Science at the UK CMRC Conference, 1-2 Sept 2014

[charles shepherd]

Dr Jarred Younger at Stanford in March proposed the term 'Sickness Response' instead of 'Sickness Behaviour' as it's primarily a response driven by biology. I've seen it used in a paper by at least one other researcher, can't remember where.
See the relevant section in my blog:
Sickness response vs sickness behaviour

Thanks Simon

I think I will rename this as 'sickness response' in any further scribbling on the issue

 

[biophile]

Sickness behaviour is usually used in the context of immune response.

Illness behaviour is a more common term in the context of CBT.

Not that I disagree with the criticisms about how these various terms are used and conflated.

Sickness response sounds OK.

 

[lansbergen]

Sickness response sounds OK.

That is what I tought in first instance but now I think it can be problematic. It is not a response to sickness but a response that cause sickness. The psych will twist it to claim it as a response to sickness.

 

[NK17]

Sickness Response does very well for ME .
The term behaviour is a slippery slope and semantics as we very well know, are extremely important for us.
Thank you @Simon for reminding us about Dr. Jarred Younger's research.

 

[NK17]

That is what I tought in first instance but now I think it can be problematic. It is not a response to sickness but a response that cause sickness. The psych will twist it to claim it as a response to sickness.

Isn't it a response to sickness that generates or perpetuates more sickness? If we hadn't lost the normal homeostasis or dynamic equilibrium of neuro- immune-endocrine systems, we wouldn't experience a consequent response?

 

[A.B.]

Isn't it a response to sickness that generates or perpetuates more sickness? If we hadn't lost the normal homeostasis or dynamic equilibrium of neuro- immune-endocrine systems, we wouldn't experience a consequent response?

Sickness response is not pathological. It's a normal response to illness, like fever. It protects the individual and the "herd".

A sickness response that doesn't end *might* be pathological.

 

[MeSci]

I'm interested in @Jonathan Edwards's distinctions between symptoms and underlying pathologies (if I have recalled his posts correctly - apologies if not, but I have only just managed to struggle to the end of this thread and resisted posting too many replies in case others had already made the same comments).

I sense that we have similar views in that there are two main ways to treat an illness, and they both have value and can be used together if required. Also that the way we categorise illnesses is flawed, as illnesses with similar symptoms can have different underlying causes/pathology and illnesses with different symptoms (e.g. ME and RA) can have similar or even the same underlying causes/pathology.

For some time I have been sceptical about dividing what now appear to me to be related illnesses (my particular interest is gut dysbiosis as an underlying cause/pathology) into a veritable dictionary of different names based largely on symptomatology.

I also have doubts about the wisdom of treating some symptoms (e.g. fatigue in ME) in ways that may actually exacerbate or perpetuate the illness in the longer term.

So simple symptom treatment for, e.g. headache or high blood pressure can sometimes usefully be provided.

But the underlying causes for these symptoms may be very different, and to improve longer-term outcomes, different approaches and disease categories need to be applied. And some short-term interventions can make things worse in the longer-term.

And, as you say, everyone is different and needs to be treated as such.

I am struck by the differences between the modern, 'Western' paradigm of illness and, for example, Chinese medicine and Ayurveda, and think that we may benefit from taking the best from a range of approaches whilst discarding the wrongheaded stuff from the different approaches. They probably all have good and bad aspects.

Hope this makes sense!

 

[lansbergen]

Sickness response is not pathological. It's a normal response to illness, like fever. It protects the individual and the "herd".

A sickness response that doesn't end *might* be pathological.

Fever is part of the defence response to infection. It is not a response to illness/sickness, At lerast that is what I was teached.

 

[biophile]

That is what I thought in first instance but now I think it can be problematic. It is not a response to sickness but a response that cause sickness. The psych will twist it to claim it as a response to sickness.

Good point, but while I understand the need to abandon tainted terminology, I also wonder when we stand ground. There is probably better terminology to be used, e.g. "pathology-mediated behaviour/response" (?), but the psychobabble is going to follow us no matter where we go. Psychobabblers often fancy themselves as enlightened messengers of the mind-body connection. Whenever a new pristine term is created or adopted to reflect pathophysiology, there will be attempts to claim it for psychobabble. At some stage we have to stand up for the adopted terminology, use it correctly, and claim it back.

 

[A.B.]

Fever is part of the defence response to infection. It is not a response to illness/sickness, At lerast that is what I was teached.

I think you might be misunderstanding what sickness response is. It's a cytokine mediated change in behaviour. The change in behaviour is caused by physical and mental symptoms which in turn are caused by the cytokines, which are released by the immune system when it detects an infection, injury, or something else which causes it to spring into action.

Yes that's right. The immune system can control human behaviour.

