocery stores and pharmacies), especially in areas of significant community-based transmission’. The WHO’s guidelines aren’t so strict possibly because they’re dealing with a broader base in which effective face masks are less readily available and need to be prioritised.
Also related to masking is a New England Journal of Medicine article on aerosols and droplets generated by speech, which have been implicated in Covid-19 transmission. A simple experiment was conducted using laser light scattering to illuminate droplets from a speaker without a mask, and then with one, and the difference was quite dramatic. Update 78 shows the video, and it’s worth a thousand words.
This update also highlights a website which I intend to explore further, especially as I seem to be spending a lot of time in the world of disease, pathogens and the fight against them. It’s called Regulatory Focus, and there’s a further link to its covid-19 therapeutics tracker, which tracks all the research and studies, of antivirals, monoclonal antibodies and any other medications that might relate in any way to the pandemic, and another link takes us to the covid-19 vaccine tracker. It provides information on phase trials, the vaccine type, the institutions and sponsors involved, etc.
In update 79, Dr Seheult picks out a few of the vaccine trials that seem to show most promise and are most likely to be available by 2021. First is the Moderna mRNA-1273 candidate, which will inject mRNA to produce proteins that generate an immune response. Now the standard clinical trial process for testing a vaccine involves three phases. Phase 1 tests primarily for safety, phase 2 largely looks at appropriate dosage, and phase 3 is the final, large human population trial. These phases have been fast-tracked more than ever before, as is well known, sometimes without the usual animal testing, which would generally raise ethical issues, but that doesn’t seem to be happening for covid-19 trials. The University of Oxford candidate is ‘a chimpanzee adenovirus vaccine vector called AZD1222’. It injects an epitope for an antigen into the patient. An epitope is a region of an antigen that antibodies detect and bind to. Other candidates come from the Merck company, Johnson & Johnson and Pfizer.
Update 80 deals with a very controversial issue, which is possible research industry malpractice, in the form of massaged results relating to a relatively small company, Surgisphere. Interestingly, it involves an overstatement of deaths here in Australia, among other inconsistencies, which have led to retractions of papers on hydroxychloroquine and chloroquine in prestigious journals such as the Lancet and NEJM. It seems that the papers may have exaggerated negative effects from the use of these anti-malaria medications, with or without the addition of a macrolide (a class of antibiotics), which has just added to the controversy surrounding them. There’s also a question about the use of the anti-parasite drug ivermectin, and some common heart medications, due to these now-retracted results.
Interestingly, update 81, posted back on June 9, highlights Australia as still succeeding in keeping numbers down as we head into winter. That’s not the case today (August 11). It goes on to introduce another website, Covid-trials.org, comprising data on ‘over 1400 trials’ (now over 1900) worldwide relating to covid-19, including ‘alternative therapy’ and ‘traditional Chinese medicine’. Hmmm. And of course all the more promising treatments. This and the previously mentioned vaccine and therapeutics trackers provide a wealth of ongoing detail about the who, the how, the what, the how much, etc.
The update also describes a trial of hydroxychloroquine ‘as post-exposure prophylaxis’ published in NEJM. 821 people known to be exposed to the virus were treated with either hydroxychloroquine or a placebo, and then tested for the virus. The result was a non-statistically significant prophylactic effect. There were minor gastrointestinal side-effects in the hydroxychloroquine group, but no cardiac arrhythmias, often associated with the drug. Dr Seheult explains something about these arrhythmias, which is interesting enough for me to dwell on.
When we look at an electrocardiogram (ECG) we find something like the drawing here, with a P-wave, and a T-wave at the end. Some medications can cause a prolonged QTc (the c stands for ‘corrected’), and in combination with others, this can result in cardiac arrhythmias, which generally have two types, as shown in the illustration at the top of this post – an over-fast beat (tachycardia) or a too-slow one (bradycardia).
So, although the positive effects of hydroxychloroquine in this study were minor, there may have been a greater benefit from adding zinc to the treatment, as Seheult suggests, because the drug acts as a zinc ionophore. An ionophore is a fat-soluble transporter material which can carry non-fat-soluble minerals like zinc through the fatty cellular membrane. Zinc inhibits the RNA-dependent RNA polymerase of the coronavirus, but it seems that as of mid-June no full-blown studies had been done to show a benefit, or otherwise, from the combination.
References
Coronavirus Pandemic Update 77: Remdesivir Update; COVID-19 in Mexico
Coronavirus Pandemic Update 78: Mask Controversy; Vaccine Update for COVID-19
Coronavirus Pandemic Update 79: COVID-19 Vaccines to Keep an Eye On – mRNA, Antigen, Others
Coronavirus Pandemic Update 80: COVID-19 Retractions & Data (Hydroxychloroquine, ACE Inhibitors)
Coronavirus Pandemic Update 81: New Data on Hydroxychloroquine Side Effects & Prevention of COVID-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
https://jamanetwork.com/journals/jama/article-abstract/2766943
https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker
https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-therapeutics-tracker
more covid 19: vitamin D, helper T cells, testing
I’m continuing with my gleanings from the Medcram Covid-19 updates presented by Dr Roger Seheult, though I’m not up to date with them, because they’re quite comprehensive and nuanced, and I want that detail more than anything. I’m also reading the book Outbreaks and epidemics: battling infection from measles to coronavirus, by Meera Senthilingam, which among other things, highlights the importance of preparedness, co-ordination and resourcing to deal with new and unexpected pathogens but also upsurges and cross-border spread of diseases we haven’t sufficiently dealt with in the past. As we hurtle at an unprecedented rate towards a number of vaccines against SARS-CoV2, for example, we may have to deal firmly, on a governmental level, with the anti-vaccination movement and its disinformation campaigns, but we also have to deal with grossly uneven levels of healthcare within and across nations. This current pandemic has been revelatory, for all but those on the front lines, of the variable impact such outbreaks have on the different levels of empowerment within societies. To take a stark example, Boris Johnson, the British Prime Minister, very likely owes his life to the fact that he is the British Prime Minister. Had he been a fifty-something person of colour living in Dagenham (or most anywhere outside of a UK city), his Covid-19 case would surely have turned out quite differently.
