Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis, Bjornevik et al (2022)

[chrisb]

If EBV as relevant to ME it would probably be through allowing an immune response to occur that generated signals like those in infections that alter our metabolism through making us feel ill

Are there not dangers in drawing distinctions between "feeling ill" and "being ill"? If you are not ill, but only feel ill, why not just ignore the feelings? Any worsening might merely be a worsening of feelings.

 

[Robert 1973]

I’ve not read this paper, but I’m wondering if there is any possibility that a prospective study like this could be used retrospectively to test whether EBV infection increased risk of developing ME/CFS or any other conditions. I assume it would depend on the consent that participants gave, and I’m guessing that would have been specific to notification of an MS diagnosis, but it could be useful if it allowed for wider access to anonymised medical records retrospectively.

 

[Jonathan Edwards]

I’ve not read this paper, but I’m wondering if there is any possibility that a prospective study like this could be used retrospectively to test whether EBV infection increased risk of developing ME/CFS

I don't see why not really.

It seems a very good idea - especially as there is already a positive comparator disease.

 

[Arnie Pye]

The article linked by @Mij has this comment :

Canada has the highest rate of MS in the world, with an estimated 100,000 people living with the disease, according to the MS Society of Canada.

But I have also read this in the past :

Title : Multiple sclerosis in the Orkney and Shetland Islands. I: Epidemiology, clinical factors, and methodology.
Link : https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC1052085/

An epidemiological and clinical study of multiple sclerosis (MS) in the Orkney and Shetland Islands showed that the prevalence rate of the disease is the highest in the world (309 and 184/100 000, respectively).

I don't have numbers showing the rate per 100,000 for Canada so I can't compare Canada and the far north of Scotland - so Canada and Scotland can fight it out between themselves.

And this (which is very old - published in 1956) is an interesting comparison :

Title : The low incidence of multiple sclerosis in areas near the equator may be due to ultraviolet light induced suppressor cells to melanocyte antigens
Link : https://pubmed.ncbi.nlm.nih.gov/2940440/

It occurs to me that it would have been helpful if medicine had been less sexist in the past so we had better statistics about the true incidence of MS from 100+ years ago (although I'm aware that scanning machines have been required to get better statistics as well). I know that MS has frequently been related to Vitamin D levels. And societies have become more likely to spend much of their time indoors compared to those from 100+ years ago.

Does anyone know if incidence or severity of EBV has ever been related to vitamin D levels?

 

[Robert 1973]

I don't see why not really.

It seems a very good idea - especially as there is already a positive comparator disease.

I’ve just emailed the corresponding author to ask.

 

[Mithriel]

The rate of MS in Scotland is very high and the Highland Clearances saw a forced mass emigration to Canada in particular so it could be one explanation. MS has a genetic link in the same way ME does.

It is often said that the risk of MS depends on where you spend your childhood so it was no surprise to me that MS patients were all white when I started attending a therapy centre in 1994 but that has not changed much if at all even though the population is now mixed and children have grown up here, It is not racism. The local hospital refers to us now and volunteers and staff are a racial mix so I wonder if it is a genetic thing. If vit D was a factor then you would expect children with darker skin to be more at risk in northern countries.

I have never known anyone with MS to have PEM as it is found in ME. As one woman said when I asked her, she took a long time to get anywhere but she could usually keep going for as long as she wanted. They feel that they get a background fatigue with no cause and that they can need rest simply because it can be an effort do do things with neurological damage.

 

[Arnie Pye]

The rate of MS in Scotland is very high and the Highland Clearances saw a forced mass emigration to Canada in particular so it could be one explanation.

Ooh, good point!

I found this from the MS Trust in the UK, which may be of interest :

https://mstrust.org.uk/a-z/how-common-multiple-sclerosis

And for something more detailed [at least in some respects]- The Multiple Sclerosis International Federation, Atlas of MS, 3rd Edition (September 2020).

https://www.msif.org/wp-content/upl...on-Epidemiology-report-EN-updated-30-9-20.pdf

 

[Amw66]

The rate of MS in Scotland is very high and the Highland Clearances saw a forced mass emigration to Canada in particular so it could be one explanation. MS has a genetic link in the same way ME does.

