Last month's CDC Grand Rounds on Chronic Fatigue Syndrome featured presentations by Dr. Charles Lapp, Dr. Elizabeth Unger, Dr. Anthony Komaroff, and Dr. Avindra Nath. A short Q&A session followed the final presentation.
The full transcript of Part I is below. I have begun with a brief summary of the first three speakers, including my commentary.
You can read Dr. Nath's presentation as well as the Q&A session that followed the presentations here:
CDC Grand Rounds: Chronic Fatigue Syndrome: Advancing Research and Clinical Education, Part II
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Dr. Charles Lapp
Dr. Lapp's talk centered on the presentation of the illness, which he characterized as abrupt (developing over a few hours or days), with waxing and waning progression, and usually following an infection. He stressed that the disease could be devastating in its severe form, and frequently occurred with comorbidities. To diagnose the disease, Dr. Lapp recommended taking a complete history, including "psychosocial factors," as well as ruling out overlapping illnesses with exclusionary tests.
Dr. Lapp did not cover treatment, but rather presented his "four pillars of management": Education, Behavioral modification, Pharmaceutical management of symptoms (such as antidepressants), and Non-pharmaceutical interventions (such as exercise).
In this final section of his talk, Dr. Lapp's suggestions fell afoul of the observations of many patients, as well as other expert physicians. Intolerance of antidepressants, especially the tricyclics, has been noted by specialists, including Dr. David Bell, whom Dr. Lapp cited in his presentation. According to Dr. Bell, a bad reaction to tricyclic antidepressants was virtually diagnostic of ME/CFS. Antidepressants have also been the most consistently negatively rated class of pharmaceuticals in several patient surveys, including a large survey conducted by the ME Association, and a smaller survey conducted by ProHealth.
Dr. Lapp's recommendation of graded exercise also flies in the face of patient experience. There is no evidence that graded exercise benefits ill patients, and plenty of proof that it causes harm. Yet doctors, some of whom should know better, seem to feel that by not taking exercise their patients will get worse. Dr. Lapp's suggestion to "begin with five minutes" of exercise makes very little sense, because a patient who cannot spontaneously walk for five minutes is certainly too ill to begin any exercise program, however innocuous seeming. This was a disappointing end to an otherwise good overview of the disease.
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Dr. Elizabeth Unger
The next presentation was by Dr. Unger of the CDC, who reviewed some facts about ME/CFS, based on the CDC's own studies. Because she did not draw on outside sources, her portrayal of the disease was somewhat skewed. For example, Dr. Unger stated that "compared to healthy controls, persons with CFS had more exposure to significantly more stressors and are likely to have a higher allostatic load, that is, a measure of the physiologic consequences of chronic neuroendocrine response to stress."
The "stress" theory was one espoused by Dr. Stephen Straus, and by others who adhere to "psychosocial" models of causation. However, the assessment of pre-illness "stress" in ME/CFS patients is retrospective, which means it is inherently unreliable. The only reliable way to gauge "stress" as a factor in the development of an illness is to start with a population that is unstressed, introduce "stress," and see how many develop the disease. Until that is done for ME/CFS, "stress" cannot be included as an etiological factor.
The claim that "stress" plays a role in the development of ME/CFS is also contradicted by Unger's own study, which found that ME/CFS patients are as emotionally and psychologically sound as healthy controls,
in spite of being very ill. If stress were a significant factor in the development of the illness, how is it that ill patients - who are the most stressed of anyone - are able to cope so well?
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Dr. Anthony Komaroff
The third presentation was by Dr. Komaroff. He was asked to briefly summarize the IOM report, the P2P workshop, and the AHRQ review.
Dr. Komaroff stressed that the reports had found considerable evidence that ME/CFS is a biological illness. The IOM panel concluded that “ME/CFS is a serious, chronic, systemic disease that often can profoundly affect the lives of patients” and that ME/CFS is not, as many physicians believe, a psychological disorder.
The P2P report concurred in this and called specifically for research on the possible role of herpes viruses in ME/CFS. He then described the IOM's new case definition for SEID. (Scroll down to Dr. Komaroff's presentation to see the slide.) Although Dr. Komaroff did not dwell on the AHRQ report, he did mention that it stressed the need to test the IOM's case definition before adopting it.
