Science Series

2006

Chronic Fatigue Syndrome

Efforts by the National Institutes of Health to Understand CFS and Plan for Future Research

JUNE 2003 NIH Scientific Workshop Focuses the Discussion

What is CFS?

Why is CFS a Problem?

What is NIH Doing 

About CFS?

Research on What 

Causes CFS

Models for Future 

Research

Methodological and 

Other Issues to be 

Resolved

What is CFS?

Chronic Fatigue Syndrome (CFS) is characterized 

by incapacitating fatigue (experienced as profound 

exhaustion and extremely poor stamina) and problems 

with concentration and short-term memory. It is 

accompanied by flu-like symptoms such as pain in 

the joints and muscles, unrefreshing sleep, tender 

lymph nodes, sore throat, and headache. Distinctive 

characteristics of the illness is post-exertional 

malaise—a worsening of symptoms following physical 

or mental exertion occurring within 12 to 48 hours 

of the exertion and requiring an extended recovery 

period.

The symptoms of CFS are highly variable and 

fluctuate in severity, which complicates treatment 

and the person’s ability to cope with the illness. Most 

symptoms are not obviously visible, making it difficult 

for others to understand the vast array of debilitating 

symptoms with which CFS sufferers must cope.

Why is CFS a Problem?

It is estimated that as many as 800,000 people 

nationwide suffer from this illness, and 90 percent 

of these individuals have not been diagnosed and 

therefore are not receiving proper medical care for 

their illness. CFS strikes people of all age, racial, 

ethnic, and socioeconomic groups, and research has 

shown that CFS occurs about three times as often in 

women as in men.

What Is NIH 

Doing 

About CFS?

As part of National Institutes of Health (NIH) 

program to combat this syndrome through 

increased research, the NIH Office of Research 

on Women’s Health (ORWH) and the TransNIH Working Group for Research on Chronic 

Fatigue Syndrome cosponsored a scientific 

workshop, Neuroimmune Mechanisms and 

Chronic Fatigue Syndrome: Will Understanding 

Central Mechanisms Enhance the Search for 

the Causes, Consequences and Treatment of 

CFS, in June 2003. Although research to date 

has identified neither a cause nor a cure for CFS, 

evidence suggests that CFS alters the immune 

and neurological systems. With that evidence in 

mind, distinguished experts from outside the NIH 

community joined in this workshop with intramural 

NIH scientists to explore the mechanisms by which 

hormones and proteins that regulate the immune 

system act as intermediaries between the brain and 

other body systems. 

Because fatigue can be understood in terms of central 

nervous system (CNS) functioning, the scientific experts 

at this workshop theorized that studying CFS and related 

disorders should focus on the CNS. Significant CFS 

symptoms such as pain, sleep disturbance, and impaired 

cognitive functioning are also best understood in terms of 

CNS function.
Science Series

2006

Research on What Causes CFS

Research during the past 15 years was stimulated first by the observation that about 70 percent of people with CFS reported that 

their illness started with a viral or bacterial infection, particularly an upper respiratory or influenza-like illness, and that they never 

recovered from that infection. As a result, early studies focused on viral agents, particularly viruses that had the ability to persist 

or be dormant, such as herpes viruses. Many viral and other microbial agents have been studied and then discarded as being the 

primary cause of CFS.

The second wave of research focused on immune-related findings, triggered by CFS patients’ reports of more frequent and severe 

illnesses and longer recovery times. Two other areas of investigation have been the autonomic nervous system and objective 

measures of sleep. Recently, researchers focusing on a fifth topic of investigation have asked whether a genetic predisposition 

exists for fatigue in general, and more specifically for CFS. A theory that has permeated the literature since CFS was first 

described attributes the illness to some form of atypical depression or other psychiatric disorder that has yet to be well defined.

Models for Future Research

Any model of CFS must take into account a wide variety of published observations and findings. For instance, some experts 

believe that CFS is part of a family of disorders and thus is not a unique, identifiable disorder. Previous studies have detected 

a variety of biological abnormalities that are not specific for CFS and that are not consistently associated with severity or type 

of symptoms. The many meanings of “fatigue” also need to be addressed by investigators when designing studies that clarify a 

model for CFS; “fatigue” is a broad term that needs clearer definition and specification.

Many researchers believe that changes in physical and mental functioning at the core of CFS are not well understood, but 

that most symptoms and findings can be explained by problems related to hormones that influence the activities of nerves. 

Researchers will need to design their studies to focus on models that can link mechanism and causation. 

Some areas ripe for investigation include whether neuroendocrine dysfunction is the cause or the result of physical inactivity, why 

significantly more women than men get CFS, what are the biological underpinnings of perception, and how perception is altered 

in individuals with CFS.

For More Information . . .

...on NIH CFS research, the Institutes that support CFS research, and this workshop, please 

contact the NIH Office of Research on Women’s Health, Bethesda, MD, at 

http://orwh.od.nih.gov/cfs.html 

or by telephone at 301-402-1770.

Methodological and Other Issues to 

be Resolved

A variety of issues that are as yet unresolved include:

• CFS studies must be conducted in multiple locations with 

adequate numbers of participants to ensure statistical 

power, and they must be long enough to account 

for cycles of remittance and relapse that are commonly 

seen in people with CFS.

• Procedures such as sampling time, specimen shipping 

conditions, processing methods, and preservation must 

be standardized.

• Useful characterizations for CFS symptoms must be developed so those symptoms can be measured accurately. 

• A n animal model for CFS needs to be developed.

• Researchers should take advantage of the newest scientific methods and techniques in order to provide immediate 

insights into CFS symptoms. Use of these approaches 

will ensure that studies undertaken are interdisciplinary 

in nature.

• Unexplained variability in signs and symptoms of CFS 

underscore the vital importance of medical histories as a 

key element to explain this chronic disease.

To address these issues, NIH released a Request for Applications in July 2005, Neuroimmune Mechanisms and Chronic 

Fatigue Syndrome (RFA-OD-06-002), to solicit research grant 

applications that explore topics raised at the scientific workshop. NIH also supports ongoing investigator-initiated research through its Program Announcement, Chronic Fatigue 

Syndrome: Pathophysiology and Treatment (PA-05-034).