Update 74 is quite brief and mainly touches on vitamin D, the ‘sunlight’ vitamin, also obtained from foods such as fish, especially salmon and tuna, and egg yolks, and mushrooms raised using UV light – but mostly from the sun’s UV. Vitamin D enhances bone and muscle strength and function. A Lancet article is discussed, which correlates ‘vitamin D status’, presumably meaning bodily levels, with Covid-19 mortality. Some surprises in the data – vitamin D deficiency was common in ‘sunny’ Italy and Spain, but less of a problem in Nordic countries, perhaps due to a high vitamin D diet. Deficiencies were greater in poorer regions and in black communities, as of course were higher Covid-19 mortalities. in fact, ‘black people in England and Wales are 4 times more likely to die from Covid-19 than white people’ according to the UK’s Office for National Statistics.
The Lancet article referred to points out two aspects of vitamin D’s possible protection against Covid-19. First, it ‘supports production of antimicrobial peptides in the respiratory epithelium’, which sounds positive, and second it may help to reduce the inflammatory response to the virus because it’s known to interact with and promote the ACE-2 protein, which the virus suppresses. Other articles emphasise the benefits, with no attendant harm, of vitamin D supplements, particularly for the elderly. There have been no systemised, detailed trials as yet relating vitamin D levels to Covid-19 outcomes, but it seems like a no-brainer.
Update 75 continues the argument about SARS-Cov2 attacking the lining of the blood vessels, i.e. the endothelium, with the resultant effect on von Willibrand factor. This happens in the lungs as well as the vascular system, creating clots as well as the growth of new blood vessels as a type of immune response. This essentially marks it out from any kind of influenza. The New England Journal of Medicine has an article, published late May, looking exactly at these differences in the autopsies of Covid-19 victims – endothelialitis (inflammation of the endothelium) and angiogenesis (the formation of new blood vessels). They compared Covid-19 lungs with the lungs of ARDS (acute respiratory distress syndrome) victims, associated with influenza A (H1N1), and with uninfected lungs. They found ‘alveolar capillary microthrombi’ – often difficult to detect with scans – in the Covid-19 lungs at nine times the level of the influenza lungs, and new vessel growth at almost three times that of the influenza lungs. Clearly the new vessel growth is caused by the blockages, and the need to circulate around them. Microscopic analysis shows lymphocytes infiltrating the lungs, adding to inflammation, stiffness and tissue damage. The clotting prevents oxygen being picked up from the alveolar space, leading to low oxygen saturation of the blood. Scanning electron micrographs of the lung endothelium revealed viral particles in the extracellular space, suggesting strongly that the virus itself, and not simply the immune response to it (perivascular inflammation) is causing damage. Dr Seheult brings up NAC again here, as a possible disruptor of the cascade of events, especially in the suppression of superoxide and in the cleaving of disulphide bonds in VWF.
An article in Science, which refers to the adaptive immune system, is next discussed. The adaptive immune system, as opposed to the innate immune system, is a system that creates a memory of a pathogen in order to develop an enhanced response, a system exploited by vaccines. This system includes T cells, of which there are three types, memory, cytotoxic and helper. These cells are apparently involved in lifelong immunity. Vaccine researchers are concerned to create antibodies as protection against the virus, but T cells are also important in this regard, and researchers have found that many infected patients, and non-infected people, do have T cells that attack the virus, probably because they have been infected with other coronaviruses that share proteins, such as the spike protein, with SARS-CoV2. Researchers in fact found that Covid-19 patients all harboured helper T cells that recognised the SARS-CoV2 spike protein, and other SARS-CoV2 proteins, again suggesting the possibility/probability of lifelong immunity. Many others harboured the same helper T cells, which may be protecting them against the worst Covid-19 symptoms, before the fact. This is possibly a very important, and highly explanatory finding. Or maybe not. T cells are long-lasting, so these findings are certainly positive.
Update 76 starts with antibodies, and it’s a bit difficult to follow. It looks at the CDC’s ‘interim guidelines for Covid-19 antibody testing’, and a CNN health article summerizes it thus:
The CDC explains why testing can be wrong so often. A lot has to do with how common the virus is in the population being tested. For example, in a population where the prevalence is 5%, a test with 90% sensitivity and 95% specificity will yield a positive predictive value of 49%. In other words, less than half of those testing positive will truly have antibodies’, the CDC said.
This is hard to follow, but 5% prevalence is fairly standard for this virus, at least at the outset. And so false positives are a problem. To be clear about testing – a person either has the disease or not. If you have it and you test positive, fine, that’s a true positive. If you have it and test negative, that’s a false-negative. If you don’t have it and you test positive, that’s a false-positive. If you don’t have it and test negative, that’s a true negative.