In his discussion of the IOM's new case definition, Dr. Komaroff touched on the origins of both the original case definition proposed by the CDC and the name, chronic fatigue syndrome. "As a member of that group," he said, "I would note that we were all focused on developing a case definition. No one really thought about the name, and when someone proposed the name chronic fatigue syndrome, people said 'Why not?' That was a big mistake."
Dr. Komaroff's review of the IOM report was thorough and accurate. However, he made an interesting comment when discussing the case definition for SEID. He said it was "shorter and simpler" (then contradicted himself by saying it was
not simple), but that it was "the best we can do."
In light of the long track record held by the CCC, it is puzzling that Dr. Komaroff should say the SEID case definition is "the best we can do." (Obviously, experts in this illness have already done better.) By all accounts, the case definition for SEID is far too simple, and likely to include people with a number of other illnesses (including depression). Perhaps, Dr. Komaroff's apparent blind spot concerning the CCC was due to his involvement with the devising the original CDC case definition, which has since proved inadequate.
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You can view a video of the entire session HERE.
You can see the slides that accompanied the four presentations HERE.
This transcript was first published on ProHealth.
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CDC Grand Rounds: Chronic Fatigue Syndrome: Advancing
Research and Clinical Education
Transcript by Erica Verrillo
On February 16, 2016, the CDC hosted a one-hour session on
ME/CFS. Featured speakers included Dr. Charles Lapp, Dr. Beth Unger, Dr.
Anthony Komaroff, and Dr. Avi Nath, who is heading the NIH study on ME/CFS. The session was introduced by Dr. Harold
Jaffe, CDC Associate Director for Science.
Dr. Jaffe: Chronic
Fatigue Syndrome is an important public health problem. Though many questions
about the disease remain to be answered, we know that the disease is real, and
that patients suffer greatly. Furthermore the economic impact of the disease is
felt across the country. Chronic Fatigue Syndrome is a biologically based
illness that affects individuals in nearly all aspects of their lives,
significantly affecting their ability to work and support their families.
Sadly, studies show that patients experience significant barriers in terms of
receiving appropriate health care. This needs to change. We need to enable
health care providers to better recognize and offer treatments for this
condition.
Today we will learn that while there is no cure, there are
management and therapeutic advances that can help patients. We need biomarkers to help make the disease
more clearly diagnosable. We are aware that just the name “chronic fatigue
syndrome” is imperfect in many ways, and can be unhelpful to clinicians and patients.
However, we should not let legitimate arguments about nomenclature impede our
scientific progress. CDC’s approach to reducing CFS morbidity includes working
partnerships with clinical research experts, patient advocacy groups and other
governmental agencies. At a time of unprecedented attention to this profoundly
disturbing condition, CDC is committed to the broad outreach and clinical
education efforts, of which this session is just one part. Again, the message
is CDC is in this for the long run, we are not going to wait.
____________________
Dr. Charles Lapp [4:23]: Let me start by saying that in 1991
one of my colleagues, David Bell, wrote a book entitled “The Disease of a
Thousand Names.” That title exemplifies the confusion we have about this
illness. The signs and the symptoms are so general and so diverse, that chronic
fatigue syndrome mimics many other disorders and has earned numerous monikers
over the years, including Royal Free Disease, Iceland Disease, Tapanui Flu,
“Yuppie Flu” (by the way, that came from the eminent medical journal, Rolling
Stone Magazine), Myalgic Encephalomyopathy, Chronic Fatigue and Immune
Dysfunction Syndrome, SEID (Systemic Exertion Intolerance Disease). For this
presentation, I will be using the more common name chronic fatigue syndrome,
which was chosen because 100% of the study’s subjects experienced an unusually
severe and persistent type of fatigue.
There is no explanation why individuals contract chronic
fatigue syndrome, but we do know that the majority of cases occur acutely over
hours to days, and typically follow a bacterial or viral-like illness.
Let me introduce you to a typical case. This is an actual
clinical case from my practice.
Jane was a 37-year old internet technologist for a community
bank. She had been physically active in sports and had been working out and had
been maintaining her own household when she contracted a flu-like illness in
2011. She was bedbound at first, and very slow to recover. Within days she
noticed an unusual fatigue after minimal activities, then insomnia, then
achiness in the joints and generalized muscle pain and weakness.
