Saturday, July 6, 2019

Advances in Understanding CFS

Source: JAMA
Date:  July 5, 2019

Advances in understanding the pathophysiology of Chronic Fatigue
Anthony L. Komaroff
- Brigham and Women's Hospital, Harvard Medical School, Boston,
  Massachusetts, USA.

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

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.1

Over the past several years, the National Institutes of Health (NIH) has
expanded its research efforts directed toward this disease. It has
initiated an unusually comprehensive multisystem study at the NIH
Clinical Center, funded 3 extramural ME/CFS research centers and 1 data
coordinating center, awarded supplemental support to 7 existing grants,
and held regular telebriefings on the illness (as has the Centers for
Disease Control and Prevention).2

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

Since the early 1990s, multiple studies have compared patients with
ME/CFS with healthy age- and sex-matched controls and found
abnormalities of the central and autonomic nervous system.3

Neuroendocrine abnormalities were among the first evidence reported and
involve impairment of several limbic-hypothalamic-pituitary axes
(involving cortisol, prolactin, and growth hormone end products). A
general downregulation of the hypothalamic-pituitary-adrenal axis is
seen in patients with ME/CFS, in contrast to the upregulation of the
hypothalamic-pituitary-adrenal axis seen in major depression.

Impaired cognition has been found by many investigators, including
slowed information processing speed and impaired memory and attention
that are not explained by concomitant psychiatric disorders.

Magnetic resonance imaging has revealed increased numbers of punctate
areas of high signal in white matter. Functional magnetic resonance
imaging has demonstrated different responses to auditory and visual
challenges and to tests of working memory, as well as altered
connectivity between different brain regions.

Positron emission tomography and magnetic resonance spectroscopy
recently have demonstrated that patients with ME/CFS have a widespread
state of neuroinflammation (particularly activation of microglial cells)
as well as increased ratios of choline-creatinine and increased levels
of lactate that correlate with levels of fatigue.4 Spinal fluid contains
increased levels of proteins involved in tissue injury and repair.

Autonomic nervous system abnormalities have been repeatedly demonstrated
in ME/CFS, particularly altered systemic and cerebral hemodynamics that
correlate with symptoms.5 At the NIH conference, it was reported that
with prolonged upright posture, abnormal increases in heart rate and
decreases in blood pressure are common; even when heart rate and blood
pressure responses are normal, substantial cerebral blood flow
reductions are noted.

Metabolic Changes

Recently, it has become possible to measure simultaneously thousands of
metabolites in a sample of blood or other fluid. Several such
metabolomic studies have revealed that in patients with ME/CFS, levels
of many metabolites are lower than normal, as occurs in hibernation.6
Cellular energy generation from all sources is impaired, including
energy from oxygen, sugars, lipids, and amino acids. In other words, the
human organism may feel that it lacks 'energy' because its cells have a
problem generating (and possibly using) energy. In addition, many
studies have reported markers of both oxidative stress and nitrosative
stress (eg, increased levels of inducible nitric oxide synthase).

Immunologic Changes

Many phenotypic and functional abnormalities have been reported in
lymphocytes. The most consistently reported are increased numbers of
activated cytotoxic CD8+ T cells and poorly functioning natural killer
cells. Blood levels of many cytokines are significantly higher in
patients with ME/CFS, especially in the first 3 years of illness.
Moreover, the levels of many of the circulating cytokines correlate
positively with the severity of symptoms. Abnormal levels of several
cytokines in spinal fluid also have been reported.

At the NIH conference, new HLA associations with both presence and
severity of ME/CFS were reported. In addition, investigators performing
single T-cell receptor sequencing reported expansion of CD8+ T-cell
clones; characterization of the antigenic targets is under way.

Provocation Studies

In patients with ME/CFS, physical, postural (orthostatic), and cognitive
challenges often produce a flare of symptoms, typically after a 12- to
48-hour delay, a condition called postexertional malaise. Provocation
studies seek to clarify whether challenges that make people with ME/CFS
feel worse also make a biological abnormality worse. If so, it becomes
more likely that the abnormality may be causally connected to the
symptoms of the illness.

The NIH conference summarized evidence from multiple studies
demonstrating that during exercise, the tissues of patients with ME/CFS
have difficulty extracting oxygen, leading to a lower anaerobic
threshold; with exercise, patients also have lower heart rate, blood
pressure, and preload, several of which become much more prominent
during a second exercise test repeated 24 hours after the first.7,8

Potential Unifying Models

What if ME/CFS reflects the activation of biologically ancient,
evolutionarily conserved responses to injury or potential injury, a
pathological inability to turn these responses off, or both? Several
presentations at the NIH conference, citing work in animal models,
indicated that low-grade neuroinflammation triggers protective
behavioral changes, including reduced activity and appetite and
increased sleep; this helps to focus the available energy on preventing
or healing the injury. This stereotyped behavior change is likely
triggered by a 'fatigue nucleus' (a group of neurons); the nucleus is
triggered, in turn, by the cytokines produced by neuroinflammation.

The neuroinflammation could have different triggers in different
individuals. In some, it could be induced by brain infection (such as by
chronic herpesvirus infection), autoantibodies, neurotoxins, or chronic
stress. In others, inflammation outside the brain may be activating the
innate immune system inside the brain, both through humoral signals that
breach a porous blood-brain barrier and by retrograde signals sent up
the vagus nerve. Several conference presentations included evidence that
gut inflammation may be one peripheral trigger of neuroinflammation: the
gut microbiota of patients with ME/CFS often include high numbers of
proinflammatory species and low numbers of anti-inflammatory species.

The relatively hypometabolic state seen in patients with ME/CFS might
also reflect a second and possibly related biologically ancient response
to injury. Such hypometabolism is seen during the state of dauer (ie, a
developmental larval stage) in the worm Caenorhabditis elegans and
during hibernation in more complex animals. Dauer and hibernation allow
animals that perceive a vital threat (such as crowding in worms or
winter in bears) to throttle down nonessential, energy-consuming
metabolic processes to preserve the energy needed for vital functions;
ie, the animal is temporarily sacrificing its ability to function in
order to remain alive. Signals that initiate (and end) dauer and
hibernation are known; investigators are pursuing whether they have been
activated (or not deactivated) in patients with ME/CFS.


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.

Article Information

Corresponding Author: Anthony L. Komaroff, MD, Brigham and Women's
Hospital, 1620 Tremont St, Boston, MA 02120 ([email protected]).

Published Online: July 5, 2019. doi:10.1001/jama.2019.8312

Conflict of Interest Disclosures: Dr Komaroff reported receiving
personal fees from Ono Pharma and Serimmune Inc and grants from the NIH.

Additional Contributions: Peter C. Rowe, MD, Department of Pediatrics,
Johns Hopkins University, provided valuable comments for which he
received no compensation.


1. Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome: Redefining an Illness. Washington, DC: National
Academies Press; 2015.
2. Koroshetz W, Collins F. Moving toward answers in ME/CFS. NIH
Director's Blog. March 21, 2017.
Accessed June 22, 2019.
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chronic fatigue syndrome. Semin Neurol. 2011;31(3):325-337.
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widespread metabolite abnormalities in myalgic encephalomyelitis/chronic
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spectroscopy. Brain Imaging Behav. 2019.
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8. Nelson MJ, Buckley JD, Thomson RL, Clark D, Kwiatek R, Davison K.
Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in
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