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A Tale of Two Viruses: Why AIDS Was Pinned to HIV, but CF Remains a Mystery

Jemal

Senior Member
Messages
1,031
This was posted by XMRV Global Action on Facebook. It's a column by Prof. Racaniello.

The detection of a new virus called XMRV in the blood of patients with chronic fatigue syndrome (CFS) in 2009 raised hope that a long-sought cause of the disease, whose central characteristic is extreme tiredness that lasts for at least six months, had been finally found. But that hypothesis has dramatically fallen apart in recent months. Its public demise brings to mind an instance when a virus *was* successfully determined to be behind a mysterious scourge: the case of HIV and AIDS. How are these two diseases differenthow was it that stringent lab tests and epidemiology ruled one of these viruses out, and one of them in?

This is the conclusion:

In retrospect, it is clear that the properties of AIDS made it an easy disease to understand. While the path to understanding CFS has been clouded by non-scientific issues, in the end the main reason why we do not understand this disease is because it is extraordinarily complex. But that never stopped a good scientist.

http://blogs.discovermagazine.com/c...-deduce-what-does-and-doesnt-cause-a-disease/
 
Messages
5,238
Location
Sofa, UK
I think it's a good analysis, there is much that is very positive here and that we should applaud. For example:

Why do the stories of AIDS and CFS have such different outcomes? One reason is that it has been difficult to reach a consensus on a clinical definition of CFS...The case definition for CFS has undergone a number of revisions over the years. When different research groups use different definitions of the disease, it becomes difficult to compare findings. Most importantly, there is no indicator or diagnostic test that can be used to identify CFS, and since diagnosing CFS is a long and difficult process, cohorts established by different investigators vary, leading to different findings, confusion, and contention.

Another problem is that in contrast to their excellent work on AIDS, the CDC has stumbled when tackling CFS. The CDC has dismissed evidence that CFS is an organic disease, and spent funds on investigating psychiatric and trauma-related causes, rather than infectious origins. The agency also diverted funds designated for CFS to other programs. These and other missteps alienated the CFS patient communitythe opposite of what the agency accomplished with the AIDS community.

Why have investigators failed to identify a virus behind CFS? ... One explanation for this dilemma is that an infectious agent does not cause CFS. However, there is plausible evidence for an infectious etiology, including observations that the disease is known to occur in outbreaks. Furthermore, in many cases the onset of symptoms appears to begin with a flu-like illness. Additionally, CFS is a heterogeneous disease, and may be caused by several different agents or a combination of viruses and non-infectious conditions. Another possibility is that an infection initiates an immune response that spirals out of control, leading to CFS symptoms. This scenario implies that at least some CFS patients have underlying deficits in immune regulation. If thats true, it will be very difficult to identify the virus involved because it will likely have been eliminated from patients systems by the time CFS symptoms become apparent.

That's getting to the heart of so many of the core issues that we would wish to highlight as campaigners, and so much better than the average article, that IMO we should be enthusiastic in our support for Dr Racaniello's analysis here - it's a breath of fresh air.
 
Messages
5,238
Location
Sofa, UK
Also, the article links to a very interesting-looking article from 1959, by Henderson and Shelokov:

http://www.nejm.org/doi/full/10.1056/NEJM195904092601506

DURING the past ten years an impressive number of outbreaks of bizarre, clinically similar illnesses have been reported from several areas of the world. The cases have shared the features of a protean symptomatology, including fatigue, headache, alterations in emotional status, aching muscular pain, paresis and paresthesias. Regarding the severity of the illnesses, few significant and consistent physical findings and abnormal laboratory determinations have been noted. The courses of the patients have been unaccountably prolonged and debilitating and marked by frequent exacerbations. Cases have been confined principally to young and middle-aged adults; females have been more frequently and severely afflicted.

Evidence from this time period is of great interest to me, because i generally find these accounts to be substantially free from the political spin that surrounds modern accounts, and thus, I believe, more objective in their description of the raw data. I am also intrigued by the comments from this time period where the authors tend very much to describe the outbreaks and the illness as a new phenomenon with which they were previously unfamiliar. I think that such evidence points clearly towards the conclusion that ME/CFS is primarily a modern phenomenon, which must be crucial in considering its aetiology. I'm not convinced by the common argument of (pseudo)sceptics that this illness has always existed but was previously unremarked; accounts like this which view the emergence of ME/CFS from within the historical context of their time strongly suggest that a new phenomenon is being described.

