Chronic fatigue syndrome - Study: Presence of murine leukemia virus related gene sequences found in CFS patients

Chronic fatigue syndrome
FDA Note to Correspondents

For Immediate Release: August 23, 2010
Media Inquiries: Shelly Burgess, 301-796-4651, shelly.burgess@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

Study: Presence of murine leukemia virus related gene sequences found in CFS patients

Researchers have found murine leukemia viruses (MLV) related gene sequences in blood samples collected from patients diagnosed with chronic fatigue syndrome (CFS) and some healthy blood donors, according to a study published online today by the scientific journal Proceedings of the National Academy of Sciences (PNAS).

Investigators from the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research and the National Institutes of Health Clinical Center, in collaboration with a physician scientist at Harvard Medical School, examined blood samples from 37 patients diagnosed with CFS and from 44 healthy blood donors.

MLV is a type of retrovirus known to cause cancer in mice. Several different MLV gene sequences were identified in samples from 32 of the 37 patients with CFS (87 percent) and 3 of the 44 (7 percent) healthy blood donors. Investigators performed DNA sequencing on all positively amplified samples to confirm MLV like gene sequences.

This study supports a previous investigation [Lombardi et al. Science October 23, 2009 326: 585] that showed XMRV, a genetic variant of MLV-like viruses, to be present in the blood of people with CFS. The study demonstrates a strong association between a diagnosis of CFS and the presence of MLV-like virus gene sequences in the blood. The study also showed that MLV-like viral gene sequences were detected in a small fraction of healthy blood donors. Although the statistical association with CFS is strong, this study does NOT prove that these retroviruses are the cause of CFS. Further studies are necessary to determine if XMRV or other MLV-related viruses can cause CFS.

A previous study, published in 2009, reported finding XMRV infections in a high percentage of CFS patients and a small percentage of healthy blood donors. However,
several other studies from the United States (including a recent report from the Centers for Disease Control and Prevention), the United Kingdom, and the Netherlands have found no evidence of XMRV or other MLV-like viruses in the blood of people with CFS.

For more information:

► * Murine Leukemia Virus Gene Sequence Study - Questions and Answers
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm223232.htm


► * Xenotropic Murine Leukemia Virus-related Virus - Overview (CDC)
http://www.cdc.gov/xmrv/index.html


► * Xenotropic Murine Leukemia Virus-related Virus - Questions and Answers (CDC)
http://www.cdc.gov/xmrv/questions-answers.html


► http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm223277.htm


New study on the detection of murine leukemia virus-related virus gene sequences in the blood of patients with chronic fatigue syndrome (CFS) and healthy blood donors - Questions and Answers

Questions and Answers

1. What are murine leukemia viruses?

Murine leukemia viruses (MLV) are retroviruses known to cause cancer in certain mice. In 2006, investigators found that a type of MLV, called xenotropic murine leukemia virus-related virus (XMRV), could potentially infect humans. XMRV is one of a number of MLVs that appear to be transmitted to humans.

2. What is CFS?

Chronic fatigue syndrome (CFS) is a debilitating disorder defined solely by clinical symptoms and the absence of other causes. It’s unknown what causes CFS.

3. Has MLV or XMRV previously been associated with CFS or other disease?

A previous study, published in the journal [Lombardi et. al. Science October 23, 2009 326: 585], reported finding XMRV in a high percentage of CFS patients and a small percentage of healthy blood donors. However, other studies conducted in the U.S., Netherlands, and UK did not detect evidence of XMRV or other MLV-related viruses in CFS patients.

XMRV was first identified in tissue samples from some prostate cancer patients in 2006. However, one subsequent study failed to find XMRV in prostate cancer tissues, and another study found the virus only rarely in such tissues.

4. What did the new study evaluate?

Investigators from the Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research, the National Institutes of Health (NIH) Clinical Center, and Harvard Medical School have published a study in the scientific journal Proceedings of the National Academy of Sciences that examines the presence of MLVs in blood collected from two groups -- patients diagnosed with CFS and healthy blood donors.

This study tested blood samples collected from the New England area in the mid-1990s from 37 patients diagnosed with CFS, as well as samples from 44 healthy blood donors collected in the Clinical Center Blood Bank, NIH, between 2003 and 2006. Investigators performed DNA sequencing on each sample that produced positive product for verification of MLV-like gene sequences. Diverse MLV gene sequences, similar to that of the recently discovered XMRV, were identified in samples from 32 of the 37 patients with CFS (86.5%) and 3 of the 44 (6.8%) healthy blood donors that were tested.

