ME/CFS: An Infectious Disease by Dr. Rosemary Underhill

[Gemini]

I believe certain enteroviruses are as well, but perhaps someone else can verify this?

@M Paine re:viruses with tropism for B-cells, I did some additional checking. There is evidence enteroviruses have been shown to replicate in B-cells.

www.ncbi.nlm.nih.gov/pmc/articles/PMC3060663

 

[alex3619]

The issue with supposedly nonpathogenic organisms becoming pathogenic in a new locale has been known for decades at least. Taken outside of their niche, many bacteria can become pathogenic. Staph aureus for, example, is normally found on human skin. However if it gets into internal organs than it becomes very serious. Candida can often reside harmlessly in the gut, and almost harmlessly in other places, but if it gets into the heart it can kill. Location matters.

So if something goes wrong in ME, and local normally symbiontic organisms become an issue, then it could cause problems.

However this does not explain why these organisms were not cleared.

The term "scarring" is probably a bad choice. It might confuse the issue.

Lipkin et. al. have the tech to detect all known viruses. Even animal viruses. So a known viral infection, abnormal or not, should show up if it were acute. However I do worry that if the problem is a huge range of viruses doing something specific, rather than a specific virus, this could be overlooked. So the viral cause might be about what it is doing, such as where it is, rather than a specific virus. Normally viruses at low incidence are ignored as causal, and this may be a problem with the standard paradigm of infection causing disease.

An unknown virus still remains possible, though increasingly unlikely.

Non-replicating non-lytic viruses may also be an issue, as there may not be enough viral particles in blood to be detectable. This would include enteroviruses.

(PS Kudos to anyone who can tell me why I used symbiontic rather than symbiotic.)

 

[lansbergen]

(PS Kudos to anyone who can tell me why I used symbiontic rather than symbiotic.)

Thinking of symbiontic systems being disturbed?

 

[halcyon]

Non-replicating non-lytic viruses may also be an issue, as there may not be enough viral particles in blood to be detectable. This would include enteroviruses.

The persistent enterovirus infections found in ME patients may be non-lytic but my guess is that they actually are lytic but just replicate very slowly and are kept local in certain tissue by neutralizing antibodies in the blood and the effects of persistent immune activation. I do not think that they are non-replicating though. Dr. Chia and others have shown the presence of replication intermediates (dsRNA) and heavy active infection of intestinal epithelium which is a tissue that is turned over rapidly. If there was no replication occurring I don't think that a persistent infection could be supported by these tissues.

My other guess is that increased metabolic activity enhances the expression and replication of these viruses which is why exertion makes us sick and why not resting during the acute infection can lead to ME.

 

[alex3619]

If there was no replication occurring I don't think that a persistent infection could be supported by these tissues.

New cells are made from old cells. An old cell with viral particles will divide and you have two cells with viral particles.

The existence of viral intermediates does not mean they replicate. Far from it. That is one of the assumptions that kept people from realizing that enteroviruses have a non-lytic lifecycle. The issue is that the virus itself cannot be properly assembled, and so cannot lyse the cell. It might however make the cell less viable, which in theory would mean the cell would die sooner. However there are cytoplasmic bridges between some cell types that may mean that protovirus particles can travel cell to cell.

I don't recall offhand how many lifecycles enterviruses have. I think its three, and EBV has four? For enterviruses this includes both a nonlytic and a very slow lytic variant. It seems that under some conditions enterviruses can lose part of their genetic code. So they either replicate more slowly or cannot complete the replication cycle at all. However a cell that cannot complete the cycle can still produce weird virus derived chemicals.

This is all very new virology, and I would love to see something more definitive on this, even if that is to prove its wrong.

 

[alex3619]

My other guess is that increased metabolic activity enhances the expression and replication of these viruses which is why exertion makes us sick and why not resting during the acute infection can lead to ME.

I think the not resting during acute infection part is partially right. However exertion also means the immune system is more suppressed due to having less energy and responding to exertion induced hormones.

However I do not think that explains PEM at all. If this were the case then Lipkin et. al. would have found enterovirus in a large subset of the patients tested.

 

[halcyon]

However I do not think that explains PEM at all. If this were the case then Lipkin et. al. would have found enterovirus in a large subset of the patients tested.

He only looked in plasma which won't contain any virus in these chronic infections. If you're only going to look at blood you have to look very hard in the buffy coat because you can find small amounts of the virus in PBMCs. They're of course trivial to find in the tissue as Chia and others have shown.

