The Wry Observer’s Covid-19 update (193)

Yesterday’s “The Times” carried a long piece by Tom Whipple and Rhys Blakely titled “Lessons from the front line of our war on Covid-19”, comprising interviews with “scientists” -structured format, the same questions for each. The experts were Dame Sarah Gilbert (BSc, PhD), Dame Kate Bingham (MA, MBA), Sir Jeremy Farrar (BSc, MPhil, FRCP, FRS, FMedSci), Sir John Bell (BMedSci, BMBChir, FMedSci, FREng) and Professor Devi Sridhar (BS, MPhil, DPhil).

Have you noticed anything?

Of the five, only two have medical degrees. Those two (Farrar and Bell) specialise in infectious diseases, and immunology/genetics respectively. The other three are not doctors.

So to suggest that their contributions come from the front line is nonsense. The front line is where the hospital beds are. While they are all noteworthy (and worthy) brilliant people to say they are on the front line is akin to saying that the experience of the First World War is entirely derived from Army HQ in Montreuil-sur-Mer and the War Office in London.

The questions were:

1. What do you wish you had known in January 2020?
2. What has been the lowest point?
3. What has been the highest point?
4. What do the public still not understand that you wish they would?
5. What do we still not understand that you wish we did?

Sarah Gilbert highlighted teamwork in producing the vaccine, with her low point being the discovery of extremely rare serious adverse events from vaccination. Kate Bingham wished she had known more about asymptomatic transmission. Her low point was a moral one – that we were buying vaccines from India when the UK was relatively well-protected, but many countries had not begun vaccinating. She indicated we still needed better fundamental science understanding. Jermey Farrar said of January 2020 that “We knew everything we needed to know…”. His low point was the failure to introduce interventions to slow down and reduce the wave of infections in Q4 of 2020. He reckoned we underestimate our vulnerability to shared global threats. John Bell wished we had known how rapidly vaccines would appear, because it would have “been easier to get through the first year”. His low was in April 2020 when the NHS was under pressure; people were dying and there was no end in sight. His comment on what is still not understood is reproduced here in full:

“This is a disease of two types, severe disease associated with inflammatory pneumonia that is often fatal, and less-severe, flu-like disease or asymptomatic disease. It is increasingly clear that the vaccines after two (or three) doses have a remarkable impact on the incidence of the most severe disease, including pneumonias that cause the majority of deaths from Covid. Since the summer the vast majority of people dying have been unvaccinated or immunosuppressed and these accordingly account for the vast majority of people in the ICU. That has not always been made clear in the data and the immunological basis for this protection is not at all clear. What none of the vaccines do very well is to stop the transmission of the virus and this is exacerbated by the diversity of the variants. Until a transmission-blocking vaccine arrives, we will continue to have low-grade disease, sometimes like influenza, but largely benign, and fully vaccinated people will therefore have little to fear from the worst form of the disease. This along with drugs and antibodies mean that it is time to get back to normal living.”

Like John Bell, Devi Sridhar wished we had known that vaccines and therapies were round the corner; her low point was the heavy death toll in January/February 2021. She was also concerned about the impact of Long Covid.

For some reason Sir Martin Landray (PhD, FMedSci – medical degrees not listed) is not in the print version but online he wished that there had been a trials network already in place. He oversaw the RECOVERY trial of dexamethasone, so perhaps unsurprisingly his high point was the proof of success.

You may be able to access the full article at https://www.thetimes.co.uk/article/lessons-from-the-frontline-of-our-war-on-covid-19-lckcgdr88. If you hit the subscriber firewall that’s too bad. I think that John Bell’s comment as shown encapsulates much of the truth. As for the remainder it is mainly the view of non-clinicians, and even those who have medical training are not at the sharp end, but are backroom people. And some of what they have said appears to display some disconnection with reality. For example, how could Jeremy Farr say that in January 2020 “We knew everything we needed to know”? by golly we did not. Maybe he has been misquoted, but if not he is plain wrong. John Bell and Devi Sridhar would have been a lot happier had they realised early that there was a clear clinical pattern to severe disease, that it had been described previously and that there were already treatments for it. John Bell at least realised that there were two groups of SARS-CoV-2 patients, though he did not specify (as I think he should have done) that it’s the severe disease that is Covid-19 and the rest don’t matter a lot on an individual basis. And I am bemused that Martin Landray takes the RECOVERY trial as a high point when, if he had read the books, he would have realised it was completely unnecessary and only confirmed what was already known. And I don’t think Long Covid is clinically any different from all the other postviral syndromes we already know about (I had one, years ago, so I believe in it as a concept, but this one is nothing special).

My answers to those questions would be as follows.

