Posts Tagged ‘Covid-19’
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
SARS-Cov2 and oxidative stress
So I feel it’s time for me to get back to the epidemiology and immunology stuff that I know so little about, especially as it pertains to SARS-Cov2. Watching Dr Seheult’s Medcram updates again after a long hiatus, and catching up with them from the end of April, I note that he’s arguing – and I presume this is a mainstream view, as he clearly keeps an eye on the latest research – that the virus mostly does its damage in attacking the body’s endothelium, and that this in turn causes oxidative stress. The endothelium is a thin layer of cells, or a layer of thin cells, that form the inner lining of the blood and lymph vessels (one day I’ll find out what lymph actually is and does).
Oxidative stress is associated with an imbalance in the level of oxidants such as super-oxide anion and hydrogen peroxide, reduced forms of oxygen (with extra electrons). I don’t really understand this, so I’ll start from scratch. But just preliminary to that, the effects of oxidative stress are manifold. Here’s a summary from news-medical.net:
Oxidative stress leads to many pathophysiological conditions in the body. Some of these include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, gene mutations and cancers, chronic fatigue syndrome, fragile X syndrome, heart and blood vessel disorders, atherosclerosis, heart failure, heart attack and inflammatory diseases.
It’s known that SARS-Cov2 enters via the lungs, and does damage there, but it’s now thought that most of the damage is done in the endothelium. To understand this, Dr Seheult is going to teach me some ‘basic’ stuff about metabolism, oxidation, energy production and such. So, we start with mitochondria, the energy-producing organelles inside our cells, which have their own DNA passed down the female line. Looking into a mitochondrion, we have the matrix inside, and around it, between the inner and outer membranes, is the inter-membrane space (IMS). Our food, broken down into its essential components, carbs, fats and proteins, is absorbed into the matrix, and somehow turned into ‘two-carbon units’ called acetyl coenzyme A. This is metabolism, apparently. These molecules go through a famous process called the Krebs cycle, of which I know nothing except that it’s about more metabolism… Although now I know that it produces electrons, tied up in two important molecules, NADH and FADH2. These electrons ‘love to be given up’, a way of saying they ‘want’ to be reduced. The molecule that gives up electrons is said to be oxidised, the receiving molecule is reduced. So think of a molecule being reduced as the opposite of losing, rather counter-intuitively. The oxidised molecule is the one that loses electrons. All this is about energy production within the matrix, and the aim is to end up with a molecule I’ve heard and forgotten much about, adenosine triphosphate (ATP). This molecule is the energy molecule, apparently, and the energy is produced by ‘knocking off’ one of the phosphates, according to Dr Seheult, leaving, apparently, adenosine diphosphate (ADP) plus ‘energy’ (clearly, this part needs a little more detail). So going from the diphosphate form to the triphosphate requires energy, going the other way releases energy – none of which really explains why ATP is the body’s energy source. Anyway…
Returning to the carbs, fats and proteins, they go through these mitochondrial processes to produce electrons which want to reduce stuff. So NADH goes to the membrane which separates the IMS from the matrix of the mitochondrion, where proteins can be found that are willing to accept electrons, i.e. to be reduced. The electrons are brought in ‘at the very top of the scale’ (?) and lose some of their reducing ability, so they go down to a lower state of reduction, and protons are pumped into the IMS. (I’m sure this is all true but making sense of it is another matter. It certainly makes me think of proton pump inhibitors, drugs that reduce gastric reflux, but that would be the subject of another set of posts). Then ‘it goes to another species’ by which I think Seheult means another protein, judging from the video, but what he means by ‘it’ I’ve no idea. The NADH? The wave/body of electrons? Anyway, things keep going down to a lower level, becoming more oxidised, and more and more protons are pumped out. So there comes to be a very high concentration of protons (H+) in the IMS, creating a very low PH (high acidity). Meanwhile, the electron transport chain has gone down so many levels that it can only reduce oxygen itself, which by accepting electrons turns finally into water. It’s apparently essential to have sufficient oxygen to keep this cycle going, and to keep the protons pumping, because the protons in the IMS want to move to a place of lower concentration, in the matrix. In doing this, they pass through a channel, which involves, somehow, a coupling of ADP to ATP. Without enough oxygen, this process is stymied, ATP can’t be supplied, leading to insufficient energy and cell death.
So, I think I understand this, as far as it goes. Now, if you over-eat, with lots of high-calorie fats and carbs entering the cells, you’ll likely end up with a surplus of electrons, tied up in NADH and FADH2, which can cause problems. This is where super-oxides come in.
Oxygen is the final electron acceptor in the electron transport chain, and when you add an electron to this final acceptor you get a super-oxide, an oxygen molecule with an additional electron, aka a radical. These are very reactive and dangerous. They can cause DNA damage and serious inflammation, and the body uses them to kill bacteria. If you add another electron, you get H2O2, hydrogen peroxide, and another one again produces a hydroxy radical, OH. Another electron gives water, so it’s these intermediate molecules that are called ‘dangerous species’. Cells such as neutrophils (a type of white blood cell) make these, via an enzyme called NADPH oxidase, as part of their defence against antigens, but an accumulation of these radicals is problematic and needs to be dealt with.
One enzyme the body uses to bring down these accumulating radicals is super-oxide dismutase (SOD), which takes two super-oxides and converts them into O2 and H2O2. SOD comes in three types, related to where they reside – in the mitochondria, the cytosol and the extracellular matrix. These enzymes are powered by zinc, copper and, in the mitochondria, manganese. So what happens to the extra hydrogen peroxide created? An enzyme called glutathione peroxidase (GPx) reduces H2O2 to water by giving it two electrons. Where do these electrons come from? According to Seheult, and this is presumably ‘basic’ microbiology, the antioxidant glutathione has two forms, oxidised and reduced. The reduced form is 2GS-H, with a hydrogen bonded to the sulphur group. The oxidised form is G-S-S-G, a disulphide bond replacing the hydrogen. With the reduced form, GPx donates its extra two electrons to H2O2, reducing it to water. The glutathione system is recharged by reducing it back with NADPH, which has two electrons which are converted to NADP+ (?) Glutathione reductase is the key enzyme in that process. It might take me a few lifetimes to get my head around just this much.
Meanwhile there’s another system… Catalase, an iron-boosted enzyme, can convert two molecules of H2O2 into O2 and H2O. This occurs in organelles called peroxisomes. The major point to remember in all this is that super-oxides are harmful species that can cause oxidative stress, and the major solutions come in the form of SOD and GPx. In fact the general name for these harmful molecules – super-oxides, hydrogen peroxide, and hydroxy radicals – is reactive oxygen species (ROS).
So we have to relate all this to the effects of SARS-Cov2, which enters the body through the ACE-2 (angiotensin-converting enzyme-2) receptor. According to a 2008 research paper, ACE-2, the receptor for which is blocked by SARS-Cov2, ‘confers endothelial protection and attenuates atherosclerosis’. Quoting from the paper, we find a section called ‘ACE-2 modulates ANG II(angiotensin 2)-induced ROS production in endothelial cells’. The researchers’ essential finding was that ‘ACE-2 functions to improve endothelial homeostasis’, and it seems this function is being disrupted by SARS-Cov2. As Dr Seheult puts it, SARS-Cov2 inhibits the inhibitor, that is it inhibits ACE-2, which normally acts to regulate angiotensin 1,7 (not explained in this particular video), thus allowing NADPH oxidase to keep producing super-oxides, with the resultant oxidative stress. As Seheult concludes here, subjects with compromised systems caused by diabetes, cardiovascular disease or obesity, affecting the production or effectiveness of SOD and GPx, might be relying on ACE-2 and angiotensin 1,7 to maintain some semblance of health. Are these the subjects that are succumbing most to the virus? That’s to be explored in future videos, and future posts here.