 

[halcyon]

It might however make the cell less viable, which in theory would mean the cell would die sooner.

It absolutely does I'm sure. Ignoring the effects of innate immune activation in the cell (and those surrounding it), we know that VP1 is present in these infected cells, which means that viral translation is occurring. That being the case, the viral proteases are likely also being expressed, and these will for sure interfere with normal protein synthesis and operation of the cell.

It seems that under some conditions enterviruses can lose part of their genetic code. So they either replicate more slowly or cannot complete the replication cycle at all.

Some have found this and others (Tam and Messner) have found persistence without any loss or mutation of the viral genome so it's unclear.

However a cell that cannot complete the cycle can still produce weird virus derived chemicals.

Yes and even the presence of dsRNA alone is thought to be a potent inducer of interferon.

 

[alex3619]

Thinking of symbiontic systems being disturbed?

The science fiction writer known as Hal Clement (not his real name - I think it was Harry Clement Stubbs, not so catchy) wrote about symbiotic organisms, rather than symbiontic ones. A generation of budding scientists read his fiction. It became the normal usage. In a much later addition he added a postscript apologizing for the confusion.

One person's actions, in the right place and time, can change the world forever, even if it was a mistake.

 

[SOC]

The science fiction writer known as Hal Clement (not his real name - I think it was Harry Clement Stubbs, not so catchy) wrote about symbiotic organisms, rather than symbiontic ones. A generation of budding scientists read his fiction. It became the normal usage. In a much later addition he added a postscript apologizing for the confusion.

One person's actions, in the right place and time, can change the world forever, even if it was a mistake.

There's a similar example in the world of mathematics. A single book, Hutton's Mathematical Dictionary in 1795, accidently (presumably) exchanged the meanings of the words trapezoid and trapezium. Now North Americans use the words backwards from the rest of the world, much to the confusion of mathematicians, engineers, and students worldwide.

It doesn't take much for one guy in the right position to confound issues and confuse billions of people for centuries. (SW, I'm looking at you)

Trapezium
There are two common definitions of the trapezium. The American definition is a quadrilateral with no parallel sides; the British definition is a quadrilateral with two sides parallel (e.g., Bronshtein and Semendyayev 1977, p. 174)--which Americans call a trapezoid.

Definitions for trapezoid and trapezium have caused controversy for more than two thousand years.

Euclid (Book 1, Definition 22) stated, "Of quadrilateral figures, a square is that which is both equilateral and right-angled; an oblong that which is right-angled but not equilateral; a rhombus that which is equilateral but not right-angled; and a rhomboid that which has opposite sides and angles equal to one another but is neither equilateral nor right angled. And let quadrilaterals other than these be called trapezia."

Proclus (also Heron and Posidonius) divided quadrilaterals into parallelograms and non-parallelograms. For the latter, Proclus assigned trapezium to "two sides parallel," and trapezoid to "no sides parallel." Archimedes also defined a trapezium as having precisely two parallel sides (Heath 1956, pp. 188-190).

According to the Oxford English Dictionary, the confusion of trapezium and trapezoid between the United States and Great Britain dates back to an error in Hutton's Mathematical Dictionary in 1795, the first work of its kind in the United States, which directly reversed the accepted meanings. Hutton assigned trapezium to "no sides parallel" and trapezoid to "two sides parallel" (Simpson and Weiner 1992, p. 2101).

After 1795 in the United States, the Hutton definitions became standard, while in the British empire, the Proclus definitions remained standard. Two hundred years later, the controversy remains. Country by country, region by region, and even teacher by teacher, the definitions of trapezoid and trapezium are commonly swapped.

It is perhaps therefore best to tread extremely carefully into questions of definition for these two simple plane figures. W. E. Greig (pers. comm., Mar. 10, 2007) has proposed that the American trapezoid (i.e., the British trapezium) be dubbed the "trapeziam" (with the -am suffix indicating "American"), but adding yet another term to the word soup seems unlikely to help resolve the confusion.

http://mathworld.wolfram.com/Trapezium.html

 

[jimells]

Trapezium

It seems like Sir Simon took this lesson to heart when he and his "school" decided it would serve their purposes to have multiple contradictory definitions of our illness.

