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Wednesday, January 6, 2010

Chronic Fatigue Syndrome in "not caused by single virus" shock!

Late last year, Science published a bombshell - Lombardi et al's Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. This paper reported the presence of a recently-discovered virus in 67% of the blood samples from 101 people with chronic fatigue syndrome (CFS).

The question of whether people with CFS are suffering from an organic illness, or whether their condition is partially or entirely psychological in nature, is the Israel vs. Palestine of modern medicine - as a brief look at the Wikipedia talk pages will show. So when Lombardi et al linked CFS to xenotropic murine leukaemia virus-related virus (XMRV), they were hailed as heroes by some, less so by others. For some balanced coverage of this paper, see virology blog. Everyone agreed though that Lombardi et al was, as the saying goes, "important if true"...

But it wasn't, at least not everywhere, according to a paper out today in PLoS ONE: Erlwein et al's Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome. The findings are all there in the title - unlike Lombardi et al, these researchers didn't find XMRV in the blood of any of their blood samples from 186 CFS patients.

Still, before people start proclaiming that the original finding has been "debunked", or decrying these results as flawed, some things to bear in mind...

This was a different country. Erlwein et al used patients attending the CFS clinic at King’s College Hospital, London, England. The patients in the original study were drawn from various parts of the USA. So the new results don't mean that the original findings were wrong, merely that they don't apply everywhere. Notably, XMRV has previously been detected in prostrate cancer cells from American patients, but not European ones, so geographic differences seem to be at work. So maybe XMRV does cause CFS, it's just that the virus doesn't exist in Europe, for whatever reason - but bear in mind that even the original study never showed causation, only a correlation. There are many viruses that infect people in certain parts of the world and don't cause illness.

On the other hand, it was a similar group of patients in terms of symptoms: Diagnosing CFS can be difficult, as there are no biological tests to confirm the condition, but Erlwein et al say that
Both studies use the widely accepted 1994 clinical case definition of CFS. Lombardi et al. reported that their cases ‘‘presented with severe disability’’ and we provide quantifiable evidence confirming high levels of disability in our subjects. Our subjects were also typical of those seen in secondary and tertiary care in other centres.
But the first study selected patients with "immunological abnormalities", although we're given few details...
These are patients that have been seen in private medical practices, and their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to perturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assays), and elevated cytokines particularly interleukin-6 and interleukin-8.
The biological methods were similar: Both studies used a standard technique called nested PCR. (Lombardi et al also used various other methods, but their headline finding of XMRV in 67% of CFS patients vs just 4% of health people came from nested PCR.) PCR is a way of greatly increasing the amount of a certain sequence of DNA in a sample. If there's even a little bit to start with, you end up with lots. If there's none, you end up with none. It's easy to tell the difference between lots and none.

But there were some differences. The first study only looked at a certain kind of white blood cells, whereas the new study used DNA from whole blood. Also, the first study targeted a larger span of viral DNA - from 419 to 1154:
For identification of gag, 419F and 1154R were used as forward and reverse primers.
Than the second one, which examined the section between positions 411 and 606. As a result, primer sequences used - which determine the DNA detected - were different. However, the authors of the new study claim that they would definitely have detected XMRV DNA if it had been there, because they used the same methods on control samples with the virus added, and got positive results...
The positive control was a dilution of a plasmid with a full-length XMRV (isolate VP62) insert, generously gifted by Dr R. Silverman.
Silverman was one of the authors of the original paper - so hopefully, both research teams were studying the same virus. But (although I'm no virologist) it seems possible that the new study might have been unable to detect XMRV if the DNA sequence of the virus from British patients was differed at certain key ways - the whole point about nested PCR is that it's extremely specific.

Finally, there are stories behind these papers. The first study, that suggested that XMRV causes CFS, was conducted by the Whittemore Peterson Institute, who firmly believe that CFS is an organic disorder and who are now offering XMRV diagnostic tests to CFS patients. By contrast, the authors of the new study include Simon Wessely, a psychiatrist. Wessely is the most famous (or notorious) advocate of the idea that psychological factors are the key to CFS; he believes that it should be treated with psychotherapy.

I'm sure we'll be hearing a lot more about XMRV in the coming months, so stay tuned.

ResearchBlogging.orgErlwein, O., Kaye, S., McClure, M., Weber, J., Wills, G., Collier, D., Wessely, S., & Cleare, A. (2010). Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008519

Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, & Mikovits JA (2009). Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science (New York, N.Y.), 326 (5952), 585-9 PMID: 19815723

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