an autodidact meets a dilettante…

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

Archive for the ‘medcram’ Category

stuff on covid19 and immunology

leave a comment »

 

Canto: Well it’s a great time to be living in quiet South Australia, with a global pandemic raging in many places elsewhere..

Jacinta: Particularly the US, which we’ve long been focussing on, maybe in a schadenfreude kind of way.

Canto: Yes or maybe in a lazy way, because we’re so inundated by American media, social media, cable news, the NYT, the WaPo, the Atlantic, Politico, the Medcram lecture series, it just seems easier to plug into US info these days. Which makes me wonder…

Jacinta: And all hell’s breaking loose with Trump having come down with covid19 and the misinformation machine starting to overheat. Currently – October 5 – according to the Worldometer figures, which we’ve been using since the start of the pandemic – the USA has suffered 214,611 deaths, more than a fifth of the world’s deaths by that database’s figures. 

Canto: Yes, we’ve noticed that the US media always has figures a little below ours – I presume because they’re using the Johns Hopkins figures, which seem to have a time lag. We can’t say which is more reliable of course. Complete reliability for all sources is unlikely. 

Jacinta: In any case the USA has spectacularly failed to get on top of this virus, and is still experiencing high case-rates and death-rates, though the variations between states are constantly changing, and tell their own complex story. Overall, though, unless something drastic happens, the US is on track to have suffered 250,000 to 300,000 deaths by the end of the year – and I haven’t accounted for the winter season. 

Canto: Yes and that’s no outlier prediction, that’s just a very simple forward projection. 

Jacinta: I’m half-wondering when the Trump administration will try to throw cold water – or bleach perhaps – at the covid figures, as they’ve tried to misinform with everything else to do with the virus, including Trump’s condition and the timeline of his infection. But I want to look at what we’re hearing from the Walter Reed medicos about his treatment, and more generally about immunology and the virus’ progress. From the figures, it doesn’t seem as if anything is working very effectively, but Trump will be getting treatment that isn’t widely available to anyone else in that country, and we’re getting no clear answers as to how he’s faring. 

Canto: The treatment everyone’s reporting on currently is the ‘antibody cocktail’ produced by the drug company Regeneron. This was made available through an emergency use authorisation, and unsurprisingly there’s now demand pressure on the product. He’s also on the antiviral remdesivir, and the steroid dexamethasone, and it seems he’s been given oxygen, though medical and other experts have had to read between the lines of public announcements to work out what exactly is going on. 

Jacinta: Yes, many experts suspect he’s been sicker than he’s been prepared to admit, and of course the Democrats and health officials are all wishing him well and ‘praying for him’ in their American way. Frankly, I hope he dies, for the simple reason that his death will likely save thousands of lives, as it will stem the flow of misinformation, and scare even his dumbest followers into wearing masks, physically distancing and generally starting to act sensibly and humanely. It will have been the best thing he’s ever done with his life. But enough controversy, let’s look at immunology and treatment. According to the NYT, Trump has also been taking Vitamin D, zinc, the hormone melatonin, and famotidine, an anti-heartburn medication. 

Canto: So he’s fit as a fiddle, then? 

Jacinta: Hmm. As we know, Dr Seheult on Medcram has spoken of the benefits of zinc and vitamin D, as well as remdesivir and dexamethasone, but none of these treatments have been subjected to rigorous clinical trials in relation to SARS-CoV2 as yet. It’s my guess that Trump himself is pushing the envelope to be treated with these drugs, though it could also be that he’s actually quite sick, as I’ve said. And unless he actually dies, it could be that we’ll never know. 

Canto: He won’t die. Anyway, what about Regeneron, and these monoclonal antibodies? 

Jacinta: Well we’ve talked about them before, but they’ve been mostly used in the past against cancer cells. In fact they’re finding uses in many medical fields but they’re tricky to manufacture, and would be expensive to roll out…

Canto: Actually I’ve heard some reports that it’s polyclonal antibodies they’re giving him. Is there a difference? I thought maybe because they were giving him a ‘cocktail’ of monoclonal antibodies, this amounted to polyclonal…?