 

[redaxe]

I found this section of the article extremely interesting

Histopathology
In some early outbreaks, blood from patients was inoculated into monkeys. An agent was repeatedly transmitted to monkeys from two patients from the Adelaide outbreak [96]. When the monkeys were killed minute red spots were observed along the course of the sciatic nerves. Microscopically infiltration of nerve roots with lymphocytes and mononuclear cells was seen and some of the nerve fibers showed patchy damage to the myelin sheaths and axon swelling. There was associated perivascular round cell infiltration without significant cellular damage. [96]. In the Los Angeles outbreak, inoculated monkeys showed diffuse perivascular infiltration, but less cell destruction than would be expected to result from inoculation with polio virus [39]. Blood from a child in Boston resulted in diffuse perivascular cuffing around blood vessels of the dorsal root ganglia, cervical and lumbar nerve roots and in the brain and spinal column of inoculated monkeys [96]. These findings can be compared with a limited number of autopsy findings from sporadic patients. A study of four patients, reported that one case showed a marked dorsal root ganglionitis and two other cases showed mild excess of lymphocytes with nodules of Nageotte in the dorsal root ganglia. The pathological picture of mild diffuse changes was thought to correspond closely to what might be expected from clinical observations of patients with neurological involvement in ME/CFS [97]. A hypothesis has been offered, that ME/CFS might be caused by infection of the dorsal root ganglia with varicella-zoster virus (VZV) [98].

I didn't know they transferred blood from these early cases into monkeys. It sure seems like the the doctors of the earlier generations might have been a bit more adventurous then we are today? Or is it an animal welfare thing that prevents this from happening now?

I noticed this too

Healthcare providers: Nurses nursing patients with ME/CFS have a high attack rate in hospital epidemics [[39],[47]]. Medical staff are also at increased risk [39]. Fifteen years following the Royal Free outbreak, two psychiatrists, postulated that the outbreak was due to mass hysteria, because no pathogen had been identified and there was a relatively high incidence of the illness in nurses who, they said, were “socially segregated young women” [88]. The psychiatrists did not interview any of the patients. They disregarded low grade fever, lymphadenopathy, cranial nerve defects, a multitude of other symptoms and signs, and well-defined secondary cases of the illness. Sixty years after the outbreak, some patients still suffer from pareses resulting from the outbreak (Underhill, unpublished observation). The erroneous hysteria hypothesis persists to this day.

So apparently some of these people from the Royal outbreak are still alive - are these people in a special register so they can be autopsied when they die? - surely we can test their nervous system tissue for viral RNA and DNA. This should be much easier now with the advancements in PCR and genome sequencing. Surely this is an opportunity that should not be missed - It's something that Ian Lipkin should be able to get involved in.

I don't think the earlier autopsy's were able to dig deep enough - they found early evidence of cell destruction but that was decades ago, why is this not being followed up with modern technologies that allow us to do protein and genome sequencing???

 

[alex3619]

I didn't know they transferred blood from these early cases into monkeys.

I tracked down that research a few years ago. They also used rabbits and mice. I might have it backwards, but I think the rabbits had no damage, whereas the mice all died. Or the other way around. In other words, whatever was in the blood was fatal for one species, and apparently innocuous to the other.

Nobody questions that viruses can trigger ME. The argument is about what happens next.

What outbreaks have given us, and we have failed to respond to, is highly homogeneous patient populations for study.

Its suspected that outbreaks still occur, they are just not classified the same way since the pathogen is often isolated. So we have post giardia, post SARS and post Q fever, as well as post EBV (long after mononucleosis is supposed to settle). Now we also have post influenza. Each is a little different in outcome, but then the classic ME outbreaks differed between outbreaks too.

 

[jimells]

@alex3619 and now I'm hearing reports on the radio about post-Ebola problems, too.

 

[jimells]

two psychiatrists, postulated that the outbreak was due to mass hysteria, because no pathogen had been identified and there was a relatively high incidence of the illness in nurses who, they said, were “socially segregated young women” [88]. The psychiatrists did not interview any of the patients. They disregarded low grade fever, lymphadenopathy, cranial nerve defects, a multitude of other symptoms and signs, and well-defined secondary cases of the illness.

Yes, the psychobabblers have a very long list of crimes, ahem, "mistakes" to be held accountable for. Withing the past year I heard a report that HPV vaccine adverse effects in young Japanese women were being attributed to "mass hysteria". Morons. How can anybody buy this rubbish?

 

[lookinglass]

Excellent review article.

Dr. Underhill summarizes research into the role of infections in ME/CFS going back decades covering outbreaks worldwide.

