Chronic Immune Diseases ME/CFS

Chronic Fatigue Syndrome

ME/CFS also is known as myalgic encephalomyelitis (ME), post-viral fatigue syndrome, chronic fatigue and immune dysfunction syndrome. ME/CFS shares overlapping symptomology with several diseases, including hypothyroidism, Lyme disease, lupus, and fibromyalgia syndrome (FMS). ME/CFS differs from fibromyalgia syndrome in that FMS is characterized by acute pain associated with fatigue symptoms.

Chronic Fatigue Syndrome (ME/CFS) is a complex illness characterized by severe, prolonged fatigue in addition to numerous other recurrent clinical symptoms including pharyngitis, persistent low grade fever, lymphadenopathy, myalgia, arthralgia, headache, sleep disorders, difficulty in concentrating, and short term memory loss.

Over the past several years, scientists at REDLABS U.S.A., in conjunction with R.E.D. Laboratories in Belgium have been unraveling the biochemical and molecular mysteries surrounding ME/CFS. The result of these efforts has been to create a number of objective clinical laboratory assays that can assist the physician in not only making the diagnosis of ME/CFS, but can also help in staging the severity of disease and monitor the course of the disease should the patient begin therapy.

What is Chronic Fatigue Syndrome?

Chronic Fatigue Syndrome (ME/CFS) is characterized by the sudden onset of a strong, semi-persistent notable fatigue. Often patients complain of extreme exhaustion and tire easily in the course of normal activities. In extreme cases, sufferers are unable to perform normal tasks due to the debilitating effects of the disorder.

What Characterizes Initial Onset

The onset on ME/CFS symptoms is characterized by a major insult to the immune system. For some people, this may take the form of an upper respiratory infection or gastrological illness, manifesting in flu-like symptoms. Most often, minor illnesses, compounded by unusual stress, can provide a sufficient trigger for the illness to manifest.

CDC Guidelines for Research Purposes

According to The United States Centers for Disease Control and Prevention (CDC), clinically evaluated, unexplained chronic fatigue cases can be classified as chronic fatigue syndrome if the patient satisfies both the following criteria (determined for research purposes only):

1. Clinically evaluated, unexplained persistent or relapsing fatigue that is of new or definite onset (i.e., not lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.
2. The concurrent occurrence of four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours. These symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.

Chronic Fatigue Syndrome is considered if the above criteria are met and all exclusionary testing indicates normal function. (See Diagnosis for exclusionary tests)

Can Anyone Get ME/CFS?

According to a large 1999 US study, the highest rates of ME/CFS were found among women in general, minority groups (African- and Hispanic-Americans), and people with lower levels of education and occupational status. Chronic fatigue is most often experienced by individuals 40 to 50 years old; it is least prevalent in people under 29 or over 60. This disorder, however, occurs in both sexes and at all ages and in all racial and ethnic groups.

Women. Although ME/CFS occurs much more commonly in women, they do not appear to have more severe symptoms than men with the disorder.

Ethnic Groups. Although previous research found that Caucasian women have higher rates of ME/CFS than women from other ethnic groups, reports now indicate that such estimates most likely reflect the greater socioeconomic ability of Caucasian women to receive treatment.

Stress-Related Occupations. One study of nurses found that those who were exposed to poor working conditions and threats of accidents faced a higher risk for ME/CFS symptoms than those without these experiences. This finding suggests, perhaps, that stressful work puts people at higher risk for ME/CFS. Stress alone does not cause ME/CFS, however.

Children. Children and adolescents are not immune to its effects. Most studies indicate that girls are more apt to develop ME/CFS than boys, although one study found the incidence of the syndrome to be equal. According to a 1999 study, half of the children and adolescents with ME/CFS also suffer psychiatric disorders, primarily anxiety, and also depression.

According to The Center for Disease Control (CDC), ME/CFS affects more than 1 million people in the United States. According to The University of Maryland Medical Center, four in every 1000 Americans are affected by ME/CFS. CFS patients are denied insurance benefits and do not seek medical treatment.

CFS is considered a serious medical problem. Many patients are desperate for testing that confirms their disease, and for treatment that will ease their symptoms so that they can lead productive lives.

What Casues ME/CFS?

The direct cause of ME/CFS is unknown; it has been suggested that immune dysregulation, depressed cortisol or a viral trigger may be responsible for the sudden onset of symptoms. Current scientific evidence suggests a correlation between the Human Herpes Virus, HHV-6A, and ME/CFS.

While it is unclear what the direct cause of ME/CFS is, current research at REDLABS U.S.A. and R.E.D. Laboratories Belgium and other university and private foundations, are working to solve this complex problem.

