The long awaited Food and Drug Administration (FDA) and National Institute of Health (NIH) paper has finally been published. The paper was published today in one of the world’s most eminent scientific journals, the Proceedings of the National Academy of Sciences (PNAS.) The abstract of the FDA/NIH study can be found here: http://www.pnas.org/content/early/2010/08/16/1006901107.abstract?sid=0caef811-3af1-40e8-80db-269182b6307c
The entire 6 page FDA/NIH study in PDF form can be found here: http://www.pnas.org/content/early/2010/08/16/1006901107.full.pdf
The FDA/NIH study authors found a Murine Leukemia Virus-like Virus in the blood of 32 out of 37 (86.5%) CFS patients. This contrasted the Murine Leukemia Virus-like Virus being found in the blood of 3 out of 44 (6.8%) of healthy controls.
Eight CFS patients who were gag-positive in this study (based on blood that was banked 15 years ago) were retested with blood drawn from 15 years later (drawn in 2010.) Seven out of the eight CFS patients remained gag-positive. The one patient who had now returned a negative gag result still hadn’t recovered from their CFS.
The FDA/NIH study results have not only confirmed but extended the results of the Lombardi-Mikovits paper published in October 2009. This 2009 paper found XMRV in the blood of 68 out of 101 (67%) CFS patients. This was in comparison to just 8 out of 218 (3.7%) healthy controls being XMRV positive.
XMRV vs MLV
The Lombardi-Mikovits paper in 2009 detected XMRV while the FDA/NIH paper detected MLV. XMRV is the initialism for Xenotropic Murine Leukemia Virus- related Virus. MLV is the initialism for Murine Leukemia Virus. Mikovits, Lo and Alter seem to have unanimously confirmed that both studies found the same retrovirus (Alter and Lo are two of the FDA/NIH study authors.) This retrovirus is a human retrovirus that is a member of the Gammaretrovirus family. There are a family of these Gammaretroviruses that are Murine Leukemia Virus-related Viruses and this is what both studies have detected.
The FDA/NIH study detected four slightly different types of these MLVs. This is similar to the other infectious retroviruses, HIV and HTLV which have several variants. The FDA/NIH study shows that there is a genetic diversity among MLVs infecting humans. Seven out of eight gag-positive CFS patients tested in the FDA/NIH study had their MLV mutate during the 15 year period in which their blood was drawn on the separate occasions. Since the WPI’s October 2009 study, the WPI have found more than one strain of MLV and this supports the FDA/NIH study results.
The FDA/NIH study authors wrote that “In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs.” ‘Polytropic’ forms of MLV can infect mice cells and non-mice species cells. ‘Xenotropic’ forms of MLV can’t infect mice cells anymore but can infect non-mice species cells. This supports the notion that the Lombardi-Mikovits paper and the FDA/NIH paper found the same retrovirus. The FDA/NIH study not just confirmed but also improved upon the Lombardi-Mikovits study by determining that the retrovirus studied can infect mice cells. The XMRV versus MLV confusion in this situation only centres around the semantics and nomenclature of retroviruses, not the science.
Prior to the FDA/NIH study being released, there was a lack of clarity concerning the nomenclature of the retrovirus the Lombardi-Mikovits and FDA/NIH studies found. This suggests that the proposed renaming of XMRV to HGRV may have stemmed from the FDA/NIH study result. Dr Alter has commented that a superior name (to XMRV) for the retrovirus is Murine Leukemia Virus- related Virus.
CFS Cohort Used
The majority of the CFS patients used in the FDA/NIH study were from the New England area. None of these CFS patients were related and almost none had regular social contact. Dr. Anthony Komaroff (a CFS physician) supplied the CFS patients. The patients were deemed to be CFS patients based on many laboratory tests, a patient questionnaire, a physical examination and the patients fulfilling specific CFS criteria. This specific CFS criteria was the 1988 CDC criteria for CFS. There was a lack of diversity of CFS criteria in the mid 1990s (when the patients were diagnosed as CFS patients.) The 1988 CDC criteria, also known as the Holmes criteria, differed majorly from the current CDC CFS criteria. The 1988 CDC criteria excluded psychiatric diagnoses and required the presence of eight secondary symptoms for the patient to be diagnosed with CFS. This contrasts the current CDC criteria which does not exclude psychiatric diagnoses and requires just four secondary symptoms for the patient to be classified as having CFS.
Criticisms of the FDA/NIH Study
The FDA/NIH study only tested a small number of CFS patients and healthy controls and hence the exact MLV positive percentages may not be entirely accurate. The study found 3 out of 44 healthy controls to have a MLV which equates to 6.8%. If one of the healthy controls that was MLV positive was not included in the study by chance, the MLV positive percentage would be reduced to 4.5%. If one of the healthy controls that was MLV negative was by chance replaced with a MLV positive healthy control, the MLV positive percentage would change to 11.4%. This variation of between 4.5%-11.4% MLV positive based on just one person in the study having a different result highlights the lack of precision that underscores the 6.8% healthy control MLV positive figure.
