The Wry Observer’s Covid-19 update (38)

Difficult to believe that time has gone so fast, and it’s a week since the last episode of the Update, but I plead alternative commitments (writing a piece for our local newspaper, watching a web lecture, doing the allotment, going out for lunch and BREAKING THE LOCKDOWN AT LAST! It was outside, and we were properly distanced, and a swarm of bees did appear to distract us, but it was a great day. Mind you it would appear that half of England headed for Camber Sands or the Dorset beaches, and also that the concept of social distancing has been forgotten already. But at last the awful daily briefings have stopped. We stopped watching a while back as they became repetitive and uninformative; the questions from the press were irrelevantly focussed; and I got fed up with seeing the faces I had written to (who have never replied) ignoring so far as I could see any of my suggestions.

Well, you will say, they must have been deluged with stuff. Maybe so, but increasingly it seems my stuff was pretty well on the ball. The webcast I watched was presented by two rheumatologists, Professor Ernest Choy from Cardiff and Professor Dennis McGonagle from Leeds. It told me four things; first, that you have to hit Covid-19 with the immunosuppressives at just the right time (after the viral peak and at the beginning of the cytokine storm); second, that low oxygen saturation allied to abnormal blood tests predicts the latter (and yes, my protocol had an omission – the C-reactive protein also goes sky high so it should be included with the D-Dimer and ferritin); third that my protocol for treating the storm was on the nail and fourthly – beautifully illustrated with immunological slides – that rheumatologists are the best people to be treating cytokine storms because they actually understand the immunological principles and have experience of the treatments to use.

I remain convinced despite their positive analysis of the RECOVERY trial – which has a complex protocol which we rheumatologists don’t normally have recourse to – may have proved the point about steroids but still had flaws and also introduced a delay in treating seriously sick people. What harm could it have done to bang in a large slug of steroid? The risk of making infection worse, or allowing infection with something else, was small and manageable set against the likely suppression of the cytokine storm that was going to do all the damage.

As the lockdown begins to lift the post-mortems on the handling of the pandemic are beginning to be aired. In a way much of these are unfair, because at the outset what has become clear, or at least clearer, was completely not clear.  International comparisons are thoroughly confusing (reason not clear). Why was there an excess death spike in England but not, apparently, in the other home nations (reason not clear)? How reliable are the Covid-19 tests (not as reliable as first thought)? Should we maintain the 2-metre distancing rule (well, it’s down to 1 metre + whatever the + means)? Why are BAME people more likely to die (lots of talk about inequality and poverty, none about genetics)? Why exactly was there such a problem in care homes (people being displaced from hospital, close contact spread, infected carers)? Why don’t children appear to spread the virus (don’t know)? Should we open schools (on balance, straightaway; they should never have been closed)? What role did the media play in inducing mass hysteria (a big one, and often based on ignorance of science and medicine)? And so on.

I do wonder whether my 37,000 words so far have materially affected the management of the great plague. Writing them, and all the associated articles and letters has certainly kept me quiet, but it has been extremely frustrating to watch as the powers that be came to their conclusions days or weeks after I had. And I had told them, too. I sent links to the blog, emails with suggestions, even a full treatment protocol. Not a word.

If you can’t stop the virus from spreading (and as lockdowns ease across the world it appears you can’t), you can’t apply reliable tests to prove that you have it – or haven’t – or that you have had it – in which case it’s unclear whether immunity is long-lasting – we will have to live with SARS-CoV-2 for a while. Meanwhile there remains one thing you can do. You can stop people dying if they get it. That is a scientific issue; the moral issue is how you might determine which sufferers you prioritise, on the basis that applying treatments to restore a miserable existence may not be the right thing to do. The one certainty of life is death.

The Wry Observer’s Covid-19 update (37)

The 2 metre social distancing rule may be bent; some doubt has been cast on the studies used to recommend it on the basis that they are not direct evidence, but projections and deductions that may not be scientifically sound.  Indeed one can imagine, as one pushes through the crowd outside the door of one of our pubs, that unless someone puffs directly in your face or cough or sneezes, no droplets containing virus can possible come near you.  It makes economic sense to reduce the distance whatever the science of course.

The heightened risk to BAME people has also been in the headlines.  A preliminary inquiry was criticised for redacting the recommendations but when these finally came out I thought they should have stayed redacted.  There was no science in them at all, merely a pile of “woke” jargon about developing culturally competent assessments, involving communities and one bit that really stuck in my throat: ““In the absence of some of the more textured data it would be difficult to drill down into a very local, community level, understanding and, therefore, would limit the ability to decide how best to target and allocate resources”.  What on earth does that mean?  Will it help explain why Bangladeshis are more susceptible than Africans?  Does it unravel the likely contributions of sex, weight, diabetes, Vitamin D levels?  Does it research the possible, likely even, effects of genetic difference?  All that requires proper scientific research, not some socially aware, politically correct guff.  Where is reference to the research suggesting having blood group A might be a factor (it’s less common in white people).  Deprivation and poverty are not exclusively BAME issues, and certainly the hospital consultants of Asian origin who have tragically died in service could not remotely be described as deprived (I just hope their families are properly compensated).