1. I wish we had realised sooner that this was a virus that could cause severe and rapidly deteriorating disease, and that the pattern of this had been recognised earlier as being due to a hyperimmune state. I suspect that if I had still been working I would have done so. You see one rare thing, as I have, you don’t forget it.
2. My low point was when I identified this cause of serious illness in May 2020, flagged up both the investigations necessary and the treatment that would work, and then found I was completely ignored. And others (mainly rheumatologists) had come to the same conclusion. Why were we not listened to? Finding I was right added to my distress. It seemed that none of the decision-making experts were the right experts. Also when the “puzzle” of genetic susceptibility and some ongoing systemic effects, also provoked by vaccines, remained puzzles long after I had given the answers. It’s all been vaccines, vaccines, vaccines. What really mattered, and still does, is identifying the development of severe disease and treating it promptly and properly. Yes, vaccines do appear to reduce severity and risk of hospitalisation, but don’t abolish it.
3. Highest point? Being proved correct on steroids and biologic drugs – although as these treatments for cytokine storm were already established there was no need for trials. Waiting for the result of RECOVERY wasted months. So it’s also a low point, as above.
4. I actually think that the public understand what has happened better than the “experts” in many ways. This is thanks to the presence of rigorous analysis of data by the right experts on external sites such as the “Daily Sceptic” (and dare I say my blog)
5. The experts have never made it clear that there is a distinction between dying with Covid-19 and from Covid-19, partly because they have continued to conflate the terms SARS-CoV-2 and Covid-19. Neither have they acknowledged that projectional modelling is no match for retrospective data. They presided over a sloppy rule re-writing for death certificates which allowed anyone with Covid-19 on the certificate to be classed a Covid death. PCR testing was allowed at cycle thresholds that led to large numbers of false positives. The experts, supposedly experienced epidemiologists, allowed the flooding of care homes with hospital discharges, spreading SARS-CoV-2 into care homes. They failed to acknowledge, until very recently, that vaccination does not stop transmission, nor that anything short of a total lockdown can never work.

I’ll stop here, as our allotment shed was shredded by Storm Eunice and I need to sort out ordering a new one.

The Wry Observer’s Covid-19 update (187)

The tide is surely turning. I hope so.

In today’s “The Times” (and backed up by Professor Tim Spector who has been running the respected ZOE study) it seems that the politicians, and clinicians outside the DoH, are optimistic that the Omicron peak has been reached, at least in London, and that the rest of the UK will follow.  Work from both the UK and Denmark confirms that Omicron is much less likely to produce severe illness, which the brigade suggesting that the South African experience was due to a population difference should find encouraging.  Today’s figures are in line with this; no sudden spike n admissions, and certainly no increase in deaths. It is also now clearly being suggested that the problem in the UK is not the numbers of SARS-CoV-2 patients being admitted to hospital, but the large numbers of staff who are isolating because of a positive test – which is what I suggested yesterday.

If someone has a positive test, whether it be PCR or lateral flow (LFT), the likelihood that they will be infectious once the LFT reverts to negative is close to zero.  I suggest therefore that the testing strategy for NHS staff be changed.  LFTs will confirm infectivity and should become the baseline for testing.  If staff are forced to isolate on the basis of a PCR test they may remain off work far longer than is necessary, not least as we still have no idea what the PCR cycle threshold is in current use.  I suspect it is over 30 in most labs, so the false positive numbers must be very large.  Indeed, if Omicron is overall little worse than a bad cold I am beginning to wonder why we are testing at all.  Caution is reasonable; over-caution is damaging. My sources suggest that Covid-19 is still a major problem in the over-65s, and one must take special precautions with this group, maybe, but anyone who develops serious disease needs serious treatment – and it still seems that patients are presenting quite late and thus missing, perhaps, the window of opportunity.

Meanwhile I awoke from a nightmare early this morning having been informed my PCR test was positive, and I needed to repeat it until it wasn’t.  It took me a good ten minutes to get the whole dream out of my head and force myself to remember I had not had one.  And, just in case, I did an LFT this morning (I have no symptoms, so you might wonder why I am obsessing.  No comment.).  It was, of course, negative.

I was also, once fully awake and calmed down, thinking about clinical trials again.  I believe that the dexamethasone and tocilizumab trials were unnecessary.  Back in May 2020 I postulated that the IL-1 antagonist, anakinra, might also be a useful agent, as in other cytokine storm syndromes and in Kawasaki disease.  It has an advantage over tocilizumab of being cheaper and has a shorter half-life.  Lo and behold!  There’s a paper in “The Lancet” testing it!  See https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00216-2/fulltext, and yes, it appears to reduce severity in patients with investigation markers of a cytokine storm.

What a surprise.  It actually appeared in August but I took my eye off that ball, not least because an earlier paper (https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30556-7/fulltext) found no benefit.  Suffice it to say that the European Medicines Agency licensed its use in Covid-19 on December 17^th.  As with the other two, I wonder how many lives might have been saved if the need for a trial had been discounted in May 2020 as I argued, scientifically but unsuccessfully.  I will put this point to the inquiry.

Postscript: Today (5th January) the BBC reports that “PCR not needed after positive lateral flow under new plans”.

The advice appears to rely on the same NEJM paper as I quoted on 3rd January. Is the DoH finally listening to me, or is this a happy coincidence (in which case I will claim that I was there first).

The Wry Observer’s Covid-19 update (185)

Happy Boxing day!  I hope readers had a decent Christmas; ours somewhat marred, because our sone had been in contact with someone testing positive for coronavirus, so we were reduced to a WhatsApp conversation.  Never mind; he will come for New Year, and we will pretend it’s Christmas all over again.

This set me wondering.  The hysteria over Omicron and its modelling has been fuelled by suggestions that only worst case scenarios have been discussed, and while this does not appear to be true it is certainly the case that the media has ramped up the pressure.  Neither has it helped that the devolved administrations have adopted more stringent avoidance measures, once more resurrecting the debate on who has over-reacted, and who has not reacted enough.  Sure, there is an increase in cases, but not quite as dramatic as reported if one looks at the dates of tests rather than the dates of reports.  Sure, there has also been a small rise in hospitalisation numbers, but this has not taken account of those admitted with, rather than from Covid, nor the still alarming rate of hospital acquisition.  And it does appear than the symptoms are more common cold-like than previous variants.  In which case, does any surge matter?  What would we find if we tested people with a cold?  After all we know that there is a large group of coronaviruses that cause these.

