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Posts Tagged ‘inflammation

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

My current health condition 1: it’s bizarre

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I can bear any pain as long as it has meaning

Haruki Murakami

stuff to learn about

I haven’t written for a while because I have a new health problem which flared up last Saturday, February 29, 2020. I had been feeling mild pain in my shoulder and I was lying on my bed reading when I tried to get up. Shooting pain from my shoulder down my left arm was so excruciating that I fell back on the bed and and lay down for a while before trying to get up again. Again I couldn’t get up because of the pain. I called for help but even with two of us it was difficult. I may have had a panic attack and exaggerated the pain of rising – I was gasping a lot. To cut a long story short Sarah called an ambulance (and the paramedic got me into a sitting position easily enough). I spent the next few hours in emergency at the Royal Adelaide Hospital.

Due to being given Panadol in the ambulance, and a long wait in reception while the painkiller took effect, by the time the friendly, efficient and strikingly beautiful (oh dear) young intern saw me, the pain, my only symptom, had much reduced. She found that, yes, I could move my arm above my shoulder, flex my elbow and my wrist, and no, I couldn’t precisely describe the nature or location of the pain. She checked my arm for swelling or redness (none), and asked about any recent history of injury to the region (none). I was beginning to feel like a fraud, a malingerer, a milquetoast.

So after some more prodding and questioning and advice from higher authorities, I was released with a report for my local doctor.

I’m very left-handed, so this left arm pain is quite a problem for me. I was due to work on the Monday and I needed some pain relief. It would have to be over the counter at first. The report’s only solid conclusion was ‘skeletal-muscular pain’. Since I needed to work on Monday and Tuesday I could only get to the GP on Wednesday. So on Sunday I started doing what research I could. I’ve never taken regular medication for anything, and I’ve never experienced regular pain like this. The only over-the-counter treatments for pain are ibuprofen and paracetamol as far as I know. Only ibuprofens is an anti-inflammatory. Paracetamol works on pain centres in the brain. Which one would work best? Was it all in my mind? But don’t we always feel pain via the brain? Isn’t that how the nervous system works?

I obtained both medicines. Over the next day or so I experimented with both, singly and in combination, and I got through Monday and Tuesday’s work. The pain never went completely away, though the teaching days, when I had to concentrate on and interact with my students and other teachers, helped to distract me from it, which gave me that guilty ‘it’s all in the mind’ feeling.

Even so, on Wednesday (March 4), the pain came roaring back. My subjective sense told me that the paracetamol was much more effective than the ibuprofen, another surprise. I visited my GP, who smiled at the hospital report, saying, ‘yes, they wanted you out of there as soon as possible – they’re there for acute, intensive care stuff, it’s understandable – a GP can refer you to a specialist, and we can go from there’. So he filled out a referral form for St Andrews Hospital, for an x-ray and an ultrascan. I rang them and organised an appointment, for Friday, March 6 at 11am.

I was still in pain, though. The OTC medication had reduced the pain to more bearable levels, but I still hadn’t worked out which worked best. Unlike me, Sarah was on many medications, for pain and other problems, including Prodeine (paracetamol plus codeine) and a set of tablets which combined paracetamol and caffeine. I was taking the tabs at the upper level of what was recommended, and beyond. I was trying to monitor the pain, what it felt like. It was always a low-level throbbing, which increased and became a shooting pain if I used the arm too much. It was a strange delayed pain – I would engage in a flurry of physical activity, such as preparing a quick meal, and then lie down, knowing that the pain would rise up as a result of the activity, then slowly subside. I had difficulty sleeping, and I dreaded dressing myself in the morning. Typing this is giving me an ache, and I’m experimenting with dictation – I find the Apple dictation system a pain (mentally speaking). I have to learn more about how to use it effectively.

Stupidly, I hadn’t asked my GP about stronger prescription medication. The day after the consult (Thursday, March 5) I had Sarah ring the surgery – I was experiencing bouts of serious pain, and was finding it hard to track what medication was working, or not. The doctor wrote a prescription, which Sarah collected and had made out at the pharmacy around the corner. It was for ibuprofen (200mg) and codeine phosphate hemihydrate (12.8mg). I was skeptical about the efficacy of ibuprofen, and I had been researching anti-inflammatories, and inflammation generally.

What, exactly, is inflammation? There are, supposedly, five signs of it, remembered under the acronym PRISH – pain, redness, immobility, swelling and heat. My only symptom was pain. There was certainly no redness or swelling. Immobility wasn’t a real problem either. I could move my arm above the shoulder, I could flex my elbow, etc, but some pain would come afterwards. Heat wasn’t something I could measure, but it didn’t seem an issue. Only pain. And I hadn’t pinpointed any cause of all this. I remembered what I’d said, quite often (or at least I thought I did – maybe I was mostly saying it to myself) to the intern at emergency: ‘It’s bizarre!’

Anyway, I’ll wind up this piece, and start on a new one, dealing with my time at St Andrews Hospital, the x-ray and the ultrasound.

Written by stewart henderson

March 8, 2020 at 12:43 pm