“Mainstream” medicine is doing a very poor job at treating these diseases because standard laboratory test are usually normal, there is no simple treatment that works for all patients and they cannot be cured in the eight minute standard visit. Consequentially, millions of patients with chronic fatigue syndrome and fibromyalgia have gone without comprehensive treatments and have had to suffer for years with a poor quality of life. Even though these are complex diseases, the physiological causes underlying these conditions can usually be uncovered with specialty testing and then multi-faceted treatment protocols that address the numerous physiologic dysfunctions are successful. The doctors are committed to reversing these devastating illnesses.

back to top

The study product is free of charge. You don’t have to be a patient to enroll (product is shipped), and there is no obligation other than accurately reporting your response

Study Name: THE ROLE OF D-RIBOSE IN PATIENTS DIAGNOSED WITH FIBROMYALGIA

ENROLLMENT CRITERIA

INCLUSION:

• Adults between 18-78 years of age
• Previous diagnosis of fibromyalgia by a physician, (ACR guidelines)
• Completion a questionnaire for major and minor diagnostic criteria for CFS/Fibromyalgia symptoms and whether a diagnosis of CFS exists
• Signed informed consent form

INTRODUCTION
Fibromyalgia is a chronic pain syndrome, which has been described in the literature for over 200 years. It is believed that fibromyalgia may affect millions of individuals in the United States alone. Fibromyalgia, as defined by the American College of Rheumatology, includes: diffused widespread pain, presence of multiple tender points, sleep disturbances, fatigue, reduced exercise tolerance, and irritable bowel syndrome.

Previous research involving muscle biopsies of tender points/sites, analyzed for high-energy phosphate levels, mainly adenosine triphosphate (ATP), revealed decreased energy compounds, suggesting a metabolic abnormality². Therefore, some have argued that by replenishing these decreased energy levels, symptoms may be lessened or alleviated. D-ribose, a naturally occurring pentose sugar, aids in the formation of adenine nucleotides, via an intermediate compound called phosphoribosyl-1-pyrophosphate (PRPP), which is essential for de novo synthesis and salvage of nucleotides 5.

Since the majority of fibromyalgia patients complain of chronic fatigue and with the possibility that reduced ATP levels are present at points of tenderness, supplementation of D-ribose may offer a clinical benefit in lessening or relieving symptoms to improve ones quality of life.

OBJECTIVES
The goal of this study is to determine the potential benefit of D-ribose versus placebo in patients afflicted with the diagnosis of fibromyalgia. Endpoints of this study will assess levels of relief in symptoms of fatigue and pain, as well as potential benefits in their quality of life, assessed by questionnaires.

Summary of Objectives:

• Demonstrate a significant reduction in the symptoms of pain and fatigue
• Demonstrate an improvement in ones quality of life

back to top

1.Clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that is of new or definite onset (has not been 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. Concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue:

A. Self-reported impairment in short term memory
B. Sore throat
C. Tender cervical or axillary lymph nodes
D. Muscle pain
E. Multijoint pain without joint swelling or redness
F. Headaches of a new type, pattern, or severity
G. Non refreshing sleep
H. Postexertional malaise lasting more that twenty-four hours

Problem with the definition is that it is a research definition and excludes many people with the syndrome.

back to top

A history of widespread pain. The patient must be experiencing pain or achiness, steady or intermittent, for at least 3 months. At times, the pain must have been present:

A. On both sides of the body
B. Both above and below the waist
C. In the Mid-body-for example, in the neck, midchest, midback, or headache.
D. Pain on at least eleven of the eighteen tender points

Problem with the definition is that it is a research definition and excludes many people with the syndrome. 

back to top

1. Disordered sleep
2. Hormonal deficiencies (not picked up on standard blood tests)
3. Nutritional deficiencies
4. Infections
5. Mitochondrial dysfunction

back to top

Associated Conditions

• Chronic Sinusitis
• Multiple Chemical Sensitivity (MCS)
• Sensitive to medications
• Allergies
• Sensitivity to temperature or barometric changes
• Intolerant to alcohol
• Hypoglycemia
• Dizziness
• Low blood pressure
• Low grade fevers
• Heart palpitations
• Frequent infections
• Irritable Bowel Syndrome
• Vulvadynia
• Headaches (migraine and tension)
• Depression
• Autoimmune diseases (lupus, RA)
• Restless Leg Syndrome
• Weight Gain
• Increased thirst
• Low body temp
• Insulin resistance
• Yeast overgrowth
• Carpal tunnel syndrome
• Painful or irregular menstrual periods
• Extreme exhaustion
• Sleep disturbances
• Brian fog
• Shortness of breath
• Confusion with numbers, names, words etc.
• Mood swings
• Numbness or tingling

back to top

back to top

Component Six:
Maintenance Here is where the patient is weaned to just a few core medications and supplements to remain symptom free and maintain their health. Significant recovery or complete resolution of symptoms is the rule rather than the exception when a multifaceted treatment plan is instituted.

back to top

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are illnesses that often coexists and affect millions of Americans. Symptoms vary amongst individuals and commonly include severe fatigue, sleep disturbances, cognitive problems, commonly called brain fog, muscle pain and multiple infections. Unfortunately, many individuals and physicians continue to deny that these syndromes are legitimate diseases. The medical literature is, however, very clear that these are legitimate diseases and individuals with these syndromes have measurable hypothalamic, pituitary, immune and coagulation dysfunction. These abnormalities then result in a cascade of further abnormalities, in which stress plays a role by suppressing immunity and hypothalamic-pituitary function. The pituitary and hypothalamic dysfunction results in multiple hormonal deficiencies that are often not detected with standard blood tests, as well as autonomic dysfunction, including neutrally mediated hypotension. The immune dysfunction, which includes natural killer cell dysfunction, results in opportunistic infections and yeast overgrowth, making the symptoms worse. Recent studies have shown that the coagulation dysfunction is usually initiated by a viral infection and has genetic predisposition. This abnormal coagulation results in increased blood viscosity (slugging) and a deposition of soluble fibrin monomers along the capillary wall. This results in tissue and cellular hypoxia, resulting in fatigue and decreased cognition (brain fog). Neurotransmitter abnormalities and macro and micro nutrient deficiencies have also been shown to occur with these disorders.

