Epistemic Status: moderately confident. Spent several weeks on this in an effort to be more complete and careful than most of my lit reviews.
Chronic fatigue syndrome is something of a medical mystery. Some doctors question whether it’s a real disease at all. There are no well established treatments. We don’t know what causes it.
There’s a lot of evidence that CFS has something to do with immune and hormonal dysfunction, and is frequently associated with infectious diseases, particularly the Epstein-Barr virus and other herpes viruses (not all of which are sexually transmitted.) There are also some immunotherapy options that seem to be effective in a subset of CFS patients, in particular corticosteroids.
Corticosteroids seem to help for a sub-population of CFS patients. Rituximab, bacterial therapy, and intravenous immunoglobulin may also help for some CFS patients, but the evidence base is smaller or less consistent for those.
Chronic Fatigue and the HPA Axis
The hypothalamus/pituitary/adrenal (HPA) axis is a system of interconnected hormone signaling processes involved in the body’s response to stress. Cortisol, the “stress hormone”, is produced by the adrenal glands in response to signals from the pituitary gland and hypothalamus.
Cortisol suppresses inflammation, which is why it’s often used as a treatment in autoimmune diseases. It also promotes alertness and increases blood sugar, to ready the body for action.
There’s evidence that patients with chronic fatigue syndrome have lower cortisol levels, or are less able to produce cortisol in response to the appropriate stimuli.
There are a number of small studies showing that CFS patients have lower cortisol than healthy people. 14 CFS patients had significantly lower salivary cortisol levels compared to 26 cases of depression and 131 controls. In 15 CFS patients and 20 controls, mean salivary cortisol levels were significantly lower for CFS patients. Urinary free cortisol was significantly lower in 121 CFS patients compared to 64 control patients. 10 melancholic depressives had higher urinary free cortisol than 15 controls, while 21 CFS patients had lower urinary free cortisol. In 10 patients with CFS, 15 patients with major depression, and 25 healthy controls, baseline serum cortisol levels were highest in the depressives, lowest in the CFS patients, moderate in the controls.
However, not all studies replicate the finding. In 22 CFS patients and 22 healthy controls, one study found no difference in urinary or salivary cortisol. In another study of 10 CFS patients vs 10 controls, patients were slightly but significantly higher in salivary cortisol.
One possible explanation for the discrepancy is that cortisol levels fluctuate greatly throughout the day, and in response to conditions that vary from day to day (food intake, stress, etc). All these studies sampled patients over the course of a day or less. It’s not surprising that small studies should find discordant results, especially given the possibility that not all CFS patients are alike.
One finding that does seem consistent is that chronic fatigue patients have a blunted cortisol response to ACTH, the hormone produced by the pituitary that normally stimulates cortisol release, and they have an exaggerated drop in cortisol levels in response to challenge with corticosteroids (cortisol and its molecular analogues reduce ACTH levels in a negative feedback loop.) So, even if cortisol is not always lower in CFS patients, it may be more sluggish to rise and quicker to decline. In 21 CFS patients vs. 21 healthy controls, patients with CFS had normal baseline salivary cortisol but showed enhanced and prolonged suppression of salivary cortisol in response to dexamethasone challenge. Prednisolone challenge suppresses both salivary and urinary cortisol more in CFS patients (n=15) than controls (n=20).
Upon challenge with ACTH, the increase in plasma cortisol was significantly less for 20 CFS subjects vs. 20 controls. In 22 CFS patients vs 14 controls, CFS patients also had a blunted DHEA response to ACTH; DHEA is a steroid hormone and androgen precursor, which is generally produced in response to exercise. In other words, the steroid-promoting effects of ACTH are weaker in CFS patients, while the cortisol-reducing negative feedback effects of corticosteroids are stronger.
Perhaps relatedly, CFS patients have blunted salivary cortisol response to awakening compared to healthy volunteers. Another study compares that female CFS patients have lower lower morning salivary cortisol than controls. This may be related to the unrefreshing sleep and constant fatigue that CFS patients experience.