She soon found
it difficult to recall recent conversations and events. Reading concentration
was limited and she had trouble comprehending what she had read, or seen on TV.
She would search for words, lose her train of thought, and friends would
sometimes have to finish sentences for her.
Sleep had always been good but now she was restless at night, and would
awaken unrefreshed, even after many hours of bed rest.
She felt stiff and sore
and foggy, and for an hour or two after awakening, she noticed dizziness or
light-headedness on getting up quickly. On a couple of occasions she saw stars,
but no tunnel vision and no syncope. Now she was unable to keep up the house,
and she had to rely on friends and family to help her with the cleaning,
laundry, and shopping.
She would attempt to keep up at home and at work, but
exertion would inevitably make the symptoms worse, and if she exerted too much
she would end up sick and chair bound for one or two days afterward. An evaluation
by her primary care physician revealed rather low blood pressure, but there was
no immediate orthostatic blood pressure drop and otherwise the examination was
unremarkable. Blood work was unremarkable.
Having no explanation for her
symptoms, despite the profound reduction in her physical abilities, Jane became
anxious about her future and frustrated and discouraged as well.
This clinical case demonstrates all the key features of CFS:
- Exertion intolerance and debilitating fatigue
- Post-exertion relapse and malaise
- New onset of sleep problems
- Cognitive difficulties
- Orthostatic intolerance
- Symptoms wax and wane
- Whole body flu-like arthralgias and myalgias, or widespread
body pain
- The cause of CFS symptoms is unknown, but there is an
identifiable trigger in a majority of the cases that we see.
Precipitating Factors and Natural History
- Symptoms develop over hours or days
- Up to 85% report a trigger (bacterial or viral infection in
75% of cases)
- Natural course of the illness is to wax and wane
- Unpredictable onset and severity of symptoms, many relapses
occur spontaneously and last for an indefinite period of time, which make it
difficult for a person with CFS to plan ahead, or function on a regular,
predictable or sustained basis
- Most adults do not return to their pre-illness level of
function, total recovery is uncommon
Individuals with CFS are also more likely than the general
population to suffer comorbidities such as fibromyalgia, irritable bowel and
bladder, Sjogren’s, Ehlers Danlos syndrome, and several other medical
conditions. Sadly, it is an “invisible illness,” and to the casual observer
patients appear entirely normal and healthy, but the gravity of the disease is
such that it totally changes one’s lifestyle, and the lives around that patient
as well.
One of my patients pointed out to me, “This illness can take
away everything, your dignity, your livelihood, your family, your marriage, and
even all of your money.”
As you can imagine, the symptoms of chronic fatigue syndrome
overlap with many disorders, including depression, MS, systemic lupus,
endocrine disorders, hepatitis, and many other illnesses. So, in order to
confirm a diagnosis of chronic fatigue syndrome one needs to exclude disorders
that could plausibly explain the exertion intolerance and the other
symptoms. The essentials of an
evaluation include a thorough history, a thorough psychosocial history, such as
a history of dysfunctional childhood, prior verbal or physical abuse, substance
abuse, a complete physical examination, a mental health examination. Such an
evaluation typically takes about 30 minutes to 60 minutes in my office.
Lastly, it’s recommended to obtain basic screening lab
tests. They may include a CBC with differential, sed rate, urinalysis, thyroid
tests, metabolic panel, glucose, BUN, creatine, electrolytes, and other lab
tests to rule out other possible sources of fatigue such as infection,
autoimmune disorders, endocrine or hormonal problems, celiac disease, etc . The
results of these tests are usually unremarkable.
The IOM recommends making the diagnosis actively. That means
making the diagnosis promptly, even before one excludes other plausible causes.
The IOM criteria for SEID provide a brief and simple method for diagnosing CFS.
But many clinicians, including myself, corroborate the diagnosis with
established instruments such as the Fukuda criteria of 1994, or the Canadian
Consensus Criteria.
Making the diagnosis promptly reduces anxiety and
uncertainty for the patient and reduces medical costs, because numerous
exclusionary lab tests and procedures would not be needed.