And of course the whole BAME issue has been stirred into the Black Lives Matter protests.  All lives matter (careful, Wry Observer, people are being hounded for saying that) but readers will know that I recommended withdrawing BAME staff from front-line Covid-19 care a long while back until we knew why they were at higher risk.  But apropos the wild calls to knock down every statue, rename every road and investigate every possible connection with slavery and expunge it, just remember that everybody was in the slave trade; the British, Portuguese and others bought their slaves from African or Arabs, so we had better start investigating which groups did the selling, and expunge them also.  And anyone in the sugar or tobacco industries.  And cotton while we are about it.

Be historical, not hysterical.  The last time this happened in a big way in England was about 500 years ago, when churches were stripped of their statues of saints, wall paintings and other symbols of Catholicism.  It was indeed the Great Iconoclasm.  Must we repeat it?  Why not leave things as they are and be reminded of the sins of the past – not that they were sins back then, always.

Off-topic.  Sorry.

 

The Wry Observer’s Covid-19 update (36)

Today the papers are full of the “amazing” advance in Covid-19 treatment using a cheap drug.  Not as amazing as I would like, and I wonder how long it will be before the researchers lose their timidity about steroids and actually try a blockbuster dose.  Dexamethasone in small doses does work, but curiously is better in the late, serious patients than in ones treated earlier (I have yet to see the whole data set, so don’t know what early and late may mean, nor what doses were used, or what with).  Hit early and hit hard, I say, and get on with it.  I recall an article many decades ago pointing out that the success of high-dose steroids in a condition called dermatomyositis was so striking that a clinical trial would have been both unnecessary and unethical.  Same here.

Another report flagged to me (I don’t read “The Guardian”) is an apparent government review into Vitamin D and its possible benefits particularly in ethnic minorities.  Yet another piece of the jigsaw that I and some others have already put in.

I am still waiting for a response to my letter and protocol sent to Matt Hancock at the Department of Health.  I sent a copy to my own MP and had a note back, thanking me and saying it would be passed on – to the Department of Health…

There’s an excellent article on the problems of testing from Johns Hopkins at https://www.medscape.com/viewarticle/932105?nlid=135939_864&src=WNL_mdplsfeat_200616_mscpedit_rheu&uac=308617HG&spon=27&impID=2422455&faf=1#vp_3

 

The Wry Observer’s Covid-19 update (35)

I do hate to say “I told you so” when lives are at stake, but I did say way back that firing steroids at patients should be part of the medical management of Covid-19.  The RECOVERY trial has now reported – no, you’ll never guess – that dexamethasone reduces deaths in ventilator patients by one-third.  See https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_final.pdf?utm_medium=email&utm_source=CampaignMonitor_Editorial&utm_campaign=LNCH%20%2020200616%20%20House%20Ads%20%20SM+CID_21329544b8519b460dcee39c1a25bfb5

I suppose that a hypothesis required proving.  How long will it be before high-dose steroid is administered as soon as it becomes plain that the clinical situation is serious, but before it gets to a ventilator situation?  Er, like I suggested

You learned it here first.

Meanwhile deaths continue to fall, and the argument between the “The lockdown should have happened earlier” and the “The lockdown should not have happened at all” continues to simmer, or occasionally rage.  Masks were not thought necessary for the public; now some evidence suggests they might reduce transmission by 40% so perhaps they are necessary.  I think they are, especially having observed the complete abandonment of social distancing among visitors to Rye.  But, as Matthew Parris wrote in his “Spectator” piece, what do I know?

I have written a piece for our local online newspaper “Rye News” which seems to be welcome.  The first part is at https://www.ryenews.org.uk/news/coronavirus-where-are-we-going.

Meanwhile Richard Horton, editor of “The Lancet”, has launched a coruscating attack on the way the coronavirus has been handled, saying “The UK response to coronavirus is the greatest science policy failure for a generation”.  His small book setting this out is on its way, and I will comment on it in due course, but given “The Lancet” had to retract a paper on the benefit of hydroxychloroquine in Covid-19, not to mention its publication of Andrew Wakefield’s fraudulent trial suggesting a link between measles vaccine and autism which resulted in loss of herd immunity to the measles virus, I have to wonder if the pot is calling the kettle black.

The Wry Observer’s Covid-19 update (34)

On 24^th April I asked whether the apparent predisposition of ethnic minority groups to Covid-19 was genetic, and subsequently I have emphasised the likelihood, partly because of my concern that the arguments over causation appeared to have moved from the clinical and scientific to the socio-economic.  I have also suggested that trying to run an inquiry now would be like writing a book about a holiday halfway through it, and either inventing or guessing what will happen during the half you haven’t had yet.  As the data change, so will the conclusions.  Yes, we should have an inquiry.  No, we should not have it now; there are still too many unknowns.