Current research suggests that many triggers can initiate a cascade of events, causing the hypothalamic, pituitary, immune and coagulation dysfunction. The most common initiating cause is a viral or bacterial infection, which is very commonly Epstein Bar Virus (EBV), Cytomegalovirus (CMV), HHV6, mycoplasma, Chlamydia pneumonia or Lyme’s disease. When specialized testing is utilized, these infections are found in 30-80% of CFS and FM patients. Many people with these syndromes can pinpoint the start of their disease to a viral infection that never got better usually during significant life stressors.

Effective treatment, with 70 to 90 percent of individuals achieving significant clinical benefits, can be achieved by simultaneously treating the above problems that an individual is found to have. The mix of treatments needed varies from patient to patients, but there is consistent abnormal pathophysiology. For instance, a high percentage of individuals with these syndromes have low thyroid. This is, however, usually not picked up on the standard blood tests because the TSH is not elevated in these individuals because of the pituitary dysfunction. Many of these individuals will also have high levels of the anti-thyroid reverse T3, which is usually not measured on standard blood tests. In addition, the majority of individuals can also have a thyroid receptor resistance that is not detected on the blood tests. Consequently, thyroid treatment, especially with timed release T3 is effective for many patients. T4 preparations (inactive thyroid) such as Synthroid and Levoxyl do not work well for these conditions. In addition, adrenal insufficiency and growth hormone deficiency are also very common with these disorders, and supplementation with these hormones can often have profound effects. As with thyroid testing, these deficiencies are, unfortunately, usually not detected with the standard screen blood tests and require more specific testing.

When an individual is found to have one of the viruses discussed above, these can be treated with resulting improvement in symptoms. It can require a combination of medications, supplements and sometimes intravenous treatments to eradicate some of the persistent infections.

Although a concept that is sometimes uncomfortable and foreign to traditional medical styles of thinking, the need for multiple interventions is required for effective treatment of an illness that affects a critical control center (such as the hypothalamus), which impacts the multiple systems noted above. Unfortunately, there is not a single treatment that reverses hypothalamic dysfunction directly. Thus, this situation is different from illnesses that affect a single target organ and which can be treated with a single intervention. For example, pituitary dysfunction itself often requires treatment with several hormones. This effect is multiplied in hypothalamic dysfunction, which affects several critical systems in addition to the pituitary gland. An integrated treatment approach based on simultaneously treating the above problems is significantly beneficial in CFS and FMS. Individuals with these devastating syndromes can “get their lives back” despite the fact that they were previously told, “There is nothing that can be done,” or “It is all in your head.”

back to top

There is mounting evidence that there is low thyroid activity present in the majority of chronic fatigue syndrome and fibromyalgia patients. Studies demonstrate that in addition to an increased incidence of primary hypothyroidism in chronic fatigue syndrome and fibromyalgia, there is a combination of secondary, tertiary and thyroid resistance in the overwhelming majority of CFS and FM patients, despite having normal thyroid tests because these latter forms of tissue hypothyroidism are not detected by standard thyroid function tests. Thus, many chronic fatigue syndrome and fibromyalgia patients are erroneously told over and over that their thyroid levels are fine.

The combination of factors present in chronic fatigue syndrome and fibromyalgia, including hypothalamic and pituitary dysfunction, diminished T3/rT3 production ratios and thyroid resistance, results in most, if not all, chronic fatigue syndrome and fibromyalgia patients having inadequate tissue thyroid effect. T4 preparations such as Synthroid and Levoxyl rarely work and Armour thyroid, a pig glandular product, is somewhat better, but definitely not adequate for most patients. The treating physician must know when to use a T4/T3 combination or straight T3. T3 works the best for many of these patients, but Cytomel, a very short acting T3 available at normal pharmacies, is also a poor choice because the varying blood levels can cause significant side effects. Compounded timed release T3 is usually the best treatment. However, to achieve significant improvement, the treating physician must be very knowledgeable about T3 and must realize that when on T3, standard bloods blood test will lead one to dose incorrectly and not obtain significant benefits. This includes doctors who previously felt that they were thyroid experts and had been using thyroid with in chronic fatigue syndrome and fibromyalgia for a long time. Ultimately, it is the expertise and dosing of the T3 or T4/T3 combinations and the makeup of the medications that determines the optimal treatment regimen and is one major component in the treatment of in chronic fatigue syndrome and fibromyalgia.

back to top

Points addressed:

• A review of the literature regarding evidence of significant hypothalamic-pituitary-adrenal axis (HPA) dysfunction in CFS and FM.
• Indications and efficacy of treatment with physiological doses of cortisol
• Expected risks and benefits of such treatment

Abstract:

There is clear evidence that adrenal axis dysfunction is present in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM) 1-21,23-28 and that treatment with low physiologic doses of cortisol have been shown to be safe, appropriate and effective.8,9,10,23,30 It should be considered the standard of care to treat patients with CFS and FM who have baseline cortisol levels under 12 ug/ml.8,9,10,31,32,33

Evidence for significant HPA axis dysfunction with resultant adrenocortical dysfunction:

A study published in the Annals New York Academy of Sciences entitled Evidence for and Pathophysiologic Implications of Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Fibromyalgia and Chronic Fatigue Syndrome discussed the evidence for HPA axis insufficiency in CFS and FM. They conclude, “Our group has established the impaired activation of the hypothalamic-pituitary-adrenal axis is an essential neuroendocrine feature of this condition.” 27

Cleare et al published a study in the American Journal of Psychiatry that obtained 24-hour urine collections from 121 consecutive patients with CFS. They found low 24 hour cortisol levels in all of the CFS patients. The authors conclude, “Urinary free cortisol was significantly lower in the subjects with chronic fatigue syndrome regardless of the presence or absence of current or past comorbid psychiatric illness…From whatever cause, low circulating cortisol is associated with fatigue; furthermore, raising cortisol levels can reduce fatigue in chronic fatigue syndrome. Thus, this study provides further evidence that adrenocortical dysfunction in chronic fatigue syndrome, whatever the etiology and whether primary or secondary, may be one piece of the multifactorial jigsaw underlying the production of symptoms in chronic fatigue syndrome.” 7 The authors agree that treating this adrenocortical dysfunction with cortisol replacement is a fundamentally necessary part of the appropriate multi-system treatment of this condition.

