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Covid-19

Is smoked salmon dangerous to eat?

Earlier this week the UK issued a safety alert about the presence in smoked salmon of the bacteria, Listeria.  This alert was precipitated by reports of 14 cases of Listeria gut infection in the past 2 years, with 8 since the start of 2022; 3 of those infected had died.  These cases had in common that they had eaten contaminated ‘ready to eat smoked fish’, predominantly smoked salmon.  The UK Health Protection Agency recommended that ‘vulnerable’ people – which included women who are pregnant, those with a weakened immune system including those who are on steroids and “those aged over 65” – should heat any raw smoked fish before eating.  Is this just scare mongering or is the advice reasonable?

What is Listeria

  • Listeria is a bacterium first identified as a cause of human infection around 100 years ago 
  • There are many different species of Listeria but mainly it is one, Listeria Monocytogenes, that is relevant to humans
  • Listeria can grow in many foods and when we eat a contaminated food, Listeria can lead to infection called Listeriosis
  • The infection varies in severity from being asymptomatic, to a mild gastro-enteritis, to a severe infection that spreads from the gut to other sites within the body
  • Severe infections are very rare but can exceptionally be fatal
  • As stated above in the recent alert, only some groups of the population are at risk of getting severe infection eg pregnant women and those with weakened immune systems
  •  (Pregnancy is associated with a reduction in the level of immunity so the mother’s immune system doesn’t ‘reject’ the foetus)

What foods can carry Listeria?

  • Many raw animal products can carry Listeria, these include:
    • Unpasteurised milk 
    • Cheeses made from unpasteurised milk, especially soft brie/camembert-type cheese
    • Shellfish
    • Cold smoked fish (smoking doesn’t kill Listeria)
    • Cured meats
  • But the fact that a food carries Listeria doesn’t mean that it will cause infection, there needs to be a sufficient concentration of the bacteria
  • Food regulators will therefore test batches of foods such as those above and identify not only if Listeria is present, but if the concentration is higher than acceptable
  • They take samples of the salmon and try and grow Listeria in the lab
  • Concentration is based on counting the number of colonies of the bacteria per gram of food stuff.  
    • Below 10 colonies per gram is acceptable
    • Between 10-100 colonies per gram is a ‘grey zone’
    • Above 100 colonies per gram is unacceptable and the batch is withdrawn from sale

How common is it that food like smoked salmon is contaminated?

  • It is impossible to ensure that cold smoked fish is consistently free from Listeria
  • The answer to “how common does contamination occur?” is, of course, that it varies!
  • I found a research paper from 20 years ago that had tested a large number of samples selected from 19 batches of smoked salmon packaged in Europe, North America, and Australasia
    • Listeria was detected in at least 10% of the samples collected in the large majority (16/19) batches
    • However, as I mentioned above, that does not mean that the concentration of Listeria was high enough to make people ill 
  • The risk depends on the processing plant, how the salmon is prepared, packaged, and stored
  • Accurate data rely on food safety authorities to have the testing regimes in place to monitor the levels

Risk factors for Listeria in smoked salmon 

  • Listeria can survive in fridge temperature eg 40
  • Indeed can continue to multiply at this temperature, but won’t multiply in freezer 
  • Hence the longer the salmon is stored, even in the fridge, if Listeria is present, the higher the concentration
  • Risk not reduced by how salty is the fish or when vacuum packing is used
  • It is only heating by cooking that destroys Listeria  

What is the incubation period for getting ill?

  • The incubation periods is the time from ingestion of a contaminated food to becoming ill
  • What is interesting about Listeria is that, unlike what we know about other bacteria contaminated food when infection happens very soon after ingestion, the incubation period following Listeria contaminated food can be much longer
  • The figure below shows the results from one study of 37 cases of the range of the incubation period
  • As you can see, in most patients, it is just a few days but in some it can be a month or longer
  • Indeed cases with illness starting 3 months after the presumed exposure have been reported
  • With such a long exposure it can be very difficult to link an illness to what was eaten so long ago
  • Although modern investigation techniques identify the specific DNA ‘signature’ of the Listeria in each patient which can then be linked to a specific batch of salmon

Why the sudden concern?

  • Outbreaks of Listeria from cold smoked salmon are not new
  • It is difficult to get accurate data because many cases are presumably under-reported
  • The number of cases in the current outbreak is similar to other outbreaks in the past
  • I can’t find evidence that the risk of smoked salmon being contaminated during its production and handling has increased (or gone down!)
  • The overall number of reported cases relative to the millions who eat smoked salmon is tiny

Conclusion 

  • The recent publicity is timely as it reminds us that:
    • many raw foods can be a source of bacterial infection in general 
    • cold smoked salmon is potentially a risk for Listeria in particular 
  • The risk of getting seriously ill is tiny, has probably not changed and should not be a worry
  • We do need to be vigilant, and for smoked salmon in particular, do not keep beyond its use by date (this message is my main reason for writing this blog)
  • As with cheeses from unpasteurised milk, given that smoked salmon is not one of life’s essentials, it should be avoided by pregnant women and those who have impaired immunity (but this is not new advice although not often publicised)
  • Nothing to stop enjoying it cooked with scrambled eggs!

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The new booster vaccines from Moderna and Pfizer: what are the facts?

Health Updates on Sept 7 2022 12:21PM EDT-Published on Sept 6 2022 4:50PM EDT

The UK, US, Canada and other countries have announced a programme of a 4th vaccine dose, with the possibility of using the new vaccines developed by Moderna and Pfizer, designed to increase protection against the Omicron variant. Studies published last week have evaluated whether these new vaccines offer any additional benefit

The existing vaccines

  • The vaccines in use up to now were all developed to combat the original Wuhan strain
  • They have been of proven success in reducing the severity of Covid-19 infection
  • Somewhat surprisingly, this success has continued despite the emergence of new variants over the 18 months since these original vaccines were launched
  • The problem with these vaccines has been their limited ability to prevent infections happening.  Although most infections – especially with the current prevalent Omicron variants – are mild, there are still concerns about long Covid-19 in some sufferers as well as work and school absences from mild infections
  • Some of the ‘Wuhan’ vaccines’ failure to prevent infection is due to waning immunity but some may be related to the reduced protection they provide against the new variants
  • Thus it would appear to make sense to develop vaccines that are effective against the newer strains

Why haven’t new vaccines been developed before now?