She presents evidence supporting the hypothesis that ME/CFS is an infectious disease; discusses the immune system & host factors; & offers suggestions for further rese

www.medical-hypotheses.com/article/S0306-9877(15)00382-5/fulltext#s0090

Dr. Underhill trained as a physician, surgeon & obstetrician in London & has significant knowledge of the Royal Free outbreak.

She was on the writing committees for the "ME/CFS Primer for Clinical Practitioners" & "A Consensus Manual for the Primary Care and Management of CFS" & has presented CFSAC Testimony on this topic.

Article is very timely. Should be required reading for new ME/CFS researchers entering the field, at NIH for example.

Excellent review article.

Dr. Underhill summarizes research into the role of infections in ME/CFS going back decades covering outbreaks worldwide.

She presents evidence supporting the hypothesis that ME/CFS is an infectious disease; discusses the immune system & host factors; & offers suggestions for further research--

www.medical-hypotheses.com/article/S0306-9877(15)00382-5/fulltext#s0090

Dr. Underhill trained as a physician, surgeon & obstetrician in London & has significant knowledge of the Royal Free outbreak.

She was on the writing committees for the "ME/CFS Primer for Clinical Practitioners" & "A Consensus Manual for the Primary Care and Management of CFS" & has presented CFSAC Testimony on this topic.

Article is very timely. Should be required reading for new ME/CFS researchers entering the field, at NIH for example.

great article gemini. Thank you for posting. I more than "like" it. It feels absolutely right.

 

[heapsreal]

Theyalso used rabbits and mice. I might have it backwards, but I think the rabbits had no damage, whereasthemice all died.

@alex3619 maybe us humans gave mice xmrv. Ahhaaaaa

 

[BurnA]

I think the not resting during acute infection part is partially right. However exertion also means the immune system is more suppressed due to having less energy and responding to exertion induced hormones.

However I do not think that explains PEM at all. If this were the case then Lipkin et. al. would have found enterovirus in a large subset of the patients tested.

I know I associate my onset with exercising while coming down with an infection. I only had a sore throat so didn't pay too much attention to it.
However, if not resting during acute infection is to blame, then wouldn't this be a lot more prevalent in sports people who are constantly training or competing ?
Any generally who really rests up with a viral infection unless it is accompanied with fever and malaise ? Sore throat, runny nose, congestion - don't most people carry on regardless ?

 

[alex3619]

Any generally who really rests up with a viral infection unless it is accompanied with fever and malaise ? Sore throat, runny nose, congestion - don't most people carry on regardless ?

According to the Dubbo studies the most likely predictor is severity of infection. So we are not talking a mild sniffle. We are talking about the kind of infection (or more accurately, response to infection) that causes you to collapse, and everything stops.

On the flip side, maybe the way societial expectations have people pushing on is a risk factor for ME. Or not. We lack the research but it cannot be excluded.

ME is not due to some minor sniffle, a mild cold or flu. Its much more than that. Being active with a mild flu or cold is not likely to produce problems. Pushing yourself if the severity of the infection is high might cause problems. Empirically I think this is what they found in the outbreaks. leading to a recommendation of bed rest in the early phase.

 

[BurnA]

According to the Dubbo studies the most likely predictor is severity of infection. So we are not talking a mild sniffle. We are talking about the kind of infection (or more accurately, response to infection) that causes you to collapse, and everything stops.

On the flip side, maybe the way societial expectations have people pushing on is a risk factor for ME. Or not. We lack the research but it cannot be excluded.

ME is not due to some minor sniffle, a mild cold or flu. Its much more than that. Being active with a mild flu or cold is not likely to produce problems. Pushing yourself if the severity of the infection is high might cause problems. Empirically I think this is what they found in the outbreaks. leading to a recommendation of bed rest in the early phase.

I am not sure I agree that it is not due to some minor sniffle cold or flu. Ok I think rhinovirus doesn't cause ME. But I had a viral infection and the only symptoms were sore throat and congestion, runny nose. No fever, no malaise no headache, no gastro issues. Apart from the sore throat which became quite bad after a few days it was similar to every other cold I ever had. I never considered resting up simply because I didn't feel too bad. In fact I felt well enough to continue exercising initially which is why I associate exercise with my me/cfs. For all I knew at the time it was just another cold.
I didn't know about coxsackie virus then and that symptoms could be similar to rhinovirus.
I am fairly sure others would fall into my category too from what stories I have read.

I did read that a lot more doctors than patients developed ME during the hospital outbreaks which would suggest that resting could play a part.