Let’s consider the prognosis for these patients. In a
systemic review of the natural course of CFS, a median of 39.5% of adults with
CFS improved and a median of 5% experienced full recovery. The likelihood of
recovery decreases with baseline illness severity, duration of the illness, and
the presence of comorbid psychiatric conditions.
Children and adolescents fare somewhat better, with one
paper reporting 60% recovery at five years, and 88% at twelve years after the
onset of their illness. In another longitudinal study of 25 adolescents with
CFS compared to 25 controls, 80% of the patients had remitted over a course of
25 years, but many still reported more impairment than the controls.
The management of chronic fatigue syndrome can be briefly
summed up by these four pillars:
- Education – Reliable information should be provided to the
patients, and an excellent source is online at the CDC.gov/cfs website.
- Behavioral modification is effective to limit depression,
anxiety, and abnormal coping mechanisms, such as denial and escape avoidance.
- Pharmacologic therapy – Sleep disruption and pain are
usually addressed first, and may require consultation with a sleep specialist
or pain management group. We generally avoid narcotic medications, but helpful
therapies include tricyclics such as amitriptyline, cyclobezaprine, the NSRIs,
such as duloxetine and milnacipran, anti-epileptic medications like pregabalin.
The next step is to address severe symptoms and comorbidities that the patients
suffer.
- Non- Pharmacologic therapy might include Epsom soaks, hot
and cold packs, liniments, massage, osteopathic manipulation, acupuncture, and
the like. Another form of non-pharmacological therapy is staying active, but
not too active.
We recommend starting with very low levels of activity, and
proceeding slowly. Brief intervals of activity should be followed by adequate
rest in order to avoid a flare of symptoms or to avoid the post-exertional
malaise. Consider beginning to active stretching and range of motion exercises
against gravity. Then follow with light resistance training with light weights
for example, or elastic bands. We then advance to certain types of aerobic
activities such as tai chi, yoga, walking, bicycling, or aqua therapy. To avoid
flares, patients should limit activity by time, say less than five minutes per
day to start, and limit the number of repetitions, and if they experience any
excessive fatigue, reduce the amount of time, or the number of repetitions.
In summary, we can find chronic fatigue syndrome in both
pediatric and adult groups. It typically has a preceding medical event, often
infection. Patients benefit from earlier comprehensive evaluation and
diagnosis. The disease can have a severe
impact on quality of life, but improvement and recovery are certainly possible.
There is no curative therapy, but graded exercise and some types of
pharmacotherapy can be of great benefit. Thank you.
____________________
Beth Unger [17:42]: When designing a public health approach to
illness, one of the first steps is to understand the epidemiology of the
condition. For CFS the answer to this question is difficult because there is no
simple test to make the diagnosis, and findings will differ depending on how
the patients are identified. For example, self-report compared with clinical
assessment, as well as where the study is conducted. For example, in clinics
compared with the population as a whole. Population-based studies that include
clinical assessments are generally considered to give the most accurate
estimates. But these are complex and expensive. Extrapolating estimates from
three U.S. population-based surveys to the country as a whole, we can estimate
that at least one million Americans suffer from CFS. Most patients identified
in the population surveys have been ill longer than five years, and only about
half of those affected continue to seek medical care.
In addition, only about 20% of those identified as CFS have
been actually diagnosed by a physician. This emphasizes the need for more
physician education about this illness.
These studies indicate that CFS is three to four more times
more common in women than in men. Persons of all race and ethnic backgrounds
are affected, and there is a disproportionate burden of CFS in minority and
socioeconomically disadvantaged groups.
The highest incidence of prevalence is in 40-50 year olds,
but the age range is broad and includes children and adolescents.
It’s important to understand the economic impact of the
illness and barriers to healthcare utilization. Patients, their families, and
society all bear significant costs associated with CFS. These include direct medical costs of
provider visits and medications, and indirect costs of lost productivity.
In the U.S., the estimated annual cost of direct costs is
between nine and fourteen billion dollars. And nearly one-quarter of these
expenses is paid directly by the patients and their families.
The estimated annual cost of lost productivity is between
nine and thirty-seven billion dollars.
When CFS occurs before age 25, the ability of patients to
complete their education is significantly impaired. Inability to achieve their
full education potential can have a lifelong impact on earning potential.