  • In fact new vaccines have been developed almost continuously since the Wuhan vaccines were released
  • The two companies marketing mRNA vaccines (Pfizer and Moderna) from the outset were clear that this technology could easily be modified to create new vaccines, if new strains arose
  • Indeed regulators offered a ‘light touch’ approval process – ie because the initial vaccines that resulted from the technology were effective and safe, there was a low bar for the regulators to allow newer vaccines derived from the same approach.
  • The drug companies though had 5 problems until now in mass producing a new vaccine:

Pfizer and Moderna’s new ‘bivalent’ Vaccines   

  • On August 15th in UK and September 2nd in USA and Canada, approval was given for the use of so called ‘bivalent’ vaccines
  • The term ‘bivalent’ means simply (the clue is in the ‘bi’) that the vaccine is designed to be active against both the original Wuhan strain and Omicron as well
  • Actually, having vaccines that work against more than one variant is not unusual: I have discussed previously in this blog how the annual flu jab is ‘quadrivalent’, to be effective against both 2 strains of influenza A and 2 strains of influenza B

How easy is it to show that these new bivalent vaccines work better than the original vaccines?

  • It’s not a given that these vaccines would be more effective
  • None of the previous vaccines have been particularly effective at stopping transmission of mild illness, so why should the new vaccine be any different?
  • It is of course also difficult to do studies to show that they are more successful than the original vaccines for several reasons
    • The original studies involved tens of thousands of individuals who were randomly allocated to either the Wuhan vaccine or placebo and then followed up to see who got infected
    • To mount such a trial comparing the new versus the original vaccines might need hundreds of thousands of participants if the difference was only modest
    • Most people in the west are already protected by previous vaccines and previous infections, so whichever vaccine a participant in a trial received, then most cases of Covid-19 would be mild and would require regular and expensive  PCR testing and follow up of all the study subjects
  • Thus the only data we have is from laboratory studies comparing the level of immunity in the blood (ie antibodies) between study participants receiving the Wuhan and those receiving the bivalent vaccines
  • Scientists have now studied these laboratory results and using computer modelling tried to predict how they would translate into clinical success
  • Indeed the scientists in a paper published last week, did exactly that.  They calculated the likely risk of infection:  both (i) any infection with symptoms and (ii) severe infection (leading to being in hospital) in 3 groups of people: 
    • Those who had just had the normal course of vaccines
    • Those who had a booster with the original Wuhan vaccine
    • Those who had had a booster with the new combined vaccine 
  • What they found is shown in the graph below
    • The blue bars show the success against any infection with symptoms
    • The red bars show the success against serious infection (ie hospital admission)

*https://www.nature.com/articles/d41586-022-02806-5?utm_source=Nature+Briefing&utm_campaign=db180cc7fb-briefing-dy-20220905&utm_medium=email&utm_term=0_c9dfd39373-db180cc7fb-46471378

  • The top bars (no booster) show that there was only 50% protection against getting any infection with symptoms and around 90% against severe infection
  • The bottom 2 sets of bars show that a booster, either with the Wuhan vaccine or with the combined new vaccine, produces almost identical protection
  • Basically it’s not what booster vaccine you get, it is the fact that you get a booster that makes the difference

Conclusion

  • I have not discussed safety, but I can’t see any reason why there should be any different safety concerns with the new combined vaccine compared to the original vaccines
  • Our pre-existing level of immunity, from our previous 3 doses plus any natural immunity we have acquired from infection, still provides good protection against serious infection
  • A further booster will be beneficial but probably if this was with the Wuhan vaccine it would probably have been fine
  • Since the companies are now producing the bivalent vaccines for mass use, then that is what we will receive, but don’t expect that they will provide any special protection against getting minor infection from the current or any new main circulating variants  

Appendix of interest to the more mathematical scientists amongst the readers!

  • The above result was somewhat surprising, as I assumed the variant-based vaccines would give more immunity than older vaccines
  • The reason seems to be that because of our existing immunity, it is much harder to show additional benefit
  • In other words: if we had the pandemic starting now, and none of us had any pre-existing immunity and we were faced with the Omicron variant, we would be much better protected if we had the new combined vaccine
  • In practice we have some protection although the exact level can only be guessed at as it wanes over time 
  • This is shown in the diagram below
    • The percent on the y axis shows how much greater is our protection from having a booster compared to not having a booster
    • The curves are not straight horizontal lines because our pre-existing immunity also provides protection 
    • Thus at the extreme (right on the diagram) if there was 100% immunity prior to having any booster, then there is no scope for any additional protection
    • The lowest (yellow) curve shows the situation for a booster that is based on a vaccine not related to the main variant causing infection (eg the situation of giving the Wuhan vaccine today when most people are getting Omicron).
    • The highest (brown) curve shows the situation for a booster that is based on a vaccine which is related to the main variant causing infection (eg the situation of giving  an Omicron based vaccine today when most people are getting Omicron)
    • Ignore the  middle (orange) curve, which  is the average
*https://www.nature.com/articles/d41586-022-02806-5?utm_source=Nature+Briefing&utm_campaign=db180cc7fb-briefing-dy-20220905&utm_medium=email&utm_term=0_c9dfd39373-db180cc7fb-46471378

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Omicron BA.5 is causing a lot of trouble: here’s why it is set to continue!

Covid-19 infections are on the increase, many people are now getting their second or third Covid infection but now with Omicron BA.5* as the main culprit.  Why is this happening, and why is there so little apparent protection through immunity either from previous infections and or from the vaccines? 

*In this blog I mainly focus on BA.5 variant where there is separate information.  Much of the available laboratory and epidemiological data do combine the results from BA.4 with BA.5, as they are very similar in their effects.  Hence some places I will refer to BA.5 and other places BA.4/BA.5

How much more infectious is Omicron BA.5?

  • We are used to new strains of Covid-19 virus emerging during the 2.5 years of the pandemic and rapidly becoming the predominant strain
  • The reasons why this happens relate, firstly, to the new strains evolving to overcome the immunity mounted to older strains and, secondly, in some instances the new strains being naturally more infectious
  • You may recall the ‘R’ number being the infectiousness score of a virus
  • Indeed we were worried by the R for the original Wuhan strain creeping above 1.0 as it would represent a growing epidemic as from this slide from the BBC back in May 2020 – an R of 1.1 was ‘bad news’:
  • As a comparison the R value for BA.5 is above 3!!