Well.  Today “The Times” reports a large study that seems to indicate that being of blood group A is a risk factor.  See https://doi.org/10.1101/2020.05.31.20114991.  Ok, it hasn’t been peer reviewed yet, but still.  And does this fit with the known additional risks in different BAME groups?  Yes it does.  So before we get hung up on deprivation, racial prejudice etc let’s be sure that it isn’t in the genes, just like sickle-cell anaemia or thalassaemia.

Two good articles in “The Spectator” of 30^th May.  The first by pathologist John Lee, whose elegant piece “Count for nothing” underlines my earlier concerns that lack of confirmation of SARS-CoV-2 being present bedevils counting, and advice to pathologists not to do autopsies has hampered research into the pathological processes in the lungs (and elsewhere in the body, for that matter). See https://www.spectator.co.uk/article/the-way-covid-deaths-are-being-counted-is-a-national-scandal It is absurd on the one hand to allow Covid-19 to be implicated by presumption alone while on the other quoting death figures to several decimal places.  While some Covid-19 deaths may be missed, other deaths are quite possibly nothing to do with the virus.  Curiously we appear to have fallen into the same counting trap that was earlier decried in Belgium, which like us has a very high death rate per 100,000 population. It reminds me of an old joke.

Knock, knock!

Who’s there?

Barack.

Barack who?

What short memories people have!

The second article is by Matthew Parris: “Why has coronavirus fled London?”  (https://www.spectator.co.uk/article/covid-has-all-but-left-london-why- but you may need a subscription to read it online).  He suggests his partner thinks he is treading on dangerous ground, as he’s not an epidemiologist, saying ‘Nobody’s interested in your theories.’  Sadly that may be true as far as the high-ups are concerned, but the piece exhibits classical hypothesis development.  It notes facts, finds questions to ask about them, draws out contradictions and comes up with an explanation.  Never mind if it’s not the right one; the thought process is immaculate.

I have argued in my book “Mad Medicine” that the duty of scientists is to question facts, find out what cannot fit with a hypothesis and with a plan try and find one reason why it won’t work.  Parris demonstrates a great scientific brain, judged on my criteria, and I think he should be put immediately onto the SAGE committee, as he clearly is a sage.

He ends ‘…who cares what I think?’  Well, Matthew, if it’s any consolation, I do!  But then nobody seems to care much for what I think, either.

A BMJ piece today points yet another finger at the risks of relying on published research as being The Real, Absolute, Science Honesty, or TRASH for short.  The respected journals The Lancet and the New England Journal of Medicine have each retracted a Covid-19 article because the data could not be accessed, and thus could not be verified. Surprise!

Here also is my Rapid Response to today’s BMJ Editorial entitled: Ethnicity and Covid-19:

The rapid pace of scientific research into SARS-CoV-2 shows how reports can be overtaken by events.  The editorial by Patel et al suggests that PHE’s report of disparities between ethnic groups, with a higher incidence of Covid-19 in Black, Asian and Minority Ethnic groups (BAME) has missed a trick by failing to identify why.  I would suggest that when the report was written a “Don’t know” conclusion was better than a false one.  But today a report emerges that the disparity may be due to blood group (1).  This report, albeit awaiting full peer review, points to blood group A as a risk factor.  This may not be sufficient to explain all of the ethnic differences, but it appears to be significant, and confirms earlier small-scale results from China.  BAME people have a higher incidence of Group A than Caucasians.  It also provides a hypothesis as to why:

” Our data thus aligns with the suggestions that blood group O is associated with lower risk compared with non-O blood groups whereas blood group A is associated with higher risk of acquiring Covid-19 compared with non-A blood groups. Unlike for Chromosome 3, we found no difference between patients receiving oxygen supplementation only and those with mechanical ventilation any kind. However, it should be noted that the lead SNP at the ABO locus in our study (rs657152) has been associated with elevated interleukin-6 (IL6) levels in childhood obesity in previous GWAS, providing a hypothetical link to the established association of elevated IL-6 with severity and mortality of Covid-19.  Furthermore, genetic variation at the ABO locus has previously been associated with a number of procoagulant markers such as von Willebrand factor and Factor VIII, and the potential relationship between our genetic findings and the significant coagulopathy that is observed in severe Covid-19 warrants further attention”

This research shows the risk of jumping to conclusions of the basis of unproven hypotheses that fit a non-evidenced sociological construct.  The management of Covid-19 has nothing whatever to do with “systemic racism” in any case.  Racism must be dealt with, but it is dangerous and distracting to conflate unrelated events.

I first suggested that BAME workers in the NHS be protected by withdrawal from front-line care in my blog on April 26th.  I hold to that, whatever the reason for disparity; I am relieved though to note that, despite my Asian ethnic origin (in part) I am blood group O.

Reference

1..Ellinghaus D et al.  The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis.  medRxiv preprint: https://doi.org/10.1101/2020.05.31.20114991.