Sickness response encompasses some of the following changes in behaviour which are believed to serve a specific purpose:

Low motivation and interest to conserve energy.
Low appetite to prevent ingestion of contaminated food.
Withdrawal to avoid predators or other demanding situations that a sick person couldn't handle well.
Social withdrawal to prevent infection of peers.
Muscle aches to limit activities to the essential, again to conserve energy.

And so on. You get the idea, it's a survival strategy. I repeat, the change in behaviour is driven by mental and physical symptoms. Beliefs, thoughts, choices have nothing to do with it, despite what the psychobabblers like to say.

These effects have been observed in humans receiving injections of certain cytokines, so we know that it's real. Interestingly, fever seems to disappear after a few weeks while the other symptoms remain.

This is why researchers are excited about sickness response.

 

[lansbergen]

I think you might be misunderstanding what sickness response is. It's a cytokine mediated change in behaviour, in part driven by physical and mental symptoms which in turn are caused by the cytokines, which are released by the immune system when it detects an infection.

Yes that's right. The immune system can control human behaviour.

Driven by symptoms???? Isn't that putting the horse behind the cart?

Are you being sarcastic?

 

[Jonathan Edwards]

@Jonathan Edwards

In your summary you seemed to clearly indicate that there is an emerging consensus amongst researchers that we are looking at some sort of immune issue (but not involving chronic infection) that results in a hypersensitised central nervous system. In another thread you outlined a range of possible 'MEs' that might result in the same collection of symptoms.

This is all great to hear.

I wonder if you (or the other researchers) have then considered how this working model can reconcile the other consistent findings in ME/CFS such as executive dysfunction, autonomic dysfunction, PEM etc.

I appreciate that this may be mere speculation at this point but some of us like to speculate.

I guess the simple answer is that if all these things can occur with 'flu', which they can, it will all fit under a 'sickness response' of CNS sensitisation. (Although I don't like these catch all terms either.) Mildly vigorous exertion at a time just before you realise you have an acute viral infection can precipitate sudden onset of severe malaise at least in my experience.

But to be a bit more imaginative, I wonder if some of it has to do with salience. I spend a lot of time working on theories of perception (nothing to do with my interest in ME). It seems likely that what we rather quaintly call 'making a logical decision' is a bit more like a ladies Bingo session or a cattle auction where the person who shouts just before the hammer goes down wins. All sorts of possible ideas compete in our heads, both in terms of just what we see when we look out of the window and in terms of deciding whether to buy a house for hundreds of thousands of pounds. The system works quite well because each pathway is constantly recalibrating its 'bidding strategy' in the light of experience. And the choice of what comes through as relevant, salient or 'the right decision' can be fine tuned using synchronisation that gives preference to certain cells firing.

I suspect that when the system is sensitised by local cytokine or whatever the salience regulation mechanism goes all to pot. From the sensory point of view all you can do is go to bed and cover your head with the eiderdown. From the 'executive function' point of view decision making goes to pot and you rapidly realise it is better not to try. On the autonomic side regulatory loops may get overloaded with signals and go for an 'escape valve' response such as collapsing on the floor with 'grey-out'.

There has been a bit more discussion on PEM since your question and I agree that it is probably complicated and heterogeneous. My simple thought was that if the response is delayed, in whatever sense, it does not seem so easy to explain it simply on the basis of a sensitised neural pathway. Neural pathways work over periods of seconds, or maybe minutes for the autonomic system. I sense that some lymphocyte/macrophage interaction outside the brain might also be relevant. Maybe some macrophage influx into muscle is important - which takes about 12-18 hours. These are clearly relevant in the 'flu' situation so maybe in ME as well.

In a sense I think what the Norwegians and the group at UCL may be trying to pin down with B cell work is whether we are dealing with just some processes that I called ME3 - loops set up in the CNS - or whether there are continuing antibody-mediated loops, of the ME5 sort, keeping ME3 going. Rituximab responders may be those for whom block of ME5 allows ME3 to fizzle out. Non-responders may have a more entrenched ME3. ME3 may still involve activated microglia, and in that sense be 'immune' but it may be independent of B cells. The same might apply to ME2, which would stand in for ME5 maybe through a T cell mechanism.

That's my speculation for today (which was tomorrow).

 

[A.B.]

Driven by symptoms???? Isn't that putting the horse behind the cart?

Are you being sarcastic?

No, but I wasn't as clear as I could have been (English isn't my first language). I meant that the behaviour is driven by symptoms.

Activated immune system -> cytokines -> mental and physical symptoms -> change in behaviour.

Cytokines -> change in behaviour might also exist.

 

[medfeb]

The difficulty is in learning to write down how we think it does work. Some years ago John Kirwan wrote a paper called something like 'Do rheumatologists do what they say they do? He showed that our decisions do not follow the rules we think we are following. Unfortunately in the current bureaucratic world of NICE it is assumed that we do and the result is a disaster.