Jacinta: Well, who knows what they’re actually giving him, but according to my reading, researchers have engineered (cloned) immune cells that produce specific antibodies – antibodies to a specific antigen, or more accurately, to the epitope, or binding site, of that antigen. That’s monoclonal antibodies. Polyclonal antibodies can bind to multiple epitopes, which sounds better but maybe they’re harder to manufacture in an effective form. 

Canto: So these monoclonal or polyclonal antibodies are proteins, synthesised versions of proteins produced by the immune system. Is it that, due to the virus, the body is prevented from producing these antibody proteins naturally, or can’t produce enough of them, or what? 

Jacinta: What I gather is that the response to the virus varies – some are producing antibodies, some aren’t. A report came out last week about Regeneron’s treatment, this ‘cocktail of two monoclonal antibodies’:

The company showed slides with detailed data from 275 infected people in a placebo-controlled trial that ultimately plans to enrol 2100 individuals who are asymptomatic or, at worst, moderately ill. The analysis divides patients into two groups: those who had detectable antibodies against SARS-CoV-2 at the trial’s start and those who did not, a so-called seronegative group. The monoclonal cocktail showed little effect on people who already had antibodies against the virus. But it appeared to help the seronegative patients, powerfully reducing the amount of virus found in nasopharyngeal swabs and alleviating symptoms more quickly. 

So it appears to boost the immune system of those who haven’t, or haven’t yet produced antibodies to the virus. So, useful for those in the earliest phase of having contracted covid19. But all of this has to be more thoroughly tested – for example, would the treatment work as a general preventive? 

Canto: There’s another company, Eli Lilly, which has been trialling a single monoclonal antibody treatment, with slightly different results – both companies have given low-dose and high-dose treatments, and Regeneron found no statistically significant difference, whereas Lilly found the high dose ineffective – which is good news as the lower dose will presumably be cheaper to manufacture, with fewer adverse effects, if any. The two companies have a slightly different approach to using their medications – though this might change in such a fluid situation. Regeneron is thinking of developing diagnostic tools to identify those most in need of the treatment, e.g those with the highest viral load, and those with low antibody levels (serology). Lily, on the other hand, are thinking that any covid19-positive people at higher risk – diabetics, overweight, or simply elderly – should be given the treatment, if possible. 

Jacinta: In the meantime, the dangers of this virus are constantly being underplayed by this administration under pressure, clearly, from the Boy-King, while a large cluster of people who’ve had contact with him, either at the White House or on any of his jaunts around the country. Exactly who set off the cluster will probably never be known, because it sounds like they’re refusing, again under the orders of a clearly incompetent wee boy, to engage in contact tracing!

Canto: It’s a SNAFU to be sure. Apparently one of this number – 34 at last count –  is gravely ill in hospital. It’s like we’re watching an episode of ‘Horrible Histories’ in real time. It’s good to see that the polls are predicting a landslide. That means if the actual numbers come in and it’s close, it may be to do with the dirty business Trump and the Republican ‘leadership’ appear to be trying on vis-à-vis voter suppression. And then all hell will break loose.

Jacinta: Hell will break loose no matter what happens. This next month or two will be a cracker for us non-Americans. We’re certainly living in interesting times. But seriously, my condolences to the American people. 

References

https://www.sciencemag.org/news/2020/09/provocative-results-boost-hopes-antibody-treatment-covid-19

https://www.worldometers.info/coronavirus/country/us/

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

Coronavirus Pandemic Update 77: Remdesivir Update; COVID-19 in Mexico

Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released from UK

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

Written by stewart henderson

October 8, 2020 at 11:55 pm

covid19: ivermectin, the Moderna vaccine, vitamin D

leave a comment »

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Canto: The question of re-infection.

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

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

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

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

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

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

References

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

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

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

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

Written by stewart henderson

September 14, 2020 at 12:21 pm