So we can look at percentages and maths, and I’m following Seheult strictly here. So imagine we’ve tested 2100 people in a particular region – that’s everyone in the region. At this stage the disease has a prevalence of 5%, so about 100 out of 2100 have the disease (strictly speaking that’s 4.76%). The test has a sensitivity of 90% and specificity of 95% as above. 90% sensitivity means that the number of true positives from the test will be 90% of the number of those who actually have been infected by the virus. That means 90 people. 95% specificity is about those not infected. So you divide the true negatives by those uninfected to arrive at the 95%. The true negatives will amount to 1900. So 10 people will be false positive and 100 false negatives. When specificity rises, false positives decrease. When sensitivity increases, false negatives decrease. So with high sensitivity a negative result is more conclusive, and with high specificity, a positive result is more conclusive.
Imagine then that the prevalence of the infection has risen to 52% in the same population of 2100. That gives us 1094 with the disease, 1006 without. With the same values for sensitivity and specificity of testing, you’ll have 985 true positives and 50 false positives, and 956 true negatives and 109 false negatives. What you need to know with these results is how things stand for patient x, the person you’re dealing with. This means you need to know the predictive values, positive (PPV) or negative (NPV). This requires some simple maths. Given a positive test result, what chance is there of x having the disease? Or vice versa for a negative result. This means that for the PPV you divide the true positives by the total number of positives, and the same process applies for NPV. Going back to the situation where the prevalence was 5% we get a PPV of 47% and a NPV of 99%. What this means is that when the prevalence is low, the negative predictive value is much higher than the positive predictive value. The implication is important. It’s just not clear at this stage whether you have antibodies against the virus. So you need to raise the specificity of the test, especially if the virus or pathogen has a low prevalence. But looking at the 52% prevalence case, and using the same simple maths we find that the PPV is up at 95% and the NPV goes down to 90%. Prevalence, then, is the main determinant of predictive values.
For testing, this means, just as the disease is becoming prevalent, that’s to say, as it’s just being detected, you need a test with a very high specificity (admittedly a big ask) and/or you need to test those with a high probability, based on current knowledge, of being infected, and those in contact with them.
References
Coronavirus Pandemic Update 74: Vitamin D & COVID 19; Academic Censorship
Coronavirus Pandemic Update 75: COVID-19 Lung Autopsies – New Data
Coronavirus Pandemic Update 76: Antibody Testing False Positives in COVID-19
covid-19 stuff: NAC, glutathione, RT-PCR testing, re-positives
So, more struggles with biochemistry. Update 70 talks again about N-acetylcysteine (NAC), but goes on to talk about glutathione, and whether glutathione itself might be a type of medication. So let’s get clear, or try to.
Glutathione is a naturally occurring and abundant thiol polypeptide in animal cells. A thiol has an SH (sulfanyl) group attached to a hydrocarbon chain, essentially. As we know, it’s an antioxidant which can be reduced by NAC, and they have structural relations. As Dr Seheult describes glutathione, it’s a combination of three amino acids, with cysteine at the centre. The other two are glycine and glutamate, and the cysteine and the glycine together effectively make up N-acetylcysteine – so NAC is described as a by-product or precursor of glutathione. A case report (regarded as the weakest level of scientific evidence) describes efficacious treatment of two patients with Covid-19-type symptoms using IV and oral glutathione. This and other studies and analyses seem to be begging for full-scale clinical trials to be carried out, but nothing as of mid-May. The treatments could be effective for hypoxemia in particular, due to the action on the disulphide bonds in VWF which are leading to platelet-rich thrombosis.
In his update 71 Seheult broaches the controversial topic of hydroxychloroquine, along with azithromycin and zinc. He suggests there’s evidence that hydroxychloroquine can act as a ‘zinc ionophore’, inducing zinc uptake into cells. Zinc inhibits the RNA-dependent RNA polymerase which SARS-CoV-2 utilises to reproduce. There has been a retrospective study suggesting that treatment with this combination may ‘result in a statistically significant reduction of mortality’, though maybe this hasn’t borne more careful analysis considering the cold water being poured on chloroquine as a treatment in recent months. It may be because it just doesn’t raise zinc levels sufficiently. The findings of the study do suggest the treatment has a statistically significant effect on reducing symptoms in hospitalised patients who are not in ICU – that is, they have relatively mild symptoms. No significant effect for ICU patients.
I should add here that now in August health authorities are warning against any unprescribed use of hydroxychloroquine as a prophylactic due to ineffectiveness and side-effects.
Update 72 began by looking at the sensitivity and specificity of antibody tests available, presumably in the USA. A study examined ‘four new commercially available serological assays [i.e blood serum tests]’, from three German and one US company, and it was found that they all ‘have a sufficient sensitivity and specificity for identifying individuals with past SARS-CoV2 infection’. Of course, the principal issue with the testing is the time it takes to receive results, but maybe that’ll be addressed anon.
Apparently (news to me in very safe – so far – South Australia where hardly anyone I know has had to be tested) there’s a difference between sensitivity and specificity, illustrated by the ‘spin’ and ‘snout’ mnemonic. For a highly specific test if you test positive you’re very sure to be in trouble, and for a highly sensitive test if you test negative you’re sure to be out of danger.