Another study published in the Journal of Endocrinological Investigation performed a combination of stimulation tests on FM patients. They found over 95% of these patients had HPA axis dysfunction.3 They state, “The etiology and pathophysiology of this disease is not fully understood but the current data suggests that the PFS [Primary Fibromyalgia Syndrome] is not a primary disease of muscle. In contrast, an increasing amount of evidence suggests that the central stress axis, the HPA axis, seems to play an important role in the development of PFS…This study clearly shows that the HPA axis is underactivated in PFS...” 3

Trophy et al. administered interleukin-6 (IL-6), which is a potent stimulator of the HPA axis, and measured plasma ACTH and cortisol levels. They found a delayed ACTH response in these patients, which is consistent with a defect in the hypothalamic CRH neuronal function as an etiology of symptoms in these patients.2

Cortisol levels normally increase with pain, but it has been shown that patients with CFS and FM either cannot appropriately increase cortisol production with pain or the inability to increase cortisol causes the increased pain. A study published in the November 2005 Journal Arthritis and Rheumatism demonstrated this strong relationship between cortisol levels and pain in individuals with CFS and FM and that low cortisol levels alone explained 38% of the variation in pain upon waking. The authors conclude, “The results of this study indicate that pain symptoms in women with FM are associated with cortisol concentrations during the early part of the day…These data support the hypothesis that HPA axis function is associated with symptoms in FM and accounts for the substantial percentage of pain symptom variance during the early part of the day.” 28

A study published in the Brazilian Journal of Infectious Disease (figure 2) demonstrates that in this type of patient population a baseline cortisol level of less than 12 has a specificity of greater than 90% for adrenocortical dysfunction and a level less than 10 ug/dl has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study, as well as by others, is 12 ug/dl.31,33 In addition, a normal ACTH does not rule-out secondary hypoadrenalism, but an abnormally low or low normal ACTH level can be considered confirmatory.

A study published in the Brazilian Journal of Infectious Disease (figure 2) demonstrates that in this type of patient population a baseline cortisol level of less than 12 has a specificity of greater than 90% for adrenocortical dysfunction and a level less than 10 ug/dl has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study as well as by others is 12 ug/dl.31,33 In addition, a normal ACTH does not rule-out secondary hypoadrenalism, but an abnormally low or low normal ACTH level can be considered confirmatory.

Dynamic testing:

Dynamic testing is certainly useful in straight forward primary and secondary adrenal insufficiency, but in patients with CFS, there is a complex interaction of hypothalamic and pituitary dysfunction. This results in a complex response that is initially elevated and then blunted, resulting in what is thought to be conflicting results, depending on which stimulation test was used, how an abnormal is defined and whether or not ACTH/cortisol ratios were used. 1,3,8,9,19,34-39 Consequently, the standard criteria does not apply to these patients significantly reducing the usefulness of dynamic testing with CFS and FM.1,9,19,27,34-39

It has been shown that a single ACTH stimulation test misses the majority of FM/CFS patients that have adrenocortical deficiency, but when a combination of stimulation tests are used, such as metyrapone test, or more sophisticated analysis is used, close to 100% of these individuals have documented adrenocortical dysfunction.1,3,8,9,19,27,34-39

Numerous studies demonstrate that this lack of sensitivity likely explains the seemingly contradictory findings between studies using stimulation tests.1,3,8,9,19,27,34-40 For instance, Scott et al in Clinical Endocrinology did 1ug ACTH stimulation tests on subjects with CFS and found a significant decrease in the delta cortisol value of patients with CFS vs. normals, but found that the reliance on this test and the arbitrary cutoffs that apply significantly impacts the sensitivity of stimulation tests in the patient population. They conclude, “In conclusion, the amount of cortisol released following stimulation with 1ug ACTH, is lower in CFS patients than in healthy volunteers…We propose, as has been suggested from previous studies, that the abnormality of HPA regulation is more likely to be central in origin. The demonstration of low basal ACTH in our CFS cohort would have supported this view…There is considerable debate surrounding the optimal dose of ACTH to use, with concern that the 250 mcg dose is “superphysiologic’ and may produce cortisol responses in patients suspected of having pituitary adrenal insufficiency that are falsely reassuring...Disparities between our healthy volunteer data and those of other groups using the 1 microgram ACTH test suggest that the test may not be as reliable as previously indicated…replacement therapy may more appropriately involve not only glucocorticoid, but mineralcorticoid supplements also.” 19

Another study that clearly demonstrates this confusion and that standard stimulation tests are not a reasonable method of evaluation of adrenal-cortical dysfunction is published in the Journal of Clinical Endocrinology and Metabolism entitled Evidence for Impaired Activation of the Hypothalamic Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome. The study found that compared to normal individuals, CFS patients were shown to have significantly reduced basal glucocorticoid levels (average 89 vs 148 nmol/l) and a low 24 hour urinary free cortisol excretion (122.7 nmol/L vs 203 nmol/L). The level of cortisol binding globulin CBG was also significantly higher in CFS patients making the free cortisol index lower in the patients (2.9 vs 8.9). There was a significant attenuated net integrated ACTH response to CRH but there was an initial increased initial sensitivity to ACTH with a reduced maximal response.1

Although this cortisol response to ACTH is clearly abnormal for all of the patients with CFS, the dose response curve varies. There is an initial exaggerated response followed by an abnormally blunted response, which is not the case for patients with primary or secondary adrenocortical insufficiency without a dysfunctional hypothalamus. Consequently, standard dynamic testing is not medically useful in these patients and it is improper to use the defined normal cutoffs of response as is done with other conditions. This has been demonstrated in other studies as well.1,3,8,9,19,27,34-39

Kirnap et al in a study published in Clinical Endocrinology compared standard and low dose ACTH stimulation tests on patients with primary fibromyalgia syndrome (PFS). They found a significantly reduced peak cortisol response in the PFS verses controls. They also found that if the standard cutoff of 550 nmol/l was used with the standard ACTH stimulation, many of the patients would have misdiagnoses as normal.4

There are a number of theories that have been postulated to explain such a response. The author of this study postulates that this is due to a lack of CRH (corticotrophin releasing hormone) with a secondary hyperresponsivness from inadequate levels of ACTH. They alternatively state that this HPA axis defect could be secondary to a chronic viral infection.