I can barely turn the page without finding something else to comment on.  Another article bewails the PHE review and asks why no recommendations have been included.  Obviously the review authors have not listened to my pleas for BAME staff to be protected…  and guess what?!  Later on is a review of hospital Covid-19 admissions in the States.  (BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1966 ).  Its conclusions are

“Age and comorbidities were found to be strong predictors of hospital admission and to a lesser extent of critical illness and mortality in people with Covid-19; however, impairment of oxygen on admission and markers of inflammation were most strongly associated with critical illness and mortality. Outcomes seem to be improving over time, potentially suggesting improvements in care.”

Impairment of oxygen on admission.  Markers of inflammation.  Fancy that!  Now, what have I been saying for weeks… keep up!

The Wry Observer Covid-19 update (33)

As an example of how time changes facts I recommend an article on the BBC News website at https://www.bbc.co.uk/news/health-52993734.  It documents where UK coronavirus cases came from.

China, you say.

Wrong.  To spare you agony here is the graph constructed by the COG-UK consortium (their website is also worth a view, though rather technical, but why it hasn’t had itself plastered across the meeja I don’t know; it’s at https://www.cogconsortium.uk/.

The COG group reckon there were over 1300 separate introductions, at first from Italy in late February, , then from Spain in early March and France in late March.  The group note that the Liverpool- Athletico Madrid football match had a negligible impact, as during March there were over 20,000 people flying in every day.

That changes perceptions a bit, doesn’t it?  It proves that one should not jump to early conclusions.  It also raises more questions, like how and when it got to Spain, France and Italy.  Time will tell but I suspect if a lockdown had been in force in mid-February the UK might have been spared its fate.  Then again, telling 20,000 people a day (and that’s just Spain) they cannot enter the UK would have provoked at the very least some dissent.

Too early a lockdown – interference with individual freedom.  To late a lockdown – look what your delay has created.  You cannot win.  Best to sit and wait a bit before blaming anyone and everyone over every and any aspect of the response.  Like next year.  Meanwhile, find a treatment for Covid-19.

Meanwhile one of our acquaintances who lives at Camber Sands told us that the weekend inrush of selfish, non-distancing visitors (who, apparently, were urinating everywhere because the public toilets were shut) effectively confined them to their house.  There will be trouble ahead.  Less deaths, though, I trust!

The Wry Observer’s Covid-19 update (32)

Great cartoon on the “Spectator” newsletter…

“Help me out here – there’s a shortage of fruit pickers”

Two days ago I sent the following draft protocol to Matt Hancock with a covering letter (not reproduced here because it repeats much of what I have put in previous blogs).  We will see if there is any response.

Draft protocol for the management of SARS-CoV-2 virus and Covid-19 disease

1. Preamble

• The Coronavirus pandemic has caused widespread disruption across the world. Originating in China, the virus spread rapidly through international travel.  It has been widely feared because it is highly infectious and can cause severe illness, known as Covid-19.  While many cases of SARS-CoV-2 infection are either asymptomatic or have a relatively mild flu-like illness, large numbers of deaths have occurred.  Respiratory failure is a major cause of death, but associated with the syndrome have been widespread reports of renal failure, cardiac inflammation (myocarditis) and blood clotting abnormalities, with both small vessel blockage from clots (microthrombi) and pulmonary embolism.  It is thus a multisystem disease.  Covid-19 is primarily a disease of older people, and the incidence is higher in those with pre-existing medical conditions such as obesity and diabetes, and in ethnic minority groups.  In children severe involvement is rare, but an inflammatory-type disorder has been reported in clusters.
• The appearance of the virus in the UK is recorded as being in end December 2019 or early January 2020. There is anecdotal evidence that it may have entered the country earlier but as there has until May been no reliable antibody test to screen the population it has not been possible to confirm that sufferers from a mild Covid-19 illness in early December did or did not have coronavirus infection.

 

2. Testing

• Testing for coronavirus takes two forms – antigen testing, to confirm active infection, and antibody testing to confirm previous infection. The latter test is just coming on stream.  The former is now widely available and will indicate the incidence of coronavirus infection.  However on an individual basis a negative result in either test may be misleading, as shown in the table below.

 

Test	Positive	Negative
Antigen test (swab of throat/nose)	You’ve got it	You haven’t got it   You might have got it but it isn’t positive yet It’s a false negative   You’ve had it, and it’s over
Antibody test (blood test)	You’ve had it	You haven’t had it   You’ve got it but it’s too soon for antibodies to have been raised

• From this table it is clear that only positive antigen and antibody tests confer certainty. It has recently been admitted that false negatives may be between 2 and 20% of tests.  A positive antibody test also indicates that a person is probably immune or at least partly so, although as yet it is unclear how long immunity might last.  The uncertainty introduced by a negative antigen test means that widespread testing will not always pick up infection; allied with the possibility of asymptomatic infection, this means that antigen testing alone will not halt spread or a second wave of infection.