I did a little digging, and came up with a few papers that raised the spectre of misdiagnosis, and also had potential explanations for why some people, and populations, had an apparent degree of protection.  Thus the review by Sealy and Hurwitz (Microorganisms 2021, 9, 1643. https://doi.org/10.3390/microorganisms9081643) says “Research of cross-reactive antibodies between common cold HCoVs and SARS-CoV-2 has yielded mixed results. In a significant fraction of SARS-CoV-2-unexposed humans, cross-reactive T cells and antibodies that recognized both common cold HCoVs and SARSCoV-2 were found… The presence of cross-reactive antibody responses and cross-reactive T cell responses in humans may well impact diagnoses, prophylaxes, treatments, and outcomes of SARS-CoV-2 infections.”  Also see Beretta, Cranage and Zipeto (https://www.frontiersin.org/articles/10.3389/fimmu.2020.567710/full) .  But a report by Hemsley suggests there may not be anything in this (https://www.pennmedicine.org/news/news-releases/2021/february/antibodies-to-common-cold-coronaviruses-do-not-protect-against-sars-cov2).  Who knows where the truth is? 

I continue to try and avoid confirmation bias in my own reporting, but remain concerned by the deafening silence from “The Science” when outsiders like me ask awkward questions, or produce analyses that contradict the official line.  Not responding leaves open the question – are they not responding because they are contemptuous of the ignorance of the commentators (rude) or because they don’t actually have a resonable way of rebutting the counter-argument (not scientific).  Either way they lose the confidence of those hanging on every word, and fuel the growing groundswell of resistance to repressive measures.

I still feel somehat aggrieved that my expertise has not been tapped.  I said at the outset that the aim should be to develop treatments that reduced SARS-CoV-2 to nothing more than flu (or, in the words of my poem, a cold).  Vaccines may have helped but the key was to identify those at increased risk and protect them, and if that wasn’t possible then treat them aggressively.  As it has turned out some of my suggestions are now in use, after unwarranted and unnecessary delays, and vaccines notwithstanding it looks likely that the new mutations are taking SARS-CoV-2 towards its common cold-provoking relatives in the coronavirus family.  I have been wrong on some aspects, I admit, but on the basics of clinical management, retired or not I have mainly been right.  I suppose it’s too late to expect “The Science” to listen now…

The Wry Observer’s Covid-19 update (174)

It’s just been announced that travellers returning from abroad will no longer have to do a PCR test at 2 days (and 8 if not fully vaccinated) but can do a lateral flow test instead. This coincides with the release of a bit of research suggesting that the lateral flow test is more accurate than previously thought – but the justification for the change appears to be the imminent arrival of half-term rather than any scientific reason, the idea being that there will be less impediment to travel for those desperate to take their children abroad, and it will help the travel business..

Having had to fill in passenger locator forms (which you couldn’t do until you had a code for your PCR test) at half an hour a time, which even I found confusing, as well as pay over £100 for two to buy the tests themselves this can only be a Good Thing. Just a pity it hadn’t been changed before, not least because my test kit arrived promptly but my wife’s, ordered the same day, appears to have been lost in transit. We wait in hope.

Meanwhile the panic/fear combo has once again rolled into action, with dire warnings of a new wave because the number of “cases” is going up and at the last count yesterday was over – shock horror – 40,000! The worst in Europe! Today it’s gone up to 44,000. I really do not understand how people can be so stupid. Before running round in small circles shouting “We’re doomed!” folk should ask what might make the numbers go up. First of all these are not cases, but positive tests. Despite my best efforts even the DoH cannot make a distinction between a positive test for SARS-CoV-2 and a case of the nasty consequence of infection, Covid-19. The latter is what causes sick people to be admitted to hospital (and maybe die) and the rates of these have barely moved. Secondly it seems that it’s now the young who are testing positive, and they don’t get sick. But far and away the most important is the very simple fact that if you do more tests you will get more positive results. So what matters is not the absolute number of positive tests, but the percentage of tests that are positive. The current data does, admittedly, show a rise but only to 4.3%. Using that percentage measure we are not the worst in Europe, as the graph shows:

How many times must I say this?

And just to show that the death rate (flawed though the measure is, as it still does not distinguish between deaths from Covid-19 and deaths with it, but from other causes), here is the official “death graph”:

Now that winter is coming we will, of course, find it difficult to distinguish between Covid-19 deaths and flu deaths unless great care is taken to check that all the features of Covid-19 are present. But we can at least say that so far there is no sign of the SAGE-predicted surge. And the explanation for that is simple; as I said above, the people testing positive are those least likely to develop Covid-19. There is of course a risk that they could spread it to the vulnerable (those exempt from vaccination, those with serious risk factors and those whose immunity has worn off) but I would say “Nothing to see here yet”.

