Chronic Fatigue Syndrome: Challenges for Evaluation

Diagnosis requires that the patient have the following 3 symptoms:*

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

2. Post-exertional malaise - Worsening of a patient's symptoms and function after exposure to physical or cognitive stressors normally tolerated before disease onset.

3. Unrefreshing sleep.

At least 1 of the 2 following manifestations is also required:*

1. Cognitive impairment - Problems with thinking or executive function exacerbated by exertion, effort, stress, or time pressure.

2. Orthostatic intolerance - Worsening of symptoms upon assuming and maintaining upright posture. Symptoms are improved, although not necessarily abolished, by lying back down or elevating the feet.

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

Most series report that CFS is twice as common in women as in men. The predisposing etiologies include prior viral infection (eg, Epstein Barr, SARS-CoV-2), immune dysfunction, endocrine-metabolic dysfunction, neuropsychiatric factors, and prior malignancy.

CFS is a diagnostic dilemma for physicians and social scientists because of the varying nonspecific symptoms and lack of physical findings to support a diagnosis of actual pathology. In many ways, this is a disease of exclusion for other causes for chronic fatigue. The major test for determining physical disability is the treadmill exercise test, which provides valuable information if correctly performed. However, some CFS patients present with pre-procedure tachycardia that questions the results of this test, and the mental deficits of CFS are potentially compromised by a lack of objectivity of patients‘complaints.

This report describes the findings of medical adjudication for social security purposes of 400 cases over 7 years from a single institution. The basic evaluation included a careful history, physical exam, laboratory tests, lung function testing, ECG, and treadmill exercise testing. In cases with mental complaints (34 cases), blood levels of the cytokine’s interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were obtained because production of these cytokines have been associated with CSF-like symptoms following various illnesses.

For example, a cohort of breast cancer patients who had received chemotherapy and/or radiotherapy developed CFS-like symptoms and were found to have increased expression of RNA encoding IL-6 and TNF-α in their leucocytes.²  Increased production of these cytokines have also been demonstrated in patients with prior SARS-CoV-19 infection who developed Long Covid 19.³  TNF-α is an early cytokine to mediate pro-inflammatory responses by inducing nuclear factor kappa B (NF-kB), which is responsible for the expression of multiple proinflammatory genes in the cell nucleus.⁴  This was also shown in some patients with Immune-mediated inflammatory diseases.⁵ 

Between 2017 and 2023, 400 patients were referred for evaluation for complaints of physical weakness, pain, and mental impairment to satisfy disability or annuity requirements. Investigation standards were detailed history, clinical status, broad laboratory screening adopted to the underling diagnoses, abdominal ultrasound, lung function test, ECG and treadmill exercise.

A retrospective evaluation of these opinions was done in cases with fatigue symptoms and unexplained tachycardia at the start of treadmill-exercise testing (44 cases, 11% of the total population) that resulted in a shortened duration of exercise with a lower maximal load achieved. Evaluation of this distinct population revealed alcohol withdrawal (11), obesity (6), amphetamine ingestion (5), central analgesics (5), Bimatoprost eye drops (5), unexplained (4), untreated hyperthyroidism (3) psychopharmacosis (2), and anemia (2).

In a pilot study, 7 cases were investigated for catecholamines in blood or urine (metanephrine and normetanephrine). Drug screening tests in urine were made in 15 cases by an immune assay. Positive probes were verified by a HPLC certification test. A further cohort of 34 cases who presented with physical and/or mental symptoms of CFS were analyzed for IL-6 and TNF-α in the blood: There were 4 of 12 cases with solid tumors in remission, 5 of 8 cases with hematological malignancies in remission, and 14 cases with non-malignant diseases (7 long-covid syndrome, 2 cases with psoriasis, 1 with ulcerative colitis, 1 Crohńs colitis, 1 pancreatitis in remission, 1 small-fiber syndrome, 1 primary biliary cirrhosis in remission). Investigations included detailed history, assessment of clinical status, broad laboratory screening adopted to the underlying diagnosis, abdominal ultrasound, lung function tests, ECG and treadmill exercise testing.

For Interleukin-6 (IL-6), the commercially available Elecsys IL-6 kit by cobas was used. This is an immunological test using a biostimulated anti-IL-6 antibody together with a monoclonal IL-6 mouse antibody marked with ruthenium complex. It measures 1.5-5000 pg/ml. In a study with 817 healthy persons, an upper-range value of 7 pg/ml was determined (95%).

For Tumor-Necrosis-Factor alpha (TNF-α) the IMMULITE 1000 system was used (solid phase, chemoimmunolescent immunometric assay). The upper-normal range was determined in 58 healthy individuals (nondetectable up to 8.1 pg/mL). Between January and June of 2024 a change oft he IMMUNITE 1000 system was used which had a higher uppernormal range of 13.1 ng/ml. The values concerned in Tables 4 and 5 are designated with an asterix (*).