Follow-up samples were collected from 8 of the CFS patients in 2010, and 7 of these again tested positive for MLV-like gene sequences.

5. What did the new study conclude?

This study supports a previous investigation[Lombardi et al. Science October 23, 2009 326: 585]that showed XMRV, a genetic variant of MLV-like viruses, to be present in the blood of people with CFS. The study demonstrates a strong association between a diagnosis of CFS and the presence of MLV-like virus gene sequences in the blood. The study also showed that MLV-like viral gene sequences were detected in a small fraction of healthy blood donors. Although the statistical association with CFS is strong, this study does NOT prove that these retroviruses are the cause of CFS. Further studies are necessary to determine if XMRV or other MLV-related viruses can cause CFS.

6. Are there studies that support different conclusions?

Some previous studies from the United States (including a study by the Centers for Disease Control and Prevention), the United Kingdom and the Netherlands reported finding no evidence of XMRV or other MLV-related infections in people with CFS. These different findings could be caused by a variety of factors (for example, difference in study populations), and underscore the need for additional studies and standardized methods.


7. Can MLV or XMRV be transmitted by blood or tissue products?

Additional research is needed to investigate the possibility that these MLV-related viruses and XMRV may be transmitted by blood or human tissue and are capable of causing disease. Investigators at FDA, NIH, CDC and other scientific institutions are in the process of conducting studies to verify the capabilities of the tests used by the different laboratories for the detection of XMRV or MLV-related viruses in blood. These studies are intended to develop and standardize a highly sensitive and specific XMRV test to better study its association with disease, as well as the possibility that XMRV can be transmitted to blood or tissue recipients.

8. What are the implications for blood donors?

At present, FDA does not have a donor policy specific to XMRV or other MLVs. There is currently no evidence that XMRV or MLVs are transmitted by transfusion in humans or that XMRV or other MLVs cause human disease. FDA regulations require that donors be in good health at the time of donation.

9. Does FDA agree with the AABB recommendation to discourage donation by people with history of CFS?

FDA does not object to the AABB recommendation. The AABB recommendation is consistent with a long-standing position of the Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) Association of America that individuals with CFS voluntarily should not donate blood.

10. How are the differences between the CDC and FDA study results being evaluated?

Differences in the results could reflect differences in the patient populations that provided the samples. Alternatively, undefined differences in the method of sample preparation could be contributing to the discordant test results. All of the scientists involved are working collaboratively to design experiments to quickly answer this scientifically puzzling question. An independent investigator at the National Heart, Lung, and Blood Institute (NHLBI) set up a test set of 36 samples, including known positives and presumed negatives. Both the FDA/NIH and CDC labs participated in this test, and the results showed that both labs were able to detect XMRV present at low levels in blinded samples. Additionally, the CDC laboratory provided 82 samples from their published negative study to FDA, who tested the samples blindly. Initial analysis shows that the FDA test results are generally consistent with CDC, with no XMRV-positive results in the CFS samples CDC provided (34 samples were tested, 31 were negative, 3 were indeterminate).


11. What do these findings mean to CFS patients and clinicians who treat them?

Although this study found MLV-like viral gene sequences in a high percentage of CFS patients, this does not prove that these retroviruses are the cause of CFS or of any other disease. Moreover, other studies have not found evidence of such retroviruses in patients with CFS. Further studies are necessary to determine if XMRV or other MLV-like viruses are reproducibly associated with CFS, and if so whether the virus is a causative agent or a harmless co-traveler. The different findings from various studies reinforce the need for more research--including careful analysis of other cohorts of CFS patients from different geographic regions, studies of larger populations of healthy people, and testing of transmissibility of the agents through blood transfusions in animal models. FDA, NIH, and CDC have and will continue to collaborate with other agencies and groups involved in this research.









XMRV virus particles seen by transmission electron microscopy. Image courtesy of University of Utah Health Sciences Public Affairs.

CDC Home
Centers for Disease Control and Prevention -

XMRV (Xenotropic Murine Leukemia Virus-related Virus)


XMRV is a newly identified human retrovirus that is similar to a group of mouse retroviruses (called murine leukemia viruses, or MLVs) scientists have known about for years. XMRV refers to xenotropic murine leukemia virus-related virus. It was first identified in 2006 in tissue samples from men with prostate cancer.