It is often said that the risk of MS depends on where you spend your childhood so it was no surprise to me that MS patients were all white when I started attending a therapy centre in 1994 but that has not changed much if at all even though the population is now mixed and children have grown up here, It is not racism. The local hospital refers to us now and volunteers and staff are a racial mix so I wonder if it is a genetic thing. If vit D was a factor then you would expect children with darker skin to be more at risk in northern countries.

I have never known anyone with MS to have PEM as it is found in ME. As one woman said when I asked her, she took a long time to get anywhere but she could usually keep going for as long as she wanted. They feel that they get a background fatigue with no cause and that they can need rest simply because it can be an effort do do things with neurological damage.

All those damned Celtic genes

 

[Forbin]

I was wondering if the military kept track of ME/CFS cases so they then might be able to search their records to see if there were any common precursor infections that stood out.


Then I stumbled across Leonard Jason's just published new estimate of ME/CFS cases in the U.S. It factors in increases in the U.S. population since his earlier estimate and now includes cases under 18.

I've only read the abstract, but Jason estimates a "low end" of 1.5 million cases in the U.S.

Given the current population, this would work out to be about 1 in 220 people (about 455 per 100,000). This is an increase over his earlier estimate of about 1 in 237 adults (about 422 per 100,000).

A random cohort of 10 million people might then contain something like 45,500 cases of ME/CFS, but a cohort of 10 million young military personnel would probably have fewer cases due to the narrow age window and likely a greater proportion of men to women than in the general population.

On the other hand, occupational hazards in the military - e.g. toxic exposures and pressure to return from illness quickly - might foster additional cases of ME/CFS.

So, you still might have tens of thousands of ME/CFS cases in a military cohort of 10 million. You'd think the services would be interested in investigating this, except... if you're young and get ME/CFS I don't think you're likely to remain in the military very long. You'd probably only have a small chance of being diagnosed, let alone counted.

Service members who come down with EBV, on the other hand, would get diagnosed and would largely recover and remain in the service - and so they would be available to be counted should they later develop MS.

 

[dave30th]

A role for EBV in MS would be an entirely unique mechanism almost certainly.

I've only seen the headlines. Does the research imply that this is THE cause for all MS or that it is a necessary or contributing factor in many cases? Also, does mono/glandular fever only occur in adolescents/adults with newly acquired EBV infection? If you acquired it, like many, in early childhood, are you still prone to glandular fever, and I guess perhaps MS?

 

[Forbin]

The finding suggests a vaccine against the Epstein-Barr virus could greatly reduce the incidence of MS.

Is it possible that it's something about the immunity one develops to EBV that causes MS?

 

[Peter T]

I've only seen the headlines. Does the research imply that this is THE cause for all MS or that it is a necessary or contributing factor in many cases? Also, does mono/glandular fever only occur in adolescents/adults with newly acquired EBV infection? If you acquired it, like many, in early childhood, are you still prone to glandular fever, and I guess perhaps MS?

At the start of my ME, which was continuous with a bout of glandular fever/mono (impossible to say where one ended and the other began because of overlap of symptoms) I also tested positive for EBV. This was nearly 30 years ago so it may not be up to date, but I was told that the EBV virus is as common as the common cold viruses, that lots of people are infected with it, but only a relatively small percentage develop full blown glandular fever/mono and many escape any apparent further long term consequences

If EBV is as common as this, even if everyone who has MS does turn out to have been previously infected with EBV, not everyone infected by the virus will develop MS. This would suggested even if prior exposure to EBV is necessary for developing MS, it is not of itself sufficient to cause the subsequent MS.

Also association does not demonstrate causality. Given the frequency of EBV, isn’t it also a distinct possibility that there is a separate issue that makes people susceptible to MS also susceptible to EBV infections.

EBV infections are possible triggers for a number of other conditions distinct to MS, so this still leaves open the question why some people exposed to EBV go on to develop MS but others develop other conditions including ME or no apparent subsequent long term condition at all.

[added final sentence.]

 

[Forbin]

FWIW, I was tested for EBV not long after the onset of my first symptoms of ME/CFS. The test was negative.

 

[Milo]

Well, that was quick… (will start a new thread, i think this trial should be followed)


Moderna Starts Human Trials Of mRNA Vaccine For Virus That Likely Causes Multiple Sclerosis

 

[Jonathan Edwards]

I've only seen the headlines. Does the research imply that this is THE cause for all MS or that it is a necessary or contributing factor in many cases? Also, does mono/glandular fever only occur in adolescents/adults with newly acquired EBV infection? If you acquired it, like many, in early childhood, are you still prone to glandular fever, and I guess perhaps MS?