Finally, when there are hormonal differences in CFS patients, there are also clear anatomical differences. 8 CFS patients who had a subnormal cortisol response to ACTH challenge were found to have adrenal glands less than 50% the size of normal subjects’ adrenal glands. In each case, the symptoms of fatigue were preceded by a viral infection. So in at least some cases, CFS patients have smaller glands than healthy people, which indicates that at least some of the time, CFS is associated with a damaged endocrine system.
Chronic Fatigue and Impaired NK Function
Studies find a variety of abnormalities in white blood cells in CFS patients, but the only really consistent results are impairment of NK (natural killer) cells’ function. NK cells are cytotoxic (cell-killing) white blood cells involved in the innate immune response; they attack tumor cells and infected cells.
A study of 30 CFS patients and 69 controls found that NK cell cytotoxicity was 64% lower against tumor cell lines. In a family with 8 relatives with chronic fatigue syndrome, affected individuals had 62% lower NK activity levels (p = 0.008) against a tumor cell line than normal controls; unaffected relatives had intermediate NK activity levels. In a study of 41 CFS patients and 23 matched controls, the patients had significantly lower cytotoxic activity against EBV-infected cell lines and tumor cell lines, and patients also had significantly lower levels of NKH1+ NK cells, a subtype which comprises most of the NK cells in healthy people. A review article  explained that there are conflicting results in most immunological abnormalities in CFS; most studies, however, found reduced NK activity and reduced lymphoproliferative activities in response to antigens. Of 17 studies that evaluated NK activity in CFS patients, 15 found reduced NK cytotoxicity in the CFS patients compared to controls, and a greater decrease in activity was associated with greater symptom severity.
This suggests that CFS is characterized by a weakened immune system.
In general, NK deficiencies or reduced NK activity are associated with greater susceptibility to herpesviruses. Reduced NK activity has also been found in major depression , stress, bereavement , and sleep deprivation.
Chronic Fatigue and Herpesviruses
A number of studies have found that CFS is associated with elevated antibodies to viruses, particularly herpesviruses. It’s also often been found that CFS occurs with rapid onset, after a viral illness, and that there are outbreaks of CFS in locations where there have been disease outbreaks. However, results are not entirely consistent between studies.
In a study of 548 CFS patients vs 30 healthy controls, CFS patients did not have significantly higher rates of positive titers on antibodies to HSV1, HSV2, Rubella, CMV, EBV, HHV-6, or Coxsackie. This was a study of consecutive patients at a chronic fatigue clinic in Washington State.
In another study of 100 CFS patients referred to the lab by doctors and 92 healthy controls, there were significantly higher rates in patients than controls of prevalence of antibodies to EBV viral capsid antigen, and prevalence of antibodies to EBV early antigen, but not to antibodies to EBV nuclear antigen; there was also no significant difference between patients and controls in who had high titers of antibodies.
In a study of 26 patients from Atlanta with CFS and 50 healthy controls, there were no significant differences in the rate of prevalence of antibodies to any viruses, including HHV-6; the prevalence of antibodies in the controls was nearly 100% for all viruses tested. Also, there was no significant difference in the antibody titers for any EBV antibodies (early antigen, nuclear antigen, or viral capsid.)
In a study of four clusters of outbreaks of CFS in the Nevada/California area in the 1980’s, with 31 patients and 105 controls in total, there was no significant difference in the mean antibody titer to HHV-6, EBV-VCA, or EBV-EA. Mean VCA GMT level for cases was 239.7 vs. 254.0 for controls, a non-significant difference.
In 88 patients with CFS compared to 76 healthy blood donors in the Netherlands, there was no significant difference in geometric mean titer for EBV EA antibodies or EBV VCA antibodies. Mean VCA GMT level for patients was 39.5 vs. 38.0 for controls.