In a study published in the journal Science in October 2009, scientists reported a potential association of XMRV with chronic fatigue syndrome (CFS). In this study, XMRV was detected in approximately two-thirds of patients diagnosed with CFS. They also identified DNA of XMRV in the blood cells of some healthy persons and suggested a potential for XMRV transmission by transfusion or transplantation.

However, other recent studies, including a July 2010 research report from CDC scientists and colleagues at two other institutions, found no evidence of XMRV in CFS patients and in controls (see Updates).

More recently, investigators from the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and Harvard Medical School published a report that presents evidence of MLVs in blood samples from CFS patients and healthy blood donors. The authors state that although they found a broader group of MLVs, rather than XMRV, their results support the 2009 report in Science. The FDA /NIH paper was published online August 23, 2010, in the Proceedings of the National Academy of Sciences.

The reporting of different findings from different studies is not uncommon. Various factors may have contributed to the differences in these studies, including selection criteria for inclusion of CFS patients, clinical complexities of CFS, and possible variations in XMRV and MLV infection rates among populations in different regions. Moreover, XMRV is a recently discovered virus and much remains to be learned about this and MLV-like viruses. As additional studies are done, it is possible that new findings may emerge that differ from what has been previously reported.

The potential role of XMRV and MLVs in causing diseases such as prostate cancer and CFS remains unknown at this time. Additional research is needed to further evaluate a possible link of XMRV and MLVs with negative health outcomes, including prostate cancer and CFS. If it is determined that XMRV and MLVs may have a role in causing disease and illness, prevention recommendations can be made.

Although it is presumed that XMRV can be transmitted through blood transfusion, no such transmission event has been identified, and there is no known evidence of XMRV or MLV infection or related illness or disease in transfusion recipients. Agencies within the Department of Health and Human Services (HHS) are conducting studies to determine the prevalence of XMRV in the blood donor population.

CDC, FDA, and NIH investigators have been collaborating with scientists from other agencies and groups with regard to XMRV and MLV research, and they will continue to do so. HHS agencies will keep the public updated and informed as more information becomes available.


XMRV (Xenotropic Murine Leukemia Virus-related Virus)
► What are XMRV and MLVs?

XMRV refers to a recently discovered retrovirus called xenotropic murine leukemia virus-related virus. It was first identified in 2006 in samples from men with prostate cancer. XMRV is closely related to a group of retroviruses called murine leukema viruses (MLVs), which are known to cause cancer in certain mice.


► What is chronic fatigue syndrome?

Chronic fatigue syndrome, or CFS, is a debilitating and complex disorder characterized by profound fatigue that is not improved by bed rest and that may be worsened by physical or mental activity. Persons with CFS most often function at a substantially lower level of activity than they were capable of before the onset of illness. In addition to these key defining characteristics, patients report various nonspecific symptoms, including weakness, muscle pain, impaired memory and/or mental concentration, insomnia, and post-exertional fatigue lasting more than 24 hours. In some cases, CFS can persist for years. The cause or causes of CFS have not been identified and no specific diagnostic tests are available. Moreover, since many illnesses have incapacitating fatigue as a symptom, care must be taken to exclude other known and often treatable conditions before a diagnosis of CFS is made. For more information, see CDC's CFS Web page.


► Have XMRV and MLVs been associated with human disease and illness, including CFS?

As noted above, XMRV was first identified in 2006 in patients with prostate cancer. A study published by Lombardi and colleagues (Science, 2009;326:585) reported finding evidence of XMRV in about two-thirds of CFS patients and nearly 4% of healthy persons. However, several other recent studies found no evidence of XMRV in persons with CFS and in controls; these studies include a report published by CDC investigators and colleagues in July 2010 (see update). More recently, researchers from the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and Harvard Medical School reported evidence of MLVs in about 87% of CFS patients and 7% of healthy blood donors (Proceedings of the National Academy of Sciences, 2010).

The reporting of different research findings from different studies is not uncommon. The different findings may be due to a variety of factors, such as differences in the study populations. At the present time, the potential role of XMRV and MLVs in causing diseases such as prostate cancer and CFS and the frequency of XMRV and MLV infection among healthy persons are unknown. If it is determined that XMRV and MLVs have a role in causing disease and illness in humans, prevention recommendations can be made.