Reference
Coronavirus Pandemic Update 63: Is COVID-19 a Disease of the Endothelium (Blood Vessels and Clots)? (video by Dr Roger Seheult – clearly a hero in this time)
Covid-19, politics, government – some observations
No society can legitimately call itself civilised if a sick person is denied medical aid because of lack of means.
Aneurin Bevan, founder of the UK’s NHS
Let me look at Covid-19 cases and deaths in different countries in terms of the political persuasions (and gender) of their leadership, with some obvious caveats and reservations, e.g. that correlation isn’t causation, that there are a whole host of factors influencing how well or badly particular nations are faring, that the data coming from many nations is highly suspect, etc. My statistics come from the Worldometer site, which names a wide variety of sources, and notably tends to be slightly less conservative than the WHO and Johns Hopkins sites in terms of numbers. The differences aren’t great, but I think it’s reasonable to assume that the overall numbers are greater than even the Worldometer site has been able to confirm.
I’m doing this because I’ve been checking the stats on a daily basis for weeks now, and impressions have, not surprisingly, been forming about the relationship between national leadership and the impact of the virus. So here are some statistics, and some speculations on them, for what they’re worth.
The UK (I was born in Scotland) has fared worse than any other country, apart from Belgium, in terms of deaths per million. Conservative PM Boris Johnson, prior to catching the virus himself, seemed to suggest letting it run its course through the community, which of course would have led to a huge death rate, and generally the messages from the beginning were confused, and mostly of a softly softly nature, which has clearly proved disastrous. The NHS has suffered years of severe cuts under ten years of conservative government, and mixed messaging has continued to damage what has been a truly woeful governmental response to the crisis. Scotland, which has a female First Minister and a centre-left government, has a slightly lower ‘excess death toll’ than England, but it’s still high compared to most countries, and higher than those of Wales and Northern Ireland. England is, of course, by far the most densely populated of the four UK nations.
Belgium wears the shame of having the worst Covid-19 mortality rate of any significant-sized nation (of say, 5 million or more) on the planet. However, to be fair, Belgium appears to have an accounting system for the virus which is as anomalous as is that of Russia at the other end of the spectrum (a spectrum from inclusive, i.e Belgium, to exclusive in Russia’s case). This issue of accounting is too enormously complex and fraught to be dealt with here (though many are suggesting that measuring ‘excess mortality’ might be the best option), so I’ll take Belgium’s disastrous figures at face value for now. The country’s PM, Sophie Wilmès, is a member of the centrist Mouvement Réformateur, and heads a coalition government. In fact Belgium has long been so factionalised that coalition governments are a more or less permanent feature of government there, and internal squabbling in recent years has led to a lot of government inertia. Though clear information is hard to find, the lack of strong, supported central government is very likely negatively affecting the country’s Covid-19 experience.
Germany is generally regarded as the success story of Europe. It’s Europe’s largest country, and currently the 19th most populated country in the world. It is 12th overall in the number of cases, and 11th in the number of deaths. This may look bad, but we know that western Europe has been particularly hard-hit, and it’s worth comparing Germany to its neighbouring countries. Interestingly, Germany shares its border with no less than nine different countries, and in terms of deaths per million, which I think is a good guide of a nation’s internal handling of the pandemic, it is doing far better than its westerly neighbours (Switzerland, France, Luxembourg, Belgium, the Netherlands and Denmark), and considerably worse than its easterly ones (Austria, Czechia and Poland). Again I’m skeptical of some of the stats, especially in a country like Poland, which has descended into a quasi dictatorship under its all-powerful Law and Justice party, but there does seem to be a radical divide between the eastern and western halves of Europe in terms of the pandemic’s impact. Anyway, Germany’s centrist Chancellor Angela Merkel has been in power since 2005, and she’s recently suffered under the description, ‘leader of the free world’ in lieu of the USA’s absence of leadership. Being a former research scientist, she’s been credited, rightly or wrongly, with having shepherded the country through this crisis better than most. Wikipedia has this to say about the country’s response:
The country’s low fatality rate, compared to fatality rates in Italy and Spain, has generated a discussion and explanations that cite the country’s higher number of tests performed, higher number of available intensive care beds with respiratory support and higher proportion of positive cases among younger people.
Italy, a country renowned for its political instability, fared disastrously early on (in March and April) in terms of cases and deaths, but has reduced the numbers greatly in recent weeks. Even so, Italy’s deaths per million is one of the worst rates in the world, five times that of Germany. Italy has in recent years developed closer ties with China than any other country in western Europe, and evidence points to the virus arriving in northern Italy via a Chinese couple from Wuhan. It’s clear that there was early skepticism and government officials were caught unawares by the magnitude of the crisis, and the rapidity of spread. The wealthy and densely populated Lombardy region has been disproportionately affected. Italy’s PM, Giuseppe Conte, has held the position for two years, making him one of the longest serving leaders in Italy’s post-war history. The nation’s volatile political history makes co-ordinated strategic planning for pandemics very difficult. This article on Italy from the Harvard Business Review, aimed at an American readership, captures the problems that face individualistic nations who favour rights over responsibilities:
Consider the decision to initially lock down some regions but not others. When the decree announcing the closing of northern Italy became public, it touched off a massive exodus to southern Italy, undoubtedly spreading the virus to regions where it had not been present.
This illustrates what is now clear to many observers: An effective response to the virus needs to be orchestrated as a coherent system of actions taken simultaneously. The results of the approaches taken in China and South Korea underscore this point. While the public discussion of the policies followed in these countries often focuses on single elements of their models (such as extensive testing), what truly characterises their effective responses is the multitude of actions that were taken at once. Testing is effective when it’s combined with rigorously contact tracing, and tracing is effective as long as it is combined with an effective communication system that collects and disseminates information on the movements of potentially infected people, and so forth.
Clearly this information-collecting, when it isn’t coercive, requires compliance and collaboration for the broader good. Libertarians are reluctant, it seems, to admit this.
Sweden‘s record on the pandemic is worth comparing to the other four countries comprising Scandinavia – Norway, Finland, Denmark and Iceland. Sweden is certainly the most populous of the five, but its deaths per million tell a grim story – more than five times those of Denmark, around ten times those of Norway and Finland, and almost 20 times those of isolated Iceland. The rate is higher than that of the USA and France, and not far below that of Italy. Currently, the centre-left PM Stefan Löfven heads a highly unstable coalition, which clearly isn’t able to provide the co-ordinated response required in a pandemic. In fact the country deliberately took a ‘relaxed’ attitude to the virus, and are now paying the price, though some of the country’s epidemiologists are still standing by the nation’s approach, astonishingly enough. Around half of the country’s fatalities have occurred in nursing homes. Apart from Sweden, all of the Scandinavian countries have female leaders. Just saying.
Russia, which has recorded the third highest number of Covid-19 cases in the world, has a bizarrely low death-rate, which can’t be accounted for from an epidemiological perspective, as I’ve reported before. Dmitry Peskov, one of Putin’s favourite arse-lickers, defended the record, saying “Have you ever thought about the possibility of Russia’s health care system being more effective?” This in fact caused a spike in fatalities, as several thousand Russians immediately died laughing. A very brave doctor, Anastasia Vasilyeva, founder and head of the medical trade union Alliance of Doctors, is creating videos exposing Putin’s lies about Russia’s handling of the pandemic, showing run-down hospitals, sick and unprotected medical staff and a generally under-funded and unprepared healthcare system. She has, of course, been viciously attacked by Putin’s media thugs, arrested and generally harassed. It’s safe to say that nothing credible is coming out of Russia’s state reporting of Covid-19, and the same must be said of China, or any other state which has more or less complete control of its media. So the full truth of what is happening in Russia, and in other closed societies, will likely not come out for years.
