Chronic Fatigue Syndrome: Lots of Speculation

Humans love to find patterns in the world. Sometimes patterns exist, sometimes they are imaginary. Sometimes you can see a pattern that may be interesting and ignore its significance. As a resident I used to say that anyone who smokes three packs of cigarettes a day has to be schizophrenic, it was meant more as a joke, when, in fact, it was later discovered that tobacco helps ameliorate the symptoms of schizophrenia. I need to pay more attention.

Part of my job is to look for patterns as a key to the patients diagnosis. Diseases and pathogens tend to (more or less) cause reproducible signs and symptoms and looking for that pattern is often the most helpful clue towards finding the diagnosis. Of course things are never as easy as one would like, as you have to consider whether you are seeing common manifestations of a common disease, uncommon manifestations of a common disease, common manifestations of a uncommon disease and, the hardest, uncommon manifestations of an uncommon disease. When I have a complex or uncertain cause, I explicitly run through that, and other, litanies so I do not miss a unusual diagnosis.

Chronic Fatigue Syndrome (CFS) has, at least to my way of thinking, two patterns. I see the occasional CFS patient in clinic and, I hope, pay attention to their disease patterns. I keep in mind I may be seeing a pattern that does not exist, but looking for disease patterns is what doctors are trained to do.

The first pattern is the patient who has been fatigued all their lives. Not much to say or do for these patients; more often than not the probable cause is psychiatric.

The second type of patient has a different, more intriguing, pattern. They are usually highly functioning people who had the abrupt onset of a ‘flu’ that never left. The have marked post-exercise fatigue and difficulty concentrating for even minor tasks. It is a striking pattern, and reasonably consistent from patient to patient. They sound, for all the world, like someone who continues to suffer from an ongoing infectious disease, yet when all the markers of infection and inflammation are evaluated, they come up normal.

The CDC criteria for CFS do not do justice in differentiating what I see as two distinct clinical presentations and perhaps is a confounding variable in evaluating CFS studies.

So do these individuals with the abrupt onset have an infection or a post-infectious disease?

People have a limited repertoire with which to respond to illness. I have thought that CFS, at least for those with the sudden onset mentioned above, have had one of any number of infections: Q fever, EBV or Ross Valley Fever, or other infections. CFS is, perhaps, the final common pathway for a variety of post-infectious diseases.

The metaphor I use is a rock in a pond. The infection, whatever it was, is the rock. The CFS state is the ripples, lasting long after the rock as disappeared. It would not be the first time an infection left behind long term clinical sequelae. As one example, Irritable Bowel Syndrome is a common, and sometimes permanent, complication after a variety of bacillary diarrhea’s, especially travelers diarrhea. Infections can interact with the host and result in permanent physiologic changes long after the pathogens have moved on.

I find it particularly intriguing that CFS patients have different sets of genes activated when compared to normal controls, although it is papers such as this that let me know how little I understand on some topics. Given the growing literature on the various genetic variations that increase or decrease our risk for infections, it will not come as a surprise if some day they discover genetic polymorphisms are responsible for CFS.

Until recently my understanding of CFS was that it is probably a post infectious syndrome, perhaps in the genetically predisposed, in at least a subset of the CFS population. While the studies show various physiologic abnormalities in CFS are not always replicated, I wonder if the results are due to the inadequacy of the CDC definition in stratifying patients.

Enter XMRV (xenotropic murine leukemia virus-related virus), a retrovirus that was first reported about a year ago and is more frequently found in CFS patients and discussed on this blog .

It has been an interesting year for XMRV.

The first report found DNA from XMRV in peripheral blood mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested PCR, as compared with 8 of 218 (3.7%) healthy controls. Interesting. Maybe an infectious etiology of CFS, which would confirm my bias, and we all like our biases confirmed. From my perspective, all diseases are infectious in origin, or at least the diseases that matter.

Then there were four subsequent studies that failed to confirm the finding of XMRV in CFS. Another dead end? Maybe, maybe not.

This month another study found XMRV DNA was more common in CFS patients than controls.

We examined 41 PBMC-derived DNA samples from 37 patients meeting accepted diagnostic criteria for CFS and found MLV-like virus gag gene sequences in 32 of 37 (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors. No evidence of mouse DNA contamination was detected in the PCR assay system or the clinical samples.

Why the difference?

Previous reports of XMRV isolates from patients with CFS and with prostate cancer and from individuals in different geographic locations have described very similar nucleic acid sequences, a feature believed to be a unique characteristic of XMRVs. However, our analysis revealed three different types of MLV-related virus gag gene sequences in CFS patients. In all three groups, the sequences were more closely related to the sequences of polytropic mERVs than to XMRVs and were more distant from the sequences of ecotropic MLVs.

As I understand it, using PCR, with the wrong primers may not pick up XMRV due to variability in the virus.

Indeed, it is possible that the PCR primers used in various studies may have different sensitivity in detecting the diverse group of MLV-related virus gag gene sequences that we found in the clinical samples. The 5′ gag leader sequence of previously described XMRVs represents the most divergent segment of the XMRV genome in comparison with the genomes of the other MLVs. In particular, there is evidently a unique 15-nt deletion in the 5′ gag leader region in all of the XMRVs previously identified in patients with prostate cancer and CFS. To detect XMRVs in human samples with better sensitivity and specificity, some studies used a PCR primer spanning this unique deletion as the “XMRV-specific” primer. However, none of the viral gag gene sequences amplified from the blood samples of CFS patients and blood donors in our study has this particular deletion . As a consequence, such primers might have been insensitive in detecting the MLV-related gag gene sequences that we have identified.

As a lowly clinician I feel yet again like Mr. Gumby when presented with modern molecular biochemistry. As an old fashioned codger, I will be happier when they discover a way to grow the virus on agar.

Yet, as I am well aware, finding evidence of viral parts is humans does not mean clinical infection or causality. The classic criteria for proving the infectious etiology, Koch’s postulates, have been recognized as problematic for decades.

JC virus, Herpes simplex, and GB virus often persist or replicate asymptomatically in humans and cause no clinical disease. Association is not causation, I tell myself every day. It may turn out that XMRV causes CFS, or that XMRV is a marker of CFS and the physiologic state of CFS is permissive for XMRV replication, or XMRV may have nothing to do with CFS at all.

Still, it is an interesting finding that will hopefully shed some light on CFS. Or not.

It is an odd thing. I always say that the three most dangerous words in medicine are ‘In my experience’ , however those words mostly applied to therapy. Diagnosis in medicine is a lot less straightforward, trying to synthesize the vagaries of the history, physical, and labs into a coherent whole. Good diagnosticians are always experienced; in part because they know more, and in part because they have seen and done more. A good diagnostician is also aware of the many ways they can be fooled, and I have found the best doctors are those that are able to rapidly change their mind as new data presents itself. We all go down dead ends; the best doctors are those who do not have to collide with the brick wall at the end to know it is time to change direction.

My experience and pattern recognition suggest that some CFS patients either have or have had an infection as the cause of the disease, but I could very well be fooled.

What causes CFS? I don’t know. There are interesting hints in the presentation of some patients and perhaps XMRV will be the pathogen, or a pathogen, in CFS. The nice thing is that while it is fun to speculate, eventually the science will sort it out. Some day, if I live long enough, I may know.

Posted in: Basic Science, Science and Medicine

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