In an attempt to find a reason for unexpected severe tachycardia, catecholamines in the blood or urine of such cases were determined in 6 cases (Table 1). Three cases showed an increase of normetanephrine alone (marked *), 2 cases had an increase of both metanephrine and normetanephrine, while 1 case had low levels of both. The latter was explained by continuous treatment with opioids. An increase of both types of metanephrines is a usual reaction to stress or exercise. For an isolated increase of normetanephrine, however, there are only 2 explanations: either a pheochromocytoma or the administration of amphetamine, since this is the only central-acting drug that acts by inhibition of resorption of normetanephrine from the subsynaptic space. This leads to an increase of the transmitter in the blood in 30 minutes, eliciting an simultaneuous increase in heart rate.⁶ 

Therefore these drugs were tested in 3 cases with unequivocal positive results (case 6-8), and these data also suggest that 5 cases tried to influence the results by amphetamine ingestion.

The criteria for classification of other likely reasons for tachycardia were as follows:

• Alcohol withdrawal: reported consumption, clinical signs (tremor, sweat, etc), liver US, liver enzymes, carboxy-deficient transferrin

• Adiposity BMI grade II-IV: body mass index above 35 with lack of other reasons

• Use of central acting analgetics: opioids, tilidine, amphetamine, etc

• Use of psychopharmacology

• Use of eye drops with atropin-like components (Bimatoprost)

• Hyperthyroidism: as measured by TSH, fT3, fT4

• Heart failure: ECG, treadmill exercise, edema, dyspnoea, nocturia

• Anemia: Hb <7.6 mmol/L

• Unknown/other causes: omission of cardiac medications

The results are given in Table 2 according to incidence: alcohol withdrawal symptoms were most frequent, followed by adiposity, but drugs like opioids, amphetamine, psychopharmacologics and Bimatoprost-containing eye drops for glaucoma (all of 5 cases) were similarly important. (See figures 1 & 2).

Investigations of cytokine levels (IL-6 and/or TNF-a) in the blood were done in 34 cases with mental complaints and fatigue. Data are presented regarding main diagnosis, age, duration of CFS, strength, professional status, ESR and CRP-values, IL-6 and TNF-a-levels and main symptoms.

Table 3 gives the results in 12 cases with solid tumors in remission. TNF-a levels were modestly increased in 4 cases, but 2 of these had signs of infection. Physical ability was mainly preserved (90%).

Table 4 shows the results in 8 cases with hematological malignancies in remission. TNF-a-levels were modestly elevated in 5 of them, physical ability was moderately derceased 83%, while ESR and CRP were normal.

Table 5 shows the results in 14 cases with non-malignant diseases: There were 7 cases with long-COVID syndrome, all of which had moderately increased TNF-a levels, 2 psoriatic diseases (1 increased), 2 gut diseases (1 markedly increased), 1 small-fiber neuropathy and 1 primary biliary liver cirrhosis and 1 pancreatitis (borderline). (See Figure 3).

In cases of patients complaining of general weakness meeting the criteria for CFS, treadmill exercise is the major objective parameter to determine the degree of physical impairment. It is compromised in about 11% of the cases by an unexplained elevated heart rate, which may lead to falsely low results. This experience in a single institution shows that there are several typical reasons for this problem which should be considered for a correct evaluation: these are, according to frequency: alcohol withdrawal symptoms, adiposity, fraud by amphetamine ingestion, continuous use of central acting analgetics, side effects of glaucoma treatment by eyedrops, hyperthyroidism, use of psychopharmacologics, heart failure, and anemia. A broadened investigation is needed to identify these conditions.

In cases with significant mental complaints, it is even more difficult to obtain objective parameters for the impairment. Others have shown that cytokines like IL-6 and TNF-α play a role in breast cancer patients who develop fatigue syndrome during therapy. Our experience includes 34 cases describing clinical symptoms of chronic fatigue syndrome. Even after many years of successful therapy of their disease, cytokines, in particular TNF-α, are elevated while standard biomarkers for infection are not. While this was a rare observation in cases with solid cancers in remission (4 in 12, two with infectious reasons), it was a common observation in cases with hematological malignancies in remission (5 of 8). In cases with non-malignant diseases complaining of chronic fatigue, increased TNF-α was found in 11 of 14 cases, in particular in all 7 cases with long-COVID syndrome.

The findings of TNF-α are an association without proof of causality. However, it may suggest that chronic fatigue syndrome is based on a common biological mechanism that involves a long-term production of TNF-α in many different diseases, which leads to impairment of physical and mental capabilities of the persons affected. Although the exact mechanism is not entirely understood, the determination of TNF-α may help to verify a chronic fatigue syndrome in the setting of social medical expertise, a previously unmet problem.