CFS patients face significant barriers to receiving
appropriate healthcare. A population-based study in Georgia found that 55% of
persons with CFS reported at least one barrier to healthcare. Finances
prevented 10% from seeking care. This is twofold higher than the population
average found in the 2005 national health interview survey.
While the cause or causes of CFS are unknown, studies have
identified some factors that are associated with the illness. Risk factors may
suggest avenues to explore to discover causes, or to develop interventions.
Infections have been linked to CFS because patients often report an acute onset
after a flu-like illness that does not go away. And some patients have a
history of frequent infections prior to their illness. Epidemiologic studies do
not support association with any single pathogen.
Post-infectious fatigue, that is, failure to recover from a
documented infection occurs in about 10% of patients with a variety of viral
and non-viral pathogens, such as Epstein-Barr virus, Ross River virus, Q fever (that is Coxiella burnetii), or giardia.
The severity of the acute infection is most predictive of
subsequent illness, and there is no evidence of an unusual persistence of
infections in those who remain ill.
Compared to healthy controls, persons with CFS had more
exposure to significantly more stressors and are likely to have a higher
allostatic load, that is, a measure of the physiologic consequences of chronic
neuroendocrine response to stress. They are also more likely to have metabolic syndrome.
These associations are unlikely to be specific to CFS, as
stress is a factor in many chronic illnesses.
Twin and family studies support the contribution of both
genetic and environmental factors in CFS. No specific genes have been
identified, and a polygenetic explanation for increased susceptibility is most
likely.
CDC recently shifted its focus from population-based surveys
to studying CFS patients being cared for by clinicians with specialized
expertise in CFS. Population-based surveys are helpful to identify the full
spectrum of those affected and include a broad range of illness severity.
Patients identified from clinics tend to have more severe illness. Most studies
of CFS have been conducted in patients enrolled from single clinics and include
small numbers of patients. Many intriguing findings have not been replicated,
leading to the suggestion that heterogeneity of patients may contribute to this
difficulty.
Our study is designed to document a comprehensive picture of
CFS patients in multiple clinics, and to describe the approach that experts use
to diagnose and manage their patients. We use standardized questionnaires to
measure the major domains or characteristics of the illness. These
questionnaires measure the level of function, pain, fatigue, type of severity
of symptoms, and sleep.
We also collected medical history, family history, physical
examination results, medications, and results of laboratory tests. We included
the PROMIS instruments that were designed and validated by NIH to measure
symptoms experienced in many different illnesses to allow comparison between
illnesses. The SF 36 measures of function and multi-dimension fatigue inventory
have also been widely used in a variety of conditions. Seven clinical sites
have participated in this study, which was initiated in 2011. Five participate
under the umbrella organization of the Open Medicine Institute Consortium. The
clinicians participating are all well-known, respected experts in CFS and
include one of our speakers today, Dr. Lapp. Their expertise is what gives
credibility to the study.
We are very grateful to their patients who have agreed to be
part of this study and have accepted the additional burden of completing the
many questionnaires required.
We collected complete data of 471 patients in the baseline
study. These were distributed fairly evenly across the clinics. The mean
patient age was 48.2 years and the mean duration of illness was 14.3 years.
Most patients were female and the vast majority were white. The mean BMI was
26.6. More than three-fourths of the patients had a college education and
nearly all were insured.
While about three-fourths were unemployed, only 14% were
receiving unemployment benefits.
There were statistical differences in the demographics
between all the clinics in these measures, except the proportion not working.
The patients in these specialty clinics may not be
representative of CFS patients in other healthcare settings, as they were all
highly educated and with sufficient socioeconomic support to be able to
navigate their way to these specialized centers. Most patients had been seen
and evaluated by more than one physician prior to coming to their clinic.
We found significant heterogeneity in the patients overall,
but there were very few differences between clinics in these average
measures. [Slide] The important feature
to note is that the patients show significant functional impairment,
particularly for vitality and physical functioning, but there is a relative
preservation mental health and role emotional.
The data in our study confirms the seriousness of this
illness and the extent of impairment experienced by patients with CFS. We are
continuing this study to collect longitudinal measures of illness
characteristics and to enroll groups of patients that have been understudied,
specifically pediatrics, severely ill or homebound patients, and patients
within two years of onset of the illness. We are also enrolling healthy
controls and ill comparison groups who may present similarly to CFS. In
addition we are collecting blood and saliva on those enrolled so that they can
be tested for biomarkers that have shown promise in smaller studies.