 

Prevention of spread

• Social distancing appears to have been effective in limiting initial spread, but is unsustainable long-term. There was initially widespread obedience to distancing and isolation instruction but the early June partial release from lockdown has shown that social distancing is impossible to maintain, particularly among younger people.  This, together with the widespread presence of asymptomatic cases, means that “Track and Trace” plans will not stop spread.  Quarantine of travellers is a blunt instrument that does not have scientific justification.  Neither is it necessary to limit spread if infection does not result in serious illness (ie Covid-19).
• Given the proposals below, prevention of spread may not be an essential part of managing the ongoing SARS-CoV-2 pandemic.

 

4. Symptoms of SARS-CoV-2 infection

• Some or all of the symptoms below may be present:

• • Fever
  • Dry cough
  • Loss of sense of smell (anosmia) and taste
  • Shortness of breath or difficulty breathing
  • Chills
  • Muscle pain
  • Sore throat
  • Nausea and/or diarrhoea

 

• These may occur 2-14 days after infection. Those with symptoms should isolate or be isolated.  However medical help should be sought if there is a significant deterioration in the sufferer, as detailed in Section 5..

 

5. Severe illness

• The serious manifestations of coronavirus infection known as Covid-19 have been devastating. Patients have required prolonged intensive care, but of those ventilated for respiratory failure a large number have died – between 50 and 90%.  It is this severity that has caused widespread alarm.
• However there is now clear evidence that severe Covid-19 disease is due to a hyperimmune state, where the immunologically mediated cytokine cascade is activated abnormally in response to viral infection. This is known as a cytokine storm; cytokines are inflammatory chemicals.  Such activation was probably responsible for the sudden and severe deterioration in “Spanish Flu” patients in 1918-1919, but modern research confirms that in a cytokine storm syndrome (CSS) there is activation of a number of cytokines including interleukins 1-beta and 6.  This activation is disproportionate.  A paradigm in modern times, with proof of cytokine overactivation, is the TG-1412 drug trial conducted at Northwick Park Hospital in 2006.   This produced a clinical condition similar to Covid-19.  All were correctly treated, and none died.

 

6. Mechanisms

• The mechanism for illness (and explanation of some symptoms) is initially destruction of epithelial cells by the SARS-CoV-2 virus, which appears to infect cells by way of a cell surface receptor (ACE-2) to which it binds. This leads to widespread cell leakage and loss of cell function.  In the lungs, such destruction severely limits the ability of alveolar lining cells to transfer oxygen to red blood cells, and cellular function in other organisms may be compromised similarly – in the heart (myocarditis), kidneys (renal failure), gut (diarrhoea) and central nervous system. 
• However the damaging direct effects are intensified by the massive release of cytokines, which cause localised inflammation in the lung walls, blood vessels (vasculitis), kidney and heart muscle. Furthermore, the blood clotting system is also adversely affected (disseminated intravascular coagulation, or DIC, is a known complication in sepsis, and the mechanism is mediated through the immune system).  This leads to abnormal clotting, with small clots (microthrombi) contributing to organ damage by causing tissue ischaemia and larger clots lodging in the lungs (pulmonary emboli) further reducing the ability of the lungs to transfer oxygen.
• There is evidence from around the world that the pathology of Covid-19 conforms to this damage hypothesis. Clinical descriptions of terminal patients best fit the cytokine storm pattern, rather than being simply the result of a large viral load.

 

7. Testing in the prediction of Covid-19 development

• Not everyone’s immune system will be overactivated by SARS-CoV-2 infection – which is why many cases are asymptomatic or mild. There is currently no need on an individual basis to run, or develop, tests predicting risk in the absence of significant symptoms.  However if these develop then immediate action is required.
• Measurement of oxygen saturation. In early Covid-19 the O₂ saturation drops markedly.  This can be checked with a cheap device known as a pulse oximeter, which could be widely distributed at relatively low cost.  If the O₂ saturation drops below 93% in the presence of symptoms, hospital referral is warranted.
• Once in hospital, if the O₂ stays low then tests to look for a developing cytokine storm should be undertaken. These include serum ferritin, which can rise very significantly, and D-dimer, which is an indicator for a hypercoagulation state.
• There are numerous identified risk factors, including old age, obesity, diabetes, hypertension and ethnic origin. Many of these may be explicable.  The immune systems of older people may be less stable and more prone to activation.  In obese people the production of a pro-inflammatory hormone, leptin, is increased, and diabetes (type 2) and high blood pressure are more common.  Genetic differences almost certainly explain the difference between racial groups.