The FDA/NIH study utilised blood from CFS patients that was drawn 15 years ago. A greater number of CFS patients in may 2010 be MLV positive due to the infectious nature of MLVs. This means that more CFS patients are likely to be MLV positive now due to catching a MLV after already having CFS. For instance if I already have CFS (from a non-MLV source) and am MLV negative, then I have 15 years to be infected with MLV to change the MLV CFS prevalence. In other words, a small minority of CFS patients will be MLV positive but not have MLV as a cause of their CFS. This figure will most likely be very small if not negligible.
The FDA/NIH study used blood from healthy controls that was from blood donors. This blood was collected between the years 2003 and 2006. If MLVs are infecting the population at a rapid rate then the true prevalence of MLV in the healthy population may differ from 6.8% in the year 2010. The 6.8% figure may have been more accurate between the years 2003 and 2006.
The FDA/NIH paper mentions that “Future studies should adhere to consensus case definitions such as that developed by the Centers for Disease Control and Prevention (CDC.)” This is a very careless comment by the FDA/NIH study authors. The current CDC CFS criteria are much less restrictive in diagnosing CFS than the criteria used in the FDA/NIH study. The CDC is notorious for using flawed CFS definitions as well as controversial and heterogeneous CFS criteria. Leonard Jason has published a study showing that 38% of those with a major depressive disorder were misclassified as having CFS based on the new CDC CFS criteria. Jason’s study concludes that, “This study suggests that the Reeves et al. (2005) empirical case definition has broadened the criteria such that some individuals with a purely psychiatric illness will be inappropriately diagnosed as having CFS.” Jason’s study can be found here: http://www.co-cure.org/Jason-7.pdf
Several studies that have aimed to detect XMRV have failed to do so. The question now arises as to what retrovirological techniques are required to detect MLVs. I have written in detail elsewhere on this blog about some of the flawed techniques and non-representative cohorts the XMRV negative studies have used. I mentioned some of the flawed techniques here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/06/30/xmrv-publications-by-fdanih-and-cdc-both-on-hold/
The negative studies have used the molecular synthetic clone of XMRV, which is VP62. VP62 is a very specific sequence that fails to detect XMRV or MLV variants. The FDA/NIH paper has emphasized that MLVs are genetically variant. This means that a natural isolate is required to detect MLVs as this accommodates detecting the variants of MLVs.
Prior to the release of the FDA/NIH study, Dr Katz claimed that the Lombardi- Mikovits study was evenly poised on a pair of scales with the negative XMRV studies. He then stipulated that if the FDA/NIH study confirmed the Lombardi- Mikovits paper, it would be analogous to placing an elephant on the Lombardi-Mikovits side of the scales. As the FDA/NIH study has now confirmed the Lombardi-Mikovits study, the scientific paradigm scales are now heavily favouring a high MLV- CFS correlation.
How Does This Relate to the Future of CFS?
Despite a correlation between CFS and MLVs, causation has yet to be proven. It is currently premature to claim the scientific paradigm that MLVs cause CFS. Fulfilling Koch’s Postulate and determining if MLVs are causative of CFS is the next step scientifically. At the very least, it looks as if MLVs are a biomarker of CFS. The MLV-CFS studies also support the 2500 plus published journal articles that show that CFS is purely an organic disease. The psychosomatic proponents of CFS have had the last nail inserted into their psychological model of CFS. From “negative illness beliefs” alone it is impossible to be infected with an infectious human retrovirus that is not ubiquitous.
Dr Mikovits gives her thoughts on the FDA/NIH paper in a video found here: http://www.youtube.com/watch?v=9ZEwQUg7o6I&feature=channel&forumid=331851
Annette Whittemore congratulates the FDA/NIH study authors here: http://www.youtube.com/watch?v=ne7if7FKJFg&feature=channel
CFS Central has an excellent article about the FDA/NIH study including quotes from the study authors. This article can be found here: http://www.cfscentral.com/2010/08/fdanihharvard-xmrv-study-same-thing.html
The Wall Street Journal provides an overview of the situation here: http://online.wsj.com/article/SB10001424052748703846604575447744076968322.html
Today not only marks an historic day for the CFS community but also a victorious day for the scientific process. After being held back by government officials, the FDA/NIH paper has been published. The scientific paper has shown that the large majority of CFS patients have an infectious retrovirus that belongs to the Murine Leukemia Virus class. I’d like to finish with a quote from One Flew Over the Cuckoo’s Nest, “I mean—hell, I been surprised how sane you guys all are. As near as I can tell you’re not any crazier than the average asshole on the street.”