The Wry Observer’s Covid-19 update (130)

The schools are back!  I bet the students are glad to be returning to something near normality.  I read that the bane of mask-wearing – getting a damp face and having your spectacles steam up – may help stop transmission as the virus particles will get caught in the damp cloth.  Any crumb will do… let’s see whether there is another spike which can be attributed to transmission in school, or outside the gates.  I was impressed that the missing person carrying the Brazilian variant who had not correctly filled in their paperwork after returning from there has been identified, after the search narrowed to a handful of house in Croydon.  Nevertheless deaths and “cases” continue to fall, which is being attributed to the New year lockdown, the increasing number of vaccinated people, but not to the natural history of a an epidemic condition.  So – the lockdown is lifting, vaccinations are continuing to “ramp up” and we will see what happens to the figures.  My usual comparative graph from OurWorldinData is impressive for the UK.  What are we doing differently?  Basically vaccinating a lot more people than the other nations shown.  So I suspect that vaccination is having a major impact.  The news from Italy on hospital cases is not good, reflecting the rise shown.

The BMJ carried a Clinical update this week titled “Acute Covid-19 and multisystem inflammatory disease” (Rubens et al, BMJ 2021;372:n385), to which I responded:

“The list of types of multi-system inflammatory diseases (MIS-C) is almost identical to the list of paediatric cytokine storm syndromes listed in Cron and Behrens’ textbook (1). I think this is a story of the blind men and the elephant; different observers are seeing slightly different presentations, giving them different names but not appreciating that they are all the same thing, so perhaps this article will help to bring together the different syndromes under one name.

Kawasaki disease is successfully treated with anakinra, which is a safer anti-interleukin than tocilizumab because it has a shorter half-life. So it may have a useful role in coronavirus-induced cytokine storm (it is interesting to note that it is also used in the treatment of systemic juvenile chronic arthritis, which might almost be described as a slow-burning hyperimmune response). I am not the first to suggest this in print (2).

Dr Menakaya [author of the first Rapid Response] has commented on ethnic differences in incidence. Cron and Behrens have noted (with several of the cytokine storm syndromes they have described) that this is likely to be due to a mutation on chromosome 3 which results in increased susceptibility of the ACE-2 receptor to external stimuli – which is a mutation also associated with blood group A. There may also be influence from a change on chromosome 19. I have flagged this in previous Rapid Responses as something that needs to be thoroughly researched before pinning all the blame on societal factors, which may well be relevant to infection acquisition but cannot sensibly be a reason why infection progresses to severe disease.

I suggest every clinician involved with the management of Covid-19 should read Cron and Behrens’ textbook.

References:

(1) Randy Q Cron, Edward M Behrens. Cytokine Storm Syndrome. Springer, 2019

(2) Naim Akhtar Khan. Anakinra for severe forms of Covid-19. Lancet 2020. DOI: https://doi.org/10.1016/S2665-9913(20)30273-3“

There are 43 references, but Cron & Behrens is not among them, which seems strange when the book contains much of the background and sets down the reasons for considering the different syndromes, which the authors of the paper aggregate as multisystem inflammatory disease (MIS-C), as variations on a common theme.  That’s why I suggested that every clinician involved in managing Covid-19 should read it.

“The Times” today published an extract from another new book by Jonathan Calvert and George Arbuthnott called “Failure of State: The Inside Story of Britain’s Battle with Coronavirus” (Mudlark, coming out next week).  I think I need to spend £20 on it before deciding whether to retitle my collected blogs (publication date still not decided) as Failure of State: the Outside Story: Fruitless Banging on the State’s Window”.  Although “A New Journal of the Plague Year” is perhaps less confrontational.

Went to see the heronry below Winchelsea this morning, but most of them had gone fishing.  I spotted a couple, but on blowing up my photos there were still four on their precarious nests.  A fascinating sight.  Does one need to go to the Serengeti when there’s nature like this on your doorstep?

The Wry Observer’s Covid-19 update (116)

Time flies like an arrow. I can scarcely believe it’s a week since I last posted, but today we have a new US President, not that it will make any difference to the pandemic. And I am fuming gently once more thanks to another gobsmacking report in “The Times”, yesterday, from their Science correspondent, Rhys Blakely:

The overreaction of the immune system that leads to severe Covid-19 begins far sooner than was thought and trials of potential treatments may be intervening too late, a study suggests. Within a day or two of developing symptoms people who needed to be taken to hospital had chemical signs in their blood indicating serious inflammation. It had been thought that this dangerous “systemic” inflammatory response, which can lead to organ failure, gathered steam only later during an infection and Ken Smith, professor of medicine at Cambridge University, said that trials of potential anti-inflammation treatments may be “missing the boat” by failing to reach patients early enough.

Dr Paul Lyons of the Cambridge Institute of Therapeutic Immunology & Infectious Disease, said: “Our evidence suggests that the journey to severe Covid-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms.

“This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on.”

So far, the biggest breakthroughs in Covid treatment have involved antiinflammatory drugs administered when people are already in hospital. The new findings, which are yet to be peer-reviewed, also suggest that monitoring immune responses could potentially be a means of predicting which patients will fall seriously ill. The researchers took blood samples from 207 infected people, ranging from healthcare workers with no symptoms to patients admitted to intensive care, as well as from 45 healthy control subjects. Those who were hospitalised showed signs of an abnormal immune response.

“Evidence of abnormal inflammation is present very early and the implication of this is that we might have to act very early to prevent it — we can’t wait and watch,” Professor Smith said. “It may be, in fact, that the abnormal response is present even before symptoms develop.”

In those people with no or only mild symptoms the researchers found evidence of an early, robust adaptive immune response, tailored to the coronavirus. By contrast, patients who went on to become severely ill showed signs of an abnormal response, even in their first blood test, often taken within a day or two of symptoms appearing. Critical parts of the immune response were delayed and there were abnormally low levels of several white blood cell types.