Dr Seheult next describes a retrospective study which looks at glycosylated haemoglobin (HbA1c) as a Covid-19 risk factor. A person’s HbA1c levels (how much glucose is attached to their haemoglobin) are a measure of diabetes. A1c (blood sugar level) is measured in percentages, with 5-6% being normal. The study found that ‘high HbA1c levels is associated with inflammation, hypercoagulability and low SaO2 [oxygen saturation] in Covid-19 patients, and the mortality rate (27.7%) is higher in patients with diabetes’. So HbA1c levels need to be looked at as a priority.
The update next looks at dentistry during the pandemic, for which there’s been little guidance, at least from the CDC. Apparently, during the AIDS crisis, dentists were viewed as modes of transmission, partly due to a NYT article on the subject. In any case, fewer people are now seeing their dentists for obvious reasons, which could lead to an oral health crisis. A number of diseases, including coronary disease, are linked to periodontal problems, so this can exacerbate the pandemic – and dental health, in Australia as in the USA, is not treated with the same gravitas as other forms of health.
Update 73 starts with a look at testing, particularly the reverse transcriptase polymerase chain reaction (RT-PCR) test. So the coronavirus has these spike proteins protruding from a bilipid membrane, with the RNA wrapped inside bound together by disulphide bonds and the like, I think. The protein shell around the virus is called the nucleocapsid. Of course the RNA’s code is specific to SARS-CoV2, so a test needs to look at a segment of the viral RNA and identify it with sufficient – essentially total – specificity. RNA is made up of the four base pairs adenine (A), uracil (U), guanine (G) and cytosine (C), with A pairing always with U and G with C. With that I’m going to switch to Scientific American for more detail.
A test starts with a sterile swab from the back of the nasal passage, aka a sample. Sample collection needs to be done properly, or it could lead to a false-negative result. If there’s viral RNA present, it’s extracted and used to produce a complementary strand of DNA – that’s where the reverse transcriptase enzyme comes in, reversing the usual transcription process from DNA to RNA. This material is then amplified – thousands of copies are made – to ensure a measurable result. The different available test kits generally vary in the segment of genetic material chosen.
I’m hearing that there are serious delays, in the USA at least, in delivering test results. This is extraordinary as, according to the Scientific American article, which is dated late March,
the FDA recently began granting emergency use authorization (EUA) to rapid diagnostic PCR tests that manufacturers say can deliver results in less than an hour. The authorization allows medical devices that have not yet been approved by the agency to be used during public health emergencies.
What’s happening? According to very recent article from Quartz magazine, the problem is that there are too many kinds of tests. The EUA system was utilised, partly because of the urgency, partly because of the disastrous problem caused by the use of faulty reagents by the CDC back in February. Now there are about 150 tests that have been given EUA approval. Testing delays at first resulted mainly from lack of general lab equipment and PPR for the testers, but increasingly there are problems due to different types of tests, the variability of the tests, knowing which test to use, having the right equipment for each test, the prioritising of certain groups, such as front-line health workers, over others, confirmation of test results by other labs, and of course the overload in demand. We’re talking about the USA here, of course, and it just seems another case of lack of centralised control and uniformity in a state with a failed federal government.
Returning to update 73, Seheult describes a situation in which a SARS-Cov2-infected individual’s immune system has broken down the virus into ineffectual strands of RNA, proteins and other particles. It’s possible that a RT-PCR test could pick up on an RNA fragment, and produce a positive test result in these apparently recovered patients, and in fact this has often occurred. This is called a re-positive. The update describes a study by the South Korean CDC which provides valuable evidence on these re-positive cases. Some 280 re-positive subjects were studied, and about half of them displayed Covid-19 symptoms (on average 14 days after ‘recovery’). Presumably this re-positive finding was after they’d tested negative, i.e they’d first tested positive, then negative, then later positive again, though this isn’t clear. In any case, they checked a percentage of the subjects for antibodies and the result was almost entirely positive. They checked a larger sample for viral particles and found ‘not a single whole viral particle’, according to Dr Seheult, by which I presume he means anything that was replicable or active. They also looked at close contacts of the subjects, in large numbers, and all of them tested negative. So the finding was that these re-positives were, it seemed, the results of ultra-sensitive testing that was picking up viral RNA fragments that were in effect innocuous. This would seem to be a lesson for developing the right types of test. Hopefully a lesson learned.
References
Coronavirus Pandemic Update 70: Glutathione Deficiency, Oxidative Stress, and COVID 19
Coronavirus Pandemic Update 71: New Data on Adding Zinc to Hydroxychloroquine + Azithromycin
Coronavirus Pandemic Update 72: Dentists; Diabetes; Sensitivity of COVID-19 Antibody Tests
Coronavirus Pandemic Update 73: Relapse, Reinfections, & Re-Positives – The Likely Explanation
https://www.scientificamerican.com/article/heres-how-coronavirus-tests-work-and-who-offers-them/
https://qz.com/1886940/why-covid-19-test-results-take-so-long/
update 69: NAC, glutathione, oxidative stress, thrombosis
So we start with a closer look at glutathione, and its backbone amino acid chain, including the amino acid cysteine. Cysteine has the formula HO2CCH(NH2)CH2SH. The thiol sub-chain (SH) is important because it can bind to another form of the molecule, with S binding to S (oxidised form) rather than binding to H (reduced form) as here. So, as Dr Seheult explains, if you have two glutathiones, in this reduced form (2GSH), oxidised via hydrogen peroxide (H2O2), you will create a bond (GS-SG) between the two oxidised glutathiones, together with water. This happens in the oxidisation processes in our cells.