For identical twin pairs discordant for CFS, the twin with CFS was no more likely to have serological evidence of virus than the twin without (including EBV and HHV-6).
In 14 patients with CFS compared to 14 controls, there was no significant difference in EBV antibody titer.
In a study of 259 patients associated with the Lake Tahoe outbreak in 1984, compared to 40 healthy controls, found active replication of HHV-6 in cell cultures from blood in 70% of patients compared to 20% of controls. The reciprocal geometric mean titers for EBV VCA were significantly higher in the patient than control group (138.0 +/- 2.6 for the cases vs. 67.6 +/- 4.4 for the controls) but not for early antigen or nuclear antigen. There was no significant difference in antibody titers for HHV-6, though. Mean HHV-6 ELISA densities were 1905 for cases and 1288 for controls, a nonsignificant difference.
In a study comparing 15 patients from the Lake Tahoe outbreak who had been sick for more than 2 months to 119 patients with less severe symptoms and 30 matched controls found that a significantly higher fraction of cases than non-case patients had EBV VCA antibodies at 160 or greater, and 320 or greater. Reciprocal geometric mean titers for VCA were higher in case-patients than controls (254 vs. 115.) After retesting across 3 laboratories, the only significant difference between case-patients and control-patients was EBV EA titer, with reciprocal geometric mean titers of 22 in cases vs. 9 in controls; VCA levels were not significantly different.
In 58 CFS patients and 68 matched controls, 33 CFS patients (57%) had positive EBV VCA IgM titers, compared to 7% of controls. IgM titers to EBV are rare, are more likely to indicate active infection, and most studies find none at all.
In a study of 154 CFS patients and 165 controls from Flint and Boston, patients were significantly more likely than controls (p < 0.001) to have the presence of IgG and IgM antibodies to HHV-6, but not to have EBV-EA antibodies.
In a study of 10 CFS patients with acute mononucleosis onset, 10 CFS patients without, and 42 healthy controls found significantly higher EBV IgG VCA antibody titers in all CFS patients relative to controls, as well as HHV-6 antibody titers.
In 21 MS patients, 35 CFS patients, and 28 healthy controls, 75% of MS patients had elevated IgM titers to HHV-6 antibodies compared to 6.7% of healthy controls, and 71.4% elevated IgM titers to HHV-6 virus compared to 15% of controls. However 60-80% of everyone had HHV-6 by PCR. CFS patients were more likely to have IgG responses to early HHV-6 antibodies than controls (65.2% vs 20%) and IgM responses to early HHV-6 antibodies than controls (54.3% vs. 8.0%). This suggests a high level of HHV-6 reactivation in CFS and MS patients.
In 13 patients with CFS and 13 healthy controls, serum antibodies for HHV-6 were significantly higher in the patients; 7 of the patients and none of the controls had HHV-6 DNA, as measured by PCR.
A study of 36 CFS patients and 24 controls found that HHV-6A DNA was significantly more prevalent in CFS patients, while HHV-6B DNA was the same.
HHV-6 High IgG levels
HHV-6 High IgM levels
|Di Luca 1995
EBV-VCA High IgG levels
EBV-VCA High IgM Levels
EBV-EA High IgG levels
HHV-6 IgG GMT
The only serological differences that are consistently significantly different between CFS and normal patients are HHV-6 DNA (except for the twin study), HHV-6 IgM, and EBV-VCA IgM levels. IgM, as opposed to IgG, levels, indicate active infection, as do viral DNA levels. This suggests that chronic fatigue patients are more likely than controls to have reactivated herpesviruses, but may not be more likely than controls to have had past exposure to herpesviruses.
Chronic Fatigue and Other Infections
There are some studies that have found associations between chronic fatigue syndrome and other types of bacterial and viral infection.
Mycoplasma bacterial species can survive for a long time inside cells, evade immune response, and resist treatment with antibiotics. They can cause a form of pneumonia and a sexually transmitted disease, and have been associated with various types of cancer.