Confirming ME/CFS Diagnosis

As several diseases present symptomology similar to ME/CFS, exclusionary testing is required for an accurate diagnosis. Studies have proven that depression is often seen in patients with ME/CFS. In 1988, The United States Centers for Disease Control and Prevention (CDC), proposed a series of guidelines to define ME/CFS. Later experimentation determined these guidelines to be ineffective and in 1994 a revision was released. The CDC made a later revision in 2003 (presented here) to reflect current scientific research regarding the evaluation, classification and sub-grouping of patients.

The following are guidelines from the revised 2003 International Case Definition for Chronic Fatigue Syndrome (ME/CFS) per The United States Centers for Disease Control and Prevention (CDC).

Conditions That Exclude A Diagnosis Of ME/CFS

1. Any active medical condition that may explain the presence of chronic fatigue, such as untreated hypothyroidism, sleep apnea and narcolepsy, and iatrogenic conditions such as side effects of medication.
2. Some diagnosable illnesses may relapse or may not have been completely resolved during treatment. If the persistence of such a condition could explain the presence of chronic fatigue, and if it cannot be clearly established that the original condition has been completely resolved with treatment, then such patients should not be classified as having ME/CFS. Examples of illnesses that can present such a picture include some types of malignancies and chronic cases of hepatitis B or C virus infection.
3. Any past or current diagnosis of a major depressive disorder with psychotic or melancholic features such as:
   • bipolar affective disorders
   • schizophrenia of any subtype
   • delusional disorders of any subtype
   • dementias of any subtype
   • anorexia nervosa
   • bulimia nervosa
4. Alcohol or other substance abuse, occurring within 2 years of the onset of chronic fatigue and any time afterwards.
5. Severe obesity as defined by a body mass index equal to or greater than 45 [body mass index = weight in kilograms ÷ (height in meters)2] Note: body mass index values vary considerably among different age groups and populations. No "normal" or "average" range of values can be suggested in a fashion that is meaningful. The range of 45 or greater was selected because it clearly falls within the range of severe obesity.

Any unexplained abnormality detected on examination or other testing that strongly suggests an exclusionary condition must be resolved before attempting further classification.

Conditions That Do Not Exclude A Diagnosis of ME/CFS

1. Any condition defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, including fibromyalgia, anxiety disorders, somatoform disorders, non-psychotic or melancholic depression, neurasthenia, and multiple chemical sensitivity disorder.
2. Any condition under specific treatment sufficient to alleviate all symptoms related to that condition and for which the adequacy of treatment has been documented. Such conditions include hypothyroidism for which the adequacy of replacement hormone has been verified by normal thyroid-stimulating hormone levels, or asthma in which the adequacy of treatment has been determined by pulmonary function and other testing.
3. Any condition, such as Lyme disease or syphilis, which was treated with definitive therapy before development of chronic symptoms.
4. Any isolated and unexplained physical examination finding or laboratory or imaging test abnormality that is insufficient to strongly suggest the existence of an exclusionary condition. Such conditions include an elevated antinuclear antibody titer that is inadequate without additional laboratory or clinical evidence to strongly support a diagnosis of a discrete connective tissue disorder.

What Tests to Order Once a Diagnosis of CFS Has Been Made

A common misconception about CFS is that it has a single, unknown cause. Research has shown that CFS is indeed a heterogeneous disease and a testing strategy must be developed with this in mind. We have found that CFS can usually be broken into three broad categories that we call Type I, Type II and Type III CFS. The following diagram is a graphical representation.

Note: Click on each diagram below to view a larger version.

To understand the pathology of CFS it is important to understand what is occurring at the molecular level and why each test provides useful information. We will therefore start with the basic tests and work our way outward on the above diagram.

RNase L Protein and Activity Assay

RNase L is an interferon inducible enzyme with antiviral and apoptotic activity. When a cell is infected with an RNA virus a number of events occur that involve this pathway. Interferon levels rise which promotes the production of the 2'-5' oligodenylate synthetase. This enzyme recognizes and binds double stranded RNA thereby activating it. Once the enzyme is activated it converts ATP into a second messenger. This second messenger is a polyadenylate molecule with 2'-5' linkage and is commonly referred to as 2-5A. This molecule then binds to latent RNase L enzyme, thereby releasing its inhibitor and activating it. RNase L then proceeds to cleave single stranded messenger and viral RNA. This process ultimately results in viral destruction as well as programmed cell death. We would therefore expect to see increased RNase L activity as a normal part of a viral infection.