Levels of some types of immune cell sometimes remained low for months. This may contribute to “long Covid”, where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, the researchers said.

Lawrence Young, a virologist at Warwick University, who was not involved in the study, said: “It appears that the early immune response to virus infection dictates the severity of Covid-19. This could mean that early intervention with therapies that target the virus and/or the immune system could prevent severe disease and even the development of ‘long Covid’.”

So I wrote a letter back, which has not appeared today, although Jonathan Sumption’s comment on the value of a life in relative terms has caused considerable upset, notwithstanding medical services under pressure make decisions on relative value all the time and have done for centuries. I said:

Today you quote Ken Smith and Paul Lyons from Cambridge as suggesting that the immune system is triggered into overactivity by the novel coronavirus “sooner than experts thought”.

I wrote before (“The Times”, 26th September) that the government was using the wrong experts who, it appears, failed to realise that although the SARS-CoV-2 virus was new, the cytokine storm it provokes is not. On 28th April I wrote to the British Medical Journal saying: “I believe that an open trial of a combination regime of high-dose steroids and cytokine inhibitor(s) should be started at once, although I believe the evidence supporting such a regime is almost so powerful as to obviate the need for one.” And in a letter to “The Times” (April 30th) I wrote: “Early administration is also essential, and tests are available that would enable clinicians to see who was going to develop a cytokine storm, and thus get hold of it before it had gone too far to be treated.”

It would seem that like Cassandra I am cursed not to be believed. I have offered my advice to the Department of Health several times, and had no response. Nine months have passed. My offer of help remains open.

In other words I not only predicted the finding, and advised the right treatment, but I suggested that waiting too long in an individual was wrong. In April. It’s all in the diary! See entries 18 and 19. Treat hard, treat early. It’s what we do for inflammatory joint disease, and it works. It’s what you do for other cytokine storm syndromes. So it’s not sooner than this expert thought. I repeat: the virus is new, but what it can do, in the form of CSS, is not, so we don’t really need trials to prove what we already know. All it does is cause delay.

So I ask once more – had my advice been adopted in April (all right, May) how many lives might have been saved? Why I have not been contacted to help with planning. I know how to Zoom etc and I know what I’m talking about. Ring me.

Yet again the media are obsessing over the rising death toll, unnecessary or not. Why they find it so surprising I am not sure; there was an increase in hospital admissions in December, there is a time lag before patients end up on ICU (whether necessary or not) and a further time lag before the deaths start to happen (18 days mean). But look at the number of new cases and it’s falling; look at the percentage of tests that are positive and it too is falling a little, but it really hasn’t changed much. So it’s not exactly exciting or horrifying, except that some of it might not have been necessary…

Today “The Times” sounds a cautionary note on vaccines; it’s possible that the country is running short, so not only may some folk not get their second jab but lots may not even get their first. Which makes it all the more important to make early calls on who has it and is getting sick, and then bang in the treatment. For the life of me I cannot understand why this is not happening now, let alone last May. Answers on an email, please.

The Wry Observer’s Covid-19 update (113)

Yesterday on the BBC, and today in “The Times”, it is reported that two “new drugs” have been assessed for the management of severe Covid-19 and found to reduce deaths. It’s great news, but as regular followers of my blog, and readers of the British Medical Journal will know, it is not new. The drugs are tocilizumab and sarilumab – both of which are inhibitors of the inflammatory cascade by blocking Interleukin-6, or IL-6 for short.

Although, as I have said before, I was a bit slow off the mark in working out why Covid-19 was killing people I had it straight in my head by the end of April 2020. The problem is the development of a cytokine storm. While the immediate acute effect of SARS-CoV-2 infection was a direct one, in some but not all people the immune system was provoked into an overreaction. Cytokine storms are well-documented, as is their management. You suppress the immune system with steroids and/or specific agents that stop the inflammatory cascade. We rheumatologists know more about inflammatory cascades than most clinicians because they underpin many of the diseases we treat, so we know that we can block IL-1, Il-6, IL-17, interferon and Janus kinases among others. So it is hardly a leap of faith or imagination to use these drugs to treat Covid-19.

And it is not new. I wrote to “The Times” on April 27th suggesting this approach. I repeated my arguments in detail in a letter to the British Medical Journal the following day (both are reproduced in earlier blogs). I submitted an investigation and treatment protocol to the Chief Medical Officer, copied to the Chief Scientific Officer and the Secretary of State, in early May. I had no response from any of them.

I have up to now been grateful to have been spared the potential risk of working in a hospital, being long retired, but what has happened makes me wish that I was still working. If you are retired from the NHS you lose the opportunity to circulate ideas through the intranet; likewise if you are retired you no longer appear to matter, whatever the wealth of your long experience in medicine, being President of the British Society for Rheumatology even. How many clinicians, I ask, have actually seen and managed a cytokine storm prior to the arrival of Covid-19? There are precious few, I suspect – maybe some paediatricians, the doctors who had to deal with the TG-1412 mishap at Northwick Park Hospital some 12 years ago. And me. Yes, I have seen and treated one. And because I have seen one, I can recognise it; pattern recognition cannot happen unless you have a first comparator.

