|
CFS and FMS Research
HOST VERSES ACQUIRED RESPONSES IN CHRONIC FATIGUE DISORDERS
McGregor NR, Dunstan RH, Butt HL, Roberts TK, Klineberg IJ
Since the 1934 outbreak in Los Angeles, many epidemic and endemic chronic fatigue illnesses have been described. These outbreaks were recorded using observations and reporting of symptoms. However scientific research requires the development of definitions which are currently based upon:
a. A clinically defined group of symptoms composed of a core set of symptoms and an additional group which may not occur in all subjects.
b. The exclusion of other known fatigue-related diseases.
These research guidelines were devised to allow a standardised selection of patients for research studies. These criteria have since been modified to be more applicable to general practice and are currently used as the basis for the diagnosis of CFS.
No aetiological agent, consistent cellular or biochemical alteration has been found which could be used to differentiate the condition from similar fatigue-related diseases. The lack of objective diagnostic markers has resulted in considerable confusion in diagnosing the syndrome. This has also hampered scientific investigation of its causes and pathophysiology. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
On this basis, examination of the primary diagnostic symptoms - fatigue and pain - reveals that these types of symptoms are host based responses to an external challenge, which can be initiated by many different mechanisms. CPRU research indicates that the currently defined CFS patient groups may therefore actually represent a number of different polysymptomatic illnesses with separate aetiologies.
For more information, please refer to the conference abstract: "Host versus acquired responses in defined CFS patients".
McGregor NR, Dunstan RH, Butt HL, Roberts TK, Klineberg IJ
The primary symptom in CDC-defined CFS is fatigue, a term that has a variety of possible interpretations.
Is fatigue purely that of the patient-reported reduced ability to exercise, or is it muscle fatigue, the reporting of feeling low in energy, or a feeling of mental fatigue? CPRU research shows that simple correlation statistics will reveal high correlations between all of these symptoms. However, a more sophisticated approach, using multiple regression statistical analysis shows that they are distinct and biochemically separable events.
a) The Feeling of Low Energy.
The feeling of being low in energy and “run down” was associated with problems with memory, prolonged sleep, muscle weakness, headaches and neck pain. This was associated with alterations in the neutrophils, lymphocytes and an increased neutrophil : lymphocyte ratio.
This was also associated with a reduction in the excretion of succinic acid. This data suggests that the feeling of low energy was associated with dysregulation of citric acid cycle activity and possibly succinic acid electron transport functions. These alterations also appear associated with a non-viral pathogen immune response.
b) The Feeling of Mental Fatigue.
The reporting of mental fatigue was associated with trouble concentrating, paraesthesia, headache and the feeling of limb heaviness. An increase in urinary excretion of tyrosine and lysine was highly associated with this patient response and is highly suggestive of increased non-fibrillar proteolysis. This response appears to be a common host response to a number of different potential stimuli from cytokines, activation of RNase L through to the inclusion of persistent enteroviruses within tissues.
Lysine highly correlates with changes in urea cycle activity and may be associated with dysregulation of nitric oxide metabolism. This type of alteration is distinct from that noted for the reporting of feeling low in energy and appears to represent a different process.
c. Muscle Fatigue
The reporting of muscle fatigue was associated with feeling low in energy, muscle twitches, and stress-related problems. This response was associated with increases in urinary citric acid, tyrosine, hydroxyproline and reduced succinic acid, glutamic acid and UM27. This response appears to be associated with dysregulation of non-fibrillar proteolysis and the citric acid cycle. This was associated with the feeling of low energy and the succinic acid excretion changes. It also was linked to additional biochemical changes suggesting that the response was highly associated but distinct.
d. Chronic Pain
The patient responses to the visual analogue pain scale of average pain intensity were associated with increases in total urinary metabolite excretion. This was suggestive of a low grade aminoaciduria as well as increased tyrosine, aspartic acid, serine and glutamic acid as well as a reduction in leucine. This data suggests that the non-fibrillar proteolytic changes associated with chronic pain are consistent with a host response and are consistent with reports of reduce total muscle protein and RNA noted in both chronic pain and CFS patients. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
e. Conclusions
It was found that different fatigue and pain measurement data were highly supportive of a series of common host responses to any of a number of different stimuli. The current definitions are not standardised for these measures and do not require their separation as different symptoms.
McGregor NR, Dunstan RH, Butt HL, Roberts TK, Klineberg IJ
Although it has been proposed that CFS has a viral origin and claims of improved symptoms after antiviral treatment have been made, no consistent single viral agent has been found. However, increased prevalence of the reactivation of multiple viruses has been detected. In addition, increases in the 2,5A synthetase RNase L pathway associated with reactivated Herpes simplex-6 (HSV-6) have also been found in CFS patients. However, when CFS patients were tested for evidence of viral associated changes in lipid metabolism, no evidence for a single entity was found.
a. Viral Reactivation
The reactivation of the persistent herpes family of viruses may be the result of increased protein turnover and is therefore likely to be a secondary phenomenon. Interestingly, analysis of lipid metabolism alterations associated with EBV antigen has linked EBV early antigen with a change in lipid metabolism. This was found to be unique to defined CFS patients, but unrelated to the difference between CFS patients and controls.