 

8. Treatment

• In the first instance a judgement must be made as to whether a cytokine storm has developed or not. If it appears likely, then immediate immunosuppressive measures should be taken.  There is a perception that this may be detrimental in patients with an infection, but experience suggests that the potential benefit outweighs the risk.  This is because the clinical syndrome is not caused by the infection per se, but by the hyperimmune state it induces.  While antiviral drugs such as remdesivir may reduce viral load they will not have any significant impact on a cytokine storm that has already developed.
• Treatment should include:

 

• • High dose steroids, preferable by intravenous administration
  • Anticytokine therapy, in the form of a “biologic” agent. IL-6 is blocked by tocilizumab; IL-1 beta by anakinra.  Either or both should be considered
  • Low molecular weight heparin (LMWH) given in treatment, not prophylactic doses
  • Oxygen administered by CPAP (artificial ventilation will, because of the structural damage that has caused the hypoxia, be less than effective)
• There is some evidence for the benefit of Vitamins C and D, which might be used as adjuncts. However, the importance of early intervention cannot be overstated; the regime should be given as soon as the tests and clinical state combine to predict Covid-19 development.  Waiting until the patient is sick enough to be on an intensive care unit will jeopardise their survival.
• The three-part regime above comprises drugs that are already available and in widespread use. In rheumatic diseases, and others, they have a profound immunomodulatory effect and their safety is well-documented.
• There is already some evidence that patients with rheumatoid arthritis (RA) on biologic agents are statistically less likely to develop Covid-19 from SARS-CoV-2 infection. Late intervention, as with the use of chemotherapy in cancer, or immunomodulatory therapy in inflammatory arthritis, is proven to be substantially less effective.  Thus, trials of regimes (if trials are even necessary) will produce poor outcomes if too little is administered too late, and failure may be failure of the timing (and composition) of a regime rather than innate inefficacy.

 

9. Potential benefit

 

• If it proves possible to stop SARS-CoV-2 from developing into Covid-19 by early intervention then other, expensive options become redundant. Ventilation is supportive but ineffective; knowing now the lung pathology, this is unsurprising.  In retrospect the provision of large numbers of ventilator beds in Nightingale hospitals will be seen as an expensive diversion; that said, at the time that could not have been foreseen, and the construction of the hospitals was a triumph of emergency planning.
• The widespread provision to the population at large of pulse oximeters, which currently retail between £30-40, would be a small investment laid against the benefit of their predictive diagnosis of hypoxia. Most importantly much of the public panic and hysteria would be mitigated by the knowledge that even if one got ill, one might know if the  clinical state might be deteriorating at a stage when there was a high probability of a cure and a high probability also that very severe disease would not occur.  Early intervention would also prevent some of the later consequences of severe inflammation such as permanent renal and cardiac damage, lung fibrosis and stroke.

 

10. Other remarks

 

• Vaccination.  While the development of a vaccine may be of benefit it cannot be relied upon or result in benefit.  In the first place it may never be possible, as has been the case with HIV.  Secondly, mutation of the virus will render a vaccine useless.  Thirdly, any immunity conferred may not be long-lasting.  Thus to rely on vaccine development as an essential part of returning the country to normal is inappropriate.
• Reconstitution of the SAGE Committee. The key to downgrading the threat of SARS-CoV-2 is to develop appropriate medical treatment of Covid-19.  Epidemics of “ordinary” influenza have never provoked any lockdowns or major economic disruption.  Why?  Because they do not, and are not perceived to, cause significant numbers of deaths (though it should be noted that the 1968 influenza pandemic caused twice as many deaths as Covid-19 has done to date, but without widespread panic).  If treatment stops deaths, the problem is solved without recourse to all the other measures dear to epidemiologists.  Thus the priority should be to develop therapies.  The SAGE committee comprises scientists and clinicians who are both removed from the acute care front line and have no practical experience of the management of either the cytokine storm syndrome or the hypercoagulation states seen in Covid-19.  It is essential that clinicians with such experience are included – not just in any subcommittees, but on the SAGE committee proper.  Such clinicians include clinical immunologists and rheumatologists, these latter because of their extensive experience with the use of steroids and biologic agents.

 

• Presentation of data to the public.
  • Focus of briefings. The basic messages promulgated by government have been repeated daily and ad nauseam. There must be a change of focus.  The media is obsessed with individual case stories, with the problems faced with testing, PPE provision, care home deaths and risks to NHS staff.  Public fear has been fuelled by hyperbole and gloomily presented data on hospital admissions and deaths.  Yet there has been almost no focus on how to treat Covid-19, other than occasional reference in vague terms to a few drug trials (details for which have been hard to find, but from which many rheumatologists and immunologists would argue are inappropriate in regimes, dosages and timing).  This is because all “The Science” has been presented by experts with the wrong experience.  The experts are public health doctors, microbiologists, epidemiologists and infectious disease specialists; they are good on the management of epidemic disease, but not on the clinical management of very sick patients with multisystem disease caused by immunological turmoil.  The public, and particularly health professionals, should have much wider understanding of the basics of Covid-19; how it causes damage, what treatments are being tested and why, and what the potential benefits might be.  This requires presentations by pathologists, rheumatologists and immunologists, and will put a positive “spin” on strategy, which is currently seen as muddled and at times contradictory.
  • Death/incidence figures. The numbers of cases (individuals with positive antigen tests), hospital admissions, ICU admissions and deaths have been presented in an unnecessarily sensational way.  Precision to six or seven significant figures does not imply accuracy.  There are many questions to be asked; how many tests are repeats; how many hospital admissions turn out not to be Covid-19 related; how many deaths are presumed to be Covid-19 related but are not, not least because death certification in the community requires only presumption without proof.  The precision is spurious, and as a result does not command confidence.  Worse, with a couple of welcome exceptions, it is the absolute numbers that are quoted, not the numbers per 100,000 population.  The latter offers a superior way of comparing international figures (hampered though that is by differences in counting).   Media sources have made much of the number of excess deaths; while this may be of interest, it may be followed in later months by a fall in the number of deaths, on the basis that there has been a “cull of the susceptible”.  This point has not been made in response, and must be emphasised.
  • Transparency. I have found it most disappointing that communications made in good faith to senior figures in NHS England and Parliament by myself and others have been not only ignored but also unacknowledged.  If suggestions do not have a basis in science or clinical practice, and there is evidence to that effect, the correspondents should be notified and not left frustrated that their input has been discarded without proper consideration.  In particular, the scientific deliberations of SAGE and other subcommittees should not only be distributed in digest form to healthcare professionals, but there should be a formal conduit for responses and proposals.