So the eight-month delay in implementing my original proposal has various explanations. First, no-one had seen the syndrome before. Second, the apparent need to do a trial, because that’s what you do in science. I confess that I did originally suggest this, but only until it became completely clear that what we were seeing was a known condition with a new cause. Third, that no-one believed me. This was not entirely true, because (and again I have mentioned this in previous blogs) other rheumatologists had come independently to the same conclusion, but although they have been well-placed to influence thinking they appear to have been as unsuccessful as I have been. One might term this the Galileo syndrome. The closed minds of SAGE, the Modern Spanish Inquisition, brook no intervention or input from without, despite the members of SAGE having completely different and indeed inappropriate clinical experience. Fourth, what I perceive to be a state of learned hopelessness among NHS acute medical staff; when someone became acutely unwell and began to sink, they gave up through ignorance, offering only supportive care. I have attempted to find out whether any ICUs were using my protocol, or something like it, but no-one has responded to my questions. So maybe some are using it. If any reader knows of such units in the UK I would be pleased to hear of them.

In the last week there have been new stories of individual deaths that have tugged at the heartstrings. One of these had, from the report, deteriorated beyond the point of no return before they got to hospital. But why? If another of my suggestions had been adopted they would never have got that bad; checking their O2 saturation at home, using a cheap pulse oximeter, the warning sign of significant hypoxia would have been picked up. Another story attributed death to a blood clot on the lung. But for how long have I been arguing that a cytokine storm is accompanied by serious changes in blood coaguability, which can be stopped by administering anticoagulants (and predicted from blood tests)? Months is the answer. So why is it not being done?

Right from the start, before vaccines were more than a glint in the eye, I have argued that SARS-CoV-2 infection is not so serious a problem if you can stop people dying from developing Covid-19. And, with steroids and IL-6 blockade (sometime soon I expect that the IL-1 blocker, anakinra, another of my recommendations, will also surface) it can be done. It remains only to ask: If the Bamji Protocols had been introduced in May 2020, how many deaths from Covid-19 would have been prevented? Not all, of course; definitely hundreds and maybe thousands. So while some physicians have been suggesting that lockdown sceptics and deniers have blood on their hands just think about those in power, and “The Science”, who have prevaricated over introducing successful therapy. Might they not also be tarred with that brush?

I would be fooling myself if I thought that I would now get any credit for my proposals, or any acknowledgement that delay in implementing them has led to unnecessary deaths. We should perhaps be grateful that they have now been implemented, or at least recommended. Because SARS-CoV-2 isn’t going away; we are not going to eliminate it, so vaccination or not there are still people who will get very sick – not many, but with good, aggressive treatment even they may survive.

I am still waiting, as a member of the Top Four priority groups, to hear when I will get my vaccination. The map shows we are in a huge empty space between Hastings and Ashford. I will drop everything and go, assuming my car battery is not flat – and with the cold weather, and the fact that it warned me there might be trouble ahead, I cannot be certain. Perhaps I will nip down to my garage and check. There’s no street parking where we live, and the garage is 5 minutes’ walk. Mask on…

The Wry Observer’s Covid-19 update (109)

A bit of a gap for many reasons:

1. Celebrating Christmas
   1. Enjoying Boxing Day
   1. Hardware failure required attention
   1. Housework as cleaner furloughed (again)
   1. Trying to make sense of the figures

With one desktop (Liz’s) out of action for 2 months and no prospect of repair some time had to be devoted to what would replace it.  The spare laptop was proving very slow, and suddenly died.  Fortunately a raffle-won Ipad could be commissioned – so at present a replacement laptop is not needed, but I have to learn how the thing performs best for me.

As for the figures I wrote a letter three days ago:

Letter to “The Times”, 28^th December

While there has certainly been an increase in hospital admissions attributed to coronavirus infection there has not been a “surge” in cases.  The relationship between positive tests and actual cases remains unclear; false positives and multiple testing of individuals both overstate positivity.  Absolute “case” numbers may be rising, but this is because the total number of tests is rising. A better measure of true increase is the percentage of the total tests that are positive.  While it is not easy to calculate this exactly (because of delays in results becoming available) my analysis shows that the overall percentages positive for October, November and December (to date) were 6.4,6.8 and 7.2 respectively.  I see no surge.

It is possible to predict a worsening outcome from a combination of falling oxygen saturation and rising markers of inflammation in the blood.  If pulse oximeters were distributed to every household we would have an early warning system that might allow those with normal levels to remain safely at home.  The cost of this measure is around £180 million, which is insubstantial compared to the ongoing costs of acute hospital care.

In fact the percentage has gone over the 10% level in the two following days, and hospitals have been filling up, but don’t they always at this time of year?  The UK maintains such a low bed base that being overwhelmed is a normal winter phenomenon.  However the intensity of treatment required for Covid-19 does undoubtedly put extra pressure on the staff, but there are numerous posts and tweets that tweak the presentation of figures and show that overall the current death rate is not hugely in excess of what one might expect.  How much is anyway due to Covid-19 is a moot point; if 30% of hospital cases are nosocomial, in other words acquired in hospital, then one has to suspect that the original thing that was serious enough to cause admission in the first place may well have been the cause of death.  It would be helpful therefore if these cases could be excluded from the published figures (or given alongside) so that we can get a better handle on how much was community-acquired, and where (for instance in care homes or other high-risk environments).

An interesting news item appeared this week about a child admitted with query Covid-19 who turned out to have haemophagocytic lymphohistiocytosis (HLH).  What a surprise (not).  HLH is just another cytokine storm syndrome so the clinical appearances would be almost identical to Covid-19.  So another “small earthquake, not many dead” story.