BA.4/BA.5 are now the predominant strains in many countries

  • The  figures below are from the USA (but other countries are the same!) and show that BA.4/BA.5 from being barely registrable on 7th May (blue arrow) by 9th July BA.5 accounted for 70% of all new cases (red arrow)
Source: https://erictopol.substack.com/p/ba5-chapter-2

Could we face other, even more infectious, strains?

  • Coming to terms with BA.5 is challenging enough but are there still other new strains to come?
  • This of course would always be expected in a pandemic
https://www.euronews.com/next/2022/07/15/is-covid-ever-ending-meet-centaurus-the-latest-omicron-subvariant-that-could-become-dominant
  • Indeed this week a new strain from India (unhelpfully given the nickname “Centaurus” and currently referred  to as BA.2.5!) is increasing there and has been found in the UK, Germany and Netherlands
  • The worry is that this new strain could bypass our immune system (see below) like BA.5 
  • For now I will focus on BA.5

How different is BA.5?

  • Well here is the interesting thing!
  • Genetically it is very similar to the other Omicron variants from BA.1 onwards that had been responsible for all the cases since the beginning of the year
  • When I say the genetics are similar, I mean that the detailed DNA of the virus and its all-important spike protein are similar to other Omicron variants and, indeed, quite different from the earlier variants
  • In the picture below, the relationship between the structure of all the major variants of Covid-19 since the start of the pandemic is shown
https://erictopol.substack.com/p/the-ba5-story
  • Essentially how close to each other the different variants are positioned on this drawing is an indication of their genetic similarity
  • It is easy to see that BA.4 and BA.5 are positioned very close to the other Omicron (BA) variants and some way from older variants like Delta 
  • But this is not the whole story!
    • Although BA.5 is similar genetically, the same cannot be said for the body’s immune response 
    • In practice the body’s immune system ‘sees’ BA.5 as no more similar to the other Omicron variants than it does to the original Wuhan variant
  • Look at this picture where a laboratory examined the immune patterns of the different Covid-19 variants
https://erictopol.substack.com/p/the-ba5-story
  • In simple terms the closer two variants are placed in the diagram, the more likely the body’s immunity to an infection from them is similar
  • What this picture clearly shows is that (to me surprisingly!) BA.4 and BA.5 are very different from the other Omicron variants in this respect
  • As a consequence, the immunity from a prior infection say with the first Omicron variant BA.1 (we may have caught in January this year) would provide less protection  against BA.4 or BA.5 than it would do against the original Wuhan variant!
  • Why is this so: basically BA.4 and BA.5 have a few extra crucial mutations –  not only in the spike protein – but in other key bits of the virus that allow the virus to stick to our cells and multiply 
  • Thus BA.5 can easily evade the immunity we have established with previous infections both from other Omicron as well as non-Omicron variants

Do these theoretical differences transfer into what is happening ‘on the ground’?

  • The above all refer to research from the laboratory; do these worrying trends reflect what is happening in terms of reinfection rates? 
  • Thus one measure of how successful BA.5 is at evading our immune response from previous infections is to look at the risk of second infection
  • Here are some data from France showing the risk of a second infection following a first infection with different variants within each particular wave (typically over the 2.5 years of the pandemic each wave lasts around 6 months)
  • At the start of the pandemic with the Wuhan variant, reinfections during that first wave were very rare – so rare that there were headlines if there was a second case in the same person!
  • With Omicron in the current wave, second infections, and maybe third or more, are increasingly common.  Given the above information about the differences between the Omicron variants, this is perhaps not surprising 

What about vaccines? 

  • It is well known a full course of vaccines, including boosters, protect against getting serious infection and this applies to all the known variants including BA.4/BA.5
  • Similarly the vaccines do not protect against getting any infection, and that is as true, or more true, for BA.4/BA.5 than older variants
  • Hence, we would not expect the current vaccines to prevent mild infections with BA.5
  • There are new vaccines, designed to be more active against Omicron, which are being trialled, but my guess is they may still not be much use against BA.5

The big question is about severity

  • Does it matter if our immunity to BA.5 is weak, if the infection from it is less severe and/or that our vaccines will still protect us from any severe consequences?
  • As overwhelmingly most of the population at risk of severe infection from BA.5 (ie age over 60) have been vaccinated, it is very difficult to know what the severity would be if they had not been vaccinated 
  • There have been recent rises in the absolute numbers of cases admitted to hospitals in many countries, who have tested positive for BA.5
  • These rises are driven by the growth in the overall number of cases and not by any difference in the severity of infection caused by BA.5 compared to other Omicron variants
    • ie if the hospitalisation rate during the current BA.5 wave is say 1/1000 cases
    • in a region with 1 million cases there would be 1000 hospital admissions
    • in a region with 100,000 cases, there would be 100 hospital admissions

But what about long Covid?

  • What causes and drives ‘long Covid’ is still a mystery
  • There is no evidence that any particular variant is associated with a greater risk of long Covid than any other variant, and that is just as true with BA.5
  • But recent data from the USA suggests that the likelihood of having long lasting symptoms following an infection with Covid, increases with each infection
https://www.webmd.com/lung/news/20220707/each-covid-19-reinfection-increases-health-risks
  • This study published last week does have some weaknesses and it may be that by chance alone, the more bouts of infection, the greater the chance that one will have longer lasting symptoms
  • Many people will though now be having  a second or even a third infection from BA.5, because it is so much more infectious – and this theoretically increases the likelihood of long Covid
  • It does not seem likely that BA.5 on its own poses a greater risk of long Covid

Conclusion

  • It is certainly the case that BA.5 has shown we are going to have to live with the risk of having repeated minor infections with Covid-19 and there is no obvious end in sight
  • Existing vaccines and even previous infections do not offer the protection against mild infection with all its consequences including the risk of long Covid
  • Mask wearing, which was compulsory in many situations and now only advisory, absolutely cannot be off the agenda

And finally..

The author of this blog succumbed to my first infection a month ago, nasty but fortunately short-lived but may have coloured my views a little!

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Monkeypox: why the sudden concern?

The media have been full of headlines about a tiny number of cases of the viral disease monkeypox.  What do we know about it, why has there been a recent surge and, given the experience with Covid-19, should we be getting concerned?

What is monkeypox infection like?

  • Monkeypox is a viral infection that causes flu-like symptoms
  • It also causes swelling of the lymph nodes
  • It has a characteristic blistering rash especially on the hands, feet and face
  • Most people recover within 2 weeks

Is there more than one kind of monkeypox?