 

11. Conclusion

 

The focus of health services must now be to downgrade the danger of SARS-CoV-2 infection by finding and employing effective treatment to prevent its progression to the Covid-19 syndrome. The unreliability of testing, of contact tracing and quarantining, and the failure of social distancing measures post-lockdown combine to produce a potential cycle of recurrent lockdown and release, with dire effects on the national economy.  With effective Covid-19 treatment it becomes unnecessary to do any of these things, relieves pressure on vaccine development, defuses the current hysteria and “coronaphobia” and will save lives.  Early appropriate testing in sick people will prevent the NHS from being overwhelmed as it will direct effective treatment and shorten hospital stays.

If SARS-CoV-2 had only ever produced a mild flu-like illness none of the extreme measures employed to date would have been necessary.  It should be the task of medicine to ensure that its capacity to kill is downgraded to such an extent that it can be seen as an irritant rather than a threat.

End of protocol.

Comments from readers welcome.  Two last things.  The article below describes the Kawasaki-like illness in children as a new syndrome, and recommends adding intravenous gammaglobulin (IVIG) to the treatment cocktail.  I have been wondering whether to include that in my protocol, but rather doubt that availability is sufficient.  But I think I will.  See https://www.medscape.com/viewarticle/932008?nlid=135885_5642&src=wnl_newsalrt_uk_200609_MSCPEDIT&uac=308617HG&impID=2412718&faf=1

And secondly a study has shown rather alarming spread and persistence on surfaces of a virus.  It’s not clear whether the virus they used is differently robust from SARS-CoV-2 but it should make people think.  See https://www.sciencedaily.com/releases/2020/06/200608092951.htm?utm_medium=email&utm_source=CampaignMonitor_Editorial&utm_campaign=LNCH%20%2020200610%20%20House%20ads%20%20JO+CID_3ce09f7eddbeffd75f0880fa3b4de691

 

 

The Wry Observer’s Covid-19 update (31)

359 new deaths. At least it appears not to have “jumped” today. Today’s “The Times” brings a deep depression on me. It appears that the Francis Crick Institute is now researching what tests might be done on people to predict whether they will develop severe Covid-19. I first identified two tests in my blog on May 1st, and another a couple of weeks later. Fine, you might say, great minds are thinking alike here but if there is clear evidence that some abnormal tests are a marker, as was quite apparent at the end of April, why has it taken a month not to introduce them but to research them?

This adds even more weight to my contention that a serious error has been made in excluding front-line physicians from SAGE. It is quite clear that there will be a second wave, whether or not we have a Track and Trace system. Why? Because there are large numbers of asymptomatic SARS-CoV-2 carriers who will not be picked up in a timely fashion. Also because social distancing, especially among the young, has been abandoned (come to Rye or Camber Sands and you will see proof). We cannot keep locking and unlocking the nation piecemeal; people will rebel. So let’s just abandon the whole exercise as a waste of time and money, and concentrate on what matters:

How do you stop SARS-CoV-2 from developing into Covid-19?

1. Identify who has it through testing (though this is not reliable)
2. Check those with symptoms:
a. Pulse oximetry showing an oxygen saturation of less than 91-93%
b. Elevated serum ferritin
c. Elevated D-dimer
3. Treat aggressively in the event of abnormalities – because these suggest the development of a cytokine storm and coagulation defect leading to thrombosis, using
a. High dose steroid
b. Cytokine antagonist (anakinra, tocilizumab, known as biologics)
c. Low molecular weight heparin (LMWH)

All of these treatments are in use (for other things), safe (when used and monitored properly) and theoretically effective. There is already anecdotal evidence from centres that use such a regime, as well as ancillary evidence suggesting people on these, especially the biologics, for other conditions have a reduced incidence of Covid-19.

The fuss over ethnicity persists. In the British Medical Journal this week there’s an editorial suggesting we need a public inquiry now, “before a second wave develops”; BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m2052. As we are continuing to learn more and more about how the virus causes damage, how it spreads, how it may not produce symptoms, for me an inquiry now is a complete waste of time, but the authors suggest that the ethnic issue requires “representation from the communities affected”.

