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

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keeping it simple, for now

 

Jacinta: Let’s look at monoclonal antibodies briefly before we continue with those medcram updates. Francis Collins, the somewhat controversial but scientifically reliable directer of the NIH in the USA, recently described ‘monoclonals derived from people who’ve survived covid19’ as the best hope for treatment in the absence of a vaccine. So what are these monoclonals? There are lots of useful videos on youtube that provide detail. I’m picking one from the JAMA network. The technology for producing these types of antibodies was developed in the mid-seventies. It was called ‘murine hybridoma’ technology, murine meaning ‘mice’. I remember first reading about monoclonal antibodies in a Scientific American article in the early eighties. It went straight over my head of course, but now it’s time to get a grip on them. So mice were injected with an antigen, which in general terms is a pathogen that induces an immune response. In more specific terms an antigen is a molecule or structure, part of a larger pathogenic molecule, that can be bound to by an ‘antigen-specific antibody’ or B cell receptor. B cells are lymphocytes that secrete antibodies. So the researchers induced this response, then isolated B cells from the spleen of the mice, which they fused with myelomas (cancerous plasma cells). Cancer cells are notoriously long-lived – see ‘the Immortal Life of Henrietta Lacks’ – so these fused cells, called ‘hybridomas’, act like B cells in producing antibodies, and like tumour cells in their ability to replicate. So these hybridomas can be grown in culture and each one can produce a single antibody type, which targets a single antigen type. Hence monoclonal. They can clone themselves for a specific antigen. So, once you know your antigen, you can create a ‘monoclonal’ specifically for it, or two or three to choose from. And now, with covid19 and with technological development, we can isolate monoclonal antibodies not from mice but from recovered covid19 patients. So that’s a somewhat over-simplified account – for more detailed info on monoclonal antibodies, this zero to finals video is excellent, and there are doubtless others. The target for this work is generally the S-protein of the SARS-CoV2 virus, with various particular sites being looked at, and a number of teams working on the research. Some are pretty well ready to go, with specific antibodies or sets of antibodies. The argument is that they could be used for high-risk groups such as ICU workers and nursing home clients, as a kind of temporary vaccine. 

Canto: Okay, something else to keep track of. So update 93 discusses an article published in Nature Medicine – all the authors appear to be Chinese – which looks at 37 asymptomatic covid19-infected subjects and their antibodies, compared to those of 37 symptomatic subjects. 

Jacinta: So they looked at their immunoglubulin G (IgG) levels. These are the most common types of antibody, created and released by plasma B cells. They graphed the IgG during the acute and convalescent phases, and they defined the acute phase as that in which the viral RNA was detectable in a respiratory specimen, and the convalescent phase as from eight weeks post-release from hospital. What the graph shows is that the IgG levels decreased from acute to convalescent in both symptomatic and asymptomatic cases, but more in the symptomatic cases. They also looked at ‘neutralisation rates’, which presumably refers to the effect of antibody activity. A positive effect means more neutralising antibodies are produced. These seemed about the same between the phases for both groups, but another graphic shows that in the convalescent phase, the symptomatic group have substantially more neutralising antibodies. It seems from this admittedly small study that asymptomatic subjects are at risk of reinfection, after a period of time.

Canto: And even symptomatic subjects after recovery, as we have obviously no longitudinal studies on anti-viral IgG levels, as the study points out. 

Jacinta: Well that takes us to the next study, from Spain, which managed to round up almost 52000 participants. The study tells us between late April and mid-May the estimated seroprevalence (the percentage of inhabitants that had the virus) for the whole country was around 5%, depending on different test types and results, and with great variation between regions. Findings were that prevalence increased with increasing age. Looking at different jobs, those working in healthcare were clearly more at risk, and to a lesser but still significant degree, those working in nursing homes…

Canto: Which is still largely healthcare, but less trained, and often less prepared for this onslaught…

Jacinta: Point taken. And those living in the larger municipalities were more often infected than those in less densely populated regions. Interestingly, they found that the rapid (and cheap) fingerpoint test, which provides results within ten minutes, was pretty close to being as effective as an immunological assay, which is important as the delay in test results has been a major issue.

Canto: Amazing. Why aren’t they using this all the time? Everywhere?

Jacinta: That’s another issue – maybe later. Anyway, much of this study confirms the many smaller studies that have been conducted. They found that healthcare workers comprised 24% of all confirmed cases. This may be partly because they had more access to testing. There is so much to glean from this study, I can only skim. But here are some very interesting remarks in their conclusion:

One in three infections seems to be asymptomatic, while a substantial number of symptomatic cases remained untested. Despite the high impact of covid19 in Spain, prevalence estimates remain low, and are clearly insufficient to provide herd immunity. This cannot be achieved without accepting the collateral damage of many deaths in the susceptible population and overburdening of health systems. In this situation, social distance methods and efforts to identify and isolate new cases are imperative for future epidemic control.

