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covid19: sensible testing, mostly

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Audrey Tang

Written by stewart henderson

September 17, 2020 at 12:03 am

Posted in covid19, Taiwan, USA

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covid-19, more on fructose, vitamin D, treatments and the vagaries of testing

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Canto: Ok, so note that in the graphic from the previous post, Australia is third highest in the group of 31 countries studied for caloric intake from sweeteners, but we don’t use HFCS much at all.

Jacinta: It might be a misleading graphic too. You might be forgiven for thinking that it somehow shows the USA as the most unhealthy, sweet-toothy country on the list, and Australia in third position, but since we’re more concerned here with links between fructose and covid-19 co-morbidities such as obesity, diabetes, cardiovascular problems and oxidative stress, the graphic doesn’t tell us much.

Canto: Yes so I found on this indexmundi site a list of 195 countries – and that’s all of them – showing prevalence of diabetes 1 and 2. That’s to say, the percentage of the adult population (from 20 to 79) that is diabetic. The USA ranks 43rd on that list, and Australia is down at 137th, level with Finland and Japan. But the site doesn’t name sources, and provides an end-note on the unreliability of much evidence: ‘National health authorities differ widely in capacity and willingness to collect or report information’. I should also add that though the USA is 43rd, the only other major nations above them are just about every Middle Eastern country, Pakistan, South Africa, Egypt, Sudan and Mexico. Make of that what you will.

Jacinta: Let’s avoid that rabbit hole, and return to medcram update 83, which briefly describes vitamin D3 (cholecalciferol) metabolism. This may involve a bit of repetition but that’s rarely a bad thing for us. So the D3 that we absorb or ingest goes to the liver and is hydroxylased at the 25th position (25-OH), but it doesn’t become activated until it’s again hydroxylased at the first position by the kidney (1,25-diOH, aka 1,25 dihydroxy vitamin D). And there’s another enzyme that can convert the vitamin to inactive forms. 

Canto: With that, Dr Seheult looks at another article from 2013 which describes a rat study that indicates that if fed on a high fructose diet, lactating rats suffered reduced rates of active intestinal calcium transport and active vitamin D. Or, more, accurately I think, they didn’t get the increased rates and levels that would be expected during lactation. So, because calcium is essential for skeletal growth, the study says ‘our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children’.

Jacinta: Interesting, and I presume that means consumption by the mother during pregnancy. Anyway, in more detail, what they found was that increased fructose intake inhibited the enzyme that converted vitamin D into the active form in the kidney, and promoted the enzyme responsible for the inactive forms. Disturbing, as Seheult says, for the excessive fructose in American diets, which may consequently affect calcium and vitamin D levels, though that would surely require more research. 

Canto: Well, the same group released more research in 2014 which found that chronic high fructose intake in calcium-sufficient rodents (rats and mice) reduced their active vitamin D levels. And a 2015 study from Iran looked at something different but again having to do with effects on enzymes and metabolism. They looked at S-methyl cysteine (SMC), and this recalls the investigation of N-acetyl cysteine (NAC) a few updates ago. Found naturally in garlic and onions, SMC is described as a hydrophilic cysteine-containing compound, which they investigated for its putative effects against oxidative stress and inflammation. So they induced oxidative stress in rats via a high-fructose diet over 8 weeks and then dosed them with SMC. Results from the high fructose diet were – here goes – increased blood levels of glucose, insulin, malondialdehyde, and tumour necrosis factor-alpha.

Jacinta: Okay so the increased insulin is presumably a reaction to the increased glucose. Its role is to absorb excess blood glucose, and too much of it can result in hypoglycaemia, low serum glucose levels. Malondialdehyde (MDA) is described as a marker for oxidative stress, so it’s not good. Tumour necrosis factor (TNF or TNFα) is a ‘multifunctional cytokine’, and although cytokines (types of proteins) perform many vital functions, the cytokine storm that appears to be associated with oxidative stress and covid-19 is a bad thing. 

