Advances in understanding the pathophysiology of Chronic Fatigue Syndrome, by Anthony L Komaroff in JAMA [Preprint July 5, 2019]


Viewpoint extracts:

When does an illness become a disease? When the underlying biological abnormalities that cause the symptoms and signs of the illness are clarified.

The illness now called myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) was first described in the mid-1980s. At that time, nothing was known about its underlying biology. Indeed, because many
standard laboratory test results were normal, some clinicians explained to patients that ‘there is nothing wrong.’ There was, of course, an alternative explanation: the standard laboratory tests might not have been the right tests to identify the underlying abnormalities.

Over the past 35 years, thousands of studies from laboratories in many countries have documented underlying biological abnormalities involving many organ systems in patients with ME/CFS, compared with healthy controls: in short, there is something wrong.  Moreover, most of the abnormalities are not detected by standard laboratory tests. In 2015, the Institute of Medicine of the National Academy of Sciences concluded that ME/CFS ‘is a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients,’ affects up to an estimated 2.5 million people in the United States, and generates direct and indirect expenses of approximately $17 billion to $24 billion annually…

A 2-day conference at the NIH in April 2019 highlighted recent progress. New research was presented that both reinforced and expanded on previous reports. Equally important, several plausible models were proposed that could explain many of the abnormalities that have been described.

The Central and Autonomic Nervous System

Metabolic Changes

Immunologic Changes

Provocation Studies

Potential Unifying Models


A great deal more is known today than 35 years ago about the underlying biology of ME/CFS. It is clear that many biological measurements clearly distinguish patients with ME/CFS from healthy control individuals.

At the same time, some areas of ME/CFS research remain a challenge, and research has not yet given practicing physicians 2 important tools. First, there are as yet no US Food and Drug Administration-approved treatments. Second, although various biological measurements distinguish patients with ME/CFS from healthy controls, none yet have demonstrated the high sensitivity and specificity required for a good diagnostic test. However, 1 small study (20 cases and 20 controls) described at the NIH conference (and recently published9) reported perfect sensitivity; the specificity of the test in individuals with other fatiguing illnesses remains to be shown.

With growing international interest in the illness, and increased research support from the NIH, the day is coming when physicians will be able to explain to patients not only that there is something wrong but also that advances in understanding the pathophysiology have led to effective therapy.

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