Treatment:

Further supporting the use of low dose cortisol in these patients is the fact that such treatment has been shown to improve the HPA axis response in these patients. This is counterintuitive to what physicians are taught and have found with higher pharmacological doses of glucocorticoids. In a study published in the 2001 Journal of Clinical Endocrinology & Metabolism entitled Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy, the authors utilized ACTH and cortisol responses to CRH, insulin stress test, D-fenfluramine and 24 hour urinary free cortisol in 37 patients with CFS and treated these patients with low dose cortisol. They found that the treatment resulted in significant improvement and not only was there no adrenal suppression, but rather there was an improvement in the HPA axis as documented with CRH testing. They concluded, “In this group, there was a significant increase in the cortisol re¬sponse to human CRH, which reversed the previously ob¬served blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone (same as cortisol) treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.” 8

In a randomized, double-blind, placebo controlled, crossover, intent to treat trial published in The Lancet, patients with chronic fatigue syndrome were treated with low dose hydrocortisone (5-10 mg/day) or placebo. The study found significant improvements in those treated with low dose hydrocortisone vs. placebo and 28% improved to normal levels. The authors concluded, “This study shows that low-dose hydrocortisone results in significant reduction in self-rated fatigue and disability in patients with chronic fatigue syndrome…The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone.” 9 This demonstrates the effectiveness and appropriateness of this treatment.

Another randomized control trial published in JAMA also found significant improvement in fatigue scores with hydrocortisone replacement, but they used excessive dosing of 25-35 mg of cortisol. It is recommended that dosing be limited to 5-15 mg/day, as these doses have been shown to not be associated with any untoward effects and carries little to no risk of adrenal suppression.10,23,30,31 This considerable safety and negligible risk is also confirmed in endocrinology texts.54

Bashetti has published a number of studies on cortisol and CFS. He writes in the Journal of Endocrinology and Metabolism, “Hydrocortisone, the glucocorticoid that is routinely prescribed to correct the chronic cortisol deficiency of patients with Addison’s disease, has recently been confirmed to be significantly effective also in the treatment of chronic fatigue syndrome (CFS). This comes as no surprise if we consider that CFS and Addison’s disease share 26 features.” 41

A randomized, double blind placebo-controlled, intent to treat study by Teitelbaum published in the Journal of Chronic Fatigue Syndrome documented the effectiveness of an integrative treatment approach to CFS and FM that includes low dose cortisol (7.5-20 mg/day). The authors conclude,” Significantly greater benefits were seen in the active group than in the placebo group for all primary outcomes. Using an integrated treatment approach, effective treatment is now available for FMS/CFS .” 31

A subsequent editorial in the peer reviewed, Journal of the American Academy of Pain Management reviewed this study and agreed that an integrative approach that includes low dose cortisol is the standard of care for these conditions. The author states, “The study by Dr. Teitelbaum et al. and years of clinical experience makes this approach an excellent and powerfully effective part of the standard of practice for treatment of people who suffer from FMS and MPS [myofacial pain syndrome]— both of which are common and devastating syndrome.” 48 The consensus opinion among those who are experts in the treatment of CSF and FM is that a treatment approach that includes low-dose cortisol is the standard of care.

A subsequent commentary by Teitelbaum published in JAMA states, “Our previously published pilot study and the work of Jefferies suggests that using low-dose hydrocortisone in CFS as dosages of 7.5 mg to 20 mg/day is safe and effective. These low dosages have not caused adrenal suppression…We recently completed a randomized, double-blind study that tested the effectiveness of treating patients with fibromyalgia and CFS for hypothalamic dysfunction in an integrated manner. This included treating suspected hormonal deficiencies (including low hydrocortisone) and the sleep disorder simultaneously. Using this protocol in 72 patients resulted in a significant improvement in active vs. placebo group.” 42 Cortisol replacement appears to be an essential part of a comprehensive treatment approach that can be used successfully in the treatment of CFS and FM.31,42

A study published in JAMA found that nearly half of the patients treated with mineralcorticoid reported complete or nearly complete resolution of CFS symptoms.43

The safety of low dose glucocorticoids was addressed in a 48 page review article published in last month’s Annals of Rheumatic Diseases entitled Low-dose glucocorticoid therapy in rheumatoid arthritis - A review on safety: published evidence and prospective trial data. This extensive review assessed the incidence and severity of adverse effects of long-term low-dose glucocorticoid therapy in rheumatoid arthritis. This review considered low dose as any dose below or equivalent to 40 mg hydrocortisone (this patient received a fraction of this dose 10mg/day).  They concluded, “Adverse-effects of glucocorticoids are abundantly referred to in literature. However, in the available literature on low-dose glucocorticoid therapy very little of the commonly held beliefs about their incidence, prevalence and impact of GC [glucocorticoid] proved to be supported by clear scientific evidence. Additional data from the randomized controlled clinical trials reviewed showed that the incidence, severity and impact of adverse effects of low dose glucocorticoid therapy in rheumatoid arthritis trials are modest, and often not statistically different to those of placebo.” 10

Low dose cortisol has been shown to improve immunity, as opposed to the well known immunosuppressive effect of pharmacological doses of glucocorticoids, 23,30,45,46 and has been shown to improve recovery from chronic infections such as EBV.47,22,29

In summary, it is becoming clear that the majority of patients with CFS and FM suffer from clinically significant adrenocortical dysfunction and that physiologic replacement of cortisol is an appropriate intervention in these patients. Cortisol doses of 5-15 mg/day have been shown to be safe, with little associated risk including adrenal suppression, and have the potential for significant clinical benefit. The current evidence supports the use of physiologic doses of cortisol in the treatment of CFS and FM, and a therapeutic trial of cortisol should be considered in these patients, especially those with basal cortisol levels less than 12 ug/dl.

1. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP, et al. Evidence For Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients With Chronic Fatigue Syndrome. J Clin Endocrinol Metab 1991;73:1224-1234.
2. Torpy DJ et al. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6 in fibromyalgia. Arthritis and Rheumatism. 2000; 43: 872-880.
3. Calis M, Gokce C. Investigation of the hypothalamo-pituitary-adreanl axis (HPA) by 1ug ACTH test and metyrapone test in patients with primary fibromyalgia syndrome. J Endocrinol Invest 2004 27:42-46
4. Kirnap M, Colak R, Eser C, Ozsoy O, Tutus A, Kelestimur F. A comparison between low-dose (1 microg), standard-dose (250 microg) ACTH stimulation tests and insulin tolerance test in the evaluation of hypothalamo-pituitary-adrenal axis in primary fibromyalgia syndrome. Clin Endocrinol (Oxf). 2001 Oct;55(4):455-9
5. Griep EN, Boersma JW, de Kloet ER. Altered Reactivity of the Hypothalamic-Pituitary-Adrenal Axis in the Primary Fibromyalgia Syndrome. J Rheumatol 1993;20:469-74
6. Jens Gaab, PhD, Dominik Hüster, MSc, Renate Peisen, MSc, Veronika Engert, BSc, Vera Sheitz, BSc, Tanja Schad, BSc, Thomas H. Schürmeyer, PhD, MD and Ulrike Ehlert, PhD. Hypothalamic-Pituitary-Adrenal Axis Reactivity in Chronic Fatigue Syndrome and Shealth Under Psychological, Physiological, and Pharmacological Stimulation. Psychosomatic Medicine 64:951-962 (2002)
7. Cleare AJ, Blair D, Chambers S, Wessely S, Urinary Free Cortisol in Chronic Fatigue Syndrome Am J Psychiatry 158:641-643, April 2001
8. Cleare A et al. Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy. The Journal of Clinical Endocrinology & Metabolism 2001. 86(8):3545–3554.
9. Cleare AJ et al. Low-dose hydrocortisone in chronic fatigue syndrome: a randomized crossover trial. Lancet 1999 Feb 6;353(9151):455
10. Gaab J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH, Ehlert U. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med. 2002 Mar-Apr;64(2):311-8
11. Altemus M, Dale JK, Michelson D, Demitrack MA, Gold PW, Straus SE. Abnormalities in response to vasopressin infusion in chronic fatigue syndrome. Psychoneuroendocrinology 2001 Feb 1;26(2):175-188
12. Scott LV, Svec F, Dinan T. A preliminary study of dehydroepiandrosterone response to low-dose ACTH in chronic fatigue syndrome and in healthy subjects. Psychiatry Res 2000 Dec 4;97(1):21-28
13. Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG. Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology 1999 Oct;24(7):759-68
14. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000 Jan;25(1)
15. Scott LV, Medbak S, Dinan TG. Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers. Biol Psychiatry 1999 Jun 1;45(11):1447-54
16. De Becker P, De Meirleir K, Joos E, Campine I, Van Steenberge E, Smitz J, Velkeniers B Dehydroepiandrosterone (DHEA) response to i.v. ACTH in patients with chronic fatigue syndrome. Horm Metab Res 1999 Jan;31(1):18-21
17. Z Crofford L. The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome. J Rheumatol 1998;57 Suppl 2:67-71
18. Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y, Kitani T. Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome. Int J Mol Med 1998 Jan;1(1):143-6
19. Scott LV, Medbak S, Dinan TG The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol (Oxf) 1998 Jun;48(6):733-7
20. Scott LV, Medbak S, Dinan TG. Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiatr Scand 1998 Jun;97(6):450-457
21. Strickland P, Morriss R, Wearden A, Deakin B A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls. J Affect Disord 1998 Jan;47(1-3):191-194
22. Bender CE. The value of corticosteroids in the treatment of infectious mononucleosis. JAMA 199;529, 1967
23. Jefferies W. Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story, Med Hypotheses, 1994, Issue: 3, Volume: 42, Page: 183-9, ISSN: 0306-9877
24. Cleare AJ; Bearn J; Allain T; McGregor A; Wessely S; Murray RM; O'Keane V. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome, J Affect Disord, 1995 Aug 18, Issue: 4 Volume: 34 Page: 283-9
25. Moutschen M; Triffaux JM; Demonty J; Legros JJ; Lefèbvre PJ; . Pathogenic tracks in fatigue syndromes Acta Clin Belg, 1994, Issue: 6 Volume: 49 Pagination: 274-89 ISSN: 0001-5512
26. Carruthers et al. Myalgic Encepalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome.Vol 11(1) 2003
27. Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci 1998 May 1;840:684-697
28. Samuel A. McLean,1 David A. Williams,1 Richard E. Harris,1 Willem J. Kop,2 Kimberly H. Groner,1 Kirsten Ambrose,1 Angela K. Lyden,1 Richard H. Gracely,1Leslie J. Crofford,3 Michael E. Geisser,1 Ananda Sen,1 Pinaki Biswas,1 and Daniel J. Clauw1. Momentary Relationship Between Cortisol Secretion and Symptoms in Patients With Fibromyalgia. Arthritis & Rheumatisim Vol. 52, No. 11, November 2005, pp 3660–3669
29. Manji RJ et al. Depression of cell-mediated immunity durng acute infectious mononucleosis. N Engl J Med 291:1149, 1974
30. Jefferies W. Cortisol and Immunity. Medical Hypotheses 1991;34:198-208
31. Teitelbaum J, Bird B, Greenfield R, Weiss A, Muenz L, Gould L. Effective Treatment of Chronic Fatigue Syndrome (CFIDS) & Fibromyalgia (FMS) - A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat Study. Journal of Chronic Fatigue Syndrome Volume 8, Issue 2 – 2001
32. Takeshita S et al. Intravenous immunoglobulin preparations promote apoptosis in lipopolysaccharide-stimulated neutrophils via an oxygen-dependent pathway in vitro. APMIS 2005:113:269-77.
33. Wolff FH, Nhuch C, Cadore LP, Glitx CL, Lhullier F, Furlanetto TW. Low-dose adrenocorticotropin test in patients with the Acquired Immunodeficiency Syndrome. Braz. J. Infect. Dis. Apr. 2001, vol.5, no.2
34. Tordjman K., Jaffe A., Grazas N. et al. The role of the low dose (1 mg) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995; 80:1301 5.
35. Dickstein G., Schechner C., Nicholson W.E., et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of the day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773-8
36. Crowley S., Hindmarsh P.C., Honour J.W., Brook C.G.D. Reproducibility of the cortisol response to stimulation with a low dose of ACTH (1-24): the effect of basal cortisol levels and comparison of low dose with high dose secretory dynamics. J Endocrinol 1993;136:167-72
37. Baraia-Etxaburu Artetxe J., Astigarraga Aguirre B., Elorza Olabegova R., et al. [Primary adrenal failure and AIDS: report of 11 cases and review of the literature]. Rev Clin Esp 1998;198:74-9.
38. Zarkovic M., Ciric J., Stojanovic M., et al. Optimizing the diagnostic criteria for standard (250-mg) and low dose (1-mg) adrenocorticotropin tests in the assessment of adrenal function. J Clin Endocrinol Metab 1999;84:3170-3.
39. Abdu TA, Elhadd T.A., Neary R., Clayton R.N. Comparison of the low dose short synacthen test (1 mg), the conventional dose short synacthen test (250 mg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 1999;84:838-43.
40. Courtney CH et al. Authors’ Response: HPOA Axis Testing after Pituitary Surgery. Journal of clinical Endocrinology and Metabolism 2005;90:6744
41. Riccardo Baschetti, M.D. Investigations of Hydrocortisone and Fludrocortisone in the Treatment of Chronic Fatigue Syndrome The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2263-2264
42. Teitelbaum et al. To the Editor re: McKenzie et al. Low-Dose Hydrocortisone for Chronic Fatigue Syndrome. 281 No. 20, May 26, JAMA,1999 Vol. 281 No. 20, May 26, 1999. JAMA May 26, 1999 (281)20:1888
43. Bou-Holaigah et al. the relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995;274:961-7
44. Bashetti R. hydrocortisone and chronic Fatigue Syndrome. Lancet 1999;353:1618
45. Grayson J et al. Immunoglobulin production induced in vitro by glucocorticoid hormones:T-cell dependent stimulation of immunoglobulin production without B cell proliferation in cultures of human peripheral blood lympocytes. J clin Invest 68:1539,1981
46. Jeroen TJ et al. Altered Glucocorticoid Regulation of the Immune Response in the Chronic Fatigue Syndrome. Annals of the New York Academy of Sciences 917:868-875 (2000)
47. Chappel MR. Infectious mononucleosis. Southwest Med 43:253,1962
48. Blatman H, Effective Treatment of Fibromyalgia and Mypfacial Pain Syndrome: A Clinician’s Perspective. Journal of the American Academy of Pain Management. April 2002.