Does anybody know how I can view this article without paying for it? It's from 1959 and an important historical document; it's disappointing if it is still not publicly available.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I posted this on another thread but it belongs here too. One person had a comment saying that AIDS is real, CFD is not a disease. My reply, awaiting moderation, is:

11. Alex Young aka alex3619 Says: Your comment is awaiting moderation.
January 12th, 2012 at 9:14 pm

In reply to: . Jon Says: January 12th, 2012 at 2:27 pm There is only one difference between AIDs and CFS. AIDs is a real disease that results in death if not treated. CFS is not a disease at all.

This is a technicality. CFS is a syndrome and a number of definitions describe a heterogenous patient mix. The core disease that has occured in many geographical clusters (epidemics) is Myalgic Encephalomyelitis. The number of biophysical abnormalities is huge (thousands), but not routinely tested for indeed most pathology labs do not even have the required tests.

Let me give some examples of these things to give an idea of the issues:

1. Many with long term ME have heart damage. It is now apparent that this kind of damage might be unique to the disorder, but for most of the last ten years this was confused with regular diastolic heart failure/dysfunction. Heart biopsies frequently find viral infection when the biopsy is done, but biopsies are rare.
2. Abnormal immune chemistry abounds. Take for example 37 kDa RNase L. It is found in most ME patients. It is also found in MS and Rheumatoid Arthritis patients, so it is not diagnostic. Most of the abnormal chemistry is shared, and so not diagnositc.
3. Three abnormal findings have high diagnostic value and await validation: spectral coherance EEG (Komaroff); post exertional pathophysiology (Pacific Labs, Lights) and severely decreased NK cell function with a low bright cell to dim cell ratio (Bond University).

This latter makes ME a type of non-HIV AIDS affecting NK cells and not T cells different, but not entirely different. ME has much lower mortality in the medium and short term, but the long term is questionable it doesnt kill as fast, but it does kill. Lymphoma is very common in ME patients, and some cases of Karposis sarcoma have been claimed, normallly found in HIV AIDS. However, ME morbidity is similar to HIV AIDS morbidity shortly before death ME is much more disabling during most of the disease history. Imagine feeling like an AIDS patient weeks before death, but it goes on and on and on for years and decades.

Bye, Alex

PS, not part of the reply to the article, I had to be highly selective in my examples. There were so many I could have talked about, but I wanted a one page reply not a book.

PPS I can't get the Henderson article but two similar articles are here, download the pdf:
http://journals.lww.com/smajournalonline/Citation/1959/06000/Epidemic_Neuromyasthenia.27.aspx
http://journals.lww.com/smajournalonline/Abstract/1959/10000/Epidemic_Neuromyasthenia.6.aspx
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Of course 'Jon' could have been making the point that as far as he is concerned 'CFS' is a construct and not a disease per se I suppose...

Either way there are some good and not so good comments after that article. You reckon L. Hart is that lawyer Mikovits once had? Louise Hart I recall from Cohen's article was commenting quite 'vigorously' at one point.

Anyway, I digress and I can't sleep so am tired and I have a stack of papers to read... ho hum.. diversion therapy is required methinks...

Sorry!
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Firestormm I thought of that interpretation, then had to decide that most will not see it that way and I should be addressing them. I am not really addressing Jon. Its the wider audience that has to be reached, not one individual. I too have been doing diverstion therapy - I have been rewatching the old TV show Dark Angel. Bye, Alex
 

Ember

Senior Member
Messages
2,115
Prof. Racaneillo correctly implicates the failed consensus on a case definition in the failure of CFS research:

Why do the stories of AIDS and CFS have such different outcomes? One reason is that it has been difficult to reach a consensus on a clinical definition of CFS. At the onset the case definition of AIDS was simpleKaposis sarcoma or opportunistic infectionswhich made it possible to rapidly and accurately identify new cases, especially among different research groups around the country.... In part due to the standardized case definition of AIDS, identification of a candidate virus was relatively rapid.

But he side-steps the CDC's role in the ongoing research problem. In his November article on Prof. Racaneillo's blog, David Tuller more accurately describes the CDC's role in designing a Tower of Babel for us:

Other CDC efforts, such as the multi-million-dollar public awareness campaign to brand the name chronic fatigue syndrome, dismayed much of the patient and advocacy community, given ongoing and fervent attempts to have the illness officially renamed ME. And in a highly controversial move, Dr. Reeves spearheaded in 2005 the creation of the new, purportedly more precise method of identifying patients; critics feared the approach would wreak havoc with epidemiologic studies by mixing a lot of people with depression but not CFS into samples of people all presumed to have chronic fatigue syndrome.