Final remarks – from what we’ve seen so far, right-wing, limited government, libertarian-type governments do worse than strong, centralised governments, especially those led by women. Closed societies generally can’t be trusted on their reporting, so it’s virtually impossible to judge their performance vis-à-vis the pandemic.
Next time I’ll look at some countries in Eastern Europe and the Middle East.
References
https://www.worldometers.info/coronavirus/
https://www.theguardian.com/commentisfree/2020/apr/04/tories-protect-nhs-coronavirus-slogan
https://www.abc.net.au/news/2020-05-18/why-belgium-has-a-high-number-of-coronavirus-deaths/12259032
https://www.livescience.com/results-of-sweden-covid19-response.html
https://hbr.org/2020/03/lessons-from-italys-response-to-coronavirus
Covid-19: lies, damn lies and statistics
Canto: So Russia is being described as a ‘late arriver’ with regard to Covid-19. It now has the second-highest number of cases, as everyone knows. Yet the mortality figure is astonishingly low. It’s only natural to be suspicious as there’s surely no obvious epidemiological explanation. It’s worth comparing Russia to Germany, whose figures few would quibble with, given its reputation for efficiency. It’s been treated as the European outlier in terms of its response, but nobody appears to be praising Russia for its tiny mortality rate. Why would that be?
Jacinta: Just looking at some reporting, various reasons have been given. Take this one from Dr. Elena Malinnikova, the chief of infectious diseases in the Russian Ministry of Health:
The low mortality is due to timely detection of infection as well as the fact that that Russians tend to see their doctor soon after symptoms appear.
Canto: Hmmm. Other nationalities don’t see their doctor, when there’s a killer pandemic on the loose? And ‘timely detection of infection’ sounds overly vague to me.
Jacinta: Let’s try another one. ‘Russian journalists have reported that more than 60% of all cases diagnosed in the country have been in Moscow, which has a younger and healthier population than rural areas’.
Canto: Yeah, but in the USA it’s the richer, more heavily populated regions of the north-east that have been hardest hit. The rural regions much less so.
Jacinta: Okay. In the article linked to above, Kent Sepkowicz, a physician and infection control specialist, provides good reasons why Russia’s mortality figures don’t make much sense on their face. And before I report on that, let’s look at rough reported mortality rates of a few countries, for comparison. I’ve just looked at total reported deaths as a percentage of total cases. As of May 20, the USA’s mortality rate is around 6%, the UK’s a horrendous 14%, Germany’s has gradually risen to 4.6%, and Brazil, another latecomer like Russia, and now with the fourth largest number of cases, is at 6.5%. Russia, on the other hand, is at 0.95% mortality. That’s a huge disparity, which we might call ‘Russia’s miracle’. But, as Sepkowicz points out, despite reports that Russia is doing well on testing (more than ten times that of Brazil, and somewhat more than the USA, and they might’ve started earlier too), Russia scores poorly on the comorbidity front, otherwise known as ‘pre-existing conditions’, such as heart disease, chronic lung disease, diabetes and obesity. It has an ageing population, and smoking is far more prevalent there than in European countries and Brazil. The testing regime is definitely not so much better than other countries to account for Russia’s apparent success – both Spain and Italy have done more tests per population.
Canto: Hello, are you saying there’s something shifty in the works? Vlad and and his charming circle would never lie to us, surely?
Jacinta: I don’t know that they’d gain much from fudging the figures…
Canto: Are you kidding? Isn’t that like saying Vlad wouldn’t gain much from rigging his election results? What he loses in international credibility, he might gain on the national scene, and that’s more important for him. But maybe there’s some less nefarious reason for the low mortality – I know they’re counting the numbers differently in some way. But the deaths from Covid-19 are the deaths from Covid-19. It should be a straightforward matter.
Jacinta: What about the deaths from x, y or z, exacerbated by Covid-19 infection?
Canto: I think that’s what they’re doing in Russia. Unless they’re certain that it was Covid-19 directly, they’re not counting it, even if they’ve tested positive for the virus, and then they die. They might be arguing that they were going to die anyway, Covid-19 just hastened the end.
Jacinta: Very dodgy if true. You could say that about anyone who’s a bit peely-wally.
Canto: Anyway let’s look at another country in this very complicated trans-national battle against the virus. Brazil’s an interesting one. I’m noting that countries with right-wing laissez-faire governments tend to be killing their citizens at a faster clip than leftist or centrist governments. Whadyareckon?
Jacinta: That’s a bit crude, but let’s look again at the reported figures and give number of deaths per number of cases as percentages. I’m going to leave out Russia and China, as I don’t trust what they’re reporting – which isn’t to say I entirely trust the other nations, but you have to draw the line somewhere. Britain, as mentioned, is very high at 16%, and has a conservative government. A very interesting country to look at is Belgium, which has the highest death rate per million of population of any major country in Europe. It’s death-to cases percentage is also high, at just over 16%. The country’s political situation is horrendously complex. They’ve had a caretaker PM for a year or so, and there’s basically a caretaker government after messy election results in March, in the middle of the Covid-19 crisis. This interim government is supposedly in place just to manage the crisis. Clearly it’s not going well. It would be reasonable to put their problems down to no strong central government, à la the US. Now, Brazil has a notoriously extreme-right government at present, and I’ve already given its deaths-to-cases ratio, but the number of cases is rising rapidly, as are the number of deaths. Now, let’s have a look at Scandinavian countries, often glorified as models of good government. I’ll include in that vague grouping, in order of population: the Netherlands (17m), Sweden (10m), Denmark (5.8m), Finland (5.5m) and Norway (5.4m), and I’ll exclude Iceland, which has all the advantages of a distant island re isolation (it’s 87th in the world for cases). On deaths-to-cases: The Netherlands 13%, Sweden 12%, Denmark 5%, Finland 4.7% and Norway 2.8%. On those statistics, it seems that the smaller the country, population-wise, the better managed it has been in terms of preventing mortality, which does make some sense.
Canto: Okay so I’ll look at their current governments. the Netherlands is clearly hard-hit, Covid-19-wise. It has a multi-multi-party system (that’s not a typo) and is currently governed by a centre-right or conservative-liberal party, VVD, presumably supported by the next largest party, PVV a right-wing nationalist group. The left appears to be divided amongst a number of smaller parties, and the current government has been in power for ten years. Sweden, also faring badly under Covid-19, currently has a minority government with a social democrat PM after a controversial and inconclusive election in 2018. So it’s a centre-left government relying on centre-right parties. The social democrats have been in power, mostly as a majority, since 1917, but there has been a movement towards the right in recent years. Denmark, doing better than the previous two, but faring much worse than we are here in Australia, where we have a death-to-case ratio of 1.4%, has again a multi-party system – and by the way, all of these Scandinavian countries, except Finland which is a republic, are constitutional monarchies practising parliamentary democracy like Britain, and, in a weird way, Australia, New Zealand and Canada. The leftist social democrats are currently in power in Denmark, and they have a far tougher position on physical distancing than the Swedish government. Finland Has both a President and a Prime Minister, somewhat like France. The Prime Minister, Sanna Marin, made news worldwide as the youngest PM in the world when elected late last year. She’s a social democrat and heads a coalition government, which seems to be the case with most Scandinavian governments.