>> click here to download

Numerous studies have demonstrated a high incidence of chronic infections in chronic fatigue syndrome and fibromyalgia. These include viral infections of Epstein bar (EBV), cytomegalovirus (CMV), human herpes virus-6, (HHV-6), and bacterial infections such as mycoplasma, chlamydia pneumonia (CP) and Borrelia burgdorferi (Lyme disease). There is controversy regarding the presence of active infection in these conditions because physicians, including infectious disease specialists, do not understand that the standard way to diagnose acute infections, an elevation of IgG and IgM antibodies, is not a sensitive means of detecting chronic infections in these patients (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21). With an acute infection, the body will start producing IgM antibodies against that infection and then start producing IgG antibodies after a few weeks so there is an elevation of both IgG and IgM antibodies. Chronic reactivating infection, such as those mentioned above, do not stimulate IgM antibodies as they are not new infections but rather intracellular reactivating infections, so most doctors, again including infectious disease specialists, will tell patients who have elevated IgG antibodies that they had an old infection or previous exposure and that there is no evidence of or they do not have an active infection because that is what they learned in medical school. This standard way of detecting active infections has clearly been shown to be inaccurate and miss the overwhelming majority of patients with active infections (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16, 17,18, 19,20,21).

Polymerase chain reaction (PCR) testing is much more sensitive in a research setting than in the clinical setting because if the blood sits for more than a few hours, the infectious organism’s DNA degrades and often goes undetected. In a clinical setting, it is a specific test (if it is positive you know you have an active infection), but suffers from low sensitivity (often negative despite an active chronic infection). Additionally limiting sensitivity is the fact these infections are not concentrated in the blood or serum but rather in the tissues, especially nerves, brain and the white blood cells. Physicians must have a high incidence of suspicion and look for elevated IgG or early antigen (EA) antibodies along with other signs of chronic infections including low natural killer cell activity, high RNAse-L activity, high ACE (> 35), coagulation activation, high tumor necrosis factor (TNF), low melanocyte stimulation hormone (MSH), high interleukin-6 (IL-6), low WBC, increased 1-25 vitamin D/1-25 vitamin D ratio and elevated or decreased total IgA, IgM or IgG levels. Chronic infections are almost always present in those whose symptoms started very acutely, especially with an infection, those who’s symptoms were ever associated with swollen lymph nodes or sore throat and those with significant cognitive dysfunction or flu-like symptoms. It must be remembered that in order to have the highest probability of successful treatment, a multi-system approach should be initiated (see new standard of treatment).

Herpes Viruses (Epstein Bar, Cytomegalovirus and HHV-6)

EBV, CMV and HHV-6 cause or contribute to the symptoms of a large percentage of CFS and FM patients. As stated previously, the presence of active infections correlate with an elevated IgG antibody, despite the lack of IgM antibodies (10,11,12,13,14,15,16,17,18,19,20,21). These infections are generally not acute but rather intracellular reactivation of an old infection, an elevation of IgM antibodies is typically not seen with active infections of EBV, CMV, HHV-6, (10-21). Due to the immune dysfunction seen in CFS, in addition to a lack of IgM antibody formation, there may also be a lack of IgG antibodies present despite the presence of an active infection in CFS patients (22,17,23). This has also been demonstrated to be the case with AIDS patients, as demonstrated in the study published in the New England Journal of Medicine entitled Absence of detectable IgM antibodies during cytomegalovirus disease in patients with AIDS (22). It has also been shown that the presence of antithyroid antibodies in CFS patients has a significant correlation with active HHV-6 infection (24).