  • Like Covid-19, there is more than one genetic strain
  • There appear to be 2 major strains, one predominant in Western Africa in countries such as Ghana and Nigeria, and the other in Central Africa in countries like Democratic Republic of Congo
  • The Western Africa strain has a very low mortality – even in poor rural populations – of around 1%, whereas mortality is much higher – 10% – from the Central Africa strain
  • Fortunately the strain identified as causing cases in Europe and America is the milder West African strain

Why have public health experts got excited recently?

  • Basically up to the last week or so, cases of monkeypox were only seen in Africans or in people from Africa who had spread the infection elsewhere
  • The recent concern is that the new cases in Europe, Australia and North America do not seem to have had any African contact 
  • Obviously, the number is growing but around 200 cases have now been diagnosed in the past week outside Africa which is more than the entire total of non-African cases diagnosed since 1970
  • Why this should be so is unknown

How does monkeypox spread? 

  • Monkeypox spreads differently from Covid-19 
  • Basically it requires much closer contact 
  • Also – unlike Covid-19 –  asymptomatic spread, ie catching the disease from someone without symptoms at the time of contact, is (or was) very unusual

Anything unusual about the new cases in Europe?

  • As mentioned above, the lack of contact with an affected African individual is very unusual 
  • Secondly, and at this stage only based on individual reports, there does appear to be asymptomatic spread, which could be worrying
  • Thirdly, the recent cases have been proportionately greater in gay and bisexual men aged 30-50
  • Whether this suggests that it is transmitted by sexual intercourse is unknown, but monkeypox had not been thought to be a sexually transmitted infection

What do we know about the monkeypox virus?

  • Monkeypox virus is much larger than the Covid-19 virus 
  • Its genome is DNA rather than RNA (like Covid-19) and this is important as DNA viruses are more resistant to mutations, so for example it is much less likely than Covid-19 to mutate into more transmissible forms (like Omicron)
  • The genome of the virus was sequenced last week (in Portugal) and we still need to see if there are any mutations that might evolve as new cases emerge

What about the connection with smallpox?

  • This is probably the good news bit!
  • Smallpox and monkeypox viruses are closely related
  • Smallpox was only transmissible from person to person and hence a widespread international vaccination campaign led to the complete eradication of smallpox
  • The last case of smallpox in the world was in Somalia in 1977
  • Thus for decades there have been no new cases of smallpox and there is no need for anyone now to be vaccinated it
  • Studies from Africa show that smallpox vaccine provides 85% protection against monkeypox which is good news for older generations who have received this vaccine
  • Interestingly smallpox vaccines are used as a treatment for new cases of monkeypox, as well as for protecting close contacts
  • There are also specific monkeypox vaccines that have been developed for use in Africa, which seem to be very effective with low risk of side effects

The outstanding questions:

  • If this virus is now spreading from asymptomatic cases, that will make quarantining and containing spread more difficult.
  • Whilst older people will have been vaccinated against smallpox, and hopefully protected against monkeypox, if any kind of outbreak takes hold it could it spread quite quickly amongst generations who were not vaccinated 
  • Remember it is a mild disease, but I’m not sure that any country would wish to see an outbreak, or any individual developing an infection, even with ‘only’ a 1-2 week duration of being unwell, given what we have all gone through with Covid-19!

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New Omicron variants coming our way soon: how protected are we?

As the original Omicron variant continues to mutate, its greater ability to transmit has been offset in terms of the public health risk by (i) the milder illness it causes and (ii) the protection against severe disease from both natural infection and the current vaccine regimes.  However, should we now be worried about the new variants now spreading from South Africa to Europe and North America?

A bit about the original Omicron 

  • The original Omicron variant when originally identified was not thought to have significant subvariants 
  • Then in South Africa, in late 2021, 3 sub-variants of Omicron were identified, and are now referred to as BA.1, BA.2 and BA.3
    • These 3 had many different genetic mutations from the original Omicron, but also differed from each other
    • All these subvariants were associated with mild infection, although some of the protection against serious infection will be a consequence of immunity from either, or both of, vaccines and natural infection
  • One or more of these variants rapidly predominated in Europe
  • Indeed in the UK, during the 2021/22 winter peak of Omicron, around 95% of new cases reported were from BA.2
  • There have been many reports now of people having a repeat attack from one of these original Omicron variants, but these have also been mild
  • As a consequence, and despite the greater transmissibility of Omicrons BA.1-3, the milder disease consequent on our natural and vaccine immunity led to the lifting of behaviour rules and also a reduction in self testing which has had a knock-on effect on our not knowing the exact numbers of cases

What are Omicron BA.4 and BA.5?

  • These are two quite different subvariants of the original Omicron BA.1-3
  • Both were first identified in South Africa this year in two provinces: BA.4 in Limpopo in the far north and BA.5 in KwaZulu-Natal in the south east. 
  • These two subvariants have some of the same mutations as the original Delta variant
  • They also have different mutations on the spike protein to other Omicron subvariants,  which makes them more sticky onto human cells and hence more likely to lead to infection
  • Thus, not surprisingly, there has been a massive increase in the proportion of cases in South Africa due to these subvariants over a very short time
  • As shown in the picture below, almost all cases in South Africa now are either BA.4 or 5
https://www.nature.com/articles/d41586-022-01240-x?utm_source=Nature+Briefing&utm

Have these variants spread to other countries?

  • Indeed yes and they are already contributing to a growing proportion of cases in the few countries that have been able to test for these
Proportion of current cases due to BA.4 or BA.5: selected European countries
  • Thus they probably amount to 15% of all cases in the UK (both variants combined)

Do we need to worry about these subvariants?

  • Obviously, the big question!
  • Compared to the original Omicron subvariants, BA.4 and 5 are probably more transmissible so the absolute number of new cases is likely to increase (compared to what the numbers would have been if BA.1-3 were predominant)
  • Indeed, the number of notified cases in South Africa has risen from around 1000/day in mid-April to over 10,000/day by the end of last week, a tenfold rise in less than 4 weeks
  • As a consequence of the numbers alone, this has had a knock-on effect on the numbers being admitted to hospital; and indeed the challenge of increasing sickness amongst South African health workers with the new sub variants
  • As with the original Omicron subvariants, the disease though is predominantly mild

What about protection from vaccines and previous infections with the older Omicron subvariants?