I am bemused by this. It’s not a scientific justification but a politically correct one. Consider as an analogy sickle-cell anaemia. This affects black people. It has nothing to do with deprivation or discrimination because it is a genetically determined condition. Another condition, beta-thalassaemia, affects people of Middle-Eastern and Eastern European origin. Again, no mystery here – it’s genetic. So, given that there is evidence of predisposition for BAME people (or at least, some of them) on a genetic basis, what contribution can community representatives make to a scientific and clinical investigation. Socio-political correctness trumps science? I think not.

The text of my BMJ response is reproduced below.

Dear Editor,

There should be an inquiry into the response to Covid-19, but not now. There are still too many unknowns, both epidemiological and clinical, for an inquiry to be able to draw any sensible conclusions. In response to the five points suggested for scrutiny I suggest:

1. A major exclusion from discussions has been that of clinicians at the sharp end. The problem with Covid-19 is that it may kill people; local government leaders are unlikely to be able to contribute anything sensible to the clinical discussion of how to stop it killing people.

2. Any review of procurement must be set in context with the similar problems faced by other countries. Furthermore, as it becomes increasingly clear that mechanical ventilation is unhelpful in many cases (because it will not restore blood oxygen levels if the alveolar epithelium is significantly damaged) the whole purpose of setting up ventilator-equipped Nightingale hospitals must be reviewed.

3. I don’t think that structural disconnect between health and social services altered the spread. What mattered was the SARS-CoV-2 was far more infectious than believed. The care home “epidemic” may well have been caused by the central directive to empty hospitals without testing patients before discharge; the only benefit of involving more agencies would have been to increase the pool of those whose working principle, when confronted with a plan, is to work out what could possibly go wrong with it.

4. It is apparent that any ethnic predisposition to Covid-19 may have a genetic basis, and attempts to present the subject in sociological terms is unscientific and runs the risk of serious predisposing factors being overlooked. What purpose is served by bringing in representatives from “the communities involved” other than to pay lip service to political correctness? Unless the proposed representatives have a firm grasp of statistics, epidemiology, genetics and risk factor correlation their presence would be a hindrance.

5. Brexit is irrelevant.

What is actually required is not some multi-function set of panels looking at peripheral issues, which will end up, as with all inquiries, stuffed with the wrong people, but an immediate development of treatment to stop Covid-19 from being a serious clinical problem. There is growing evidence (and the fact that it is growing so rapidly underlines my contention that an inquiry now is a waste of time, because the Science is constantly changing) that the serious multisystem disease seen is a function of (1) deep viral exposure and (2) a subsequent cytokine storm. The first has been partly addressed by PPE; the second has hardly been addressed at all.

There are two stages for this second part.

First, the development of risk-indicating tests. The required tests are already available; oxygen saturation measurement (as Dr Rammya Mathew suggested in a previous column (1), and as I have been arguing for weeks, availability of pulse oximeters enables this), and tests in deteriorating patients that point to cytokine overactivity and thrombotic risk such as serum ferritin and D-dimer.

Second, the development of cytokine storm management. In those who have abnormal tests showing they are developing a cytokine storm, the use of cytokine blockers, low molecular weight heparin in treatment not prophylactic doses, and steroids (in high dose, given early) must be instituted. Early. Current thinking that one should reserve these for late cases is analogous to treating cancer only when it gets to stage 4; it then does not work. Neither does dribbling in too little. Likewise treating with antiviral agents may reduce the ongoing storm but will do nothing to mitigate a storm that is already present. Which is the more important – the storm or the virus? My money is on the storm.

These are the measures that need to be in place before a second peak. Then patients may get SARS-CoV-2 but not die from Covid-19. A second wave is unstoppable if, as in Singapore, it transpires that large numbers of infected people are asymptomatic. That is why what matters is treating the severely ill with things that work. Deciding that is a matter for clinicians, not epidemiologists, public health doctors, social service or community groups or a public inquiry.

In conclusion Stephen Glover points out that in the 1968 influenza epidemic (which killed twice as many people as Covid-19 has yet done) there was no panic. He asks why (2). That might be an interesting subject for an inquiry.

It is now six weeks since I first wrote about the likelihood of severe Covid-19 being due to a cytokine storm. Clinicians with experience of dealing with this have not been consulted, as far as I am aware. I have had no response to my repeated attempts to highlight this with the powers that be – not even acknowledgement of receipt of my communications. If I am proved correct (and I concede that The Science may yet come up with alternative mechanisms for severe illness), I wonder how many lives would not have been lost.

References:

1. Mathew R. Innovation during the pandemic. BMJ, 12th May 2020. https://doi.org/10.1136/bmj.m1855

2. Glover S. News spreads faster than the virus. The Oldie, June 2020, 63

I am currently writing an open letter to Matt Hancock, with a draft protocol for where to go from here. As it appears that he doesn’t answer emails I shall send it the old way, on paper in an envelope, first class. I have an appropriate stamp of HMS Warspite firing a full broadside on D-Day 1944.  Copies to… many!