In a study of 200 CFS patients and 100 controls, 52% of CFS patients had Mycoplasma infections compared to 7% of controls, and 30.5% of CFS patients had HHV-6 infections compared to 9% of controls, as measured by forensic PCR.
In 100 CFS patients and 50 controls, 52% of CFS patients had PCR results positive for Mycoplasma genus, compared to 14% of controls (p < 0.0001).
In 258 patients from Dubbo in rural Australia, exposed to Epstein-Barr virus, Ross River virus, or Q fever, 35% had a post-infective fatigue syndrome at 6 weeks and 12% at 6 months, at which point 11% (28 patients) met criteria for chronic fatigue syndrome. 
Out of 51 patients infected with acute Parvovirus B19, 5 went on to meet criteria for CFS. Those with prolonged fatigue and CFS had significantly higher rates of serum B19 DNA.
In 50 patients with postviral fatigue, 6 were associated with a local epidemic of Coxsackie virus, and 9 from a different viral epidemic of unknown cause; 30 had high antibody titers to Coxsackie virus, but none to other viruses.
Chronic fatigue syndrome seems to frequently follow acute infections, and it is associated with high DNA levels of pathogens, often ones (like viruses or Mycoplasma bacteria) that can persist in the body indefinitely.
Corticosteroids Relieve CFS In A Sub-Population of Patients
In a study of 37 patients with chronic fatigue syndrome and 28 healthy controls, the CFS group had higher baseline cortisol levels but weaker cortisol responses to CRH and fenfluramine, and lower urinary cortisol levels. In a subset of responders (8 out of 23 patients) treated with low-dose hydrocortisone for 28 days, the blunting of the cortisol response recovered, and CRH again caused a strong cortisol spike. In these patients, fatigue dropped to the same level as the normal population.
In a randomized trial of 32 CFS patients with no comorbid disorders, self-reported fatigue scores fell by 7.2 points in treatment group vs. 3.3 points in placebo group (p = 0.009), and 28% of treated patients reached normal levels of fatigue, compared to 9% of the placebo patients. This was a crossover study: patients received either hydrocortisone or placebo for one month, and then the reverse.
Patients with CFS have higher DHEA levels than controls; there is a correlation between higher DHEA and more disability; untreated CFS patients have a blunted DHEA response to CRH challenge compared to controls and hydrocortisone-treaded CFS patients; basal levels of DHEA also went down after treatment with hydrocortisone.
In a much older study from 1948, 53 patients with chronic mononucleosis, with “infectious mononucleosis cells” in the blood, presenting with weakness or ease of fatigue, responded only to a preparation of adrenal cortical extract (“cortalex”). “There was but little subjective improvement during the first week, but a definite feeling of well being developed during the second week and was quite definite during the third week. After this the medication was discontinued and the improvement usually continued. In a few patients it was necessary to increase the dose, or resume it after its discontinuance. Associated with the subjective improvement, there was a decrease in the size of the spleen.”
However, when patients are not selected for having a blunted cortisol response, sometimes trials of corticosteroids on CFS don’t show positive results.
A crossover study of 80 patients given hydrocortisone and fludrocortisone found no significant difference from placebo in reported fatigue. Note that the treatment group here did not see a larger response than placebo to an ACTH injection. So this negative result would still be consistent with the hypothesis that steroids work only when they recover the cortisol response to CRH or ACTH.
A controlled study of 63 patients given low-dose hydrocortisone vs. placebo found no significant difference in wellness score over a period of 3 months, but significantly more patients (53% vs 29%, p =0.04) experiencing an improvement of >5 points on the wellness score, which could be consistent with the drug being effective on a sub-population.
