Anyone who has lived with the crippling fatigue, un-refreshing sleep and cognitive problems (affecting memory and concentration) of Chronic Fatigue Syndrome (CFS) can confirm it is a very real, debilitating physical illness. Unfortunately, for many years, not everyone else has agreed. Long dismissed in the medical community as a psychological condition—or simply as a prolonged state of exhaustion—new research gives evidence that CFS is, in fact, a biological disorder with specific stages.
With viral-like symptoms—like swollen lymph nodes, chronic sore throat and mild fever—and suspected to be triggered by malingering viral infections, like the Epstein-Barr Virus (EBV), chronic fatigue syndrome has been long suspected to be an immune system disorder. A study published in Science Advances on Feb. 27 found specific immune system differences in those who had the disease three years or less and in patients with the disease for more than three years compared to healthy controls.
Between 1 million to 4 million in the U.S. have CFS or myalgic encephalomyelitis, known as ME. An estimated 84 to 91 percent battling this illness are living without a diagnosis, thanks to the complex nature of the disease and skepticism of the serious nature of the disease by healthcare providers.
Last month, the IOM suggested renaming CFS/ME to more accurately describe the disease by its most central symptom—post-exertional malaise, which is a sustained decrease in energy after minimal physical and cognitive activity. To counter the trivialization of the term “chronic fatigue,” the Institute of Medicine (IOM) proposed renaming the illness SEID for systemic exertion intolerance disease, while also giving more specific criteria for its diagnosis.
“This [latest] study delivers what has eluded us for so long: unequivocal evidence of immunological dysfunction in ME/CFS and diagnostic biomarkers for disease,” says senior author W. Ian Lipkin, MD, also the John Snow Professor of Epidemiology at Columbia’s Mailman School.
Researchers at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health studied blood plasma samples of a total of 298 ME/CFS patients and 348 healthy controls to determine the levels of 51 immune biomarkers. Patients living with CFS for three years or less had increase amounts of cytokines, cell-signaling molecules that are involved in regulating the immune system’s response to infection, inflammation in trauma.
Early patients had a “prominent activation of both pro- and anti-inflammatory cytokines,” according to the study findings. The pro-inflammatory cytokine Interleukin-17A was found to be elevated in early-stage patients. Additionally, there was a significant presence of the cytokine called interferon gamma (or IFN-gamma), which plays an important role in immunoregulatory functions and is associated with antiviral activity. IFN-gamma is produced mainly by activated T-cells, natural killer cells, in addition to activated macrophages in the periphery and microglia, which is responsible for central nervous system protection against different kinds of pathogenic factors.
Interferon gamma may disrupt immune homeostasis, increasing susceptibility to developing certain types of autoimmune reactions. Additionally, it may speed up the deterioration of tryptophan, spurring the depletion of serotonin and melatonin in the central nervous system. These neurotransmitters play critical roles in sleep, digestion, mood and memory. IFN-gamma has also been linked to the fatigue following many infections, including EBV, according to the study release. Earlier studies have also associated cytokine fluctuations with severity of fatigue in CFS patients.
While unrelenting fatigue is the most common symptom of the disorder, it may also include unusual headaches, gastrointestinal problems, endocrine dysfunction, orthostatic intolerance (symptoms that worsen upon standing and improve upon lying down), joint and muscle pain, and muscle weakness. It is estimated that at least a quarter of those with CFS/ME are bed- or home-bound at some point living with the disease.
“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,” said 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.
Longer duration ME/CFS subjects, in contrast, had lower levels of cytokines than in healthy controls. Levels of CD40L were significantly different from short-duration subjects. This cytokine is involved in B cell maturation. The study cites a randomized trial of a monoclonal antibody that targets B cells, which demonstrated symptom improvement in some ME/CFS patients.
“Early diagnosis may provide unique opportunities for treatment that likely differ from those that would be appropriate in later phases of the illness,” said Hornig. “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.”
In October 2014, Stanford University School of Medicine researchers found differences in the white matter of the brains of CFS patients compared to healthy subjects. In CFS patients, researchers found an abnormality in the nerve tract connecting the frontal and temporal lobes in the right hemisphere of the brain. The greater the degree of abnormality was associated with a greater severity of the patient’s condition.
A thickening of the gray matter at the frontal and temporal lobes in the right hemisphere was also found in CFS patients. Additionally, there was reduced overall white matter in the brain, suspected to a result of chronic inflammation. White matter is made up of nerve tracts that connect gray matter areas of the brain and allow nerve cells to properly communicate with one another.
“CFS is one of the greatest scientific and medical challenges of our time,” said the study’s senior author, Jose Montoya, MD, professor of infectious diseases and geographic medicine. “In addition to potentially providing the CFS-specific diagnostic biomarker we’ve been desperately seeking for decades, these findings hold the promise of identifying the area or areas of the brain where the disease has hijacked the central nervous system.”