My concern is about the loose language in the abstract and muddled thinking the may be behind it - both of which are now common in immunology in a way they were not thirty years ago.

There is no such thins as THE cause in this situation, or even the leading cause. Strictly speaking the data suggest that EBV is may be a nearly necessary permissive causal factor. I think there was at leat one EBV negative case so not completely necessary.

It is worth standing back and considering that discussion of causation in medicine has always been pretty naïve in rigorous mathematical terms. Is water the cause of all diseases because without water there would be nothing to be diseased? But at least in the 1980s people like Stastny developed pretty good accounts of disease causation for things like autoimmunity and cancer. Sadly those insights seem to be almost entirely lost in immunology, although the cancer people have continued to make progress.

Glandular fever is a presentation of EBV infection that seems only to occur in people not previously infected who reach adolescence. In infants the infection is usually mild and once infected there is probably an effectively zero reinfection rate because the virus incorporates permanently into the B cell population - a bit like AIDS although it is not a retrovirus. There are rare caveats. EBV can probably be eradicated with rituximab and in such cases re-infection would theoretically be possible. But repeat clinical illness unlikely. Things are further complicated if you have a genetic or nutritional (Africa) immune deficiency and then EBV plays by different rules.

I think the implication of the study is that you are more likely to get MS if you have encountered EBV at any age. I doubt that the glandular fever episode has anything to do with it. The long term effect on the B cells is the same whether you get EBV in infancy or adolescence as far as I know.

 

[Jonathan Edwards]

Is it possible that it's something about the immunity one develops to EBV that causes MS?

BY far the most likely explanation is that the effect is due to the unique ability of EBV to 'cyber-attack' the entire antibody producing process. During acute infection, as in glandular fever, the virus makes B cells grow in an uncontrolled fashion. We use that effect in the lab to 'immortalise' B cells. It sort of turns B cells into cancer cells that cannot die. But you recover from glandular fever when cytotoxic T cells that recognise EBV grow up and police the system again, keeping levels of virus down to a minimum. The virus is not cleared, however, so we have always expected that after EBV infection autoimmune diseases might be more common.

It is a bit as if you have a virus in your computer that stops your music software turning off so you get constant noise. Your virus protection software keeps trying to shut things down but it never manages to wipe the malware out completely.

If EBV is a near necessary permissive factor for MS but not for the more typical autoimmune diseases it may be telling us something very interesting. It may indicate that the error in antibody production in MS is not quite like in RA or lupus. We already know that in a way. In MS there are no proven antibodies to any specific self antigen that are easily measured as in RA and lupus. It seems that there are rogue antibody-producing B cells but the bad thing about these cells may not be that they attack self but rather that they like to wander into the brain, which cannot tolerate antibodies of any sort at high levels.

 

[chillier]

There is no such thins as THE cause in this situation, or even the leading cause. Strictly speaking the data suggest that EBV is may be a nearly necessary permissive causal factor. I think there was at leat one EBV negative case so not completely necessary.

It is worth standing back and considering that discussion of causation in medicine has always been pretty naïve in rigorous mathematical terms. Is water the cause of all diseases because without water there would be nothing to be diseased? But at least in the 1980s people like Stastny developed pretty good accounts of disease causation for things like autoimmunity and cancer. Sadly those insights seem to be almost entirely lost in immunology, although the cancer people have continued to make progress.

The EBV negative MS cases could also either be incorrect MS diagnoses or false negative serology. I don't know what the error rates are for these tests but with the large cohort here it would presumably not be surprising to see a couple no?

What is the definition of causation in your opinion? Do you mean that it is both necessary and sufficient to lead to MS? Colloquially people talk about smoking causing lung cancer or obesity causing diabetes but what they really mean is they are risk factors. Presumably the only situations where a 'cause' is both necessary and sufficient are things like pathogens causing disease, where hosting the pathogen is synonymous with having the disease? If Sars-Cov2 gets into your body you effectively have Covid-19, asymptomatic or not (although i suppose you could get really pedantic and say the virus doesn't always cause Covid-19 for the vaccinated).

