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By NCF Medical Committee © 2015 — Reprint by permission only

From Spring 2015 Forum

Di-lu-tion = the action of making something weaker in force, content, or value.

As long-term patients, decades of having this illness has taught us all a great deal. Loss and perseverance is something we all share in this life experience. As patients who have had the unfortunate experience of losing fellow patients who were personally close, the outcome of this illness has hit very close to home. Each one of us has faced our own unique challenges but we have continued to survive the uncertainty of each day along with the lack of freedom to do as we desire — something that most people, quite frankly, take for granted. Along the way, the talk of a name change (remember Chronic EBV?) has been discussed extensively. Would this be any different?

The Institute of Medicine has issued an official report titled “Beyond Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: Redefining an Illness” dated February 10th, 2015 [1].

According to the report brief: Between 836,000 and 2.5 million Americans suffer from myalgic encephalomyelitis/chronic fatigue syndrome — commonly referred to as ME/CFS. This disease is characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, autonomic manifestations, pain, and other symptoms that are made worse by exertion of any sort. ME/CFS can severely impair patients’ ability to conduct their normal lives. Yet many people struggle with symptoms for years before receiving a diagnosis. Fewer than one-third of medical school curricula and less than half of medical textbooks include information about ME/CFS. Although many health care providers are aware of ME/CFS, they may misunderstand the disease or lack knowledge about how to diagnose and treat it. Such gaps in understanding lead to delayed diagnoses and inappropriate management of patients’ symptoms.

The Department of Health and Human Services (HHS), the National Institutes of Health, the Agency for Healthcare Research and Quality, the Centers for Disease Control and Prevention, the Food and Drug Administration, and the Social Security Administration asked the Institute of Medicine (IOM) to convene an expert committee to examine the evidence base for ME/CFS. In Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, the committee proposes new diagnostic criteria that will facilitate timely diagnosis and care and enhance understanding among health care providers and the public. In addition, the committee recommends that the name of the disease be changed — from ME/CFS to systemic exertion intolerance disease (SEID) — to more accurately capture the central characteristics of the illness.

The IOM’s newly proposed diagnostic criteria is as follows:

“Diagnosis requires that the patient have the following three symptoms:

  1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and
  2. Post-exertional malaise,* and
  3. Unrefreshing sleep*

‘At least one of the two following manifestations is also required:

  1. Cognitive impairment* or
  2. Orthostatic intolerance

* Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.”

Thinking back to the early days of this illness reminds us of a paper published in the journal, Lancet, on chronic Epstein-Barr viral (EBV) infections [2]. This was the neophyte era of the early 1980’s and many physicians looked at EBV as a potential culprit to explain away this disease. Chronic EBV was also known as the chronic mononucleosis-like syndrome. It consisted of a combination of nonspecific symptoms that included severe fatigue, weakness, malaise, subjective fever, sore throat, painful lymph nodes, decreased memory, confusion, depression, decreased ability to concentrate on tasks, and various other complaints with a remarkable absence of objective physical or laboratory abnormalities. The chronic mononucleosis-like syndrome was linked to EBV because many of the patients had EBV antibody profiles that suggested reactivation of the latent infection.

In 1988, a case definition for the Chronic Fatigue Syndrome (CFS) came into being [3]. This was also known to many physicians and patients as the Holmes criteria, named for the lead author. By definition, a case of CFS must fulfill major criteria, listed as 1 and 2 immediately below, and the following minor criteria: 6 or more of the 11 symptom criteria and 2 or more of the 3 physical criteria; or 8 or more of the 11 symptom criteria. The description provided here is copied verbatim from the published paper.