The key point is that we should not be making decisions based on disease names at all. Holgate quoted some ancient aphorism which is now truer than ever - something like 'do not seek to know the disease the person has, but the person who is diseased'.

It may seem problematic to have lots of criteria but the only problem may be that they are all given the same name. I agree that some of them are probably rather poorly thought out, but I am not sure that any one is 'better' than another.

Dr. Edwards
Thank you so much for your response. Your analogy does a good job of highlighting what a clinician should do and how that can go wrong. While U.S. guidelines are not as restricted as the NICE, they still lead to some of the same behavior in medical providers. In the case of ME patients, that too often short-circuits the process directly to recommendations for exercise and talk therapy or to outright dismissal.

I agree with you that the problem is that these criteria are all using the same name. But I think that is compounded by the fact that the definitions as so diverse and Oxford and Fukuda are so broad. Oxford is just medically unexplained chronic fatigue. It seems scientifically invalid to assume that everything that is medically unexplained and causes fatigue somehow belongs in the same clinical entity. That would be like taking any newly discovered animals - spiders, birds, mammals, fish - and stuffing them into the same bucket called "Mystery Animals" simply because they are all animals whose biological classification is unknown.

But that's what we get with Oxford and even with Fukuda to a lesser extent. And those criteria have driven many of the research studies that form an evidence base that leads to evidence based recommendations for CBT and GET and the associated perception that the disease is psychogenic. Even here. One of the premier health clinics in the U.S. quotes PACE as a ground-breaking study and recommends CBT to "change the cognitive responses that are thought to perpetuate CFS, such as fears about symptoms or activity, and social and emotional obstacles."

If we had only had the Ramsey criteria, the CCC and the ME-ICC all using the same name - at least initially until research could work out biomarkers and subtypes - its hard to imagine we'd have the research and clinical mess we have today. I think that the mess comes from the additional fact that the "CFS" collection of criteria are so diverse and some are overly broad. Especially when that is combined with mindless reliance on evidence based guidelines derived from such a collection.

On another note… I am encouraged by your reports on what was discussed on the biology side and the reception to the PACE discussion. This does seem to be qualitatively different and that is fantastic.

 

[Jonathan Edwards]

Is there scope for someone like yourself writing an article or two in popular science publications or the media, explaining that often illness has a random component and is beyond our control and we should not blame ourselves or anything in particular.

Not much chance I would say. Popular science has to appeal to people's preconceptions to be popular. As you say, people want to hear about something that CAUSES something. And within the medical field the sad truth is that most of my colleagues seem to be too dim to get the point - even the top flight immunologists. A lot of people seem to have a mental block about what tends to be called 'complex system dynamics'. Part of it I think is complacency. People think they know disease causation - genetics and environment. And it is only really on a forum like this that you can say 'rubbish' to people. If a practicing scientist says rubbish to anyone he will get no more grants from then on.

 

[lansbergen]

No, but I wasn't as clear as I could have been (English isn't my first language). I meant that the behaviour is driven by symptoms.

Activated immune system -> cytokines -> mental and physical symptoms -> change in behaviour.

Cytokines -> change in behaviour might also exist.

English is not my first language either.

As I understand it, behaviour changes are a healthy reaction to the threat

 

[MeSci]

There has been a bit more discussion on PEM since your question and I agree that it is probably complicated and heterogeneous. My simple thought was that if the response is delayed, in whatever sense, it does not seem so easy to explain it simply on the basis of a sensitised neural pathway. Neural pathways work over periods of seconds, or maybe minutes for the autonomic system. I sense that some lymphocyte/macrophage interaction outside the brain might also be relevant. Maybe some macrophage influx into muscle is important - which takes about 12-18 hours. These are clearly relevant in the 'flu' situation so maybe in ME as well.

Some of us have noted that our PEM is like a hangover. I understand that hangover symptoms are mainly due to dehydration and loss of electrolytes.

I suffer from solute diuresis after exertion - haven't yet analysed when it starts, but suspect that it is the day before my PEM appears. My PEM usually appears about 48 hours after the exertion, but at better times it has taken up to a week and been extremely mild - almost imperceptible. At least one other contributor, however, has said that a longer delay is associated with worse PEM for them.

So, what could be causing solute diuresis after exertion? (I had been thinking along the lines of inflammatory cytokines, but have read your reservations about this.) And could solute diuresis/dehydration/electrolyte deficiency help to solve the mystery of the delay? That it takes a while for something to cause the diuresis, and then further delay before the dehydration and electrolyte loss reach a level sufficient to cause symptoms? (Consistent with a solute diuresis cause of PEM is the fact that several people report great improvement - even remission - from being given IV saline.)

There is a thread on PEM being like hangovers here.

