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

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from The Lancet, ‘the four horsemen of a viral apocalpse’

 

Canto: So short-course use of some steroids was being advocated in the medcram update 88, though without thorough RCT evidence. 

Jacinta: Well, data was presented from the Oxford RCT on those on oxygen or on ventilators showing a statistically significant reduction of mortality from short-course (up to 10 days) low dosage of dexamethasone, a freely-available steroid medication. The study involved some 2000 patients, but only those severely afflicted were helped by the medication. 

Canto: An interesting aside to the data is that in the study males outnumbered females by almost 2 to 1, and that accords with the overall ratio of male to female covid19 patients Dr Seheult is finding, which rather shocked me. Why would more males be coming down with the disease? Presumably that’s not the infection rate, but the rate at which they need to be hospitalised. 

Jacinta: Yes, you’re right, according to this Australian site (unfortunately undated):

Reports continue to emerge that men are significantly more vulnerable to COVID-19 than women. The commonly held perception that more men smoke and this makes them more susceptible along with other lifestyle factors does not tell the whole picture. White House COVID-19 Task Force director Dr Deborah Birx highlighted a “concerning trend” that men in all age brackets were becoming seriously ill from the virus at a higher rate than women, including younger males.

They’re suggesting more research needs to be done on this gender difference, for health issues in general. Some are claiming that estrogen makes a difference. In any case I think cardiovascular problems are more common in males – but maybe not so much in younger males. 

Canto: So update 89 is fairly short, and deals with US data about cases and deaths, most of it out of date now, and more on corticosteroids and the dangers of unsupervised use. Update 90 introduces us to a tool I’ve never heard of called ‘Discern’. Very useful for we autodidacts in helping us, for example, to enlighten our doctors as to our condition. Discern is a tool for evaluating internet health info, such as medcram’s updates on youtube, or anything else on youtube. The instrument asks you to evaluate the material according to 16 different criteria. Interestingly, this tool has been tested on covid19 material by a study out of Poland done in March. The results weren’t so good, especially for news channels. 

Jacinta: Yes, physicians’ information did best – but of course we don’t go to news channels for health information, and we’d advise against anyone else doing so. The study evaluated the Discern tool itself and found it excellent, then used the tool to evaluate health information, specifically on youtube. Of course know that there’s ‘viral misinformation’ from various news outlets that gets posted on youtube. And good to see that the medcram updates were some of the most highly rated using the Discern tool. 

Canto: So we’re now into reporting from early July with update 91. It starts by looking at a ‘covid risk calculator’ in which you can type in your age, gender, BMI, underlying conditions, waist circumference, and other data which you might need a full medical checkup to find out about (and that’s overdue for me), including, for example, %FMD, a measure I’ve never heard of, but which has to do with endothelial function. 

Jacinta: FMD stands for fibromuscular dysplasia. The Johns Hopkins medicine site describes it as a rare blood vessel disease in which the cells of some arteries become more stiff and fibrous and less flexible. This leads to weakness and damage. Not sure how it relates to covid19 but surely any pre-existing blood vessel damage is a danger for those contracting the virus. 

Canto: Right, so it’s unlikely anyone will know offhand their percentage of FMD. I don’t even know my HDL and LDL levels, never mind my HbA1c or lipids. I’d love to be able to take measures of all these myself, without visiting a doctor.

Jacinta: Typical male control freak. So all of this is to measure your risk of covid19 hospitalisation, ICU admission or mortality. Fun times. So next the update looks at Gilead, the makers of the antiviral remdesivir, who donated all their supplies of the drug to the USA in early May. But of course they kept manufacturing the drug and have to recoup the money they spent researching, developing and trialling it etc. The Wall Street Journal reports that a typical course of the drug will cost over $3000 per patient. Interestingly the Trump administration is wanting the drug to stay in the USA as much as possible, rather than be available overseas, and is spending money to that effect. 

Canto: Hmm. Is that protectionism? 

Jacinta: Yes I suppose. It’s not surprising that a country wants to look after its own first, especially via a product produced within its own borders. But I suspect this government would’t be interested in helping any other country – unless there was a quid pro quo. And there’s another antiviral, favipiravir, currently being trialled in Japan and the USA (I mean as of early July), and a vaccine, developed in China, is being used on the Chinese military in what seems a rather rushed and somewhat secretive fashion – we don’t know if they got the soldiers’ permission on this seemingly untried vaccine. At least at the phase 3 level.

Canto: Very CCP. 

Jacinta: So onto update 92, and we revisit the electron transport chain, with four successive electron transfers converting molecular oxygen into water. Problems within this chain can produce reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxy radicals, which are destructive in excess. We also look, yet again, at covid19’s impact on angiotensin and particularly the production of superoxide, which in turn causes endothelial dysfunction, increased von Willebrand factor activity, which leads to thrombosis. People were presenting as ‘happy hypoxics’, looking and feeling fine but with very low oxygen levels, and autopsies revealed ‘microthrombi in the interalveolar septa’ of victims’ lungs. All this leading to a paper published in The Lancet which looked at factors in this process of coagulation and thrombosis:

We assessed markers of endothelial cell and platelet activation, including VWF antigen, soluble thrombomodulin [a marker of endothelial cell activation], soluble P-selectin [a marker of endothelial cell and platelet activation], and soluble CD40 ligand [a marker of platelet and T-cell activation], as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.