► How are XMRV and MLVs transmitted? Are certain individuals more likely to be infected with XMRV and MLVs?

The manner in which XMRV and MLVs are transmitted is unknown. It is unclear whether certain individuals are more likely to be infected with XMRV and MLVs. Studies of these viruses in humans have been under way for only a short time, and therefore these and similar questions have not been answered.


► If researchers find that XMRV and MLVs are found in a majority of patients who have chronic fatigue syndrome, does this mean that CFS may be contagious?

One study that has been conducted on CFS and close contacts suggests there is no evidence that CFS is contagious or spread person to person. Occurrence of CFS is not more common in family members of patients with CFS, and none of the features typical of contagious disease have been associated with CFS. These features include seasonal or regional occurrence, travel history, occupation, exposure to animals, injection drug use, and sexual behavior.


► Given that recent scientific papers have reported finding XMRV and MLVs in healthy people, can these viruses be transmitted through blood transfusion or organ/tissue transplantation?

XMRV and MLVs, like all retroviruses, are presumed to be transmitted by blood and tissues. Therefore, it is also presumed that XMRV and MLVs can be transmitted through blood transfusion. Since it is possible that XMRV and MLVs might infect many types of human cells, including some blood cell types, the safety of blood could be a concern if XMRV and MLV infection is confirmed to cause human illness and disease.


► What is being done to evaluate the risk of XMRV and MLVs?

The Department of Health and Human Services (HHS) is conducting studies to determine the prevalence of XMRV and MLVs in the blood donor population. Additional research is needed to determine if XMRV and MLVs cause illness and disease. If it is determined that XMRV and MLVs may have a role in causing illness and disease, prevention recommendations can be made.


► Who has collections of blood samples for this research?

The National Institutes of Health (NIH) currently funds the Retrovirus Epidemiology Donor Study-II (REDS-II), which focuses on addressing critical questions in blood safety. The REDS-II laboratory sample collection, called RADAR, has specimens from blood donors and matched recipients from various regions of the country. These matched specimens can be useful in testing for the transmissibility of "new" or "emerging" infectious agents, such as XMRV.


► If researchers have tests for XMRV and MLVs, why can’t they be used for screening of blood donors?

Although specialized research assays have been developed by some laboratories for use in XMRV and MLV studies, no standardized, validated tests are available for XMRV and MLVs. Screening tests require additional validation, for use in a large population, compared with diagnostic tests. CDC, NIH, and FDA, together with several nonfederal laboratories, are participating in an XMRV/MLV assay comparability study that is intended to help build a consensus among researchers on how to standardize these testing methods.

While it is presumed that XMRV and MLVs can be transmitted through blood transfusion, no such transmission has been identified, and there are no known cases of XMRV or MLV infection or related illness in transfusion recipients. Therefore, there is currently no requirement for testing of the blood supply for the presence of XMRV or MLVs.

If it is determined that XMRV or MLVs may have a role in causing disease and illness, prevention recommendations can be made. Such a risk, if it exists, could be decreased by developing and using blood donor screening assays or other measures. The use of a donor screening assay by blood establishments would require FDA approval of the test.

There are many steps between what is currently known about XMRV and MLVs and the release of an FDA-approved test, if such a test were warranted. The test components and procedures must be standardized, and the test performance assessed in research studies before licensure (approval) by the FDA. However, if the risk is demonstrated, these steps could be taken more quickly, as occurred for screening approval of West Nile virus.


► Should an individual with diagnosed chronic fatigue syndrome donate blood?

At the present time, there is no FDA guidance to defer donors who have CFS in the United States. However, FDA regulations require that a donor should be in good health. Medical directors at blood collection centers should exercise judgment in determining whether individuals with a history of CFS are in good health at the time of donation.


► Should an individual who has been diagnosed, treated and currently in remission from prostate cancer donate blood?

There is no known association of prostate cancer with history of transfusion. In general, FDA has not recommended deferral of donors who have a history of cancer due to lack of such as association.

►
Should an individual diagnosed with chronic fatigue syndrome or in remission from prostate cancer be an organ or tissue donor?

At the present time, there are no U.S. recommendations to defer organ and tissue donations from individuals diagnosed with chronic fatigue syndrome or who are in remission from prostate cancer.