Seheult next mentions ADAMTS13, which is also known as von Willibrand factor-cleaving protease, so it’s a zinc-containing enzyme. VWF polymerises via disulphide bonds, and ADAMTS13 can help in disrupting that process, I think. Seheult diverts us by mentioning the disulphide bonds that connect the spiral strands of keratin in hair. A ‘perm’ reduces the molecular structure, breaking the disulphide bonds, so that the individual strands can be straightened, or made more curly, after which ‘you neutralise the perm agent’?? via H2O2, allowing disulphide bonds to re-form keeping the new hair structure in place. That was almost interesting.
So what can we do to assist these glutathione-based processes in relieving oxidative stress? This is apparently where N-Acetylcysteine (NAC) comes in. This molecule, which is ‘the N-acetyl derivative of the natural amino acid L-cysteine’, is ‘an antioxidant and disulphide breaking agent’, according to a 2018 review article in the Journal of Free Radical Research (not a political journal). So NAC is a reducing agent, which, like cysteine, has an SH bond. It breaks disulphide bonds and adds hydrogen, reducing viscosity. NAC has been used as a mucolytic inhalant, and as an agent against tylenol (paracetamol) overdose. How this last effect works is complex and I’ll try to comprehend it.
As Seheult explains it, NAC would act on the metabolite of paracetamol in situations of overdose. In such cases the liver metabolises paracetamol via an alternative pathway, by means of the toxic metabolite NAPQI, which depletes the liver’s glutathione. NAC replenishes the glutathione, but I won’t try to analyse the mechanism here. The main point is that NAC’s glutathione-boosting effects may have potential in dealing with Covid-19 symptoms. According to the above-mentioned review article, glutathione depletion is related to oxidative stress associated with a wide range of illnesses and pathologies, as well as in general ageing. So, a 1997 study in Italy looked at H1N1 flu and NAC treatment in a randomised, double-blind trial of 262 individuals of both sexes, most of them suffering from non-respiratory chronic degenerative diseases. They were divided into a placebo group and a NAC tablet group for a period of six months. No difference was found in both groups contracting the virus, but the majority of the placebo group (79%) came down with symptomatic forms, compared to only 25% of the treatment group, a significant difference. The study concluded that NAC treatment ‘appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals.’
So, recognising that this update is 2-3 months old now, I went online to see if NAC treatment is being used, or more comprehensive trials are being undertaken, as I note that, though case-rates are still disturbingly high, especially in the USA, death-rates are somewhat reduced.
An article from NCBI (the National Center for Biotechnology Information), which post-dates update 69 by a couple of weeks, presents only a hypothesis:
that NAC could act as a potential therapeutic agent in the treatment of COVID-19 through a variety of potential mechanisms, including increasing glutathione, improving T cell response, and modulating inflammation.
However, it didn’t seem as if any effective clinical trials focusing specifically on Covid-19 had been completed at the time of the article. A much more recent article (July 14) in Future Medicine (not such a promising name, given the urgency), presents more biochemical detail of NAC’s action, along with the anticoagulant heparin, and mentions ongoing clinical trials, but not specific results. It also mentions NAC treatment as a preventive for frontline ICU workers and general healthcare workers. It may be that such treatment is already being applied.
So, returning to update 69, Seheult cites another article from 2010 in Biochemical Pharmacology which showed that NAC inhibited viral replication (here the virus was H5N1) and reduced inflammatory cytokines, and again they suggested it as a potential treatment in the case of future influenza pandemics. Another small trial suggested some limited efficacy for NAC in the treatment of acute respiratory distress syndrome (ARDS).
So on it goes. A 2018 article found that ‘[NAC] improves oxidative stress and inflammatory response in patients with community acquired pneumonia [CAP]’. This oxidative stress reduction may be more important for Covid-19 cases because of the possibility of thrombosis due to the effect on VWF. A 2013 study found a significant decrease in a number of coagulation factors with NAC treatment. Of course, with this blood-thinning facility, NAC should not be used for patients with increased bleeding risk during or resulting from surgery. In any case I note that NAC is on the WHO list of most safe drugs or treatments.
And there are more studies. Another 2018 study found that NAC could reverse cerebral injury from strokes exacerbated by diabetes. The study concludes that ‘the diabetic blood and brain become more susceptible to platelet activation and thrombosis’, and that NAC appears to offer protection against the risk of stroke. The study’s explanation of the process here gives me an opportunity for further revision:
[NAC protects against stroke] by altering both systemic and vascular prothrombotic responses via enhancing platelet GSH, and GSH-dependent MG elimination, as well as correcting levels of antioxidants such as SOD1 and GPx-1.
So that’s platelet glutathione, and glutathione-dependent methylglyoxal, and the antioxidants mentioned are superoxide dismutase 1 and glutathione peroxidase 1. The ScienceDirect website does an amazing job of informing us about every known aspect of molecular biochemistry, just saying. Its material on glutathione and its catalysis is exhaustive and exhausting. And it looks as though the silver lining to the tragedy of Covid-19 may be a spike in further research into this and other essential elements of the molecular basis of immune systems.
Dr Seheult goes on to cite one more study, which found that ‘NAC administration promotes lysis of arterial thrombi that are resistant to conventional approaches…’, principally by acting on VWF, and that it is even more effective in combination with ‘a nonpeptidic GpIIa/IIIb (glycoprotein) inhibitor’, with no observed worsening of symptoms or outcome vis-a-vis normal haemostasis.
