Chronic fatigue syndrome affects an estimated 2.5 million Americans. It was first described in the early 1980s, and for many years, doctors’ tests couldn’t find an explanation for patients’ symptoms, so they were dismissed and patients were told there was nothing wrong.

But a growing body of research reveals plenty of things going wrong when it comes to this illness.

“Over the last 35 years, there have been over 9,000 scientific publications that compare people with the illness to healthy people of the same age and sex,” said Anthony Komaroff, a professor at Harvard Medical School and senior physician at Brigham and Women's Hospital. “And they find a whole variety of abnormalities.”

Studies have found physical differences in the brain, as well as differences in hormone levels and electrical activity. Some of those brain changes may explain differences elsewhere in the body, such as blood pressure or digestion. Chronic fatigue syndrome also affects energy metabolism. While exercise typically makes energy metabolism more efficient, the opposite is true for people with chronic fatigue syndrome.

Another finding described in Komaroff’s article, published July 5 in the Journal of the American Medical Association, is that people with chronic fatigue syndrome appear to have chronically activated immune systems.

“It's as if the immune system were going to war against something, but what that something is hasn't been determined. And it might, in fact, be different from one person to the next,” Komaroff said. “Parts of the immune system appear to be exhausted, because they've been chronically activated for so many months and years.”

These differences can explain and help researchers to find treatments for the illness' symptoms. But to develop a treatment — or cure — that actually fixes the underlying problems that lead to chronic fatigue syndrome, researchers need to piece together a chain of cause and effect.

Komaroff said that one leading idea is that chronic fatigue syndrome could be caused by inflammation in the brain.

“There is probably in every patient with this illness a final common pathway that gets triggered in the brain that leads the brain to experience the symptoms of the illness,” Komaroff said. “What triggers that final common pathway? It appears that in many people — perhaps most — inflammation somewhere in the body, either directly in the brain itself or elsewhere in the body ... sends signals to the brain [and] leads the brain's immune system to get activated.”

Komaroff said that treatments that damp down inflammation could be promising candidates for stopping or reversing chronic fatigue syndrome.

But there’s an even more immediate challenge for many patients with chronic fatigue syndrome, and that’s getting their illness diagnosed, he said.

“Many doctors still don't know that there are over 9,000 studies in the published scientific literature that show that there is something wrong in the body,” Komaroff said. “They order their usual tests, the usual tests come back normal, and they say there's nothing wrong.”

Unfortunately, that’s not a problem that is limited to chronic fatigue syndrome.

“Any time a person walks into a doctor's office with an odd collection of symptoms [and] the doctor doesn't recognize it," he said, "there is the possibility that the doctor will not respond in a healthy way, and instead say to the patient, ‘There's really nothing wrong with you.’”

Doctors, he added, need to trust patients and be willing to do the hard work to figure out what is really wrong.