Jacinta: Yes, They seem designed that way so the parliament is more or less forced to collaborate in order to get things done. It seems a much better way to run a country, a far superior system to that of the USA, much more team-based. Anyway, statistics seem to suggest that, overall, strong central governments that can co-ordinate efforts effectively, and have the support of the people, are doing better at saving lives. It’s not a conclusive finding though, and no doubt each country has its confounding factors.
Canto: Norway, finally, has handled things in much the way you would expect of the nation rated first in the world by the OECD. On March 19 this year, their federal government was granted emergency powers by parliament until December. That’s one way of creating strong central government, albeit temporarily. The current government is essentially right-centrist, within a multiparty system where the balance is usually held by left-centre parties. Clearly, though, this is a nation where people place more faith in government than, say, in the USA. And speaking of libertarianism and such, it’s interesting to look at Brazil more closely. When we began this post a couple of days, ago, Brazil was fourth in the world in terms of confirmed cases. Now it’s up to second, that’s how fast-moving things are.
Jacinta: And it’ll never reach top spot, surely – the USA is way way ahead of the rest of the world.
Canto: So Brazil is a republic, and currently has an extreme right-wing government under Jair Bolsonaro, who, according to this very recent New Yorker report, seems to be doing everything he can to exacerbate the situation. Brazil’s rise in cases has been more recent than most, and the death toll is now rising rapidly, now up to sixth in the world.Bolsonaro is shrugging it off and encouraging defiance of state restrictions in much the manner of Trump, whom he idolises. So it seems that when you get extreme anti-government government – negligence mixed with incompetence – as in the case of Trump and Bolsonaro, the death toll will likely be devastating, and will impact mainly the poor, elderly and disadvantaged. Who would’ve thunk it?
References
https://www.worldometers.info/coronavirus/
https://edition.cnn.com/2020/05/13/opinions/russia-low-covid-19-mortality-rate-sepkowitz/index.html
https://www.nationsencyclopedia.com/economies/Europe/Belgium-POLITICS-GOVERNMENT-AND-TAXATION.html
https://en.wikipedia.org/wiki/Politics_of_the_Netherlands
https://en.wikipedia.org/wiki/Politics_of_Sweden
https://en.wikipedia.org/wiki/Politics_of_Denmark
https://en.wikipedia.org/wiki/Politics_of_Norway
The Epoch Times and the ‘CCP virus’
Jacinta: So something unusual arrived in our letterbox the other day – a newspaper of sorts. Made out of paper.
Canto: Weird. Haven’t read one of those for a while.
Jacinta: Yes, nowadays we read those things on tablets, just like the Flintstones of yore. It wasn’t a big newspaper – an 8-page broadsheet – but it was unusual in other respects. It was all about China, or rather the Chinese government – the Chinese Communist Party (CCP). And none of it was positive.
Canto: Yes, the newspaper is called The Epoch Times, and has an ‘about us’ column on page 2, which tells us it’s ‘dedicated to seeking the truth through insightful and independent journalism’.
Jacinta: ‘Standing outside of political interests and the pursuit of profit, our starting point and our goal is to create a media for the public benefit, to be truly responsible to society’. All very commendable of course, but the whole paper is devoted entirely to criticising the CCP, highlighting its nefarious tactics and giving a voice to silenced, and sometimes disappeared, Chinese citizens, and also to Australian critics of the CCP.
Canto: So it’s Australian-based, operating out of Hurstville, a southern suburb of Sydney. Apparently founded back in 2000, it also states ‘we stand against the destruction wrought by communism, including the harm done to cultures around the world’. So, what do you think?
Jacinta: Well… we’re no admirers of so-called communism (which is always dictatorial or oligarchical rule in fact). We’re into open, progressive and collaborative societies. So, while I’m sympathetic to the cause of this newspaper, here’s a criticism. It’s interesting that we’ve had this in our mail now, from this 20-year-old organisation. It comes at a time when the CCP is undoubtedly weakened by the spread of SARS-CoV-2, and will be scrambling to improve its reputation and to limit the economic damage done to China by this disaster. It’s a bit like these China critics and journalists, many of them of Chinese backgrounds themselves it seems, are ‘going in for the kill’ against a weakened adversary. All very ‘nature red in tooth and claw’. And of course I sympathise to a degree, but note that I mentioned ‘collaborative’ before, and in our last post we talked about not playing the blame game at this time. The Epoch Times has an editorial on its second page, entitled ‘Giving the Right Name to the Virus Causing a Worldwide Pandemic’. Their decision is to call it the CCP virus, a name they use throughout the newspaper. I respectfully disagree for a number of reasons. First, it would be a step backward to the Spanish influenza days. As we know, the Spanish flu didn’t originate in Spain, but much of the early reporting of it came from there, while other nations, still engaged in the HSW (Horribly Stupid War) of the period, suppressed the news to maintain morale. This was unfortunate geographical nomenclature, as many people still confusedly believe it came from Spain. Today we wisely use scientific names which refer to the type of pathogen – coronaviruses have their characteristic s-proteins, hepatitis viruses affect the liver, from the ancient Greek root hepat-, etc. This helps make clear that viruses and other pathogens have no nationality and know no borders. It also helps to internationalise science. Second, while we need to know the precise origin of this virus, and to try to shut down what at this stage looks to be the passage from bats to humans via one or more intermediaries, the priorities right now are to stop or reduce its spread, to reduce its effect on human bodies, and ultimately to develop a vaccine to stop it in its tracks. Only after we’ve achieved these things should we be looking at causes and blame.
Canto: Right, like when the Titanic’s sinking, it’s no use wasting time on causes or human failings before the event, all your energies should be spent on saving lives, getting others to collaborate on rescue efforts, and getting the hell away from there. Those other enquiries come afterwards.
Jacinta: Right. Now China is apparently trying to help with supplies of PPE and with its own clinical trials of antivirals and vaccines. Obviously there are political motives there, but if it’s providing effective assistance we shouldn’t reject it. Now, there’s a massive amount of journalism being produced as to the CCP’s motives and its effectiveness in, for example its assistance to Italy, with which it has had long-standing relations, and we shouldn’t be naïve about the CCP’s misinformation campaigns, its dubious politicking, and its cyber-warfare activities, and all of that should be reported on, but in my view, the reporting should always have this question in back-of-mind: Is it (I mean the reporting) helping or hindering the spread and/or defeat of Covid-19? That s the one and only priority at the moment. If the CCP is saving lives and reducing suffering in its own country and elsewhere at the moment, that’s a good thing, and should be welcomed.
Canto: Misinformation costs lives too though. It’s interesting that both Hong Kong and Taiwan, two regions that have reason not to trust anything coming out of the CCP, have performed far better than most in combatting Covid-19. Many Hong Kong residents have been wearing masks since the SARS outbreak of 2003, and the people themselves were ahead of their own government in wanting shut-downs. They’ve experienced only four confirmed deaths – an amazing feat. It really pays – and saves lives – not to trust the CCP, it seems.
Jacinta: So let me give a third reason. China is an economic giant, keen to expand its economic impact around the world. Twenty-five percent of Australia’s manufactured goods come from China. China is the largest customer for our Australian exports, by far. Successive Australian governments have been trying to diversify our trade relations, but it seems that market forces are moving us to an ever-closer reliance on China. So we know that too-strident criticism of the CCP, however deserving, may have a severe economic impact. It places us in a delicate position. The question then becomes one of leverage – finding ways to criticise from a position of amity, or at least some kind of partnership.