  • That at the moment is the big unknown
  • Experts are asking if this surge in cases in South Africa means that these new subvariants can evade our acquired immunity?
  • Alternatively is any protection from the vaccines/previous infections waning? Hence the increase in cases from these subvariants just represents that phenomenon and would have happened with any circulating variant.
  • This is where a research paper published this week might provide some insights to address this issue:
  • This is what the research did

Their conclusions as summarised below was interesting and perhaps sobering!

  • In brief the ability of this virus to mutate means that herd immunity is not an achievable outcome 
  • Just giving boosters of the existing vaccines derived from the original Wuhan variant may not be of much benefit

But to some extent this is the situation with seasonal flu – except that Covid-19 mutations seem to be occurring in a 6-month cycle (see this picture from this week’s Nature)

And finally are there new more effective vaccines coming on stream?

  • Before the BA.4/5 issue, both Moderna and Pfizer were already  modifying their mRNA vaccines to be effective against Omicron BA.1-3
  • They have promised results by June 30th
  • I wonder if the BA.4/5 story means that the virus is mutating so quickly that major beneficial changes cannot be achieved with these new Omicron-derived vaccines
  • The virus can mutate more quickly than vaccines can be developed to stop transmission

Conclusion

  • Covid-19 is clearly here to stay and will continue to mutate
  • The good news is that whilst repeat infections are likely, and may be impossible to prevent, the dire consequences of 2020 should not recur

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Could Covid be on the up again?

Despite the worldwide relaxation in Covid-19 mitigation and the awful situation in Ukraine displacing other news, that does not mean that Covid-19 has gone away.  What do the latest data show?

We cannot rely on the numbers of self-reported cases

  • Regular readers of this blog will know that the number of self-reported or health care professional-reported cases cannot be relied on as a source of the true underlying trends
  • Such information can only be gained from epidemiological studies of random samples of the whole population. In the UK, we have been fortunate to have 2 such studies: 
    • REACT which which has nearly 100,000 people sending in swabs every month in England
    • The Office of National Statistics (ONS) Covid-19 Infection survey which has 180,000 people sending in swabs every fortnight from all 4 countries in the UK
    • These studies therefore pick up anyone who is positive, whether or not they have symptoms and whether or not they did – or did not – report (for example) the results of a home lateral flow test
    • These studies can usefully estimate the total number of Covid-19 cases there are likely to be in the whole country
  • This is the most recent data:
  • Thank goodness we have stopped seeing these meaningless reports in the media of the number of reported cases
  • I am sure that the same under-reporting is a worldwide phenomenon, we are just fortunate in having UK funding of these population studies*

*Although the Research Lead for the REACT study told me on Friday that government funding is ceasing for that study at the end of the month as they believe it is all over!

What do these epidemiological studies show?

  • In England there has been very little change in the rate of new cases since the beginning of the year
    • Monthly rates hover around 4% or 1 in 25 of the population
    • If anything, last week saw a small rise
  • In Scotland the recent rise is more pronounced and is unlikely to be due to the normal ‘up and down’ in such data
  • A similar recent rise has been seen in Northern Ireland, with 1 in 17 of the population being positive 
  • These differences between the UK constituent nations are also mirrored by different trends in different parts of England
  • Thus for example the Southeast has had no fall
  • The current higher rates in London and the Southeast might reflect their greater social mixing and work patterns
  • There have also been differences between age groups in the trends: 
  • The take home message is that since the start of the year there has been a decline in rates, especially in children, but conversely a slight rise in those over 50
  • Childhood rates had been very high and they are now, as expected, approaching those in the rest of their households
  • The slight rise in the older age groups might reflect the expected greater mixing following the relaxation in mitigation measures

Do we know anything about hospitalisation rates?

  • Trends in hospitalisation rates based on the national reporting systems should be a reasonable indicator  of the underlying trend in the number of new severe cases 
  • As is well-known, hospitalisations have been falling since the beginning  of the year due to a combination of the success of vaccines and the dominance of the milder variant Omicron
  • Indeed declines in the number of people being admitted with Covid-19 have been observed in all the major European countries 
  • However in the last couple of weeks there has been a worrying slight increase in the number of cases admitted in the UK, but not in other major European countries 
  • By contrast, in the past week across Europe there seems to be quite a marked increase in the number of reported cases
  • It will be interesting to see if these rates translate into more hospitalised cases over the next two weeks 

Is Omicron still the main variant?

  • Indeed Omicron accounts for 99% of all UK cases 
  • The interesting thing though is the proportionate increase in the sub-variant BA.2*
  • This variant is even more transmissible than ‘regular’ Omicron but does not differ in severity
  • The figure below shows the estimated percentage of all new cases in England due to BA.2:
    • The green blobs – show the daily laboratory  reports of the proportion of samples that are BA.2 positive
    • Because the numbers tested each day are quite small, the statisticians allow for this by giving a range – the green vertical lines
    • No BA.2 cases were identified before mid-January, whereas by 20th February the proportion of BA.2 was approaching 50%

*Despite its name BA.2 is not an advert for the world’s favourite airline!

  • It seems that the vaccine protection against BA.2 is the same as against other Omicron variants. 
  • Whether previous infection with the latter protects against further infection with BA.2 is not known, but certainly there are many reports of people having a second Omicron infection 

Conclusion

  • Just because Covid-19 is not in the news, it has not gone away and might be increasing
  • No new variants of concern have arisen and the latest variant BA.2, although responsible for keeping the virus spreading within the community, is not causing any specific new medical concerns 
  • It is obvious that the overall risk of a significant infection to any fully vaccinated individual is based on the combined effects of the local infection rates and the severity risk of the predominant current variant(s)
  • There is no evidence of the risk declining and possibly a small increase in risk, but mainly of mild infection
  • Thus, despite Covid-19 not being in the news, no reason to change whatever feels individually comfortable in mask wearing etc

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Lifting all legal restrictions: does it make sense?

The UK government announced yesterday that it was planning to lift all remining legal restrictions to prevent Covid-19 transmission.  Other Western countries are acting likewise despite the current wave of Omicron infections.  Does reducing legally enforceable mitigation actions make sense?

What are the current data?

