Chronic Fatigue Syndrome

Immunology
Written By Maladywise

Factsheet

Intro

  • Uncertain cause

  • Disorder of young to middle-aged adults

  • Twice as common in women

  • Prevalence 1%

Cause

Infection

  • EBV

    • Persists for life

    • Often having a high titre of antibodies to EBV capsid suggests recent or active infection

    • Patients often attribute the start of their illness to a mononucleosis-type illness

    • Most studies show higher levels of certain antibodies to EBV in patients with CFS compared to controls

    • No evidence that chronic EBV infection is responsible for ongoing, chronic symptoms

  • SARS-CoV-2

  • Retroviruses

  • Others

  • Bacterial

Immune System differences

  • True immune deficiency is not a feature of this syndrome

  • Some immune differences are more prevalent but not obvious

  • Depressed NK cell function

  • A hypothesis is activation of the immune system in the brain leads to the production of cytokines

Endocrine-metabolic dysfunction

  • A hypometabolic state (akin to hibernation)

  • Abnormalities in the pathway converting sugars, lipids, and AA to energy

  • Decreased serum cortisol and under secretion of CRH

  • Increased IGF

  • Abnormalities in CNS serotonin activity

Neural mediated hypotension

  • May play a role

  • One study 22/22 CFS patients had abnormal tilt testing

  • Another study of 600 patients showed 77% had abnormal tilt table testing

Depression

  • Role is controversial

  • Felt to occur as a consequence of CFS

Sleep disruption

  • Possible cause

Genetics

  • Different levels of genes with roles in HPA axis and sympathetic nervous system

Clinical presentation

  • Not homogenous

  • Onset may be sudden, often associated with a typical infection like URTI or EBV, or onset can be gradual

  • Overwhelming fatigue with addition symptoms e.g. altered sleep and cognition

  • Symptoms worsened by physical activity

  • a pre-CFS medical history that is not one of the multiple somatic problems. Affected patients are typically highly functioning individual who are struck down with this disease

Exam

  • Typically normal once the original infection resolved

  • Patients often feel warm but few ever demonstrate fever

  • Joint aches without signs of arthritis

  • Muscles are easily fatigue but strength normal, as are biopsies and EMG

  • Mild cervical or axillary lymphadenitis is occasionally noted

  • Painful lymph nodes (lymphadenia) are a frequent complaint but not true lymphadenopathy

  • Biopsied nodes show reactive hyperplasia

Diagnosis

  • Moderate, substantial or severe intensity at least one-half of the time

  • Need these three symptoms

    • Substantial reduction in the ability to engage in pre-illness levels of work, school, social or personal activities for 6 months.

      • Accompanied by fatigue, which of often profound, is the new or definite onset, and is not substantially alleviated by rest

    • Post-exertional malaise, worsening of symptoms after physical or cognitive stressors that were normally tolerated before the disease onset

    • Unrefreshing sleep

  • At least one of

    • Cognitive impairment

    • Orthostatic intolerance

Investigations

  • FBC, UEC, Glucose, CMP, LFT, TSH, CK if muscle weakness

  • Sleep study if suggestive OSA

  • Investigate adrenal insufficiency if history suggests

  • Neuroimaging is not usually done unless symptoms suggestive

Management

  • Many therapies have been tried, none are curative

  • Management should be supportive and focus on treating common symptoms and comorbidities

Education

  • Explain severity is variable

  • Symptoms are valid

  • Explain studies show underlying problems with the nervous system, immune system, and metabolic system

  • Explain no diagnostic test

  • Promise to be honest

  • Address the issue of specific diagnosis

Sleep

  • Sleep hygiene if insomnia

  • Consider workup for sleep disorders

  • Can trial OTC products or TCAs e.g. Amitriptyline 10mg

Pain

  • Tension HAs, myalgia, arthralgia, skin sensitivity is common

  • NSAIDs or Paracetamol

  • TCAs

Depression / Anxiety

  • Comorbidity, but medication doesn’t help CFS

  • Medication

  • Psychotherapy

Cognitive

  • If substantial neuropsychology work up

Dizziness

  • May be role fludrocortisone or atenolol

Exercise

  • Remaining physically active is critical and may improve fatigue

  • However, PEM complicates this

  • PEM typically presents 12 to 48 hours after activity and lasts days to weeks

  • Individualized for each patient

Interventions of unclear or no benefit

  • Aciclovir - No benefit over placebo. Studies have failed to note any association with active EBV infection.

  • Antibiotics - A true positive Lyme serology merely confirms past exposure to Borrelia but not active infection. No benefit of ABx in patients with positive Lyme serology.

  • Cytokine inhibitors - Proinflammatory cytokines like IL1 may be implicated. Anakira (IL1 antagonist) showed no improvement in fatigue.

  • Galantamine - ACH-esterase inhibitor. No improvement at 16 weeks.

  • Glucocorticoids - Results inconsistent. 25-35 Hydrocortisone (5-10mg Pred) for 12 weeks in 70 patients showed modest benefit at the expense of adrenal suppression.

  • IgG - Beneficial in 1 small trial

  • Methylphenidate - One study showed a significant effect on fatigue in 17% of patients and concentration in 22%.

  • Modafinil - Mixed results

  • Rituximab - Mixed results

Other therapies

  • CBT - Can improve fatigue and function

  • Graded Exercise

    • 30 minutes of light exercise five times a week

    • Target HR < 100

    • Shows reduce fatigue

Prognosis

  • Short-term prognosis poor

  • Long-term prognosis better

  • 73% had functional impairment at 6 weeks to 6 months

  • 33% at 2 to 4 years

  • A prospective study showed only 4 of 27 achieved sustained remission during a three years observation period

References

Maladywise https://www.maladywise.org
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