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).