Canto: Good luck with that. And we need to show them that we know what’s what, and that we’re not weaklings. And join and participate in international forums that promote human and minority rights, and lend our weight to international criticism.
Jacinta: Yes, and with these caveats, I do want to endorse what The Epoch Times is doing. It’s important that people hear from and about the dissident voices within China, their courage and their suffering. Knowledge is power, and much anger and outrage is thoroughly justified. What has happened to Fang Bin? To Chen Quishi? To Li Zehua? To Ren Zhiqiang? How does the CCP justify its treatment of the late Dr. Li Wenliang and of Dr. Ai Fen? This will not be forgotten, nor will the CCP’s self-interested, deceitful, incompetent and bullying mishandling of the early stages of this outbreak. The party needs to be brought to account, by international forces, in the aftermath of the pandemic.
References
The Epoch Times, April 20, Special Edition
https://en.wikipedia.org/wiki/COVID-19_pandemic_in_Hong_Kong
https://www.australiachinarelations.org/content/understanding-australias-economic-dependence-china
https://en.wikipedia.org/wiki/Fang_Bin
https://en.wikipedia.org/wiki/Li_Zehua
https://en.wikipedia.org/wiki/Chen_Qiushi
https://en.wikipedia.org/wiki/Ren_Zhiqiang
https://www.ijidonline.com/article/S1201-9712(20)30111-9/fulltext
Covid-19 – conspiracies, remdesivir
Canto: So, getting back to Covid-19, I want to look at two unrelated issues – the limited approval of remdesivir as a treatment, and the claim by the US government that the virus escaped from a lab in Wuhan. What do you think?
Jacinta: Well let me briefly address the second matter – I haven’t yet looked into the claim, but I will say that, IMHO, the current US federal government is possibly the largest misinformation machine on the globe at present, and I won’t be happy till I see every member of that non-administration in jail.
Canto: Okay, be prepared for a life of misery. I agree though, that Pompeo is a slimeball, and it’s very likely that this is largely designed as another blame-shifting distraction by the US maladministration. I don’t remember hearing about this from any news source before Pompeo announced it.
Jacinta: Well it’s interesting that, in investigating this, we have to contend with, and generally ignore, two of the most untrustworthy governmental sources of information on Earth, the USA and China. So thank dog for independent journalists, scientists and investigators. We need them so much at this time. The Washington Post has a 2000-word article on the issue, posted on May 1, undoubtedly in response to moves by Frumpy & co to get the US public to blame China for the pandemic. The article describes an assessment from the US intelligence community:
While asserting that the pathogen was not man-made or genetically altered, the statement pointedly declined to rule out the possibility that the virus had escaped from the complex of laboratories in Wuhan that has been at the forefront of global research into bat-borne viruses linked to multiple epidemics over the past decade.
Canto: ‘Pointedly declining to rule out’ means very little. They’re making a point of saying it’s possible? Isn’t it more likely to have come from the ‘wet markets’ – wet with blood that is – as a result of that traditional Chinese fondness for dining and medicating on exotica?
Jacinta: ‘Murky’ is how the WaPo describes the origins. Some scientists are saying it’s highly likely to have been ‘naturally transmitted’, others, not so sure. But the thing is, the scientists are the ones to trust on this, certainly not the Chinese or US governments. And even then you need to check those scientists’ allegiances.
Canto: I should also point out, as so many scientists are doing, that now is not the time for playing the blame game. Knowledge is power, and we need to be pooling our global resources, and our knowledge, to combat this and future pandemics. We need to try and build trust, not to sow distrust. And this isn’t to say that accidents can’t and don’t happen in virology and microbiology labs around the world, including in the USA.
Jacinta: The WaPo also has much to say about renowned virologist Shi Zhengli, team leader at the Wuhan Institute of Virology, which is being targeted by the Trump administration’s propaganda campaign. According to Shi, ‘the institute never possessed the SARS-CoV-2 virus’, while Wuhan’s health commission has found, or claimed, that the first person who died of the virus purchased goods at the Huanan Seafood Wholesale Market.
Canto: So it may have come from seafood?
Jacinta: Don’t know. Probably they sold more than seafood there, or it was part of a wider market. Anyway, many virologists, including US scientists who’ve worked with her, vouch for Shi’s extreme rigour and brilliance. But clearly that won’t stop the US government’s attempt at character assassination. I’ve heard they’re trying to say, or infer, that the virus was engineered at the Wuhan lab – and no doubt millions of Yanks will believe this brilliant theory, that the virus was engineered by mad scientists and then let loose to kill thousands of their own people before being unleashed upon the world – to be followed up by Chinese chem-trails, no doubt.
Canto: And not just Yanks. Anyway let’s move on to a happier topic. Remdesivir.
Jacinta: Well the news is that the FDA in the USA has issued an Emergency Use Authorisation for remdesivir, and the Gilead company which owns this pharmaceutical, has issued a company statement (on May 5), and here’s a quote:
Gilead’s overarching goal is to make remdesivir both accessible and affordable to governments and patients around the world, where authorized by regulatory authorities…. Gilead is in discussions with some of the world’s leading chemical and pharmaceutical manufacturing companies about their ability, under voluntary licenses, to produce remdesivir for Europe, Asia and the developing world through at least 2022.
I’ve listened to an interview with Gilead’s CEO Daniel O’Day, and he was making all the right caring-and-sharing noises…
Canto: Can we revisit what remdesivir is and does?
Jacinta: Of course. For starters it’s not a cure, it’s essentially ‘an investigational antiviral drug’ (I’m quoting again from the company statement) which, O’Day is careful to point out, ‘has not been approved by the FDA for any use’ (meaning presumably besides this emergency use). He also admits that the drug is the subject of multiple ongoing clinical trials and ‘the safety and efficacy of remdesivir for the treatment of COVID-19 are not yet established’. It’s a nucleoside analogue, one of many that have been formulated over the years, and dozens have been approved for use in treating viruses, cancers, bacterial and other pathogens. Nucleoside (and nucleotide) analogues are designed to resemble naturally occurring molecules used to build the RNA and DNA so essential to our biology. Some of the best-known nucleosides are cytidine, thymidine, uridine, guanosine, adenosine and inosine. The difference between a nucleoside and a nucleotide is that nucleosides are nucleobases linked to a sugar molecule while nucleotides are linked to phosphate groups (oxygen and phosphorus).
Canto: And the key is that in creating an analogue which functions differently from the real thing, they’re trying to obstruct the replication of the pathogen that takes up this analogue, right?
Jacinta: Yes, you’re getting it. Remdesivir actually has several modifications to the nucleoside structure while still functioning as an analogue – that’s to say it still manages to trick the virus into utilising it, and so becoming dysfunctional in terms of replication. A professor of chemistry and biochemistry, Katherine Seley-Radtke, describes the process in relatively simple terms:
Remdesivir works when the enzyme replicating the genetic material for a new generation of viruses accidentally grabs this nucleoside analogue rather than the natural molecule and incorporates it into the growing RNA strand. Doing this essentially blocks the rest of the RNA from being replicated; this in turn prevents the virus from multiplying.
She writes that remdesivir is a three-times-modified version of the adenosine molecule. Firstly, it’s a ‘prodrug’, in that it has to be modified in the body before it becomes active. The active form has three phosphate groups and is then recognised by the RNA polymerase enzyme of the virus. The second modification is a carbon-nitrogen group attached to the sugar, which is the key to terminating the RNA strand’s production. The third modification is a little change to the molecule’s chemical bond, replacing one nitrogen with a carbon, which prevents one of the enzymes of the virus from recognising and excising ‘foreign’ nucleosides. Remdesivir’s modified adenoside remains in the RNA chain, ultimately terminating further production. Got all that?