Canto: But there were also decreased levels of glutathione (GSH), glutathione peroxidase (GPx) and catalase as a result of this fructose diet, and Seheult talked about these enzymes and such as important in reducing oxidative stress. However, the SMC dosing improved antioxidant enzyme activities and reduced levels of glucose, insulin and TNFα. 

Jacinta: So this SNC seems another promising antioxidant treatment. Meanwhile, watch your sugar intake, especially with fructose. More studies required of course, but I suppose there are ethical issues involved in fattening up and inducing oxidative stress on human subjects with a high fructose diet. Okay updates 84 and 85 deal with questions that hospitalised covid-19 patients might want answered, so we’re going to skip those or we’ll never catch up on these updates. With update 86 they’re into the second half of June and noticing a resurgence of the virus. So at the Johns Hopkins site they’ve ‘working to fill the void of publicly accessible covid-19 testing data’, because without testing you obviously can’t work out the numbers.

Canto: But more than testing itself, the turnaround of results is a problem. A young woman was just on the tube saying it took three weeks to get her test results, which renders the test useless. And another person on the tube reported that she’d tested positive, felt generally okay or asymptomatic, then tested negative, after which she came down with a heavy case replete with many of the covid-19 symptoms, and then tested positive again. How can this happen?

Jacinta: It’s still a mysterious virus, but to return to the update and Johns Hopkins, they’re generally looking at US data, but I’m interested in understanding the testing process and how well it maps the prevalence of this virus. The website has a graphic which shows the fairly rapid rise in daily testing from March through to June (with a drop-off from mid-June, when perhaps they thought it was more under control), and the number of positive daily tests, which hasn’t of course risen so much, so that the percentage of positive test results has gradually fallen. The WHO recommends that the percentage of positive tests, the positive percentage rate (PPR), in nations or states where there’s widespread testing, should be under 5% for at least fourteen days before those states can start ‘relaxing’, but I’ve read different, more flexible recommendations elsewhere from health authorities, so it seems still a matter of educated guesswork with an unpredictable pandemic. 

Canto: For the different US states, looking at the figures now in mid-August, the figures are weird. Washington has a PPR of 100% (?!) and are testing 1 in every 10,000, so it seems they’re only testing those they know are positive? That’s top of the list and bottom is North Carolina with a PPR of -13.1, and yes that’s a minus, and they’re testing -.09 in every thousand, and I’ve no idea what that means.

Jacinta: But most states’ figures are clear enough. New York is at 0.8% PPR with over 4 tests per 1000, which is good, but Nevada, Idaho and Florida are at over 16% PPR, each with around 1.5 tests per 1000, and that’s obviously a problem. An indication of the lack of centralised control of the situation – it’s hard to compare data from state to state. Anyway, the key, some say, is to scale the testing to the size of the epidemic in that nation/state, not to the state’s population – but how can you do that when you’re using the testing to determine the size of the epidemic?

Canto: Well presumably if nobody is reporting unusual, covid-like symptoms, as is the case here in South Australia, you don’t need to spend so much time, money and energy on testing. Not the case in the USA. Anyway, in this update, Dr Seheult noted, as we have been, that the case numbers for covid-19 are increasing, but the death rate is decreasing slightly, or at least levelling off. Possibly a result of more testing combined with better treatment. They may also be catching weaker levels of the virus due to measures put in place. But there’s no evidence as yet that the virus itself has become less potent, and this seems unlikely. 

Jacinta: And speaking of treatments, the steroid dexamethasone is apparently reducing mortality by as much as 35% for covid-19 patients on ventilation, according to a WHO preliminary report of work done at Oxford. It’s only good for those with severe hypoxia and associated problems though, but its a cheap, off-patent medication which can be added to the box of tricks for ICUs, once the data is confirmed. 

Canto: Okay, next time….

References

Coronavirus Pandemic Update 83: High Fructose, Vitamin D, & Oxidative Stress in COVID-19

Coronavirus Pandemic Update 86: COVID-19 Testing & Cases Increasing but Daily Deaths Decreasing

https://www.indexmundi.com/facts/indicators/SH.STA.DIAB.ZS/rankings

https://coronavirus.jhu.edu/testing

 

Written by stewart henderson

August 19, 2020 at 1:50 pm