Really exciting to see that EBV is probably necessary for MS as appears here. It was mentioned before there is a strong HLA type associated with MS. Since T cells are involved in B cell tolerance it could be that certain EBV expanded B cell clones that lead to demyelination are more easily tolerated with this HLA type. Are there other or more likely explanations for how EBV and the HLA type could drive the pathology?

 

[Robert 1973]

I’ve just emailed the corresponding author to ask.

He replied to say that unfortunately they are unable to investigate ME in their study population at this time.

I asked if that was due to lack of data, permissions, time or funding. In response he said that they would need to get permissions, develop protocols, and apply for funding. It is something they have thought about at some time, but they need to see how it fits in with their overall research plan.

I may suggest that he contacts Ronald Tomkins as they are both at Harvard but I shan’t press him further. It’s encouraging to know that they have at least thought about looking for associations with ME and other illnesses. I hope that anyone who might be in a position to collaborate on such studies will contact him.

 

[Simon M]

This excellent Scientific American article covers the paywalled article.

Some comments, mostly based on the SA piece.

Study method
Researchers had long suspected a link between MS and EBV but it's hard to study the connection when 9 in ten adults are already infected with the virus. This came from banked blood samples from 10 million military recruits, 3 per person with the first taken as a join-up HIV test. 5% of the recruits were EBV-negative.

955 of these initially-EBV-negative recruits eventually developed MS, typically 10 years after the recruitment sample. 801 of these and 1,566 controls with samples available to assess EBV infection. Controls were randomly selected and matched on age, sex, ethnicity and branch of the military.

They tested the subsequent blood samples for:
- EBV seroconversion (antibodies against EBV) i.e they had become infected by EBV.
- Neurofilament light chain, a marker of damage to neurons.


Causation evidence
801 MS cases
766 were EBV+ at recruitment
35 were EBV negative.
Of these 35
Only 1 MS case had no sign of EBV infection.
The other 34 cases had all acquired EBV before MS developed.

Having an EBV infection increased the risk of developing MS increased by odds ratio of 32, compared with those who remained EBV-free.

Of course, almost all adults have an EBV infection yet only around 125 in 100,000 people develop MS, so it isn't directly causal.

Causal here is used to mean that EBV is a necessary step for MS to develop (in almost all cases). As Jeffrey Cohen, who head the NIH Laboratory of Infectious Disease commented, the equivalent figure for increased risk of lung cancer from smoking more than 25 cigarettes a day was 25 (EBV for MS 32).

EBV infection looks like a necessary step towards MS. Clearly genetic factors play a role too, as do vitamin D levels, and quite possible other factors. But none of these individually seem to play as big a role as EBV.

Cohen also commented that the only way to prove the causal connection was to show that preventing EBV infection prevents MS. (Cue the vaccine trials, including one by Cohen).

Does anyone know if incidence or severity of EBV has ever been related to vitamin D levels?

This fancy study (mendelian randomisation) provides very strong evidence that vitamin D levels play a causal role, and no doubt explain some of higher rate of MS the further you get from the equator.

Also association does not demonstrate causality. Given the frequency of EBV, isn’t it also a distinct possibility that there is a separate issue that makes people susceptible to MS also susceptible to EBV infections.

Since neurofilament light chain increases (indicating neuron damage) were only after EBV infection that seems unlikely (plus, almost everyone is susceptible to EBV).

 

[Jonathan Edwards]

What is the definition of causation in your opinion?

The definition of causation is that it is the whole bang shoot of all the complex contributions to events from prior events - it is a field of study.

If you want a definition of a cause I think the philosophers have established long ago that 'a cause' is a bogus concept. They tried definitions like INUS ( insufficient, but necessary part of an unnecessary but sufficient condition) which show how hopeless it all is. It isn't a useful idea to my mind.

But I think it is perfectly reasonable to say that smoking causes lung cancer - we know what we mean by that. The smoking contributes causation.

I am not sure what 'false negative' EBV serology would be. I think it is pretty rare for people who have had EBV infection not to show an antibody response - unless they have agammaglobulinaemia. False positive diagnosis of MS is possible but I think relatively unlikely.

I think one would probably expect an effect from EBV on B cell behaviour not to be 100% necessary. The effect would be to increase the chances of certain stochastic events in antibody production. Being stochastic those events might happen anyway but just be more likely after EBV. The B cell system works entirely through stochastic somatic mutation followed by selection so it is set up for effects of that sort.