The end of 2020 looms, and I still have a whole sheaf of unanswered questions, some clinical, some scientific, some statistical, some economic and some political.  This is despite attempts to ask them through ministers, the CMO, the CSO, the SAGE committee and several journalists (who would have been in a position to ask them at the now reconvened press briefings.

• Are all hospitals now using a standardised protocol for the investigation and management of Covid-19 patients such that those who are seriously deteriorating are receiving timely and correct therapy?  If not, why not?
• Does therapy include the use of low-molecular weight heparin?
• Is timely therapy having an effect on the incidence of “Long Covid”?
• How does SAGE (and the government) define a surge)?
• What is the current maximum cycle threshold for the RT-PCR test?  Is it the same for all labs? Is it less than 35 (the critical point at which false positives become the majority)? If not, why not?
• Is there clear understanding of the differences between the lateral flow and RT-PCR tests?  How is a positive test defined as a “case”?
• Why are only crude numbers of “cases” given, without also giving these as a percentage of the total number of tests?
• Is it reasonable to compare one poorly conducted test, resulting in many false positives, against one with an apparent high false negative rate?
• Is there a clear relationship between waves of positive tests and lockdowns?  The data suggest otherwise.
• Why has the government not embraced, but ignored, the various eminent clinicians and scientists who have raised valid and scientifically justified criticisms of all manner of things?
• Why have pulse oximeters not been distributed to households?

I am waiting for FoI responses to a couple of these but am not holding my breath.

Meanwhile the Oxford vaccine is approved and ready for roll-out, so maybe we really will be back to normal by next Easter.  Having said that, should the focus be on the at-risk groups of getting SARS-CoV-2 (the elderly, those with concomitant health issues, care home residents etc) or on the at-risk groups of spreading it (the young who party, those others who cannot be relied on to socially distance, or cannot distance, e.g. large family groups, hospital and care home workers etc)?  Tricky.

Happy New Year!

The Wry Observer’s Covid-19 update (102)

I have started reading David Onand’s book “How Spies Think: ten lessons in intelligence” (Penguin, 2020). I haven’t got very far, but one quote is worth sharing:

Reality is what it is. We cannot go back in time to change what we have observed. More correctly, then, for our purposes reality is what it was when we made our observations. Reality will have changed in the time it has taken us to process what we saw. And we can only perceive some of what is out there. But we can make a mental map of reality on which we locate the facts that we think we know, and when we got to know them. We can place these facts in relation to each other and, via our memory, fill in some detail from our prior knowledge. Then we look at the whole map and hope we recognize the country outlined.

More often than not, facts can bear different meanings. Therein lies the danger of mistakes of interpretation.

He goes on to give examples. I can think of many parallels in healthcare research, and later Onand mentions the Black Swan issue, and alludes to confirmation bias. It’s good to know that such issues are universal.

A couple of days ago “The Guardian” noted a piece of work, as yet not peer reviewed but with an impressive array of authors, reporting on the series of “protein tests” that may predict a poor outcome with Covid-19, and stating at the outset that the research was conducted before (and was thus unpolluted by) the introduction of steroid treatment. The abstract in part says

We report that the time-resolved patient molecular phenotypes reflect an initial spike in the systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution and immunomodulation. Further, we show that the early host response is predictive for the disease trajectory and gives rise to proteomic and diagnostic marker signatures that classify the need for supplemental oxygen therapy and mechanical ventilation, and that predict the time to recovery of mildly ill patients.

The detail is fascinating and much of it is incomprehensible but while some of the tests are esoteric, several are already available. And I suggested their use in prediction back at the end of April… Of course I accept that research takes time. But it all still leaves me wondering whether lives would have been saved by the introduction of such tests on a wide basis back then (not to mention the steroids). Rather, how many lives might have been saved. In view of the continuing uncertainty on the benefit of tocilizumab it’s interesting to note that the paper (which you can currently access at https://www.medrxiv.org/content/10.1101/2020.11.09.20228015v1.full.pdf) points to the IL-6 pathway as being important. It brings me back to the argument that while the virus is new, what it provokes in terms of an abnormal immune response (aka cytokine storm) is not new, and that trials to prove treatments of this were not necessary as protocols already existed.

Meanwhile the headline this evening is that patients with allergies should not receive the Pfizer vaccine as two such have had significant reactions. Not entirely surprising, perhaps, but a wise precaution. But we are off! Meanwhile Rye and Winchelsea have moved from light to dark green, but 60 per 100,000 (the rolling rate) is still only 3 cases (our population is about 5,000) so I am not panicking yet – though I wish the jolly tourists would socially distance, and I am still wearing a mask in the town.

But now. We seem to have growing convergence between my regularly expressed hypotheses and suggestions in all three parts of the SARS-CoV-2 patient journey – individual prevention, management of severe disease and vaccination, which last I confess I did not expect for ages, if at all, as I have said. But I think I might go on for a little bit longer…

The Wry Observer’s Covid-19 update (11)

Good afternoon, children!  Are you sitting comfortably?

There are four learning points today.

1. Do not jump to conclusions before you have got the facts straight. 

Somehow I don’t think that journalists read my blog, because they keep making this mistake.  I made it myself in an earlier blog; see if you can spot it.  As I said in my last blog there was unrest at Boris Johnson’s absence from the front line, and comments along the lines of “How long will it be before he is back?”; “Who is making the decisions while he is not there?”; “Are decisions going to have to wait until he gets back?”