During the 2000s, researchersincluding many clinicians who actually treated patients and understood how seriously ill they could behad continued to be dissatisfied with the 1994 case definition, which they felt imprecisely described the condition. For one thing, the definition allowed for but did not require the presence of post-exertional malaise (reminder: read relapse or crash, rather than malaise). Yet it was increasingly apparent that post-exertional malaise, and not fatigue alone, was a cardinal symptom for many if not most patients, and one that clearly helped distinguish CFS from primary depression, as well as other chronic illnesses. The CDC definition also allowed for but did not require the presence of cognitive and neurological problems, although these appeared to afflict almost everyone with the condition.

Other research groups were using their own case definitions, making it hard to compare results. The Oxford criteria developed in Great Britain required only the presence of six months of disabling fatigue; that single-symptom criterion was criticized as so broad that it was likely to identify many people with primary depression rather than CFS. A more detailed 2003 case definition developed in Canada focused on post-exertional malaise as a cardinal symptom of what it called ME/CFS. Required symptoms also included disordered sleep, pain, and neurologic symptoms, as well as signs of dysfunction in the immune, endocrine and autonomic nervous systems.

Earlier this year, a team of top researchersnot surprisingly, without any participation from the CDCpublished a new international consensus case definition, which adopted the name myalgic encephalomyelitis and abandoned chronic fatigue syndrome altogether. Using the Canadian definition as a jumping-off point, the new international definition also dropped the construct of fatigue in favor of requiring post-exertional malaise, which they renamed post-exertional neuroimmune exhaustion. Other required symptoms include neurological and energy production impairments.

In contrast, the 2005 effort by the CDC to operationalize the earlier 1994 case definitionby introducing standardized questionnaires and measurement scales to assess levels of fatigue and functional impairmenthas found no support outside the CDC itself.

I wonder if Prof. Racaneillo is reluctant to draw a political conclusion. He writes, While the path to understanding CFS has been clouded by non-scientific issues, in the end the main reason why we do not understand this disease is because it is extraordinarily complex. Then he undermines his own conclusion by adding, But that never stopped a good scientist.

David Tuller, on the other hand, in describing the impact of the CDC case definitions, quotes Prof. Racaneillo:

Dr. Racaniello said that when he used to question colleagues about chronic fatigue syndrome, they would argue that it was an imaginary illness. Every time I asked someone about it, they would say it doesnt exist, it isnt a real disease, even as recently as the past year, he said. But once you start paying attention and reading papers, this looks like a chronic or hyper-immune activation. These patients have a lot of signs that their immune systems are firing almost constantly.

Tuller also quotes Lenny Jason, who himself implicates the failed consensus on a case definition in the failure of CFS research:

This ambiguity over definitions has made it difficult for researchers to pinpoint a biological cause, wrote Leonard Jason, a professor of community psychology at DePaul University in Chicago and an expert in CFS, in an essay published this year in The Wall Street Journal. When investigators compare very different samples, it is difficult, if not impossible, to replicate findings from one lab to another. And when consistent biological findings do not emerge, investigators might inappropriately conclude that CFS is only a psychiatric problem.

This morning, Prof. Racaneillo chooses to blame the politics surrounding the ongoing research problem on the failed research itself: The amount of money spent on a disease for research is driven in large part by how much progress is made (comment #21). David Tuller concludes differently, For the most part, the elements of the CFS program that Dr. Reeves championedthe empiric criteria, the name of the illness, (most of) the disputed website information, etc. remain in place under Dr. Unger (http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/).
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I have added another reply, in response to a comment by in vitro infidelum:

35. Alex Young aka alex3619 Says:
January 14th, 2012 at 8:46 am

I am the other Alex, there are two on this page.

I am in partial agreement with in vitro in post 33. There is still insufficient evidence to equate post viral fatigue with ME. They may not be the same thing. This is one of the problems we face. Are we talking about one or several discrete but similar diseases? Are we talking about one disease with a spectrum of manifestations? Are we talking about as subset of post viral fatigue becoming ME? (I think this latter case is the most likely at this point.) Without reliable biomarkers the research can never really address these questions.