So this was about getting to the bottom of the increased clotting. And the results were hardly surprising, but the final discussion section is worth quoting at length, as it seems to capture much that we know about covid19’s effects (at least short-term effects) at the moment: 

We therefore propose that COVID-19-associated coagulopathy is an endotheliopathy that results in augmented VWF release, platelet activation, and hypercoagulability, leading to the clinical prothrombotic manifestations of COVID-19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis. The factors responsible for this endotheliopathy and platelet activation are uncertain but could include direct viral infection of endothelial cells, collateral damage to the tissue as a result of immune infiltration and activation, complement activation, or any number of inflammatory cytokines believed to play a role in COVID-19 disease.

They suggest anti-platelet therapy and endothelial cell modification treatments as well as anticoagulation treatments, and they suggest some agents ‘which might have therapeutic potential’.

Canto: Potential? You’d think they’d be onto all this by now. 

Jacinta: Well there’s also potential for untried medications – at least untried in this context – to go terribly wrong. And it’s also likely that some hospitals are already onto using the safer forms of treatment. Dr Seheult speaks of the antioxidant N-acetylcysteine (NAC) in this context, as it has been shown to be a thrombolytic when used intravenously. There are studies pending on the effects of NAC in treating covid19 patients. 

Canto: Now, I’ve just been watching something on monoclonal antibodies as perhaps the most promising treatment yet, short of a vaccine. Can you explain….

Jacinta: Yes I’ll try, maybe next time.

References

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

Coronavirus Pandemic Update 89: COVID 19 Infections Rising in Many States; Dexamethasone Cautions

Coronavirus Pandemic Update 90: Assess The Quality of COVID-19 Info With A Validated Research Tool

Coronavirus Pandemic Update 91: Remdesivir Pricing & Disparities in Drug Availability

Coronavirus Pandemic Update 92: Blood Clots & COVID-19 – New Research & Potential Role of NAC

amhf.org.au/covid_19

http://www.discern.org.uk

https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext

 

Covid 19: corticosteroids, inflammatory markers, comorbidities

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Canto’s bronchiectasis – a relatively mild case, thank dog

 

Canto: So update 87, in late June, reflects a period when daily cases were just starting to rise, but deaths were apparently reducing – and various reasons were being given for this.

Jacinta: And interesting to note all the skepticism around Oxford University’s dexamethasone trial, which has led (the trial, not the skepticism) to a huge demand for the steroid. Dr Paul Sax of Harvard Medical School has expressed some dismay at the negativity, as this was a randomised controlled trial (RTC) of a widely available drug by a highly reputable, government-funded institution. 

Canto: Yet it seems that the website on this trial has since been taken down, so maybe there are some issues…

Jacinta: Okay, so let’s move on. Dr Seheult talks about raised ‘inflammatory markers’ in patients he observes coming in with covid-19. He names them, and I want to do a shallow dive into what they are and what they mean: Ferritin, C-reactive protein (CRP), CPK (to do with muscle breakdown), erithrocyte sedimentation rate (ESR), and d-dimer levels. So, ferritin is an iron-containing protein. It stores the iron and releases it when needed. Ferritin is mostly concentrated in the liver cells (hepatocytes) and in the reticuloendothelial cells of the immune system. That endothelial word again. As for CRP, this abstract from a 2018 paper Frontiers in Immunology tells me that ‘C-reactive protein (CRP) is an acute inflammatory protein that increases up to 1,000-fold at sites of infection or inflammation….CRP is synthesized primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes’. Need I say/quote more? And on CPK, this from the Johns Hopkins Lupus Center: 

Creatine phosphokinase (a.k.a., creatine kinase, CPK, or CK) is an enzyme (a protein that helps to elicit chemical changes in your body) found in your heart, brain, and skeletal muscles. When muscle tissue is damaged, CPK leaks into your blood. Therefore, high levels of CPK usually indicate some sort of stress or injury to your heart or other muscles.

And the US website medicineplus.gov has this to say on ESR:

An erythrocyte sedimentation rate (ESR) is a type of blood test that measures how quickly erythrocytes (red blood cells) settle at the bottom of a test tube that contains a blood sample. Normally, red blood cells settle relatively slowly. A faster-than-normal rate may indicate inflammation in the body. 

So, a fast ESR is an inflammation marker. High levels of CPK in the blood are too, presumably, as are high levels of CRP, wherever. And ferritin. Lastly, d-dimer levels, which are also related to clotting. This Australian site, healthdirect, tells me that ‘D-dimer is a type of protein your body produces to break down the blood clot’. So, a d-dimer test is ‘a blood test usually used to help check for or monitor blood clotting problems. A positive test means the D-dimer level in your body is higher than normal and suggests you might have blood clots’.