A study published in Acta Pathologica, Microbiologica et Immunologica Scandinavica entitled Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of Chronic Fatigue Syndrome Patients: Association with Signs and Symptoms found 52% of CFS patients had active mycoplamsa infection, 30.5% had active HHV-6 infection, and 7.5% had Chlamydia pneumonia infections vs. only 6%, 9% and 1% of controls, respectively. They conclude, “The results indicate that a large subset of CFS patients show evidence of bacterial and/or viral infection(s), and these infections may contribute to the severity of signs and symptoms found in these patients (25).”

A study entitled A Chronic Illness Characterized by Fatigue, Neurological and Immunological Disorders, and Active Human Herpes virus Type 6 Infection published in the Annals of Internal Medicine found 70% of patients with CFS had active HHV-6 infection through the use of primary cell cultures and confirmation using assays of monoclonal antibodies specific for HHV-6 proteins and by PCR. Again, an elevation of IgM antibodies is generally not seen (26).

As summarized below, when specialized testing is used to detect active vs. past infection of HHV-6, the overwhelming number of studies demonstrate a high incidence of active herpes virus infections. These reactivation infections often do not illicit an IgG and especially not an IgM response, so standard serologic testing is specific but not sensitive for such infections. As mentioned before, PCR testing in a research setting is much more reliable, sensitive and useful than in the clinical setting when the blood is usually not processed for 12-48 hours.

Wagner et al, found that 61% of CFS patients with elevated IgG antibodies and 81% with immune deficiency, had confirmed active HHV-6 infection vs only 19% of those patients who did not (15). This is regardless of whether or not IgM antibodies were elevated.

Below is a summary of studies that have looked at the incidence of active HHV-6 infection in CFS/FM patients vs. controls, with 83% of the studies demonstrating a large portion of CFS/FM patients have and active HHV-6 infection.

A study by Lerner found that treating patients with 6 months of Valtrex resulted in a significant improvement in symptoms (46). In a separate study, Lerner et al found that in CFS patients with elevated IgG antibody against CMV, treatment with the intravenous antiviral ganciclovir, which has a more broad spectrum coverage than Valtrex and anti-CMV activity, resulted in 72% of patients returning to their premorbid health states (total resolution of symptoms)(47). A randomized, placebo controlled study published in Clinical Infectious Diseases, demonstrated that in CFS patients with an elevated IgG antibodies against CMV, a combination of oral Valtrex and intravenous ganciclovir resulted in dramatic improvements with almost complete resolution of symptoms (27).

Montoya et al at Stanford University treated chronic fatigue syndrome patients with 6 months of valganciclovir (Valcyte) if they had elevated IgG tests for HHV-6 and EBV and had at least 4 of the following symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression. Nine of the twelve treated patients (75%) “experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities.” In the nine patients with a symptomatic response to treatment, EBV VCA IgG and HHV-6 IgG titers significantly dropped. (21)

We have been using Valcyte in our center for the treatment of chronic fatigue syndrome for over 4 years and have found it to be effective, especially in patients with the flowing: flu-like symptoms or symptoms started with a flu-like illness; elevated IgG or EA against Epstein bar virus, cytomegalovirus and/or HHV-6; low natural killer cell activity; high RNAse-L activity; high ACE (> 35); coagulation activation; high tumor necrosis factor (TNF); low melanocyte stimulation hormone (MSH); high interleukin-6 (IL-6); low WBC; increased 1-25 vitamin D/25 vitamin D ratio and/or elevated or decreased total IgA, IgM or IgG levels.

This study contributes more confirmatory evidence that IgM antibodies are not typically elevated in chronic reactivating infections so most patients are incorrectly told they do not have an active infection based on such testing. This study also demonstrated the lack of sensitivity of standard PCR testing.

There is also evidence that CFS may be due to the above discussed infections with “stealth adaptation" (28,29,30,31,32,33,34,35,36,37,38). This is primarily due to the deletion of the genes coding for the major antigenic components normally targeted by the cellular immune system. “Stealth viral adaptation” results in replication that is less efficient than conventional viruses, but has a distinct advantage over conventional viruses in not having to confront the body's cellular immune defense mechanisms. They can, therefore, evade the immune system and create persistent ongoing infections in spite of an individual's intact immune system (28-38).

A number of studies have also shown dramatic improvement in patients with interferon treatments, especially those with low natural killer cell function, (39,40,41). While ganciclovir and interferon may be effective, their toxicity precludes their use and there are less toxic means of eradicating these infections.

Mycoplasma

Numerous studies have demonstrated a high incidence of active Mycoplasma infection in CFS and FM (1,44,45,46,47,48,49,50,51,52).Nijs et al published a study in the Journal Immunology and Medical Microbiology entitled High Prevalence of Mycoplasma infections among European Chronic Fatigue Syndrome Patients demonstrated that 68% of CFS patients had an active mycoplasma infection as diagnosed with specialized polymerase chain reaction (PCR) testing where the red and white cells were immediately lysed and centrifuged to concentrate and collect the DNA (1). Being predominantly intracellular, there is typically not a significant serologic antibody response or just an isolated IgG response with this number of other intracellular infections so IgG and especially IgM antibodies are almost always in the normal range despite the presence of an active infection (1,2,3,4,5,6,7,8,9).

This study and others discussed below demonstrated that IGM antibodies are not helpful in the diagnosis of an active infection in CFS and FM. Nijs et al stated, “Mycoplasma detection based on antibody testing is characterized by a very high specificity [if IGG and IGM positive], but extremely low sensitivity [active infection almost always present without elevated IgG and IgM antibodies] renders it useless as a diagnostic tool (1).” A study by Dylewski et al in the New England Journal of Medicine demonstrates that in immune compromised patients, such as this patient, active infections correlate with elevations in IgG antibodies without elevations of IgM antibody and that a lack of elevation of IgM is not useful in these patients as a way to rule-out active infection. A high clinical suspicion must be maintained and implementation of anti-infective treatment should be based on elevated IgG levels (9).

A study entitled Diagnosis and Treatment of Chronic Mycoplasmal Infections in Fibromyalgia and Chronic Fatigue Syndrome: Relationship to Gulf War Illness published in Biomedical Therapy investigated the presence of active mycoplasmal infection by forensic PCR in patients with CFS and/or FM vs. controls. They found that 63% of CFS/FM patients had active mycoplasmal species infection compared to 9% of normals and more specifically the incidence of active Mycoplasma fermentans infection was 50% in CFS/FM patients vs. 0% of controls (2).