So I’ll end this piece wondering how things are going with NAC and other applications to reduce both respiratory and thrombotic symptoms in regions where the virus continues to be spread through a mixture of government, business and personal irresponsibility and stupidity. The battle to keep people alive and relatively healthy will, I think, ultimately win over the stupidity of some, but at a terrible and tragic cost. Vaccines are in the offing, but fear, indifference and ignorance will probably have the most adverse influence on their effectiveness.
References
Coronavirus Pandemic Update 69: “NAC” Supplementation and COVID-19 (N-Acetylcysteine)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261085/
https://www.futuremedicine.com/doi/10.2217/fmb-2020-0074
https://www.sciencedirect.com/science/article/pii/S0304416512002735
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/methylglyoxal
more Covid-19 gleanings from MedCram updates 67-69
I’m continuing my self-education re everything Covid-19 thanks to Dr Seheult’s updates and other useful sites. Update 67 carries on from where we left off, summarising again how SARS-CoV2 induces endothelial dysfunction, before focusing on thrombosis. So we repeat again that a key molecule in normal endothelial function and in the working of AT-1,7 is nitric oxide (NO). Endothelial function (and, to be clear, the endothelium lines the vasculature, which means the body’s blood vessels) is also dependent on the various other enzymes mentioned in the last post, e.g. superoxide dismutase (SOD), and glutathione peroxidase (GPx).
So how does Covid-19 bring about oxidative stress and how does this effect thrombosis? Seheult discusses an article from April this year which addresses this. It describes a previously healthy elderly male admitted to hospital with fever and respiratory symptoms. After rapid deterioration he was sent to ICU, having developed ARDS, acute renal insufficiency and other health problems. Among various measures noted was a ‘massive elevation of von Willebrand factor (VWF), as well as ‘factor VIII of the coagulation cascade’. To quote from the article:
The increased VWF points toward massive endothelial stimulation and damage with release of VWF from Weibel-Palade bodies. Interestingly, endothelial cells express ACE-2, the receptor for SARS-CoV2, thus possibly mediating endothelial activation.
To explain some of these terms: Weibel-Palade bodies are found only in epithelial cells, and they contain VWF, which are released when required for haemostasis and coagulation. VWF is a stringy material of amino acid proteins which combine with platelets (aka thrombocytes) to coagulate the blood. When endothelial cells suffer serious damage, Weibel-Palade bodies inject large amounts of VWF into the bloodstream. Dr Seheult presents the abstract from a 2017 article on the topic:
The main function of VWF is to initiate platelet adhesion upon vascular injury. The hallmark of acute and chronic inflammation is the widespread activation of endothelial cells which provokes excessive VWF secretion from the endothelial cell storage pool. The level of VWF in blood not only reflects the state of endothelial activation early on in the pathogenesis, but also predicts disease outcome. Elevation in the blood level of VWF occurs either by pathologic increase in the rate of basal VWF secretion or by increased evoked VWF release from dysfunctional/activated endothelial cells. The increase in plasma VWF is predictive of prothrombotic complications and multi-organ system failure associated with reduced survival in the context of severe inflammatory response syndrome, type 2 diabetes mellitus, stroke and other inflammatory cardiovascular disease states.
The article points out that an over-production of VWF in highly elongated form is an indication of pathology. This is apparently being seen in serious Covid-19 patients. On the molecular level, the VWF is able to remodel itself from its usual globular conformation when it senses shear forces – note this definition from Science Direct: Shear stress is defined as the frictional force generated by blood flow in the endothelium, that is, the force that the blood flow exerts on the vessel wall, expressed in force-area unit (typically dynes/cm2). The VWF, under this stress, ‘turns into an extended chain format that forms ultra-large strings to which platelets bind to initiate clot formation at sites of vascular damage’. When the shear stress reaches a certain level, factor VIII is released. All of this can be essential for haemostasis, but too much of the multimeric, elongated form of VWF will lead to thrombosis, as appeared to be occurring in the patient described above.
So, as Seheult summarises, SARS-CoV2 binds to ACE-2 receptors and reduces ACE-2 production. This reduction has the effect of increasing AT-2 production and reducing AT-1,7. This results in an increase in superoxide production, oxidative stress and endothelial dysfunction. This in turns leads to an increase in VWF activity in the bloodstream, and local thrombosis. There is evidence from autopsies that thrombosis is a feature of Covid-19 mortality.
In his update 68 Dr Seheult looks at the predisposition of some ethnic groups (in the USA) to the more severe symptoms associated with Covid-19. He discussed a May CDC MMWR (morbidity and mortality weekly report) on 580 hospitalised Covid-19 patients which found that 45% were white, as far as they could ascertain, compared to 55% in that region’s community. 33% were black, compared to 18% in the community, and 8% were Hispanic compared to 14% in the community. A smallish sample, but suggestive. The CDC also reported on New York figures showing that Covid-19 death rates among black/African Americans and Hispanic/Latino persons were substantially higher than in the white population. Many possible reasons – work and living conditions, lower access to care – all generally related to relative poverty. There may also be other, purely physiological grounds for the disparity. A 16-year-old research article published in Circulation describes the results of placing nanosensors in isolated human umbilical vein endothelial cells (HUVECS) from blacks and whites (pardon the over-simplification, I’m only the messenger), as an attempt to measure endothelial oxidative stress. I can’t follow the details of the research, but what they found was that blacks expressed much more NADPH oxidase than whites (that’s bad). Nitric oxide, a reducer of oxidative stress, was produced in greater quantities in whites than in blacks, and the bad superoxides were produced in greater quantities in blacks. I won’t go further into the complex biochemistry, but I must say I find these apparent racial differences very surprising.