The 1988 Major Criteria is:

  1. New onset of persistent or relapsing, debilitating fatigue or easy fatigability in a person who has no previous history of similar symptoms, that does not resolve with bedrest, and that is severe enough to reduce or impair average daily activity below 50% of the patient’s premorbid activity level for a period of at least 6 months.
  2. Other clinical conditions that may produce similar symptoms must be excluded by thorough evaluation, based on history, physical examination, and appropriate laboratory findings. These conditions include malignancy; autoimmune disease; localized infection (such as occult abscess); chronic or subacute bacterial disease (such as endocarditis, Lyme disease, or tuberculosis), fungal disease (such as histoplasmosis, blastomycosis, or coccidioidomycosis), and parasitic disease (such as toxoplasmosis, amebiasis, giardiasis, or helminthic infestation); disease related to human immunodeficiency virus (HIV) infection; chronic psychiatric disease, either newly diagnosed or by history (such as endogenous depression; hysterical personality disorder; anxiety neurosis; schizophrenia; or chronic use of major tranquilizers, lithium, or antidepressive medications); chronic inflammatory disease (such as sarcoidosis, Wegener granulomatosis, or chronic hepatitis); neuromuscular disease (such as multiple sclerosis or myasthenia gravis); endocrine disease (such as hypothyroidism, Addison disease, Cushing syndrome, or diabetes mellitus); drug dependency or abuse (such as alcohol, controlled prescription drugs, or illicit drugs); side effects of a chronic medication or other toxic agent (such as a chemical solvent, pesticide, or heavy metal); or other known or defined chronic pulmonary, cardiac, gastrointestinal, hepatic, renal, or hematologic disease. Specific laboratory tests or clinical measurements are not required to satisfy the definition of the chronic fatigue syndrome, but the recommended evaluation includes serial weight measurements (weight change of more than 10% in the absence of dieting suggests other diagnoses); serial morning and afternoon temperature measurements; complete blood count and differential; serum electrolytes; glucose; creatinine; blood urea nitrogen; calcium, phosphorus; total bilirubin, alkaline phosphatase, serum aspartate aminotransferase, serum alanine aminotransferase; creatine phosphokinase or aldolase; urinalysis; posteroanterior and lateral chest roentgenograms; detailed personal and family psychiatric history; erthrocyte sedimentation rate; antinuclear antibody; thyroid stimulating hormone level; HIV antibody measurement; and intermediate-strength purified protein derivative (PPD) skin test with controls. If any of the results from these tests are abnormal, the physician should search for other conditions that may cause such a result. If no such conditions are detected by a reasonable evaluation, this criteria is satisfied.

‘The 1988 Minor Criteria is:
Symptom Criteria — To fulfill a symptom criterion, a symptom must have begun at or after the time of onset of increased fatigability, and must have persisted or recurred over a period of at least 6 months (individual symptoms may or may not have occurred simultaneously).

‘Symptoms include:

  1. Mild fever — oral temperature between 37.5 degrees C and 38.6 degrees C, if measured by the patient — or chills. (Note: oral temperatures of greater than 38.6 degrees C are less compatible with chronic fatigue syndrome and should prompt studies for other causes of illness.)
  2. Sore throat.)
  3. Painful lymph nodes in the anterior or posterior cervical or axillary distribution.)
  4. Unexplained generalized muscle weakness.)
  5. Muscle discomfort or myalgia.)
  6. Prolonged (24 hours or greater) generalized fatigue after levels of exercise that would have been easily tolerated in the patient’s premorbid state.)
  7. Generalized headaches (of a type, severity, or pattern that is different from headaches the patient may have had in the premorbid state).)
  8. Migratory arthralgia without joint swelling or redness.)
  9. Neuropsychologic complaints (one or more of the following: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, depression).)
  10. Sleep disturbance (hypersomnia or insomnia).)
  11. Description of the main symptom complex as initially developing over a few hours to a few days (this is not a true symptom, but may be considered as equivalent to the above symptoms in meeting the requirements of the case definition).)

‘Physical Criteria:
‘Physical criteria must be documented by a physician on at least two occasions, at least 1 month apart.

