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Hornig/Lipkin cytokine study out now - press release

Sasha

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Microbe Discovery Project said:
Scientists Discover Robust Evidence That Chronic Fatigue Syndrome Is a Biological Illness

Immune Signatures in Blood Point to Distinct Disease Stages, Open Door to Better Diagnosis and Treatment

NEW YORK (Feb. 27, 2015)—Researchers at theCenter for Infection and Immunityat Columbia University’s Mailman School of Public Health identified distinct immune changes in patients diagnosed with chronic fatigue syndrome, known medically as myalgic encephalomyelitis (ME/CFS) or systemic exertion intolerance disease. The findings could help improve diagnosis and identify treatment options for the disabling disorder, in which symptoms range from extreme fatigue and difficulty concentrating to headaches and muscle pain.

These immune signatures represent the first robust physical evidence that ME/CFS is a biological illness as opposed to a psychological disorder, and the first evidence that the disease has distinct stages. Results appear online in the new American Association for the Advancement of Science journal,Science Advances.

With funding to support studies of immune and infectious mechanisms of disease from the Chronic Fatigue Initiative of the Hutchins Family Foundation, the researchers used immunoassay testing methods to determine the levels of 51 immune biomarkers in blood plasma samples collected through two multicenter studies that represented a total of 298 ME/CFS patients and 348 healthy controls. They found specific patterns in patients who had the disease three years or less that were not present in controls or in patients who had the disease for more than three years. Short duration patients had increased amounts of many different types of immune molecules called cytokines. The association was unusually strong with a cytokine called interferon gamma that has been linked to the fatigue that follows many viral infections, including Epstein-Barr virus (the cause of infectious mononucleosis). Cytokine levels were not explained by symptom severity.

“We now have evidence confirming what millions of people with this disease already know, that ME/CFS isn't psychological,” states lead authorMady Hornig, MD, director of translational research at the Center for Infection and Immunity and associate professor of Epidemiology at Columbia’s Mailman School. “Our results should accelerate the process of establishing the diagnosis after individuals first fall ill as well as discovery of new treatment strategies focusing on these early blood markers.”

There are already human monoclonal antibodies on the market that can dampen levels of a cytokine called interleukin-17A that is among those the study shows were elevated in early-stage patients. Before any drugs can be tested in a clinical trial, Dr. Hornig and colleagues hope to replicate the current, cross-sectional results in a longitudinal study that follows patients for a year to see how cytokine levels, including interleukin-17A, differ within individual patients over time, depending on how long they have had the disease.


Stuck in High Gear
The study supports the idea that ME/CFS may reflect an infectious “hit-and-run” event. Patients often report getting sick, sometimes from something as common as infectious mononucleosis (Epstein-Barr virus), and never fully recover. The new research suggests that these infections throw a wrench in the immune system’s ability to quiet itself after the acute infection, to return to a homeostatic balance; the immune response becomes like a car stuck in high gear. “It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop,” says Dr. Hornig. “Early diagnosis may provide unique opportunities for treatment that likely differ from those that would be appropriate in later phases of the illness.”

The investigators went to great lengths to carefully screen participants to make sure they had the disease. The researchers also recruited greater numbers of patients whose diagnosis was of relatively recent onset. Patients’ stress levels were standardized; before each blood draw, patients were asked to complete standardized paperwork, in part to engender fatigue. The scientists also controlled for factors known to affect the immune system, including the time of day, season and geographic location where the samples were taken, as well as age, sex and ethnicity/race.

In 2012, W. Ian Lipkin, MD, director of the Center for Infection and Immunity, and colleagues reported the results of a multicenter study that definitively ruled out two viruses thought to be implicated in ME/CFS: XMRV (xenotropic murine leukemia virus [MLV]-related virus) and murine retrovirus-like sequences (designated pMLV: polytropic MLV). In the coming weeks, Drs. Hornig and Lipkin expect to report the results of a second study of cerebrospinal fluid from ME/CFS patients. In separate ongoing studies, they are looking for “molecular footprints” of the specific agents behind the disease—be they viral, bacterial, or fungal—as well as the longitudinal look at how plasma cytokine patterns change within ME/CFS patients and controls across a one-year period, as noted above.

“This study delivers what has eluded us for so long: unequivocal evidence of immunological dysfunction in ME/CFS and diagnostic biomarkers for disease,” says senior authorW. Ian Lipkin, MD, also the John Snow Professor of Epidemiology at Columbia’s Mailman School. “The question we are trying to address in a parallel microbiome project is what triggers this dysfunction.”

Co-authors include Andrew F. Schultz, Xiaoyu Che, and Meredith L. Eddy at the Center for Infection and Immunity; Jose G. Montoya at Stanford University; Anthony L. Komaroff at Harvard Medical School; Nancy G. Klimas at Nova Southeastern University; Susan Levine at Levine Clinic; Donna Felsenstein at Massachusetts General Hospital; Lucinda Bateman at Fatigue Consultation Clinic; and Daniel L. Peterson and Gunnar Gottschalk at Sierra Internal Medicine. The authors report no competing interests.
 

Simon

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Distinct plasma immune singatures in ME/CFS present early in the course of the illness

Mady Hornig, José G. Montoya, Nancy G. Klimas, Susan Levine, Donna Felsenstein, Lucinda Bateman, Daniel L. Peterson, C. Gunnar Gottschalk, Andrew F. Schultz, Xiaoyu Che, Meredith L. Eddy, Anthony L. Komaroff, W. Ian Lipkin


my typed abstract, apologies for any errors

ME/CFS is an unexplained incapacitating illness that may affect up to 4 million people in the US alone. There is no validated laboratory test for diagnosis or managment despite global efforts to find biomarkers of the disease. We considered the possibility that inabillity to identify such biomarkers reflected variation in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness.

Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration and other clinical variables. Controls were frequency matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex.

We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n=52) relative to healthy controls (n=340) that are not present in longer duration of the illness (n=246).

Analyses based on duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as disociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventiona strategies and early diagnosis in ME/CFS.
 
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Bob

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Just look at that list of authors in the research paper!

Mady Hornig, José G. Montoya, Nancy G. Klimas, Susan Levine, Donna Felsenstein, Lucinda Bateman, Daniel L. Peterson, C. Gunnar Gottschalk, Andrew F. Schultz, Xiaoyu Che, Meredith L. Eddy, Anthony L. Komaroff, W. Ian Lipkin
 
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charles shepherd

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Simon

Senior Member
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Monmouth, UK
About the cohorts they used:
  • NIH (originally for XMRV study)= 147 cases, all meet Fukuda and CCC, all with viral-like onset
  • CFI cohort, =203 cases, meet either or both Fukuda and CCC. Nb 52 of NIH cohors subsequently recruited into CFI cohort - for these just the original NIH sample was used, hence the total cases of 298
  • carefully matched controls for both, by geography, season of sampling, age and sex as these can all affect immune profiles
  • ME/CFS cases split into short duration (< 3 years from onset [not diagnosis]) n=52 and long duration, n=245
Not surprisingly, there was a big age difference between short and long duration patients:
  • Short duration (mean 1.7 years ill), mean age of 40.5
  • Long duration (mean 13.2 years ill), mean age 50.2
Though illness severity (MFI Mental Fatigue was the chosen measure of severity) was similar in short and long duration cases.

And yes, that's a very big study indeed.
 
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