  • As mentioned previously in this blog, the UK’s weekly PCR sampling of a large random population provides the best data on the underlying trends in the numbers of new cases
  • These data are very clear: for the past several weeks, the underlying rate of infection is consistently around 5%
    • The most recent data on 9th February showed that 1 in 19 of the English population were infected last week.  
    •  The rate varies by age and is around 1 in 8 for children but still 1 in 40 for those over 70 
    • Indeed, in Scotland and Northern Ireland these rates are increasing slightly
  • Hospitalisations in England have dropped by 25% in the past one month
    • But as reported, hospital data are challenging as they do not discriminate between being in hospital with Covid-19 as opposed to because of Covid-19.  
    • Thus, assuming the average age of all patients in hospital for any reason is around 70, then by chance alone 1 in 40 will be positive for Covid-19. 

What is clear about Omicron?

  • The following are well known but worth repeating
  • Omicron is responsible for the overwhelming proportion of cases currently
  • Omicron is much more transmissible than any other variants, frequently before people test positive, and in both symptomatic and asymptomatic people
  • In the overwhelming majority of cases, Omicron is self-limiting illness lasting from a few days to 2 weeks.  Although robust data from non-Covid-19 viral infections are not available to allow statistical comparisons, the clinical impact of Omicron for most affected individuals is broadly similar to that from seasonal flu

Have vaccines altered the equation?

  • Again, much of the information below is well known
  • Three doses (but not 2) provide as good a protection against serious Covid-19 that could be reasonably expected from vaccines for any similar infection 
  • Current vaccines do not, however, prevent people getting a mild to moderate illness with Omicron
  • Current vaccines do not prevent reinfection in people who were infected, even in the recent past, with Delta
  • Although it is likely that vaccines have been in large part responsible for the lower risk with Omicron of severe infection, unvaccinated or inadequately vaccinated people are less likely to become seriously ill following Omicron than they were with Delta

What don’t we know about Omicron?

  • This variant has only been around for 2 months so that limits what we know
  • It is thus too early to know what the risk of reinfection with Omicron is (official data require a minimum of 90 days to prove reinfection)
  • There are no data yet on the decline in natural immunity following Omicron which would push up the risk of reinfection 
  • Data would suggest that there is a waning of immunity following 3 doses of vaccine against getting ill, but too little data to know if the protection against serious infection is longer lasting
  • We also don’t know what the risk and severity is of ‘long CoVid’ following Omicron.  Both might be lower than following Delta, but that does not mean that long Covid-19 might not be a significant problem for many

And in addition, we don’t know:

  • Given the very high rates of infection in the population, will the point be reached that so many will have had natural infection that there is the long sought-after herd immunity?
    • There is absolutely no sign of that happening and Omicron does not look like it is going to disappear
  • Could Omicron be replaced by a more severe variant?
    • No-one could be absolutely sure that this could not happen
    • There will be new mutations and some may have the double whammy of being both more transmissible and more severe
    • In evolutionary terms, Omicron has been very successful  in infecting large numbers – in part because it only causes a mild illness – so there is no ‘benefit’ in its mutating to a riskier variant

Putting it altogether!

  • The aim of legal restrictions is to add to personal behaviours to reduce the risk of transmission
  • My first question is whether there is a continuing public health need for legal restrictions to reduce transmission
    • Omicron is an infection that is (i) predominantly mild and (ii) for which vaccines have achieved their goal of minimising hospitalisations?  
    • There are economic, social and educational costs from any legal restrictions, so they are not a ‘zero sum game’ 
    • At the very least the case that there is a current public health need is far from compelling
  • My second question is whether the extant legal restrictions achieve their goal – ie do they do anything useful?
    • Transmission is at its highest ever and not decreasing
    • (Anecdotally I am more aware of friends and family getting ill than at any time during the pandemic)
    • It could be argued that the problem is non-adherence to the restrictions 
    • Alternatively, the restrictions actually do very little to control infection rates where most transmission occurs too early and silently
    • Either way, the case for retaining restrictions that don’t work in practice, independent of any need, is also far from compelling
  • Of course, politicians do not always make such decisions on scientific grounds but in this instance lifting of restrictions is defensible
  • It is also challenging to maintain messaging about desirable behaviours such as mask wearing and hand washing in the teeth of major changes in government policy 
  • Lifting the quarantine therefore would not stop me making a personal choice to continue to wear a mask on public transport 

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How worried should we be about the new variant of Omicron surging in Denmark?

I was looking at the data on the rate of new cases in different countries.  This showed the Faeroe Islands – a group of islands to the north of Great Britain – currently have the highest rates of infection in the world. On 25th January they reported 913 new cases, equivalent to almost 2% of the population, just in 1 day

Remembering my geography that these Islands are Danish, I checked and saw that yesterday (26th January) Denmark had second place in Europe, with approaching 1% of its population notifying as having a new infection

  • To see how these rates are so much higher than elsewhere, look at this graph:
  • The key question is what is the variant underlying these phenomenal rate rises and does it pose a risk for the rest of Europe and indeed the world?

What variants are infecting Denmark?

  • The key variant is the so-called BA.2, which has mutated from the original Omicron variant, (correctly referred to as BA.1)
  • Over a very small number of weeks BA.2 has become the most common variant in that country
  • Below is a screenshot (apologies for poor quality) of the graph from the main Danish lab showing the takeover by BA.2
  • It thus seems highly likely that BA.2 is more infectious, explaining the growth in the number of cases
  • My suspicion is that, given the close links with Denmark, the surge in the Faeroe Islands is also due to BA.2

Is there any difference in the infection caused by BA.2?

  • The variant is even more infectious but not more severe than BA.1 Omicron 
  • There hasn’t been a surge in the number of deaths from Covid-19 in Denmark 
  • Although there has been an increase in the number admitted to hospital, this is only to the extent that is expected from the increase in the number of cases
  • Further weeks of observation on this new variant are needed to confirm these reassuring observations 

What about other countries?

  • This is the strange thing!
  • In England, which has one of the best developed PCR laboratory services, there have only been 400 cases of BA.2 identified up to last week despite the first case being identified as long ago as December 6th
  • I cannot find any data about BA.2 in France, which also is in the middle of a major surge
  • The first handful of cases of BA.2 have now been identified in the USA
  • Why I think this is very strange:
    • Given the data from Denmark, a bit like the situation when Omicron (BA.1) arrived, we might have expected a very rapid takeover by the new BA.2 variant in all countries
    • This takeover has not happened yet in any other country, suggesting that outside Denmark, the cases of BA.2 were not so much more infectious than BA.1 – which has its own very high transmission rate

What about vaccination rates?