Confusion between PVFS and ME may also be responsible for much of the uncertainty over prognosis. For example, most cases of PVFS resolve themselves in a few months to five years at the outside. Looking at data over the five year mark, most long term ME patients never recover. If the under five year data is a combination of ME and PVFS this would explain the discrepancy. Since most people see those with PVFS recover, it would also explain why they do not understand why those with ME do not. But is this explanation correct? We need biomarkers to proceed.

Bye, Alex
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Ember,

Great post. I think though it should always be remembered that Vincent Racaniello is a virologist. That's his interest and that's his principal motivation for writing.

Edit:

Found his comment now:

21. Vincent Racaniello Says:
January 13th, 2012 at 7:35 am

The amount of money spent on a disease for research is driven in large part by how much progress is made. When HIV-1 was discovered, huge amounts of money were allocated for its study because there were so many clear paths. At one point there were seven study sections at NIH reviewing AIDS grants, and one study section for the rest of virology. That caused consternation as you might imagine. If XMRV had panned out as a CFS cause, you would certainly seen much more money poured into CFS research. Its a chicken-and-egg problem, but that is the way science works. When you get an NIH grant, you are expected to use some of the money to explore other areas, and if you get interesting results, they can be used to secure additional funding.
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
IVI's comment:

'24. In Vitro Infidelium Says:
January 13th, 2012 at 12:46 pm

VR wrote: Hoever, there is plausible evidence for an infectious etiology, including observations that the disease is known to occur in outbreaks. Furthermore, in many cases the onset of symptoms appears to begin with a flu-like illness.

There is a double dose of a priori reasoning being applied here. There is no secure epidemiology that can reliably demonstrate commonality of illnes either within reported outbreak cohorts, or between outbreak cohorts; in addition the linkage of symptom onset is a feature wholly of patient report, not of any validated assessment. That is not to say that outbreaks are not representative of occurences of highly localised epidemilogical features of M.E/CFS, nor that M.E/CFS is not characterised by an acute onset, but at this stage these remain speculative features, not definitive descriptions.

While an event characterised by multiple individuals displaying symptoms of a communicable infection which is followed by a chronicity of symptoms that are typical of M.E/CFS is clearly suggestive of an involvement of infection within the aetiology of M.E/CFS, there are simply too many confounding factors to allow a conclusion that M.E/CFS is unequivocally explained by an infection mediated aetiology. It must be asked that if the assumed infectious agent is active in a given population, then what proportion of that population will becom infected, what proportion of those infected will display acute symptoms and what proportion of those who are a) infected and asymptomatic b) infected and display an accute symptomology go to develop a chronic condition that is describable as M.E/CFS ? If we were talking about HIV, the answer to the third part of the question is would be something close to 100% for both a) and b), yet we have no such evidence in the M.E/CFS that infection necessarily equates to chronic disease. In the case of M.E/CFS infection appears only to be associative, not directly causative, something which is echoed in one of the few epidemiologically consistent observations of M.E/CFS patients, that is, there is a strong imbalance in gender representation women being diagnosed at a much higher rate than men. Unless a very unusual exposure process is in play, then the gender imbalance issue is a major stumbling block for any hypothesis of M.E/CFS that is founded on a purely infectious causation.

The patient reported association with acute onset coincident with a viral infection is also problematic. It is of course axiomatically impossibe to have planned a prospective test of a patients health prior to their reporting illness, and the patients observations may well be important evidence. However it can not be discounted that there may have been low level symptomology present prior to an acute infection, with that symptomology being entirely independent of any infection, or alternatively that an infection may be a trigger for an underlying but asymtomatic condition. Given the level of disbelief which has histerically met M.E/CFS patients encountering medical services, there may be very strng predisposition for patients to locate the commencement of chronic illness at point that is coincident with an accepted state of illness in the very natural attempt to provide validity for their very real chronic illhealth.

M.E/CFS is a complex illness that demands significant commitment of research effort, that effort can not be short cut by poorly stated hypotheses, and only through research which is conducted in relation to the known characteristics of the illness can real progress be made. M.E/CFS most certainly is not like HIV, it is nevertheless a debilitating illness and the lack of progress in understanding it undoubtedly raises questions about the perspectives of the medical profession, the research fraternity and polititions.'


I have added another reply, in response to a comment by in vitro infidelum:

35. Alex Young aka alex3619 Says:
January 14th, 2012 at 8:46 am

I am the other Alex, there are two on this page.

I am in partial agreement with in vitro in post 33. There is still insufficient evidence to equate post viral fatigue with ME. They may not be the same thing. This is one of the problems we face. Are we talking about one or several discrete but similar diseases? Are we talking about one disease with a spectrum of manifestations? Are we talking about as subset of post viral fatigue becoming ME? (I think this latter case is the most likely at this point.) Without reliable biomarkers the research can never really address these questions.