Results from this study will help to find patient subgroups
that reflect different causes or that could suggest targeted therapies.
Finally, the data clearly show that the patients in these
specialty clinics are highly educated with significant financial and social
support that enable them to reach these expert physicians. Again, this emphasizes the need for
dissemination of knowledge about CFS to the broader medical community.
It is clear that despite decades of work, CFS remains a
challenge for clinicians. Patients have difficulty finding a compassionate and
appropriate care. Physicians and other healthcare workers need evidence-based
information about CFS. CDC has responded to this need by developing a series of
continuing medical courses. In 2012 and 2013 we partnered with Medscape to
present two roundtable discussions that were targeted to primary care
physicians. These reached more than 22,000 physicians and more than 6,000
continuing medical education credits were issued. Currently, CDC has two free
online courses available on the CFS website. These are accredited for
physicians, nurses, and other healthcare professionals.
However, CFS is rarely covered in medical schools, and this
leaves a vacuum of knowledge. So we’ve begun the process of developing
standardized patient videos accompanied by educational curriculum for the MedEdPORTAL.
This is a free online service provided by the Association of
American Medic al Colleges. The materials are peer-reviewed and once approved
are made available to medical school faculty free of charge.
Finally, CDC is continuing communication with the general
public and advocacy community. An important part of this has been the
introduction of patient-centered outreach and communication calls (PCOCA
calls). These are one-hour teleconferences that are available toll-free in the
U.S. They began in 2012 and are generally held twice a year. The format is that
the CDC uses the first ten minutes to give an update on current activities of
the CFS program, and then an outside expert or group of experts presents
information on a topic of interest to the community. These talks generally last
35 to 40 minutes and are followed by answers to questions submitted to the
PCOCA email. Topics have included identifying patients for clinical studies,
exercise, infection and immunity in CFS, CFS and cognitive function, sleep research
and CFS, Stanford’s research program, and self-management strategies in CFS.
We are grateful to all the experts who graciously gave up
their time to share their insights with the patients and their families.
Most recently, we’ve begun a new initiative to include broad
stakeholder collaboration into developing educational materials. Including the
viewpoints of patients, medical professional organizations, medical educational
organizations, expert clinicians and government agencies will help assure the
quality and usefulness of these products, and help facilitate dissemination in
the medical community at large.
Our first focus will be modification of the CDC CFS web page
to incorporate recommendations of the Institute of Medicine. I’d now like to turn
the podium to Dr. Komaroff.
____________________
Dr. Anthony Komaroff
[31:07]: I was asked to speak about three recent authoritative reports , in
which experts, many of them from outside the field of chronic fatigue syndrome
evaluated the evidence that’s been published.
The first is from the Institute of Medicine of the National
Academies of Science, which issued a 300-page report in which the panel
reviewed the literature of nearly 9,000 published articles, and concluded that
ME/CFS is a biologically based illness, and proposed a new case definition as
well as a new name.
The second report was from the NIH, which held a Pathways to
Prevention conference with a follow-up report drawing similar conclusions about
the biology of ME/CFS.
Finally, the federal Agency for Healthcare Research and
Quality (AHRQ) commissioned an independent review that focused on diagnosis and
treatment.
The Institute of Medicine report first addressed the
question of the scope and seriousness of ME/CFS, drawing heavily I might say on
published studies from the CDC. The Institute concluded that between 800,000
and 2.5 million Americans have the illness. The Institute also agreed that the
costs of the illness to society were substantial, as much as 51 billion dollars
annually.
Based on their review the Institute panel concluded that
“ME/CFS is a serious, chronic, systemic disease that often can profoundly
affect the lives of patients” and that ME/CFS is not, as many physicians
believe, a psychological disorder.
Then the Institute turned to an important question: Given
that ME/CFS is defined exclusively by subjective symptoms, symptoms that any
human being can say they have, are there any confirmatory, underlying objective
biological abnormalities in these patients compared to healthy subjects and
compared to patients with other fatiguing illnesses? That includes comparison
with the biological abnormalities in some psychiatric illnesses.