In some stress situations, the cell produces odd RNA/DNA sequences resulting from: the expression of endogenous retroviruses sequences (viruses that have retro-transcribed their RNA sequences into our genome during evolution without any control from our gene machinery); release of DNA/RNA fragments from cell damage due to such things as ionizing radiations; release of chemically modified RNA/DNA fragments due to toxic chemicals and heavy metals. These abnormal nucleotides activate the innate cellular immunity mechanisms. However, this fine-tuned machine does not work as expected. This process leads to various cellular and immune dysfunctions such as a dysregulated RNase L pathway.

Overview of the Interferon Inducible 2-5A, RNase L, PKR Antiviral Pathway

RNase L is an endoribonuclease, a component of the interferon (IFN) inducible antiviral system. Upon binding of double strand RNA (dsRNA), presumably of viral origin, 2' - 5' oligodenylate synthetase (OAS) is activated and converts ATP into the second messenger, 2-5A. This molecule binds to and activates the latent endoribonuclease RNase L that cleaves single stranded RNA. Activation of RNase L leads to mitochondrial release of cytochrome and caspase-dependent apoptosis. In addition to activating OAS, dsRNA also activates a proapoptotic kinase known as Protein Kinase R (PKR). PKR phosphorylates and activates the eukaryotic translation initiation factor 2 (eIF-2) and the transcription factor NFkb, which ultimately leads to cellular apoptosis.

Collectively, these enzymes are referred to as the interferon inducible, 2-5 OAS, RNase L, PKR antiviral pathway. In a properly functioning immune system, this pathway is tightly regulated to contain a viral infection. Under excessive inflammatory response, pro-inflammatory enzymes, such as Elastase, can cleave RNase L which results in the over-activation of this enzyme. In a normal viral response, it would be common to see RNase L and PKR activity high with normal levels of Elastase and RNase L protein.

In an extreme inflammatory response RNase L activity and Elastase activity are elevated and would correlate with RNase L protein fragmentation but not PKR activation. It is for this reason that the RNase L pathway is often a starting point in the diagnosis of immune dysregulation.

Elastase and Calpain Activity Assay

Elastase and Calpain are both proteases that are associated with inflammatory responses. Elastase is a powerful serum protease involved in the neutrophil mediated host defense mechanism against invading pathogens. Pro-inflammatory mediators such as interleukin-6 and interleukin-8 activate neutrophillic release of Elastase. The dysregulation of Elastase is implicated in many diseases. Calpain (calcium-activated neutral proteinase) has been demonstrated to degrade a broad array of intra- and extra-cellular proteins. Calpain is a cytoplasmic cysteine protease believed to be involved in many physiological and pathological processes, including signal transduction, cell proliferation, cell cycle progression, differentiation, apoptosis, membrane fusion, and platelet activation. Deregulation of its activity has been implicated in various pathological conditions such as neuronal degeneration, Alzheimer’s disease, metastasis, and cataract. (REF) Calpain is believed to be elevated in the immune mediated inflammatory response.

The Link Between RNase L and Elastase and/or Calpain

In addition to the common substrates for Elastase and Calpain, when unregulated, these enzymes may act on RNase L generating the classical cleavage of the 80 kDa protein into the putative 37 kDa fragment. Studies show that this cleavage has at least two detrimental effects; first the unregulated RNase L will result in lymphocyte apoptosis and in turn, adversely affect the immune system. Secondly, the fragmented RNase L disrupts ion channels resulting in channelopathy, which, in turn, results in a host of symptoms such as unexplained sweats, transient hypoglycemia, reduction in pain sensitivity threshold, depression, visual problems, and hypersensitivity to toxic chemicals. The level of Elastase activity correlates with the fragmentation of RNase L protein to an extremely high degree (p<0.0001 in a series of 250 patients). This evidence supports the theory that ME/CFS is not only a chronic dysfunction of the immune system, but also a chronic inflammation of the immune system. Increased RNase L activity without an increase of RNase L protein fragmentation might simply indicate a viral infection. With an increase in RNase L activity and increased activity of Elastase and/or Calpain, we would expect to see elevated cleavage of RNase L protein, as is commonly seen in ME/CFS patients.

Abnormal PKR Function and Its Link to Nitric Oxide and Other Abnormalities

PKR dysregulation is inherently linked to Nitric Oxide levels. Nitric oxide (NO) is an important cellular messenger and its dysregulation has many detrimental effects in the immune system. For instance, when PKR is decreased and Nitric Oxide in turn, is down-regulated, Natural Killer Cell function and T-lymphocyte activity is excessive. This can lead to increased Th-1 immune activation. When PKR and Nitric Oxide are in excess, Natural Killer and T-lymphocyte cells activity is decreased. For instance, studies have shown that a decrease in NO results in decreased activity of NK and T-cell function against cytomegalovirus (CMV)-infected cells.