Confusion between PVFS and ME may also be responsible for much of the uncertainty over prognosis. For example, most cases of PVFS resolve themselves in a few months to five years at the outside. Looking at data over the five year mark, most long term ME patients never recover. If the under five year data is a combination of ME and PVFS this would explain the discrepancy. Since most people see those with PVFS recover, it would also explain why they do not understand why those with ME do not. But is this explanation correct? We need biomarkers to proceed.

Bye, Alex

The article has certainly led to an interesting exchange of comments I think. Kinda cuts to the chase in many respects, doesn't it?

Personally, I still feel that 'CFS/ME' is too big a 'pot' and that research will only progress if that 'pot' can become smaller 'pots' whose patients fit more relevant and testable criteria.

Even the ICCME doesn't go far enough - even if it does progress to testing. If we are considering 'viral causation' then we need to consider better testing at the point of diagnosis.

This idea of leaving it until it develops - which can be six months or more from the point of acute infection (assuming there is such a point of course) - seems to me to be too late.

But, if you don't test and find what that infection is in the first place.... what's the point of moving the diagnosis point forward e.g. from 6 months to 1 month if indeed this is even prudent for a condition that at present depends on our inability to 'recover' post-infection?

So you could - in theory - be looking at a total reorganisation of the way in which people are investigated and treated when reporting symptoms of viral infection. That each and every person is thoroughly tested to find what that virus is - not as at present when one is diagnosed generally with 'a viral infection'.

And what do you do with folk whose diagnosis is 'a viral infection' but whose virus cannot be found? This is assuming of course that a virus is responsible and I don't personally believe it is.

So define 'it' and how 'it' might infect and cause CFS/ME (whatever) in such a seemingly random (but more female orientated) group people. I don't think you ever will.

Indeed, I would rather (as I have said countless times before) they look at our immune systems - and although you still run into the same problems as above and in the article - I do believe that it is predominantly 'immune dysfunction' (even perhaps some autoimmune thing) that is preventing me from 'recovering' and indeed 'relapsing' when a(nother) virus takes hold - as has happened in my case.

As far as I am concerned there is no 'one virus' responsible and that includes retroviruses. It just doesn't make sense. But I remain open-minded when it comes to published research of any description of course - I just don't 'buy' into the speculation or indeed vaccine causation either by the way and just for the record.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Firestormm, historically I have had the perspective (since 1993) that ME (CFS to me back then) had many triggers but was actually a heterogenous mix of immune and biochemical malfunctions, but that most CFS patients (Holmes definition) had the same disorder, with a minority having other similar disorders. There is not much doubt about viral triggers. There is not much doubt about immune dysfunction. The arguments are all about where the pieces fit, how many pieces there are, and which are the most important. For that we need science, but for good science we need funding and biomarkers (probably more than one). Bye, Alex
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
On the same article comments I have added:

I suspect that for many drugs and therapies that are applied to ME patients there is a huge gap between the evidence base and actual results. Patients often respond far differently to the norm, especially for drugs that involve serotonin or vasoregulation chemistry. Similarly many of the CFS studies are a mixture of psychiatric fatigue, idiopathic fatigue, PVFS and ME. In addition, using the ICC ME severity scale, most patients in such studies are mild patients, with maybe a few moderate patients thrown in. I am at the severe end of moderate but could not get into a local study due to the issues that only moderate ME cause, particularly with capacity to travel. So there is almost NO evidence base at all for severe and very severe ME patients, and very little of relevance to moderate patients. So when someone says a treatment is based on "evidence based medicine" what they mean is they are using evidence that applies to someone else if you are moderate or worse.

As a result most doctors are experimenting on ME patients with every therapy. Patients are also experimenting on themselves. This is due to the severe underfunding of quality science over many decades. This experimentation appliesto "evidence" based approaches as much as others, perhaps more so since they have an unvalidated standard of evidence.
 

justinreilly

Senior Member
Messages
2,498
Location
NYC (& RI)
I thought this was a very good article, 'considering'. He was wrong in concluding the main problem was the complexity, though that is a big problem. Otherwise, excellent. My badgering got him to finally read David Tuller's guest post on his blog and now, to his credit he has given a shout out to it here. Overall, I think he is a good guy and fair, but he does need to be led to the truth, as many others must, so don't give up!