The Institute of Medicine found considerable evidence of
underlying neurological abnormalities as reflected by many different diagnostic
technologies. Those singled out for special mention by the panel included
slowed information processing, problems with white matter integrity,
neuroinflammation, impairment of working memory, HPA axis abnormalities, and
autonomic abnormalities. The NIH report was in general agreement with the
Institute on this issue.
The Institute of Medicine also concluded that there were
considerable immunologic abnormalities in patients with ME/CFS. They
highlighted two as being particularly well substantiated: impaired natural cell
killer cell function that correlated with illness severity, and increased
cytokine levels in blood, suggesting a state of chronic immune activation. The
Institute of Medicine noted that many, but not all patients, with ME/CFS
reported that their illness began following an acute infectious-like illness
characterized by fever, myalgias, respiratory, GI, neurologic symptoms, along
with severe fatigue, an illness from which patients say they have never
recovered.
Indeed, the medical literature includes many reports of
post-infectious fatigue syndromes linked to well-documented acute infections.
For this reason many have wondered if at least some cases of CFS may be
initiated or even perpetuated by infection. The Institute panel concluded that
there is “Sufficient evidence suggesting that ME/CFS follows infection with
Epstein-Barr virus and possibly other specific infections, viral, bacterial,
and possibly protozoal.”
NIH report concurred in this and called specifically for
research on the possible role of herpes viruses in ME/CFS.
There have been several case definitions proposed for this
illness. Perhaps the most widely used is the case definition developed under
the leadership of the CDC and published in 1994. The Institute of Medicine
panel proposed a new case definition that it hoped would be simpler and
shorter, easier to apply consistently across patients, likely to result in
fewer false negative and false positive classifications, and likely to be a
better predictor both of response to therapy as well as prognosis.
The key elements of the proposed new case definition by the
Institute are: 1) Post-exertional malaise, defined as a prolonged worsening of
a patients’ baseline symptoms after physical or cognitive exertion, or
orthostatic challenge, exertion, or stress, 2) Unrefreshing sleep, defined as
regularly feeling unrefreshed after sleeping many hours, 3) Cognitive
impairments of a side variety of types that are made worse by exertion, effort,
stress, or time pressure, and 4) Orthostatic intolerance, or symptoms that
worsen upon assuming and maintaining and erect posture and that are improved by
lying down or elevating the feet. [Slide]
The IOM case definition is shorter, but it is not simple.
But at the moment I think it is the best we can do.
The new case definition, like most that preceded it, does
not include laboratory studies. ME/CFS remains a multi-system disease for which
we do not yet have a single diagnostic biomarker. Indeed, until there is a gold
standard pathological finding for the illness, I don’t think it will be
possible to test the accuracy of any case definition. It will, however, be
possible to compare the performance of different alternative case definitions
against each other in large numbers of patients, and that already is underway.
As pointed out by the AHRQ, a new case definition does need to be tested
empirically to verify that it is superior to its predecessors.
The name chronic fatigue syndrome was coined in 1988 by a
group convened by CDC. As a member of that group, I would note that we were all
focused on developing a case definition. No one really thought about the name,
and when someone proposed the name chronic fatigue syndrome, people said “Why
not?” That was a big mistake.
Many of the patients and clinicians believe that that name,
chronic fatigue syndrome, trivializes and stigmatizes this often devastating
illness, and I certainly agree.
Many different names have been proposed. The new name
proposed by the Institute of Medicine, Systemic Exertional [sic] Intolerance
Disease [note: SEID stands for Systemic
Exertion Intolerance Disease], has some merits. It focuses on a core component of the
illness. But I think it’s too early to determine whether this new name is going
to be widely adopted by both the clinician and patient community.
In summary, the Institute of Medicine and the NIH reports
conclude that patients with ME/CFS have underlying objective biological abnormalities,
that their symptoms are not imaginary. However, none of these biologic
abnormalities is so sensitive and specific that it constitutes a biomarker, a
diagnostic test.
ME/CFS is an important disease causing great suffering to
many individuals and their families, and billions of dollars in lost
productivity to society. Finally, more research is urgently needed and indeed
the NIH along with CDC has recently announced its intention to expand its focus
on this illness, particularly in its intramural program as described next by
Dr. Avi Nath.
END PART I