Canto: So there are no easy solutions, and even a vaccine is not necessarily going to be the magic bullet everyone’s hoping for. The proof of the pudding will be in the eating, and we haven’t eaten any vaccines yet. They won’t be on the menu for a while, and it’ll be a lot longer before we can gauge their nutritional value.

Jacinta: Yes, what you’re saying is, we don’t know how long antibodies to this virus will last. We’re still in unexplored terrain with respect to this very unusual and deadly virus. An article published on the Jama Network quite a while ago is still relevant now in its conclusions, as nothing we’ve so far found disconfirms it: 

… the immune response to covid19 is not yet fully understood and definitive data on post-infection immunity are lacking. Amidst the uncertainty of this public health crisis, thoughtful and rigorous science will be essential to inform public health policy, planning and practice. 

Canto: Frustrating to many. So with update 94 we’re getting towards mid-July and they’re noting that things are hotting up, as the weather is cooling down, in Australia, though of course it bears no comparison to the US tragedy. They were talking about things getting worse in their autumn, but summer hasn’t given them any sort of break. 

Jacinta: So update 94 first looks at inhaled corticosteroids, one of many medications being considered and perhaps used by health professionals, others being ivermectin (a broad-spectrum anti-parasitic drug) and nitric oxide, all without solid RCT-type evidence. Even so, case reports and other low-level studies show promise, and these are arguably desperate times. A study presented by Dr Seheult suggested that some corticosteroids showed positive immunological effects in case reports and in vitro. Interestingly, asthmatics have been prescribed corticosteroids quite regularly…

Canto: As have I, from time to time. At least I think it was corticosteroid…

Jacinta: Well, that’s interesting, I know you’re not asthmatic but with bronchiectasis you have asthma-like symptoms at times. And the good news for you, and generally interesting news for us all, is that ‘asthma patients with covid19 do not appear to have a higher rate of hospitalisation or mortality compared with other covid19 patients’. Indeed it may be the opposite, as data from Wuhan indicates that less than 1% of their hospitalised patients had asthma, compared to 5% in the general population. In New York, too, asthma wasn’t even in the top ten comorbidities, which is pretty striking for a virus that hits the lungs first. Similarly, COPD, which your ailment is surely associated with, comes in below diabetes, renal disease and a whole range of cardiovascular issues as a comorbidity factor. A possible reason for this is that the kind of chronic inflammation produced by asthma and COPD is associated with reduced ACE2 expression, meaning fewer receptors for the virus. So these conditions could actually be protective. And they might also be on corticosteroid inhalers, which may also be protective.

Canto: That sounds great. Let’s leave it there before I hear any bad news…

References

Coronavirus Pandemic Update 93: Antibodies, Immunity, & Prevalence of COVID-19 – New Data from Spain

Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?

How do monoclonal antibodies work? Rituximab, infliximab, adalimumab and others

Coronavirus Treatment and Prevention with Monoclonal Antibodies

 

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

bronchiectasis once more – resistance, viruses, treatment

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Having fallen ill again, for the first time really in a few years, with debilitating dry coughing, breathing problems and fatigue, and having had no great relief from a first course of broad-spectrum antibiotics, I think it’s a good time to review the condition I suffer from – bronchiectasis.

I’ve tried to put it in the back of mind and have been mostly successful, except now and then to marvel that it hasn’t come roaring back for a year, then two years, then three years. Still, I’ve never quite gotten rid of a niggling cough, and every time I have a sneezing fit my mind turns, however briefly to what might finally await me…

Bronchiectasis literally means ‘widened or widening airways’. The airways leading to the lungs have become permanently distended and develop ‘cul de sacs’ in which bacteria gather as in a stagnant backwater. The increased bacterial load means that those with the condition are easier prey for bacterial and viral pathogens. The causes of this condition are various, including genetic conditions such as cystic fibrosis, or a general immunodeficiency. In my case it was most likely an early childhood infection, the cause in about a third of all adult cases. The sad thing is that with each new flare-up the damage to the airways is increased, the condition worsens, and there’s no cure, but it can be contained through specific exercises designed to clear the airways, postural drainage and other techniques. Above all (he adonishes himself) always get regular flu and pneumococcal jabs. I was diagnosed with this condition about four and a half years ago, but I think I’ve been suffering from it for much longer. Like many stupid men I’ve tended not to go to the doctor till I’m at death’s door. I’ve improved a little in that area in recent years, but not enough.