One marker for post EBV syndrome is a reduction in the oleic : linoleic fatty acid ratio. This ratio was not found to be different between CFS patients and controls but was reduced in those subjects who reported evidence of EBV activity at onset. This fatty acid ratio was not associated with any EBV antigen, but was associated with a reduction in lymphocyte mitogen responses. This suggests that the susceptibility to post EBV fatigue may be the result of host susceptibility or other acquired event, and not an EBV associated event.
Recurrent aphthous ulceration in CFS patients was found to be consistent with the reactivation of dormant viruses. This was associated with an increase in certain symptoms in both CFS and non-CFS patients, which were independent of those defining CFS.
Therefore, reactivation of the herpes family viruses is likely to increase the numbers of symptoms and may confound the ability to diagnose the CFS initiating disease entity. Research data strongly suggests that increased herpes family viral reactivation in defined CFS patients is consistent with a secondary phenomenon, and not a primary cause. It must be remembered that this does not exclude the existence of post-EBV or post CMV fatigue-syndromes, which would need to be excluded under the current definitions.
b) Persistent Enteroviruses
The infection of tissues by RNA viruses (eg enteroviruses) may result in a persistent increase in proteolysis and a continual pain fatigue syndrome. This may implicate enteroviruses in the development of a type of chronic fatigue disorder that could comply with the current definition of CFS.
Bacterial Toxicity and Fatigue/Pain Disorders
McGregor NR, Dunstan RH, Butt HL, Roberts TK, Klineberg IJ
An increased prevalence of toxic staphylococci bacteria was found in patients who reported chronic pain and/or chronic fatigue. Two particular membrane-damaging toxins were associated with symptom expression: delta-haemolysin and "horse red blood cell" haemolysin. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
In facial muscle pain patients, increases in the toxicity of these two staphylococcal haemolysins were associated with increased fibrillar and non-fibrillar proteolysis. This was evidenced by increased excretion of 3-methylhistidine and tyrosine, as well as increased reporting of pain scores, cardiac palpitations, chest pain, irritable bowel, muscle fatigue and feverishness/night sweats.
*** ( Comment: I think that it is very important to note that those control subjects who did not report any musculoskeletal symptoms or fatigue did not carry these organisms at detectable levels. - Frank Bartosy )***
Therefore, the carriage of toxic commensal organisms does initiate increases in proteolysis and may act to initiate reactivation of herpes family viruses. CFS outbreaks, such as those in Incline village where high levels of reactivation of HSV-6 were found, may be the result of the acquisition of low-grade toxic organisms such as staphylococcus, which in turn may facilitate HSV-6 reactivation.
Conclusions
Defined CFS appears to be a heterogeneous group of conditions, which has occurred as a result of lack of standardisation of the components of the definition and the reliance upon host responses as the primary defining symptoms. Close examination of the available data can allow diagnosis of a number of different fatigue-associated disorders, which are currently defined as "CFS".
© CPRU and F Bartosy 1999
References:
1. Wilson JC, Walker PJ. Acute anterior poliomyelitis: orthopaedic aspects of the California outbreak of 1934. Arch Intern Med 1936; 57:477-91.
2. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: A working case definition. Ann Intern Med 1988; 108:387-389.
3. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med 1994; 121:953-959.
4. Hickie I, Lloyd A, Hadzi-Pavlovic D, Parker G, Bird K, Wakefield D. Can the chronic fatigue syndrome be defined by distinct clinical features ? Psych Med 1995; 25:925-35.
5. Mortimore GE, Poso AR. Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu Rev Nutr 1987; 7:539-64.
6. Goodman MN. Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 1994; 205:182-5.
7. Balavoine S, Feldmann G, Lardeux B. Regulation of RNA degradation in cultured rat hepatocytes: effects of specific amino acids and insulin. J Cell Physiol 1993; 156:56-62.
8. McGregor NR, Dunstan RH, Butt HL, Roberts TK, Zerbes M, Klineberg IJ. Chronic Facial Muscle Pain and Dysregulated Cellular Proteolysis The clinical and scientific basis of Chronic Fatigue Syndrome: from myth towards management. International Meeting for Clinicians and Scientists. 1998 The University of Newcastle and Combined CFS Consumer Groups.
9. Suhadolnik RJ, Reichenbach NL, Hitzges P, et al. Upregulation of the 2-5A Synthetase/RNase L pathway associated with chronic fatigue syndrome. Clin Infect Dis 18:S96-S104,1994.
10. Stayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a specifically configured RNA drug, Poly(I)-Poly(C12U), in chronic fatigue syndrome. Clin Infect Dis 18:S88-S95, 1994.
11. Sharpe MC, Archard LC, Banatvala JE, et al. A report - Chronic fatigue syndrome: guidelines for research. J Roy Soc Med 84:118-121, 1991.
12. Levy JA. Viral Studies of chronic fatigue syndrome. Clin Infect Dis 1994; 18:S117-S120. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: A working case definition. Ann Intern Med 108:387-389, 1988.
13. Natelson BH, Ye N, Moul DE, et al. High titers of anti-Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness. J Med Virol. 1994; 42:42-46.
14. Woodward CG, Cox RA. Epstein-Barr virus serology in the chronic fatigue syndrome. J Infect 1992; 24:133-9.
15. Neil R. McGregor, R. Hugh Dunstan, Timothy K. Roberts, Mark Donohoe, Jennifer A. Watkins, Henry L. Butt, Raymond N. Murdoch. Classification of chronic fatigue syndrome patients by assessing plasma lipid homeostasis. The clinical and scientific basis of Chronic Fatigue Syndrome: from myth towards management. International Meeting for Clinicians and Scientists. 1998 The University of Newcastle and Combined CFS Consumer Groups.
16. Neil R. McGregor, R. Hugh Dunstan, Timothy K. Roberts, Mark Donohoe, Jennifer A. Watkins, Henry L. Butt, Raymond N. Murdoch. Assessment of Lipid Homeostasis in sudden and gradual onset chronic fatigue syndrome patients. The clinical and scientific basis of Chronic Fatigue Syndrome: from myth towards management. International Meeting for Clinicians and Scientists. 1998 The University of Newcastle and Combined CFS Consumer Groups.
17. McGregor NR, Dunstan RH, Donohoe M, Roberts TK, Butt HL, Watkins J, Murdoch RN. Assessment of plasma saponified lipid fractions and ratios in relationship to Epstein Barr virus antibody titres in patients reporting sudden-onset chronic fatigue. The clinical and scientific basis of Chronic Fatigue Syndrome: from myth towards management. International Meeting for Clinicians and Scientists. 1998 The University of Newcastle and Combined CFS Consumer Groups.
18. McGregor NR, Butt HL, Dunstan RH, Roberts TK, Klineberg IJ. Aphthous ulceration and symptoms in polysymptomatic and defined chronic fatigue syndrome patients. The clinical and scientific basis of Chronic Fatigue Syndrome: from myth towards management. International Meeting for Clinicians and Scientists. 1998 The University of Newcastle and Combined CFS Consumer Groups.
19. Cunningham L, Bowles NE, Archard LC. Persistent virus infection of muscle in postviral fatigue syndrome. BMB 1991; 47:852-71.
20. Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L, Archard LC. Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy. J Med 1993; 24:145-60.
21. Butt HL, Dunstan RH, McGregor NR, Roberts TK, Zerbes M, Klineberg IJ (1998). An association of membrane damaging toxins from coagulase negative staphylococcus and chronic orofacial muscle pain. J Medical Microbiology (In Press).
22. McGregor NR, Butt HL, Dunstan RH, Roberts TK, Zerbes M, Klineberg IJ. Toxic coagulase negative staphylococci are associated with changes in urinary organic and amino acid excretion in chronic facial muscle pain patients. The clinical and scientific basis of Chronic Fatigue Syndrome: from myth towards management. International Meeting for Clinicians and Scientists. 1998 The University of Newcastle and Combined CFS Consumer Groups.
For more information, please refer to:
The conference abstract: "Host versus acquired responses in defined CFS patients".
Note: The above article is an edited and simplified version of the excellent document: "Host verses Acquired Responses in Chronic Fatigue Disorders" by Neil R McGregor. (This is based on the conference abstract: "Host versus acquired responses in defined CFS patients".)
Back to [ top ]
Home | Background | Researchers | What are chronic fatigue/pain disorders? | Bioscreen Research | Tests and Treatments | Bioscreen Tests Articles | News and Notices | Book | Book Extracts and Articles | New Book | Extracts
© Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Apart from fair dealing as permitted under the Copyright Act, no portion of the contents of this site may be reproduced in any way without prior written permission. All rights reserved.
Disclaimer: The information on this site is based on theorectical and practical research work and experimental treatment and management protocols. There can be no guarantees, either implied or given, that these treatments will definitely be of benefit to everyone. In addition, some people may experience unknown side-effects. We cannot accept any responsibility, legal or otherwise, if the contents of this website adversely influences any person's health or treatment options. All treatments should be closely supervised by a competent and qualified doctor.