Canto: I refuse to confirm or deny. But I can read too. There’s a proper clinical trial of the drug being conducted in the USA at present, and other trials elsewhere. Preliminary results show faster recovery in a statistically significant number of patients, but it isn’t a cure, and will likely be part of a cocktail of treatments as other and hopefully even better antivirals are formulated. This follows the approach to treating other dangerous viruses such as hepatitis C and HIV. It’s about getting the death rate, and the badly-affected rate, down. This is as important as a vaccine, at present.
Jacinta: And I’ve heard it’s quite a tricky drug to manufacture, so getting supplies up and sharing expertise globally will be key factors in saving lives.
References
https://theconversation.com/remdesivir-explained-what-makes-this-drug-work-against-viruses-137751
Covid19: world progress, cytokine storms, our plans
Canto: So while we need to be worried about – and to know something about – the cytokine storm that the Covid19 infection can lead to (and we’ll learn about that soon), there’s also a storm of activity on the SARS-CoV-2-fighting front.
Jacinta: Yes, intravenous zinc was talked about in the Medcram series as an effective tool in fighting viral pneumonia, and a world-first trial is being conducted by Austin Health and Melbourne University to test its effectiveness for Covid-19 sufferers with respiratory problems. We’re still catching up on the Medcram series, and update 52 talks of the drug ivermectin, already on the WHO list of essential medicines. The WHO website, incidentally, is promoting a ‘solidarity’ clinical trial for Covid-19 treatments, involving, singly or in combination, remdesivir, hydroxychloraquine, lopinavir, ritonavir and interferon beta-1a. So that gives some idea of the work that’s going on to fight symptoms and reduce the death rate.
Canto: And, you know, I’ve been feeling guilty about singling out the USA as the worst-case scenario all round. It’s not actually so. It’s not fair to look at total figures and point out that the USA tops the list for Covid19 fatalities, and draw calamitous conclusions. You have to take into account its much larger population compared, for example, to number two on the list, Spain. The US has suffered about 2.5 times the fatalities of Spain, but it has about 7 times the population. In fact, if you look at fatalities as a proportion of population, there are many countries worse off than the USA – namely Spain, Italy, France, the UK, Belgium (the worst hit), the Netherlands, Switzerland, Ireland and Sweden. All European countries, notably.
Jacinta: Yes and I’m sure they’ll all have their particular stories to tell about why this is happening to them, and will be wanting to learn lessons from Taiwan, Hong Kong, South Korea, and even our big faraway island, but I really want to look at solutions, in terms of eradicating the virus, or blocking it, or building up our immunity. Having said that, flattening the curve, and reducing fatalities, is a primary focus, which means continuing the physical distancing and looking for ways to keep economies running while this goes on. In spite of patches of civil libertarian activity here and there, the vast majority of our global population is on the same page with this, I think.
Canto: Well I’m looking at an Axios article from the Johns Hopkins website. It compares global performance under Covid19 to a mock pandemic exercise, Event 201, conducted some six months ago. They’ve found some positives and some negatives in their analysis. Positives – a greater degree of compliance with physical distancing measures than expected, ‘the degree of surge capacity augmentation in the health care system which has been possible’, and the rapid growth of international collaboration among scientists, leading to a quickened progress of trials for possible treatments. Negative – disparate and often contradictory messages from authorities – mostly political authorities – leading to confusion and distrust of governments and other institutions. This is partially explained by the complexity of the virus itself, which has made it difficult to characterise to the general public, and to be fully understood by non-medical authorities, such as political leaders.
Jacinta: It’s a weird situation, as there’s no end in sight, everyone’s worried about ending restrictions too soon, yet everyone’s worried about the economy, and those countries, like Australia, that are heading towards winter, are bracing for heightened problems, while northern hemisphere countries are hoping for summer’s relief but worried about the autumn when it might be hard to cope with a second outbreak, should it come. And medicos are warning that expectations of a vaccine in eighteen months might be overly optimistic. But I want to be optimistic – I want to look at anything that’ll reduce symptoms and save lives. One treatment, among many others it should be noted, is hydroxychloraquine, which is being given so much of a bad press, because of its being over-hyped by a Trump administration intent on getting political points for a silver-bullet cure. There have already been a number of small, less-than-gold-standard studies, some in which the drug is combined with the antibiotic azithromycin, and the results appear to be all over the place. We’re still awaiting the results of randomised, placebo-controlled, double-blinded studies, which are under way.
Canto: I note that a couple of reports on chloraquine and hydroxychloraquine on the JAMA website have been taken down, I suspect because of all the politicising. That’s a shame. Anyway I mentioned the cytokine storm at the beginning of this post, so I’ll try to comprehend it. A clue to the meaning comes in this mid-March article on the Lancet website. In an early sentence it mentions ‘cytokine storm syndrome’, and in the following sentence refers to the treatment of ‘hyperinflammation’. It seems the two terms are interchangeable. Another term, in the very next sentence, is ‘a fulminant and fatal hypercytokinaemia’….
Jacinta: Sounds like they’re just showing off.
Canto: Please don’t say that about our frontline covidtroops. Okay, a better site for understanding cytokines and their storms is this from New Scientist. As we’ve guessed, it’s an over-reaction of the immune system, sometimes fatal. Cytokines are small proteins, produced throughout the body, which trigger inflammation as an immune response. Sometimes the intensity of the cytokine response results in hyperinflammation. So you might say the cytokine storm is the cause and hyperinflammation the effect.
Jacinta: So this raises questions. For example, why do some have what seems an over-production of these cytokines and others don’t, in response to SARS-CoV-2 in particular? And what do these cytokines actually do to cause inflammation?
Canto: You’re asking me? Well, it’s conjectured that younger people don’t have the developed immune system that produces all these cytokines, and that’s why you don’t see symptoms. But that raises the question – do others have over-developed immune systems, but maybe only for this particular virus? Is there a general goldilocks level?
Jacinta: And is there a way of distinguishing between those who succumb to the hyperinflammation, which in turn can cause acute respiratory distress syndrome (ARDS), and those who succumb to the virus itself? Or is it always the immune response that does people in?
Canto: I don’t think so. If the immune response doesn’t work at all, I suspect the virus will spread like a cancer to the rest of the body?
Jacinta: That can’t be right. That’d mean those kids who don’t suffer the cytokine storm, or any immune reaction, would remain infected until it spread through their bodies and they dropped dead. That definitely isn’t happening.
Canto: No, you’re right – they’re developing antibodies, presumably, (and that’s a whole other story), without going through much in the way of suffering. In fact, children’s apparent immunity to the virus is something of a mystery that demands further research. If everyone could develop that kind of immunity…
Jacinta: So many questions we can’t answer. I mean, not just the myriad questions we, as dilettantes and autodidacts, can’t answer, but the fewer but many questions epidemiologists, virologists and ICU workers can’t answer. But I propose that we continue to try and educate ourselves and explore, in our feeble but earnest way. I propose that we dedicate this blog, for the foreseeable, to exploring terms and conditions, so to speak, and treatments, such as ‘cytokine’, ‘ACE-2’, ‘hypoxia’ and ‘quercetin’ and how they relate to or are affected by the Covid-19 infection. Like putting pieces together in a jigsaw puzzle, sort of. It might help us being overwhelmed by the whole picture.