The recent flare-up has been traced to a relatively common virus, called respiratory syncytial virus (RSV). My doctor sent me for a virology swab after my second visit. On my first visit I presented with my severe cough, and I explained my bronchiectasis, which he knew something about as I’d had my records transferred to him from a previous establishment. Although I expressed concern about antibiotics, having experienced what I presumed to be resistance to erythromycin previously, I was prescribed a broad-spectrum antibiotic called roxithromycin GH. Desperately wanting to get rid of this debilitating and spirit-weakening cough, I got the set of ten tablets – a five-day dose – together with a repeat dosage. I’m currently two tablets away from finishing the repeat. It was also recommended that I get a bottle of Bisolvon®, which ‘thins, loosens, clears mucus from the chest’ and ‘helps clear stubborn chest congestion’.

This first consultation was on a Friday. I was contracted for a two-day work week at Eynesbury College starting the following Thursday, and I really wanted to be fit by then. However, by Monday-Tuesday I was worried. The antibiotics, I felt, had been initially successful but then my condition seemed to deteriorate. On Wednesday I had my second consultation. I explained my amateur theory that the antibiotics had an immediate impact, but then the resistant strain of the bacteria continued to multiply, took over the territory of the non-resistants, and the illness came sweeping back. Classic evolution, in a sense: from random variation the environment of my body selects the stronger, resistant strain. The doctor agreed, or said he did, but pointed out that the problem was that my infection was probably viral rather than bacterial. In my enthusiasm for my own cleverness I hadn’t thought of this. And this probably explained the ineffectiveness of the erithromycin in the past. Maybe I’m not resistant at all.

So I was sent to the nearest Clinical Labs testing centre for a swab. I was also advised to continue with the antibiotics. The swab is applied by means of a long needle-like instrument wrapped in something like cotton wool at one end. This material is soaked in a virus-detecting solution and inserted fairly deeply into the nasal cavity. I visited the testing centre more or less immediately after the consultation, and received word the next day that the results were out. On Friday, I think, I attended my third consultation and was given the read-out. Ten viruses tested for were presented, including influenza A and B, and types 1 to 4 paraainfluenza, all undetected. The other undetected viruses were adenovirus, rhinovirus and metapneumovirus. RSV, an RNA virus (as are most viruses), was the only one detected.

So, progress has been made, and I was prescribed one more medication, a Turbuhaler® called Symbicort®, often used for symptomatic treatment of asthma. Instructions are to inhale two doses a day of the oral powder, which consists of budesonide and eformoterol fumarate dihydrate. There are 120 doses in my inhaler.

Budesonide is a corticosteroid, commonly used in this inhaled form for long-term treatment or management of asthma and COPD. It’s been around for a while, having been patented in 1973, and in commercial use as an asthma medication since 1981. It’s also on the WHO list of essential medicines. According to Wikipedia, ‘common side effects with the inhaled form include respiratory infections, cough, and headaches’, and at the moment I have a headache, and have suffered from severe coughing fits.  I’m also producing quite a lot of mostly clear mucus, through the nose. I’ve attributed these symptoms to the virus, not the medication, but who knows?

Eformoterol is a more recent addition to the arsenal of anti-asthma type medications. This 1997 article in Australian Prescriber describes it as ‘a long-acting beta2 adrenoceptor agonist’ – a type of beta-blocker. Here’s some further interesting info from this site:

After inhalation of eformoterol powder, bronchodilatation begins within 3 minutes. This effect lasts for 12 hours with a peak effect within two hours of inhalation. These properties make eformoterol suitable for twice daily inhalation in patients who require regular, long-term treatment of reversible airways obstruction. It is not recommended for use in acute asthma. Patients should have a short-acting agonist, such as salbutamol, available to help deal with acute attacks.

Unfortunately my airways problems aren’t reversible, though particular obstructions and their causes may be treated effectively.

So what I have in my little Turbuhaler is a combo of a corticosteroid and a long-acting betaagonist (i.e. a bronchodilator). According to Wikipedia ‘combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread’.

It doesn’t seem as if there’s much I can do but wait for my condition to slowly improve. It’s been nine days since my first consultation, and I’ll be revisiting my doctor in a day or two. Mucus still flows freely and the distinctive, whistling wheeze I developed about a week ago is still present (I’ve never experienced this before). Physical exertion quickly makes me exhausted, but I’m hoping I can soon be sufficiently recovered to consider specific exercises to improve my condition and support me against further setbacks. Don’t want to end up slowly drowning in my own phlegm.

Written by stewart henderson

July 30, 2018 at 3:13 pm