Canto: With all that let’s continue with the update. In Seheult’s hospital they started using dexamethasone as soon as the Oxford results came out and they’ve seen a reduction in all these rising inflammation markers. He recognises issues here though. Is this just anecdotal? Is this just a drop in the markers without real-life effects? Could it be recall bias? We know how conveniently inaccurate memory can be. 

Jacinta: My impression is that’s not going so well, though there’s no doubt still a varied use of dexamethasone and other corticosteroids throughout the USA. We’re at the point with the updates where they’re still thinking deaths in particular are reducing. We now know better. So the update next looks at a Chinese study from mid-June entitled ‘clinical and immunological assessment of asymptomatic SARS-CoV2 infections’. This small study looked at 37 asymptomatic patients and found that viral shedding (the release of virus from an infected person into the environment – the period of contagiousness) was 19 days, presumably on average. This compared with 14 days for symptomatics. A pretty significant finding. Immunoglobulin G (IgG) levels – essentially antibodies – were about six times higher in the symptomatic cases. That seems unsurprising I think, because it’s the antibodies that largely create the symptoms – the inflammation and clotting, the cytokine storm. Another finding was that, eight weeks after being discharged from hospital, the asymptomatic cases were 40% seronegative (having no antibodies) against SARS-CoV2, compared to 12.9% for the symptomatic cases. This suggests that neutralising antibodies may be ‘disappearing’ over time, though other immune cells, such as T cells may have a mitigating effect. Overall, though, the study advises extreme caution:

Together, these data might indicate the risks of using covid19 ‘immunity passports’ and support the prolongation of public health interventions, including social distancing, hygiene, isolation of high-risk groups and widespread testing.

Canto: Not suggestions the current Trump administration would be likely to pay attention to. 

Jacinta: Well the question here is one of re-infection, and I don’t know if there are any clear answers to that. Anyway update 87 goes on to look again briefly at vitamin D, and research in the UK, where vitamin D deficiency is more of a problem, and is associated with viral chest infections and with covid19 outcomes, with people of colour being disproportionately affected. They’re looking to people to sign up with a study called ‘covidence UK’. Dr Seheult also looks at a ‘Research Letter’ from the JAMA network entitled ‘prone positioning in awake, non-intubated patients with covid19 hypoxemic respiratory failure’. Prone positioning – lying on your tummy – was highlighted in one of the earliest of these covid19 updates as improving the symptoms of patients with ARDS. The findings from this JAMA are instructive:

In this small, single-centre cohort study, we found that the use of the prone position for awake, spontaneously breathing patients with covid19 severe hypoxemic respiratory failure was associated with improved oxygenation. In addition, patients with an SPo2 [pulse oximetry, a measure of blood oxygen level] of 95% or greater after one hour of the prone position was associated with a greater rate of intubation.

So, though there’s a need for RCTs etc etc, Dr Seheult has found dramatic improvements in oxygenation in his own patients through prone positioning.

Canto: Who are we to argue? And this update 87 ends on a positive note due to these combined findings about treatment. Prone positioning, remdesivir, dexamethasone, vitamins D and C, zinc, and maybe convalescent plasma, which needs to be explored further..

Jacinta: That’s blood plasma from recovered covid19 patients, with of course the antibodies to go with it, and I’ve looked at the National Covid19 Convalescent Plasma Project website to see if there are recent studies on this, but there’s nothing since March – small studies from China, which seem promising.

Canto: Update 88 starts again with dexamethasone, the cheap and widely available steroid, which – and this is back in late June – the British government got behind after the Oxford study was published, authorising its use ‘for patients hospitalised with covid19 who required oxygen, including those on ventilators’. It’s interesting that clinical views have changed on corticosteroids for covid19 over time, and there are still concerns about dosage and time periods on the drugs. 

Jacinta: Yes, short courses of corticosteroid treatment seem to be recommended, and not just dexamethasone. And many studies showed this before the release of the Oxford data. 

Canto: So the Oxford data itself is fascinating, especially for comorbidities or previous conditions. Especially interesting to me as I have such a condition, one that fits under their heading ‘chronic lung disease’, in my case bronchiectasis. They’re finding that people with such conditions are ending up on ventilators far less than those with diabetes or heart disease. So that’s good news for me. The disease, as they’ve been finding, is that covid19 is essentially an inflammatory disease of the vascular system. However, it seems that Dr Seheult’s hopes, at the end of update 88, that the greater introduction of short-term corticosteroids, and the use of other medications that might be efficacious, would reduce the mortality rate, have been dashed. We’ll be interested to find out why in upcoming posts.   

References

Coronavirus Pandemic Update 87: More on Dexamethasone; Do COVID-19 antibodies last?

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908901/

https://medlineplus.gov/lab-tests/erythrocyte-sedimentation-rate-esr/#:~:text=An%20erythrocyte%20sedimentation%20rate%20(ESR)%20is%20a%20type%20of%20blood,indicate%20inflammation%20in%20the%20body.

https://www.healthdirect.gov.au/d-dimer-test

https://ccpp19.org/

Written by stewart henderson

August 22, 2020 at 10:57 pm