Canto: Okay, let’s try it.
References
Coronavirus pandemic update 52, Medcram youtube video
https://coronavirus.jhu.edu/news
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
https://www.newscientist.com/term/cytokine-storm/
https://www.centerforhealthsecurity.org/event201/
https://jamanetwork.com/journals/jama/pages/coronavirus-alert
Covid-19: the USA and a bit of ranting
Jacinta: So I note that, unsurprisingly, there are some Americans protesting about physical distancing and lockdowns, while their nation has proved to us all that their overall handling of this pandemic has been the worst on Earth by a long way. I mean, apologies to all those who are working their arses off on the frontline, and to the innocent victims, and to the governors and other leaders trying their level best, but the sheer size of the US failure compared to just about any other country is a fantastic advert for American exceptionalism.
Canto: Well yes, the USA has failed massively in its handling of Covid-19, though of course the virus has been very patchy in its incidence around the nation, for reasons nobody can quite understand. But here’s an interesting metric in comparing the USA to Australia, and anyone can check this on the Worldometer figures. The USA’s population is approximately 13 times that of Australia, but as of today, April 21, the death toll from Covid-19 in the USA is approximately 600 times that in Australia. Compare also Taiwan, one of the world’s best performed country so far, which has a similar population to Australia. This very close neighbour of China has a death toll so far of 6, compared to the USA’s 42,518.
Jacinta: Yes, yes, so what does this say about the USA when you get so many otherwise intelligent people there still clinging to the bullshit claim that their country is the greatest on the planet? Adam Schiff said it in his otherwise excellent speech at the end of the impeachment process – and today, listening to a Sam Harris interview with Caitlin Flanagan (someone I’ve never heard of but who seemed otherwise perfectly rational), I heard her say exactly the same thing – or not exactly. She said that she really believed (almost as if she wished it were so) that America is the world’s greatest country. As if intensity of belief counted for anything. But I doubt that the USA is ahead of the rest of the world in any field worthy of measuring, apart from military might, and that’s surely a questionable value.
Canto: Hmmm, so why don’t you tell me what you really think? But isn’t this just a bit of harmless patriotism after all? We’re expected to love our country, as a value.
Jacinta: Well, I just don’t. I’ve just never had that feeling. Call me aberrant. Or contrary. I’ve often been described as a contrarian, but on this I agree with Venki Ramakrishnan, the Nobel Prize-winner, whose excellent book Gene Machine we’ve just read. He was inundated with congratulatory calls and honorary awards from India after winning the prize, even though he’d had nowt to do with the country since he was a teenager. It started to annoy him, because as he wrote, we don’t get to choose where we’re born. An obvious truth that seems to escape most people. But I’m also a contrarian in that I often find myself undermining my own responses. For example, I want to respond to patriots by calling myself a humanist, but then I think ‘I didn’t get to choose to be a human, why should I be jingoistic about humanity? Birds are pretty cool too.’ Isn’t that contrarian?
Canto: Hmmm. Ramakrishnan was tragically led astray by the transnational values of science haha. And birds can’t do science. I wonder about the blow to US credibility of this event though. They’ve completely failed in the readiness and collaboration Bill Gates wrote about in that New England Journal of Medicine article back in late February. I mean, they’re advancing with possible treatments no doubt, but testing is a shambles from what I’ve heard, and the federal government is non-existent under the boy-king. What little there is of it just gets in the way.
Jacinta: The irony of it is that the more their government fails, the more the libertarians and the knee-jerk anti-government loons will feel vindicated. And now I hear that our own Dear Leader thinks that we should have a more co-ordinated international response but maybe without the WHO. I mean, wtf? Seems to be trying to crawl up the boy-king’s capacious arse. Wrong side of history, mate.
Canto: So I’ve been avidly watching this series of Medcram videos on the pandemic. They’re informative on the science, on immunology and new types of vaccines and treatments, but they’re also a fascinating look back on the innocent-seeming days of six or seven weeks ago, when there were hardly any deaths outside of China. Watching them only adds to my sense of the unreality of it all, somehow. Anyway, microbiology’s a fun topic to learn about don’t you think?
Jacinta: Along with all the others. It’s certainly a lot more calming and inspiring than politics.
References
https://www.nejm.org/doi/full/10.1056/NEJMp2003762
Gene machine, by Venki Ramakrishnan
Covid 19: some stuff on remdesivir
Canto: So there’s this promising new antiviral drug that researchers are working on. Remdesivir. Terrible name. Why not something more hard-hitting like rambovir or rockyvir?
Jacinta: Well I’m not sure it’s an American drug, and I don’t think it’s new. It’s new for Covid-19. Everything’s new for Covid-19. And here we should repeat the standard caveat: ‘No specific agent has yet been demonstrated to be clinically effective in the management of Covid-19’.
Canto: Well done. So I’m reading this online article from a week or so ago – and a week’s a long time in Covid-19 – on the website of the Medical Journal of Australia, and it tells me that the antimicrobial remdesivir is ‘an investigational nucleotide prodrug’ – glad it’s not one of them antidrugs – and was used on the first diagnosed Covid-19 sufferer in the US. So maybe it is American. The article doesn’t say anything about its effect on the patient, but apparently it was first developed as a potential therapy for Ebola, and there’s some laboratory evidence that it can inhibit the replication of SARS-CoV-2.
Jacinta: That’s right, so four clinical trials have already begun in the US to test the effects of remdesivir, and another two are registered in China.
Canto: Well according to this media release only yesterday (April 17) from the National Institutes of Health (NIH) in the USA, they’ve already been testing the drug on poor old rhesus macaques…
Jacinta: They infected em? Bastards.
Canto: History is written by the victors my friend. And also by those who can actually write. Anyway, they responded very well to early treatment with reduced clinical signs and lung damage in a study designed to simulate treatment procedures for human patients in a hospital setting…
Jacinta: That’s nice. They got to sleep in real beds, like middle-class macaques.
Canto: Maybe. Of course, none of this has been peer-reviewed yet, but it’s very promising. But let me give you the total lowdown. You know that there have to be control groups, right?
Jacinta: Uhhh – uh-o. So… Let me see, they were all infected with the virus, but only some got the remdesivir, right?
Canto: Well of course they had to make the comparison. So they had two groups of six rhesus macaques, and they infected both groups with SARS-CoV-2. Then 12 hours later the treatment group received an injection of remdesivir. Sorry about the other group. After that the treatment group received a booster injection every day for the next six days. The initial treatment was timed to more or less coincide with the animals’ highest projected viral load. They first examined the animals 12 hours after initial treatment, and the treatment seemed pretty effective, only one still showed some mild symptoms, while in the control group they all displayed ‘rapid and difficult breathing’ …
Jacinta: Called dyspnoea in medical lingo.
Canto: Thank you. So the study continued for seven days, and over that time the treated monkeys were found to have significantly less virus in, and damage to, their lungs than the untreated.
Jacinta: So what happened to the untreated monkeys after that?
Canto: I might say ‘don’t ask, don’t tell’, but I think it’s reasonable to assume that after seven days they were treated with remdesivir and recovered. And that they chose a short, seven-day testing period so as not to endanger any monkey lives?
Jacinta: Hmmm. I don’t know too much about monkey business… Anyway, this remdesivir is obviouly promising and we must watch out for the results of other trials. But what is this remdesivir? What exactly is an antiviral, or a ‘nucleotide prodrug’, and do they all act in the same way? I know they’re not vaccines, they don’t induce antibodies, so how do they suppress the infection?