Admittedly there are PEM symptoms which I don't think are seen in hangovers, notably swollen/tender lymph nodes. So could your suggested lymphocyte/macrophage interaction/macrophage influx into muscle fit into the solute diuresis connection?

 

[Jonathan Edwards]

I think one of the problems is that people avoid studying 'randomness' which can often be characterised.

I assume that an antibody production will be more likely to produce certain antibodies rather than others. Where we say there is a genetic predisposition to an auto immune disease is that due to some people (with a particular gene) having an antibody production process that is more likely to produce a given antibody than others. So a bit like in dependability work where they look at characterising the time to failure is there a characterisation of different time to auto-antibody based on say genetic factors. I wonder if there are environmental factors that may also effect the randomness (probably due to my ignorance about the process) but if it is a chemical process producing an antibody then do variations in compounds in cells make a difference to the process?

What worries my about the statistical analysis of different possible environmental factors is that there seems to be no account of the way a disease process may work. Given a search over enough statistical methods with a variety of fudge factors does it become possible to find one method that comes up with the desired answer (and given a dataset I could possibly use genetic program (a search technique nothing to do with genetics!) to find it).

My experience, however, is that in getting to the point where the processes are described sufficiently but abstractly enough to build a model often brings a better understanding of the system and that is the important processes. I think this is due to people finding abstract thought hard and hence its hard to layout the important features of a system and join them up. Some people can do it intuitively.

A lot of good detailed points user9876. We actually know quite a lot about the randomness of antibody production. Within the range of antibodies we can possibly make there are indeed weightings towards some being more likely to be produced than others. There are also variations between people in terms of the repertoire - things called Gm allotypes for instance. However, there does not seem to be any significant link in disease rates with these. What seems to be much more important is the setting of thresholds for feedback loops that can allow certain 'rogue' antibody species to generate an abnormal subversive loop of production.

The most obvious is complement C1q. People who have C1q deficiency virtually always get caught up in a loop that generates antinuclear antibodies. Moreover, this happens with such reliability that it usually happens young - by age 20. The DR4 HLA allotype seems to lower the threshold for the loops that allow rheumatoid factors and anti-CCP antibodies to be made in RA. And so on. There is no evidence that any of these allotypes favour the initial genesis of any of these autoantibodies but rather that they facilitate the formation of a feedback loop once generated. The chemical process of random antibdoy generation looks to be fairly impervious to environmental effects - although we may learn more on that in due course.

I agree with your thoughts about statistical analysis of complex environmental contributions. Esther Crawley is actually getting involved in complex modelling in this way. It sounds as if her husband is a statistician. I am a bit sceptical that the models will work out the way they hope - but that, as you say, will be useful if it shows that another model is needed. I also agree that once one has a model that allows abstraction of a central dynamic concept, like an inappropriate positive loop, it often becomes possible to reformulate the model in a more powerful way, with new sorts of predictions. That I guess is the essence of our 1999 Immunology paper on the concept of the self perpetuating B cell in autoimmunity.

What seems to me desperately needed is something similar to our understanding of lymphocyte loops in terms of brain loops that might explain what people call 'central sensitisation'. Influx of microglia seems an interesting concept to work with but I am finding it hard to understand why some bits of brain should get into loops and not others.

 

[MeSci]

English is not my first language either.

As I understand it, behaviour changes are a healthy reaction to the threat

I don't think that the term 'sickness behaviour' actually means behaviour as most of us understand it, which is why I agree that it is a terrible term. I understand that it actually means the physiological processes that occur in response to damage/infection, e.g. fever.

 

[DanME]

English is not my first language either.

As I understand it, behaviour changes are a healthy reaction to the threat

I think, the behaviour (and mood) changes are a symptom (like fever), which is driven by cytokines. You don't control them, but the cytokines do.

You can clearly see this, when you (or better healthy people) have the flu. The body recognises the virus and starts to ramp up the immune defence. A lot of cytokines are released into the blood stream and finally make it to the brain. You get fever, loose your appetite, are in a depressed mood, you feel dizzy and want to lie down, your muscles hurt etc. and most importantly your biggest wish is to rest and close your eyes. All this is not caused by the virus, but by your immune system. The cytokines order your brain to feel this way. It makes a lot of sense in evolutionary terms, like A.B. pointed out. Your body hinders you to waste energy (even digestion consumes a lot of energy, so the body shuts it down and uses its energy reserves instead). It is indeed the sickness response of your brain to an infection.

If the loop is stuck, hypersensitized and never ends it could cause problems like we see in CFS. Small releases of cytokines would trigger a massive sickness response, which would be appropriate for the flu, but not for a ten meter walk.

I like the theory. We only must be careful about the phrase "sickness behaviour". I think the term is correct, but nevertheless very unfortunate for our cause.