  • As frequently described in this blog, vaccines offer little protection against transmission of asymptomatic infection, but do offer some
  • For what it’s worth, Denmark (and the Faeroe Islands) have very high population rates of vaccination (2 doses) compared with the rest of the EU and the UK
  • Experts do not believe that the vaccines are any more, or any less, effective against BA.2 Omicron than they are against BA.1 Omicron 

A final comment on how is BA.2 identified?

  • First identified in the UK by the national genetic screening of samples sent for PCR testing
  • Initially considered just one of several sub-variants that typically will have arisen by chance from Omicron and possibly of little significance 
  • BA.2 has several different mutations compared to the original Omicron (called BA.1)
  • One of these differences is that the BA.1 variant of Omicron has a gene missing in its spike protein (the so-called  ‘S-gene dropout’)  – this  dropout is not seen in the BA.2 spike protein  
  • S-gene dropout is easy to detect in a laboratory, and is widely used to decide if Omicron is present
  • The worry is that the laboratories round the world have been relying on this approach to diagnose Omicron: this strategy would therefore miss detecting BA.2 Omicron

Conclusion

  • Is the BA.2 surge in Denmark a worry for the rest of Europe and the world is not easily answered
  • The infection the variant causes is no more severe and perhaps if it infects more of the population more quickly, then maybe such countries will achieve the benefit of population-wide natural immunity 
  • We also don’t know, but need to know, if this variant might lead to an increased likelihood of re-infection: ie for people who have had BA1; is there a greater chance of being reinfected with BA2 than a second dose of BA1?
  • The WHO has labelled BA.2 as a Variant of Interest as opposed to a Variant of Concern.  
  • This seems sensible, we have no need to panic but we need to keep a close eye on the rates of new cases especially if cases continue at their current high rates

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Covid-19 infection rates are still high: is there a justification for relaxing mitigation measures?

In the UK, with the pressure on hospital beds from Omicron being containable, the government announced last week a relaxation in the rules brought in to minimise transmission of infection.  In this post I consider why the data might not support this decision

What is happening to infection rates in UK, Europe and North America?

  • There is no shortage of data on reported infection rates in every country
  • In this graph I show the rates of infection since the start of the Omicron wave in 5 selected countries 
  • The broadest conclusion is that over the past 2 weeks, rates have certainly not fallen, and in France indeed are rising
  • Many other European countries are also showing even more substantial rises
  • in total, cases in the past week are 15% up from the previous week across the whole of Europe
  • We need to be careful, though, as these data are of ‘confirmed cases’:
    • If the number of people seeking to be tested falls, for reasons perhaps related to the logistics of obtaining a test – 
    • Then (everything else being equal) these published numbers of confirmed infections may underestimate the true number of cases
    • The opposite may occur, of course, if tests are easier to obtain
  • As an example, though, the UK government on 11th January removed the requirement to have a PCR test if you were asymptomatic despite having a positive lateral flow test
    • Whilst this was not unreasonable given the demand for PCR tests, it inevitably could have resulted in the initial fall in the number of PCR positive cases
    • I have shown, that after January 11 (red arrow on the graph above), there was a fall for a week but that this fall has now levelled off 
    • Given the upward/flat trend in other European countries, I question how accurate are the UK figures, reported daily in the media.
  • Thanks to KS for also reminding me that another inaccuracy in the daily data from England is that the number of cases reported excludes anyone who has been registered as having an infection in the past: reinfection

Can we know the true rates of new infections? 

  • A simple question but a bit complicated to answer (typical epidemiologist!)
  • Fortunately, in the UK, there is the Office of National Statistics (ONS) weekly survey of a random population sample, using PCR tests on everyone in the sample – whether they have symptoms
  • The most recent results, published 3 days ago, provide the best guide to the numbers of people who are positive on the day of testing in the 4 UK countries
  • The graph below shows the data for England from December 1st to January 15th, ie in the period since cases of Omicron started to be seen in the data
  • The data showed that on 15th January, it was estimated that 5% of the population were infected: 1 in 20
  • Remember also a positive PCR does not absolutely indicate a current infection
    • PCR may take a few days to become positive
    • The PCR can then be positive for 2 weeks or longer 
    • Thus ONS in their data assume that across the total number of people who  are PCR positive today, the “average” date they caught their infection is probably about 2 weeks ago
    • Thus, their most accurate assessment of the rate of new infections is on January 1st, which if sustained suggests that each week, at the start of the year, which is consistent with 5% of the population were developing a new infection
  • Now look back at the first graph, which shows the flattening trend over the past couple of weeks
  • Inevitably sophisticated data sets such as the ONS survey are playing ‘catch up’
  • Over the next couple of weeks there may be an important downward trend in new infections, but we cannot be certain yet
  • Conclusion: Difficult to be accurate but even if the weekly rate of new cases is now not quite as high as 5% of the population, it is unlikely to be much lower and the infection must be considered as still unacceptably widespread in the population

Should boosters not have impacted on these trends?

  • An obvious question, but why haven’t the rates dropped since the booster programmes have now been rolled out in many countries?
  • We know that the main effect of the boosters is to reduce severity of the infection
  • Indeed, the report this weekend from the USA showed that triple-vaccinated people had one third of the rate of symptomatic Omicron, (including those with just mild symptoms) compared to doubly vaccinated, which is great news
  • But current vaccines do not have a major effect of preventing transmission
  • The consequence is that being in a room of triple-vaccinated people does not preclude a significant risk of contracting the infection 

Is there a rationale for relaxing measures aimed at reducing transmission?

  • A summary of the above is therefore that there is still lots of Omicron around which can continue to infect fully vaccinated people
  • The data are still being collected on the chance of catching Omicron twice, but it won’t be negligible 
  • For sure, Omicron is milder, especially in fully vaccinated people, and there is a line of argument that says transmission of an infection of that (low) level of severity need not be a public health concern
  • But if we can reduce transmission even of this milder but highly infectious illness, without societal cost, why not?
  • There is a Latin expression which underpins much of medical guidance: primum non nocere (first do no harm)  
  • I mention that because wearing masks on public transport and other places, at a time when there is a background infection rate of 1 in 20, would seem to be a no-brainer
  • For statistically inclined readers, rate of 1 in 20 does not mean that if you are in a gathering of 19 people, you are protected!  In fact, with that background rate, in any gathering of just 10 people, there is a 40% chance that at least one person will be infected

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Does Covid-19 increase the risk of diabetes in children

A study published a few days ago from the United States Centers for Disease Control (CDC), suggested that Covid-19 can more than double the risk of the new development of diabetes in children.  This study adds to the information from extensive research since the start of the pandemic that Covid-19 is bad news as far as diabetes is concerned.  We already knew that in people who have pre-existing diabetes, including those who are undiagnosed, Covid-19 infection makes their diabetes worse.