Corticosteroids in Autoimmune Neurological Disorders
Chronic fatigue syndrome has similar symptoms and may have similar causes to other autoimmune neurological disorders such as multiple sclerosis and inflammatory neuropathies. Fatigue, muscle weakness, and brain fog, as well as high antibody titers for viruses, are found in these diseases. Corticosteroids are often standard treatments. This suggests that analogous treatment may be useful in CFS.
Corticosteroids (particularly methylprednisone) decreased by 63% the probability of the patient failing to recover from an exacerbation of multiple sclerosis, according to a Cochrane Review.
IVIG and/or corticosteroids are standard treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Both significantly reduce disability scores.
Demyelinating peripheral neuropathy responded to corticosteroids in six children, who regained strength and ability to walk.
Corticosteroids (prednisolone) have significant positive effects on muscle strength and ability to function in daily life for patients with myasthenia gravis, an autoimmune neurological disorder.
However, corticosteroids are ineffective in Guillain-Barre syndrome, another autoimmune demyelinating disease causing weakness and numbness. Standard treatment for Guillain-Barre is plasmapheresis and/or IVIG.
Corticosteroids suppress inflammation, so they are often effective on autoimmune disorders which damage the nervous system through inflammatory damage. While it is not known what causes CFS, if it is an autoimmune disorder, it may respond to similar treatment.
IVIG Is Not Consistently Effective in CFS
Intravenous immunoglobulin is the practice of treating immunodeficiency disorders with a variety of antibodies via injection.
A 30-person randomized trial of IVIG in CFS, with a dose of 1 gm/kg, found no significant differences in symptoms between treatment and control by the 5-month follow-up point.
A 99-patient controlled trial of IVIG vs. placebo infusion on CFS patients found no significant treatment effect on any self-reported symptom scores.
A 71-patient randomized controlled trial of IVIG vs. placebo infusion found a barely-significant (p = 0.04) difference between placebo and IVIG on symptom scores.
However, a 49-person study of patients with CFS treated with a dose of 2 gm/kg of IVIG, 40 of which had reduced T-cell counts or reduced response to skin-test antigens, found 43% of the treated group compared to 12% of controls noticed major reductions in their symptoms at the 3-month follow-up point after treatment. The responders also noticed recovery of their cell-mediated immunity findings.
It’s possible that for a sub-population of CFS patients with abnormally low T-cell counts or T-cell subtype counts, IVIG can be helpful; but it doesn’t seem to be helpful for CFS patients across the board.
Staphylococcus Toxin May Help CFS
In a randomized trial treating 100 fibromyalgia or CFS patients with staphylococcus toxin or placebo found that the treatment group had 65% responders (reduction of >50% of symptoms on a comprehensive rating scale) compared to 18% for placebo, p < 0.001. There was improvement at a p < 0.01 level in fatiguability, reduced sleep, failing memory, concentration difficulties, and sadness.
Rituximab May Help CFS
Rituximab, an immunosuppressant drug that targets B cells, was found to improve fatigue scores in 67% of 30 patients in a randomized trial, compared to 13% of placebo. (p = 0.003). There were no adverse effects except a worsening of psoriasis in two patients.
In an open-label follow-up from the same lab, 18 out of 29 patients on maintenance rituximab therapy for 15 months had clinically significant responses.
Reduced NK activity and viral reactivations naturally go together, and stress can cause both. Cortisol usually inhibits NK activity, so long-term hypocortisolism might result in NK cells that become more sensitive to cortisol, a possible mechanism for how an impaired HPA axis could result in NK dysfunction and thence viral reactivation. The picture that seems to be emerging is that prolonged stress and/or an acute viral infection can result in fatigue and immunocompromise. This would explain why there are often psychological comorbid factors.
If this is what’s going on, then the obvious intervention points would be to increase cortisol (particularly the phasic cortisol response to stress) and to increase NK activity. Administering low dose corticosteroids seems to do reasonably well at the former. It’s not clear how to do the latter, but cytokines like IL-15 might work and so might bacterial therapies like the staphylococcus toxin mentioned above.
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