Canto: Okay, so our first stop on our info crawl is Wikipedia. Think of antivirals as a counterpart to antibiotics, aimed at viruses rather than bacterial pathogens, except that, unlike most antibiotics, their aim is to suppress rather than to kill the pathogen.
Jacinta: Really? Why not aim to kill the virus?
Canto: I don’t know, perhaps that’s not so easy with viruses. Anyway, while most antivirals target specific viruses, some are broad-spectrum, and I suppose remdesivir is one of those, since it was also successful against MERS, another coronavirus, and was first developed to combat Ebola virus, which isn’t a coronavirus as far as I know.
Jacinta: Remdesivir was earlier described as a nucleotide prodrug. A nucleotide is the basic structural unit of a nucleic acid such as RNA. A prodrug is by definition an inactive biological or pharmacological compound that can be converted within the body to have active drug properties. So the field of antiviral drug research has developed a lot, especially as a result of the HIV epidemic, and those that followed. All of this has expanded our knowledge of how viruses enter hosts and proliferate. SARS-CoV-2 is a set of RNA nucleotides surrounded by a protein capsid, or capsule, over which is a lipid envelope. It enters the host via the spike protein, and through this membrane fusion it infects host T lymphocytes – white blood cells that form a part of our immune system.
Canto: Yes, and trying to describe it all in lay terms – so that we understand it – is damn difficult. We know remdesivir has been somewhat effective for a broad spectrum of action against RNA viruses, and I note in this abstract that it’s ‘a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps)’ My guess is this means it acts like a nucleotide, inhibiting these RDRps. An RNA polymerase, I’m learning, is an enzyme (a type of protein) that’s ‘responsible for copying a DNA sequence into an RNA sequence, during the process of transcription’. But maybe an RNA-dependent RNA polymerase works on RNA, in the absence of DNA. So presumably remdesivir inhibits this essential enzyme from carrying out the transcription process that replicates the virus.
Jacinta: Maybe. By the way, as we travel the net on our info crawl, we’ve discovered some amazing stuff, such as this Covid-19 pandemic series of ongoing videos from a source called MedCram that began in late January and traces the spread, and the drama. The series begins with these words: ‘one of the things that’s in the news and hopefully goes away real soon is the coronavirus epidemic from 2019…’ That, to me, was more compelling than any advertising hook I’ve ever read.
Canto: Yes I’m keen to watch the whole series. Anyway, I believe remdesivir, also called RDV, has been used in an unauthorised way on human subjects already, and news from this Chemical and Engineering News website is that, understandably, interest in the drug and in scaling up production is reaching fever pitch, with a lot of pressure on Gilead, the company that presumably has a patent on RDV.
Jacinta: Of course, as we’ve already pointed out, this is exactly not the time for one private company to get precious about its rights to profit. Scaling up, assuming the drug’s effectiveness can be confirmed, should involve multiple labs in multiple countries. Having said that, producing a drug like RDV, described as a ‘medium complexity project’ compared to an apparently simpler drug such as the antimalarial drug hydrochloroquine, already involves a chain of companies and suppliers in a multi-step process. Every step in the process would need to be efficient, to prevent bottlenecks. Scaling-up also raises questions – remember Tamiflu? Our government stockpiled it in vast amounts in spite of damning analyses by the Cochrane Collaboration and others about its limited effectiveness and problematic side-effects. We don’t yet have proper analysis of RDV’s effectiveness, and we don’t know how much of it might be required, because nobody can predict the eventual course of this pandemic.
Canto: All true, but right now people are dying, and this is clearly the worst pandemic in more than a century. There are of course candidates other than RDV, it would be unwise to focus on just one, but public and private resources should be combined to bring any possible effective treatment to fruition. That’s what I reckon.
References
https://www.mja.com.au/journal/2020/clinical-presentation-and-management-covid-19
https://en.wikipedia.org/wiki/Antiviral_drug
https://ama.com.au/ausmed/govt-stands-tamiflu-despite-damning-findings
Covid 19: hopes, failures, solutions
Covid-19 continues to be devastating, especially in the USA, where there are vastly more cases than anywhere else, and vastly more deaths, though the picture there is complex. The hardest-hit region, the New York area, is seeing devastation in poorer districts such as Queens, where the Elmhurst public hospital is inundated with uninsured, critically ill patients. New York has suffered almost half of US deaths. Some other states and regions, especially physical outliers such as Alaska, Hawaii and the Virgin Islands, have very low numbers, and it would be hard to explain why the spread of cases across the mainland has been so uneven. Of course it’s obvious that there has been no federal leadership on the pandemic.
Here in Australia, where the numbers seem to be improving (we’re 33rd on the list of total cases, down from 18th when I first started paying attention to the list about three weeks ago, and 52nd on the list of total deaths), our conservative federal government is keen to open up the country again, and has released modelling to the effect that the virus will be eliminated from the mainland if we maintain current physical distancing measures, though it’s likely to take weeks rather than months:
The model suggests that every 10 people infected currently spread the virus to five more people, on average. At that level, the virus would eventually be unable to circulate and would die out within Australia.
Sydney Morning Herald, ‘Australia in course to eliminate Covid-19, modelling shows’
Australia’s current reproduction number (R0) is just a little over .5. A maintained R0 of 1 or less will eventually eliminate the virus. Of course, there will be fluctuations in that number, so it will be difficult to project a time when things are ‘all clear’. Another difficulty with modelling is that the number of infected but asymptomatic people is unknown and difficult to estimate. For example, recent Covid-19 testing of the entire crew of the aircraft carrier Theodore Roosevelt found that a substantial majority of those who tested positive were asymptomatic, casting doubt on previous estimates (already worrying for transmission) of one in four cases being asymptomatic.
The asymptomatic/presymptomatic transmission issue was addressed by Bill Gates in this article back in February. It’s what makes SARS-CoV-2 a much more serious threat than the previous SARS and MERS viruses. Gates, in this very important article, also provides an outline of what needs to be done globally to fight this pandemic and to prepare for inevitable future ones. If only…
It’s worth comparing Gates’ call for national and global co-ordination, and more expenditure, in the fields of epidemiology and disease prevention, with another more recent article, also published in the New England Journal of Medicine, which tells a tale of Britain and its NHS, gutted by years, in fact decades of ‘reforms’ and budget cuts:
Thanks to government “reforms” of the NHS, it has become highly decentralized, with over 200 commissioning groups in England that can make independent decisions about staffing and procurement of equipment — far from the monolithic “socialist” health care system it is often assumed to be. The devolved governments in Wales, Scotland, and Northern Ireland have substantial health system autonomy. At a time when central management of staff and resources might be most helpful, the decentralized decision-making structure leads to competition for resources and inconsistent policies.
One can hope that the travesty of this virus, especially in places like the US and the UK, will lead to a rethinking of the importance of a well-funded, centralised, co-ordinating and interventionist government in modern states, with particular emphasis on the healthcare system. But I suspect that, in the USA at least, things will go the other way, and the government-hating and government-blaming will only intensify. I’d love to leave this topic and look at solutions – that’s to say I’d love to focus more on the science, but I’m barely equipped to do so. Still, I like to have a go. A very technical and comprehensive review review of pharmacological treatments has been posted recently on the JAMA website, which includes an account of how SARS-CoV-2 enters host cells and utilises those cells for reproduction.
The review claims that currently the most promising therapy is the antiviral drug remdesivir. So what is it and how does it work? I’ll try to answer that question next time.
References
https://www.nejm.org/doi/full/10.1056/NEJMp2005755?query=recirc_artType_railA_article