Update 68 also looks at increasing hospitalisations (at least in May) of young children due to Kawasaki disease, or something similar. The disease is characterised by inflammation of blood vessels. Symptoms include fever, high heart rate and possibly sepsis. There are a number of similarities to Covid-19, including ‘systemic vascular lesions’. Kawasaki disease is normally rare, and believed to be viral, or a response to a virus. A ten-year-old research paper on the disease hypothesises that the infection enters through the respiratory or gastro-intestinal systems, and so unsurprisingly there are similarities to the reaction to SARS-CoV2. Whether there’s a connection between Covid-19 and an uptick in Kawasaki disease has yet to be confirmed (but I’m behind the times on the research on this).
I’m moving now to update 69, and I’m going to follow Dr Seheult through the whole oxidative stress process again. It’s about reduction of oxygen – the adding of electrons. Adding an electron to oxygen, mediated by NADPH oxidase, produces superoxide. Add another electron and you get hydrogen peroxide. Another electron produces hydroxyl, and yet another produces water, moving from most oxidised to most reduced, and adding electrons also brings on protons. So at both ends of this chain you have neutral or positive molecules, but in between you have, I think ROS, reactive oxygen species, which are a problem. The body’s defence against these include the enzyme superoxide dismutase (SOD), which converts superoxide into hydrogen peroxide and also back into oxygen, and catalase which converts hydrogen peroxide into water and oxygen. Another important enzyme which protects against oxidative damage is glutathione peroxidase (GPx). It takes reduced glutathione (2GS-H, called a sulph-hydryl group) and uses it to reduce hydrogen peroxide into water, in the process oxidising the glutathione into a form of disulphide G-S-S-G. This oxidised form is in turn ‘regenerated back’ by taking the reduced form of NADP+ (NADPH) and converting it via glutathione reductase to NADP+.
So the point is that the accumulation of superoxide in people with diabetes, hypertension, coronory disease etc will be exacerbated by Covid-19. And going through that once more, Covid-19 blocks the ACE-2 receptor, causing an accumulation of AT-2 which stimulates superoxide production, and also a deficiency of AT-1,7, which, mediated by nitric oxide, inhibits superoxide production. The SARS-CoV2 virus also attracts PMNs (polymorphonuclear leukocytes – immune cells including neutrophils), which boost superoxide production, with attendant endothelial damage.
I’ll be continuing this series, and no doubt getting further behind, over the next few weeks.
References
Coronavirus pandemic update 67, presented by Dr Roger Seheult, as with all other updates
Coronavirus pandemic update 68
Coronavirus pandemic update 69 (first 5 minutes or so)
https://www.verywellhealth.com/polymorphonuclear-leukocyte-2252099
more on oxidative stress and covid-19
So, much of this piece will rely on Dr Seheult’s coronavirus update 65. We have this constant set of reactions in the body that reduce oxygen – adding electrons – until we get to water molecules, producing reactive oxygen species (ROS) along the way. This is often described as the oxygen metabolism process. Reactive oxygen species come essentially in three types, superoxides, hydroxy radicals and hydrogen peroxide. The three forms of the enzyme SOD, superoxide dismutase, convert superoxide into oxygen and hydrogen peroxide (H2O2), and then the H2O2 is reduced to H2O by means of glutathione peroxidase (GPx). The GPx, which is broken down in the process is recharged by the enzyme glutathione reductase (GR), which is in turn recharged by other antioxidant products. Also the enzyme catalase, which requires iron, can break H2O2 down into O2 and H2O.
People with diabetes, hypertension and overweight issues, among other things, may have compromised antioxidant systems (too many ROS), linked to angiotensin-converting enzyme 2 (ACE-2) and angiotensin-2. In creating ROS, oxygen is reduced to superoxide by means of the enzyme NADPH oxidase. So, as part of the renin-angiotensin system, angiotensin-2 (AT-2) is converted to angiotensin 1,7 (AT-1,7) by means of angiotensin-converting enzyme 2 (ACE-2). This is important because AT-1,7 effectively blocks superoxide production, while AT-2 promotes it. The virus SARS-CoV2 binds with, and so inactivates, ACE-2, preventing the production of AT-1,7. This action also means that there will be more AT-2 available, and so more superoxides. SARS-CoV2 also, according to Seheult, causes inflammation by recruiting polymorphonuclear neutrophils (PMNs), which stimulate production of superoxides by means of NADPH oxidase. So this, in essence, is why Covid-19 is bringing about oxidative stress.
Seheult next goes on to look at the research evidence for the preceding. A review article from 2005 points out that evidence from animal studies and cell culture studies shows that NADPH oxidase-derived oxidative stress is increased in vascular cells by AT-2, among other ‘agonists’ (chemicals that bind to receptors, thereby producing a response). Another article from 2012 describes several enzyme systems that act to form ROS, including ‘mitochondrial electron leakage from the electron transport chain’ as described in my previous post on the subject, and in Seheult’s update 63. It points out that ROS levels can rise dramatically in older people suffering from oxidative stress due to heart issues such as ischemia-reperfusion (referring to problems with oxygenated blood supply to the heart or other organs). It also points out that it has been shown experimentally that AT-2 stimulates an increase in ROS. A more recent article pertaining to SARS-CoV2 looked at patients in Wuhan and found a substantial increase in neutrophils in the most severe cases. Neutrophils cause ROS to be generated by NADPH oxidase. So Dr Seheult is carefully building up evidence for the case. The last point to deal with is AT-1,7 effects. Seheult has found a 2008 article entitled ‘Angiotensin converting enzyme 2 confers endothelial protection and attenuates atherosclerosis’. Seheult quotes the last line from the abstract:
These data indicate that ACE-2, in an AT-1,7-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE-2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis.