And, of course, it turns out that BJ’s approach has been quite hands-off, and he hasn’t actually been there quite a lot of the time.  Everyone assumes he was.  Fact check shows he wasn’t.  So he was not essential (which is what the cabinet collectively has said repeatedly).  Egg on face for all those who now have to find something else to criticise, because after all someone has to be blamed for this mess, whether it’s the politicians, the scientists, the medics, the Chinese, tourists, the bats or the pangolins.  Probably Boris, on the grounds that he should have been there. What’s to blame is the coronavirus, which is new, previously never seen and nasty.  Everyone reacting to it can be forgiven for caution – caution when imposing a lockdown, which would inevitably have massive economic consequences, caution in emptying hospitals in case of need, caution in taking the lockdown off in case there’s a rebound – caution in balancing the risks and benefits of saving lives and causing business disruption.  What point is there in spending millions on an inquiry, which will show in all probability that the only real issues were some sloth in sorting out PPE (in mitigation because no-one really knew how bad this was at the outset, there was no real evidence that draconian measures might be needed) and some sloth in sorting out testing in care homes.

So the expectation of the scientists and medics was that a lockdown and social distancing would mitigate deaths and stop the NHS being overwhelmed.  Tick.  The government was under huge pressure to mitigate economic collapse and so has thrown billions at protecting businesses and jobs. Tick.  If there had been no lockdown the likelihood of a high death rate was almost a certainty.  There hasn’t been.  Tick. So those who criticise the handling of it all must answer the question: which would have been worse?  Deliberately allowing huge numbers of deaths and protecting the economy? Or reducing the death rate at an economic cost?  As far as I can see every commentator has effectively rejected either option.  OK, guys, if you are so clever you provide the plan.  We won’t give you any help, because you obviously don’t trust any of the experts on whose advice, and evidence, the current plans are based.  Indeed, you want to sack them.  An analogy for you.  The Grand National is about to run.  You look at the form, the pundits’ analysis, the likely going, and you place a bet.  Your horse falls at the second.  Tough, but I hardly think you will stop buying the paper or sack your bookmaker because they “ought to have known”.  How could they?  How could anyone have known, with Covid-19, how infectious it was, what the fatality rate was?  We might now, three months in, sort of know how infectious it is but as we don’t know how many people got it without symptoms we don’t know how fatal it really is; current estimates are only based on the known cases.  So get the facts right before pontificating and reading out the “horrific” death figures like gloomy clergymen at a funeral.

2. Understand how trials work and why you can and can’t do them.

I got a bit off the lesson there and sort of onto the second, which is to teach you about trials.  if you want to compare two drugs (or scenarios, or whatever) you do what is known as a controlled trial.  You take drug 1, and either compare it against drug 2, or against nothing (so participants don’t know which they are having, the “nothing” is a dummy pill, capsule or injection).  The trial is thus blind. If the investigators also don’t know who is having what, then the trial is double-blind.  An open trial has flaws but may be reasonable if you cannot blind either investigator or participant to the intervention.

In the case of Covid-19, then, what would be interesting would be to compare lockdown against nothing.  Of course that cannot be done blind.  In fact it cannot be done at all.  How would you do it?  Let Scotland be free, and lock down England and Wales, and compare death rates?  What about all the cross-border flow of goods and their deliverers?  What about the naughty English that wouldn’t obey the lockdown (“They aren’t doing it in Scotland, so why should we?”) or those in Scotland who are frightened enough to keep social distancing and self-isolation anyway?  The cross-contamination would be so bad as to render the trial useless.  Even doing it between countries would have the same problem unless you closed all the borders.  Not practical, not least because lots of PPE, or the raw materials to make it, come from overseas.  So we might introduce a confounder.  My head spins at the thought of trying to think up a way of doing it.

3. A model is only a model

No-one is far-sighted or prophetic enough to cover all the bases.  The unexpected happens.  Different assumptions and presumptions lead to different conclusions.  We have seen that in the wildly different estimates of the likely numbers of UK deaths from Covid-19, ranging as high as hundreds of thousands.  Modelling can be no more than a guide.

4. Pre-planning on the basis of past experience may fail if something unexpected happens. 

After the First World War the French built a huge chain of fortifications along the border with Germany, known as the Maginot Line, which was pretty well impregnable.  Some years back bits of it were advertised for sale, and I half thought of buying a bunker, as the ones on offer were in excellent condition, but we had other commitments.  Anyway come 1940 it didn’t work, for the simple reason that the German army came round the top of it by going through Belgium.  I have never been clear why the French left this bit of frontier rather weak.  Perhaps because the Belgians had some pretty powerful forts themselves? Perhaps forgetting that they came that way in WW1?  Anyway the Germans landed paratroopers on the Belgian forts and that was that.

The defences of Singapore in WW2 pointed out to sea, and were formidable.  The Japanese rapidly conquered Malaya, and so arrived at the back door, so to speak, and there wasn’t time to turn the artillery round.  No-one had thought they would do that.  A little later two battleships were sent up to counter the threat and were sunk by aircraft.  No-one thought they would do that either, and so the ships had no escort and no air cover.

In reverse, of course, the Japanese did not plan for an atomic bomb.

Could these scenarios have been predicted?  With a liberally greased retrospectoscope, yes, but not at the time.  What one knows now is far different from what one knew then.  Contingency planning is sensible, but only up to a point.  The facts may not be there, alternative scenarios cannot be compared, models are imagination, not fact, and the unexpected happens.  That’s life.