These data are the ‘other side of the coin’ from the much greater body of information emphasising that pre-existing diabetes increases the risk of severe Covid-19 including death.

In this blog post I consider the evidence that Covid-19 could actually cause diabetes, especially in children.  One consequence of this being true would be to add to the case for vaccinating children 

Two types of diabetes

  • I am sure most readers will be aware that in simple terms diabetes is actually 2 separate disorders: unsurprisingly called Type 1 and Type 2
  • Type 2 is much more common
  • The major difference between the 2 types are shown below
  • As Covid-19 infection is predominantly more of a problem in the elderly, inevitably  many of the studies up to now on Covid-19 and diabetes related to Type 2 diabetes
  • These studies suggested that:
    • Patients with pre-existing diabetes who became ill with Covid-19 were more likely to lose control of their blood sugar and need to be hospitalised 
    • Mild to moderate Covid-19 infection could also unmask previously silent diabetes at an earlier age, ie such patients could well be diagnosed with diabetes in the future perhaps in response to another but non-Covid-19 infection
    • A severe infection with Covid-19 could cause such major changes to our metabolism  sufficient for  the new development of Type 2 diabetes that otherwise may not have ever happened 

Can Covid-19 cause Type 1 diabetes in children?

  • The stimulus behind my writing this post was the concern that Covid-19 can lead to the more serious and life changing Type 1 diabetes in children
  • Prior to the data this week, there was only anecdotal data from paediatric diabetic specialists reporting they were ‘seeing more new cases of diabetes’ in children since the pandemic started in 2020
  • For example, a study from London reported an 80% increase in the number of new childhood cases
  • Such findings were not universal and a group of German paediatricians reported no increase in the number of cases they were seeing
  • Neither of these studies was a formal epidemiological study, until the much needed CDC study reported last week.
  • The CDC statisticians compared the rates of new cases of diabetes in children aged under 18 between those with (blue bars) and without (orange bars) a diagnosis of Covid-19 
  • Unlike much of Europe, there is no single health care database and thus data to answer this question came from two different providers of health care data –  ‘IQVIA’ and ‘Health Verity’- and combined they cover more than 0.5 million children
  • The results are shown below
  • The data from IQVIA showed a more than 2.5 times increased risk of diabetes
  • The data from Health-Verity showed only a 30% increased risk of diabetes
    • In interpreting these results need to note that all the children in these datasets had had a clinical contact because of their Covid-19 and would not I believe have included children who were asymptomatic 
    • The ‘non-CoVid children’ were also identified differently in these two data sets and were in the Health-Verity dataset were sicker than the non-CoVid children in the IQVIA dataset for other reasons
  • If the figures are accurate then it would suggest that around 1 in 300 children becoming ill with Covid-19 could go on to have diabetes, which could be 3 times that of uninfected children

How plausible is it that infection with Covid-19 could cause diabetes in childhood?

  • The causes of diabetes in children are not fully known
  • Perhaps surprisingly, genes are less important in Type 1  childhood diabetes than they are in Type 2, adult obesity related diabetes
  • Type 1 diabetes is thought to be an ‘auto-immune’ disease in which the body produces antibodies that attack the specific, or ‘islet’, cells in the pancreas that make insulin.
  • Patients with diabetes can have high levels of such ‘anti-islet’ antibodies in their blood
  • The reasons why a virus could lead to the body’s immune system producing these unwelcome antibodies that attack our own organs is neatly shown in the diagram below:
Adapted from: https://www.cell.com/trends/microbiology/fulltext/S0966-842X(01)02097-2
  • The body responds to infection with a virus by producing antibodies, (as in red arrow on this drawing), to the green bit on the surface of the virus.  These antibodies can then knock out the virus  
  • Unfortunately  –  as shown by the blue arrow  – these antibodies that were produced to attack the virus, by a sad coincidence can also attack the pancreas
  • In other words, an inadvertent consequence of the body’s response to a virus is to produce an antibody that attacks the body: a case of ‘friendly fire’, perhaps

Do other viruses lead to diabetes?

  • Indeed, this has been a major theory for decades as to why diabetes develops in some children 
  • Supporting this theory, there are  some anecdotal reports of children who had symptoms suggestive of being unwell with ‘flu-like symptoms suggestive of a viral illness shortly before they developed their diabetes
  • In fairness, however, most cases of new onset childhood diabetes cannot be tracked to a recent viral infection
  • In the table below, I list some of the viruses linked to the onset of diabetes
  • Some of these viruses you will have heard of eg mumps
    • Rotaviruses are RNA viruses like Covid-19, but cause gastroenteritis by infecting the bowels
    • Enteroviruses are also RNA viruses which infect via the bowels
    • Some enteroviruses, including the Coxsackie virus, have been linked not only to the development of diabetes can affect the nervous system and also cause other severe diseases such as polio

Is there anything special about Covid-19 that might explain its link with diabetes?

  • This is still a topic of continuing research and data are still being collected 
  • One of the current theories about ‘Long CoVid’ has been that infection leads to the development of auto-immunity, ie the continuing symptoms with long covid are related to antibodies produced in response to the virus then attacking  other body systems. 
  • At the moment, though, there is little data that Covid-19 produces antibodies against the islet cells
  • Another compelling research idea, based on some laboratory data,  is that the virus itself, when severe, can infect the islets directly and destroy them

Conclusions

  • The recent explosion of cases from Omicron, especially in children,  has perhaps highlighted the need to consider if there are long term consequences of an otherwise mild infection
  • These recent US data do suggest that Covid-19 increases the risk of diabetes in children but do require confirmation
  • We also need to know how severe the infection from  Covid-19 has to be to pose a risk of diabetes?
  • Nonetheless a 1/300 risk, if that is what it is, is far from negligible 
  • As the debate continues about the pros and cons of vaccinating children, the potential risk of diabetes does need to be included in the discussion 

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