A study published in the International Journal of Medicine Biology Environment tested the blood of 565 CFS and/or FM patients vs. 71 healthy controls. They found 53.1% of patients were positive for mycoplasmal infection vs. only 7 out of 71 controls and 24.6% of patients had an M. fermentans infection vs. 2.8% of normals (42).

In a study published in the International Journal of Occupational Medicine, Immunology and Toxicology found that through specialized testing over half of Gulf War Syndrome/CFS patients had active mycoplasma infections that would not have been detected by standard serological IgG and IgM testing and that 78% of the patients completely recovered with appropriate treatment. Additionally, all of recovered patients that were subsequently retested no longer had evidence of infection (7).

A study and review published in the Antimicrobics and Infectious Disease Newsletter discussed the high incidence of mycoplasma infections in CFS. They discuss the fact that the culturing procedures and serological testing are insensitive for detecting intracellular infections due to the fact that there is usually a lack of hormonal response with these infections resulting in “normal” antibody titers or an isolated elevation of IgG antibodies with a lack of IgM antibodies (8). Sophisticated PCR testing found multiple species of mycoplasma in the majority of CFS patients. They found of the 87 gulf war illness-chronic fatigue syndrome patients treated with antibiotics, most relapsed after the first 6 week trial and most felt worse, but after up to 6 cycles of 6 weeks of therapy approximately 80% of these patients recovered and were able to return to their normal functional capacity. This was not a placebo controlled trial, but they discuss the fact that it is unlikely a placebo effect that most patients felt worse during treatment. They conclude stating that in order to be successful in the treatment of gulf war illness-chronic fatigue syndrome, a comprehensive treatment approach must be used that addresses the numerous physiological abnormalities, including chronic infections (8).”

A study by Nasralla et al published in the European Journal of Clinical Microbiology & Infectious Disease entitled Multiple Mycoplasmal Infections Detected in Blood of Chronic Fatigue Syndrome and Fibromyalgia Syndrome Patients investigated the presence of different mycoplasmal species in blood samples from mycoplasma positive patients with chronic fatigue syndrome and/or Fibromyalgia. They found that the majority of patients had multiple species of mycoplasmal infections, with 59% of patients having active M. Pneumonia infections, 48% having active M fermentans infection, 31% having an active M. hominis and 20% having M pentrans (43).

1. Jo Nijs J et al. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. . Volume 34, Issue 3 , 15 November 2002, Pages 209-214.

2. Garth L. Nicolson, Marwan Nasralla, Joerg Haier and Nancy L. Nicolson

Diagnosis and Treatment of Chronic Mycoplasmal Infections in Fibromyalgia and Chronic Fatigue Syndromes: Relationship to Gulf War Illness. Biomed. Therapy 1998; 16: 266-271

3. Baseman JB, Tully JG. Mycoplasmas: Sophisticated, reemerging, and burdened by their Notoriety. Emerg Infect Dis 1997 (3): 21-32.

4. Lo S-C, Dawson MS, Newton PB III. Association of the virus-like infectious agent originally reported in patients with AIDS with acute fatal disease in previously healthy non-AIDS patients. Am J Trop Med Hyg 1989 (40): 399-409.

5. Lo SC, Wear DJ, Shih WK, Wang RYH, Newton PB, Rodriguez JF. Fatal systemic infections of non-human primates by Mycoplasma fermentans (incognitus strain). Clin Infect Dis 1993 (17) (Suppl 1): S283-288.

6. Lo SC, Buchholz CL, Wear DJ, Hohm RC, Marty AM. Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain). Mod Pathol 1991 (6): 750-754.

7. Nicolson G, Nicolson N. diagnosis and treatment of Mycoplamal Infections in Persian Gulf War Illness-CFIDS Patients. International Journal of Occupational Medicine, Immunology and Toxicology 1996;5:69-78.

8. Nasrala M et al. The Pathogenesis and Treatment of Mycoplasmal Infections. Antimicrobics and Infectious Disease Newsletter 1999;17(!!);81-88

9. Dylewski J et al. Absence of detectable IgM antibody during cytomegalovirus disease in patients with AIDS. New England Journal of Medicine 1985:309:493.

10. Carruthers et al. Myalgic Encepalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome.Vol 11(1) 2003.

11. Ablashi DV, Zompetta C, Lease C, Josephs SF, Balachandran N, Komaroff AL, Krueger GRF, Henry B, Luka J and Salahuddin SZ. Human herpesvirus-6 (HHV-6) and chronic fatigue syndrome (CFS). Canada Disease Weekly Report 1991; 175E:33-40.

12. Zorenzenon M, Rukh G Botta GA et al. Active HHV-6 infection in chronic fatigue syndrome patients from Italy: New data. J Chron Fatigue Syndr 1996;2(4):3-12.

13. Knox KK, Brewer JH, and Carrigan DR. Persistent active human herpesvirus six (HHV-6) infections in patients with chronic fatigue syndrome. J Chron Fatigue Syndr 1999;5:245-246.

14. Brewer JH, Know KK and Carrigan DR. Longitudinal study of chronic active human herpesvirus 6 (HHV-6) viremia in patients with chronic fatigue syndrome. Abstract. IDSA. 37th Annual Meeting. Nov. 18-21, 1999. Philadelphia, Pennsylvania.

15. Wagner et al. Chronic Fatigue Syndrome: A critical Evaluation of Testing for Active Human Herpesvirus-6 Infection. Review of Data of 107 cases. Journal of Chronic Fatigue Syndorme;2(4) 1996.

16. 15 Krueger GRF, Ablashi DV and Gallo RC: Persistent herpesvirus infections . Current techniques in diagnosis. J Virol Methods 21 : 1- 326,1988.

17. Gerhard Rf et al. Clinical Correlates of Infection with Human Herpesvirus-6. In vivo 1994;8:457-86.

18. Ablashi DV et al. Human Herpes virus and chronic fatigue syndrome. Canad Dis Weekly Rep 1991;17S1:33-40.

19. Albashi DV et al. human B lymphotropic virus (human herpesvirus-6). J Virol Methods 1988;21:29-48.