Atherothrombosis involves disruption of atherosclerotic plaques, which can be an immediate cause of heart attacks. Another article from 2015 essentially confirms the findings, as indicated by its title, ‘ACE-2 and AT-1,7 protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response’. A more recent article, from January 2020, describes how AT-1,7 administration improves endothelial function in women who have suffered from preeclampsia (vasoconstriction, high blood pressure and organ damage due to pregnancy). To give more detail, women in the last stages of pregnancy often suffer vasoconstriction and high protein levels, which is believed to be related to AT-2 levels. Researchers administered local AT-1,7, which is ‘an endogenous inhibitor of... AT-2′, to see if this reduced vasodilation and other symptoms of preeclampsia. What they found was that ‘AT-1,7 increased endothelium-dependent vasodilation via nitric oxide synthase-mediated pathways and attenuated AT-2-mediated constriction in women who have had preeclampsia, suggesting that AT-1,7 may be a viable therapeutic target for improve d microvascular function in women who have had a preeclamptic pregnancy’.
All of this is interesting in itself, of course, and is a little crash course in how research is helping us to tweak our immune systems, but in relation to Covid-19 these finding are of importance due to the comorbidities and general characteristics of patients being hospitalised with Covid-19. Dr Seheult, in his update 65 video, shows that, contrary to what was initially thought, i.e that Covid-19 is primarily a virus affecting the lungs and respiratory system, it may be much more of a problem for those with hypertension, cardiovascular issues and obesity – all of which are related to oxidative stress, as are diabetes and many forms of cancer. They contribute to endothelial dysfunction, which inevitably leads to oxidative stress, and may lead to thrombosis. Seheult here refers to a lengthy 2018 review article, ‘nutrients and oxidative stress: friend or foe?’, which among other things makes useful dietary suggestions for the combatting of oxidative stress – whole grains, nuts, fruit and vegetables, fish and legumes.
It’s been known for some time that endothelial cell dysfunction (ECD) can lead to thrombosis, as it is a major function of these cells to prevent thrombosis. The abstract from a 2002 study finds that ECD ‘is associated with decreased synthesis and oxidative inactivation of nitric oxide (NO)’ and it lists four types of antioxidant enzymes ‘essential for eliminating ROS that can inactivate NO’. It seems that the promotion of these enzymes can be associated with diet as above and with the reduction of risk factors such as hypertension, hypercholesterolaemia (high blood cholesterol), hyperhomocysteinaemia (homocysteine is an amino acid which can contribute to arterial damage and blood clots, and the condition is often associated with lack of vitamin B-12 or folate), cigarette smoking and diabetes mellitus. NO is the key molecule in maintaining endothelial function through these enzymes.
Now I’m having a look at Dr Seheult’s update 66 on blood pressure medications known as ACE inhibitors or ARBs. He cites an editorial article for the New England Journal of Medicine, on ‘inhibitors of the renin-angiotensin-aldosterone system and Covid-19’. This is a triple hormone system responsible for blood pressure regulation and fluid balance. Now, to return to what was outlined before, angiotensin-2 (AT-2) is converted to AT-1,7 by an angiotensin-converting enzyme (ACE-2). The SARS-CoV2 virus binds to the ACE-2 receptor and inhibits the enzyme’s production. This is problematic because AT-2 stimulates superoxide production (that’s bad), while the antioxidant AT-1,7 blocks it, so reducing oxidative stress. SARS-CoV2 also stimulates the production of PMNs, as above, which activates oxidative stress. Another part of this picture is that AT-1 is converted to AT-2 by ACE. There are blood pressure lowering medications, such as benazepril and lisinopril, aka ACE inhibitors, which reduce the production of AT-2. There are also angiotensin receptor blockers (ARBs), which may up-regulate ACE-2 (it isn’t clear, apparently). ACE inhibitors may do the same. The question being asked is, assuming these medications produce more ACE-2, will this lead to more infections because SARS-CoV2 has more ACE-2 to work with? Clearly it would be important to know whether to maintain these medications or not, that’s to say, whether these medications are a risk factor for contracting the virus or recovering from it. The above-mentioned article discusses three studies from different parts of the world, each involving thousands of participants. They all found no risks associating ACE inhibitors and ARBs with a higher risk of infection, severity of illness or death from Covid-19. One of the studies found that ACE inhibitors and statins were associated with a decreased risk of mortality, but these are observational studies and further research would need to be done.
So the above is a rather technical piece, highly reliant on the experts. I write to inform myself, and I’ve certainly been informed by writing this one. Apologies for its laboriousness, but I’ll be continuing… Please consult the references yourself if there’s anything you don’t understand.
References
Coronavirus Pandemic Update 65: COVID-19 and Oxidative Stress (Prevention & Risk Factors)
Coronavirus Pandemic Update 66: ACE-Inhibitors and ARBs – Hypertension Medications with COVID-1