  1. Low-grade fever — oral temperature between 37.6 degrees C and 38.6 degrees C, or rectal temperature between 37.8 degrees C and 38.8 degrees C (See note under Symptom Criterion 1.)
  2. Nonexudative pharyngitis.
  3. Palpable or tender anterior or posterior cervical or axillary lymph nodes. (Note: lymph nodes greater than 2 cm in diameter suggest other causes. Further evaluation is warranted.”

As you can see, the 1988 Holmes criteria is far more extensive and/or thorough in its requirements than the proposed 2015 IOM’s definition.

Next, the CFS definition was updated in 1994 in a paper published by Fukuda et al. [4]. This paper addresses the criteria for chronic fatigue syndrome as well as for idiopathic chronic fatigue. From this paper, the criteria for both is determined using the following description.

  1. Clinically evaluate cases of prolonged or chronic fatigue by:
    1. History and physical examination;
    2. Mental status examination (abnormalities require appropriate psychiatric, psychologic, or neurologic examination);
    3. Tests (abnormal results that strongly suggest an exclusionary condition must be resolved);
      1. Screening lab tests: CBC, ESR, ALT, total protein, albumin, globulin, alkaline phosphatase, Ca, PO4, glucose, BUN, electrolytes, creatinine, TSH, and UA
      2. Additional tests as clinically indicated to exclude other diagnoses.
        ‘Exclude case if another cause for chronic fatigue is found.
  2. Classify case as either chronic fatigue syndrome or idiopathic chronic fatigue if fatigue persists or relapses for > 6 months.
    1. Classify as chronic fatigue syndrome if:
      1. Criteria for severity of fatigue are met, and
      2. Four or more of the following symptoms are concurrently present for > 6 months:
      1. impaired memory or concentration.
      2. sore throat.
      3. tender cervical or axillary lymph nodes.
      4. muscle pain.
      5. multi-joint pain.
      6. new headaches.
      7. unrefreshing sleep, and
      8. post-exertion malaise.
    2. Classify as idiopathic chronic fatigue if fatigue severity or symptom criteria for chronic fatigue syndrome are not met.
  3. Subgroup research cases by the presence or absence of the following essential parameters:
    1. Comorbid conditions (psychiatric conditions must be documented by use of an instrument);
    2. Current level of fatigue (measured by a scale);
    3. Duration of fatigue;
    4. Current level of physical function (measured by an instrument). ‘Subgroup research cases further as needed by optional parameters such as epidemiologic or laboratory features of interest.”

As can be seen, the 1994 Fukuda criteria introduces idiopathic chronic fatigue in its classification. This case definition had become less exclusive and therefore acted to confound or dilute the extensive qualifiers for chronic fatigue syndrome as developed by the 1988 Holmes criteria. Relative to the 1994 Fukuda criteria, the IOM’s definition is even less exclusive and thus further dilutes those homologous components of the disease that had been identified previously.

Overall, the 2015 IOM definition is a long, long way from the 1988 Holmes criteria. As such, the IOM has proposed a definition that continues the trek to dilute the original base criteria for this disease. This action, undertaken by the IOM, thus confounds the homogeneous components of the disease to thereby create a heterogeneous patient group. Heterogeneity does not bode well for the identification of the culprit responsible for the crime. Perhaps that is what the IOM is truly after!


  1. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness; Report issued 2/10/15; Reports/2015/ME-CFS.aspx
  2. Prolonged atypical illness associated with serological evidence of persistent EpsteinBarr virus infection; Tobi M, Morag A Ravid Z, Chowers I, Feldman-Weiss V, Michaeli Y, Ben-Chetrit E, Shalit M, Knobler H; Lancet.1982 Jan 9;1(8263):61-4.
  3. Chronic fatigue syndrome: a working case definition; Holmes GP1, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham Rundles C, Pahwa S, et al.; Ann Intern Med. 1988 Mar;108(3):387-9.
  4. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group; Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A; Ann Intern Med. 1994 Dec 15;121(12):953-9.

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