The etiology is controversial. A chronic viral infection has been proposed because many patients relate onset to an event similar to influenza or mononucleosis. Epstein-Barr virus is a possible cause, but immunologic markers of exposure do not appear to be sensitive or specific. Other possible but unproven viral causes include enteroviruses, human herpesvirus type 6, and human T-cell lymphotropic virus. Various immunologic abnormalities have been reported, including low levels of immunoglobulins, lowered lymphocytic proliferation and low levels of interferon- in response to mitogens, and poor cytotoxicity of natural killer cells.
Some patients have abnormal immunoglobulins, with circulating autoantibodies and immune complexes.
Other proposed but unproved mechanisms include endocrine abnormalities, abnormal levels of neurotransmitters, inadequate cerebral circulation, and elevated levels of angiotensin converting enzyme. Many patients relate symptom onset to a viral-like syndrome, with swollen glands, extreme fatigue, fever, and upper respiratory symptoms. Generally, no signs of muscle weakness, arthritis, neuropathy, or organomegaly are present. However, some definitions require the presence of low-grade fever, nonexudative pharyngitis, or palpable or tender lymph nodes. A reasonable assessment probably includes CBC, routine chemistries, ESR, and thyroid-stimulating hormone.