Columbia University. US: Researchers at the Center for Infection and Immunity
at 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
author Mady 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 Dr. Lipkin, senior author of the current
study and 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.
Support for the study was provided by the Chronic Fatigue Initiative
of the Hutchins Family Foundation and the National Institutes of Health
(AI057158; Northeast Biodefense Center-Lipkin).