What causes chronic fatigue syndrome symptoms?

Myalgic encephalomyelitis/chronic fatigue syndrome is a complex, multisystem condition characterized by profound, disabling fatigue that is not relieved by rest and by post-exertional malaise, cognitive dysfunction, and autonomic symptoms. Research over the past two decades frames the illness as the result of interacting biological processes rather than a single cause. Multiple authoritative reviews and studies point to immune dysregulation, neurological changes, autonomic nervous system instability, and altered energy metabolism as central contributors. Anthony L. Komaroff, Harvard Medical School, has summarized evidence that these systems interact and that different patients may have different dominant mechanisms.

Immune and inflammatory mechanisms

Several investigations identify persistent, low-grade immune activation and altered cytokine profiles in many patients. W. Ian Lipkin, Columbia University, led pathogen-detection studies showing that while no single infectious agent explains all cases, infections frequently precede onset and can trigger sustained immune responses. The Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, National Academy of Medicine, emphasized post-infectious onset in a substantial subset of patients. Neuroinflammation linked to peripheral immune signals is hypothesized to affect brain networks that regulate sleep, cognition, and fatigue perception.

Autonomic dysfunction and neuroendocrine changes

Autonomic nervous system abnormalities such as orthostatic intolerance, abnormal heart rate variability, and impaired blood pressure regulation are common and correlate with symptoms of lightheadedness, rapid heart rate, and exercise intolerance. Avindra Nath, National Institutes of Health, has described how autonomic instability and hypothalamic–pituitary–adrenal axis alterations can disrupt normal stress responses, sleep architecture, and energy homeostasis. These neuroendocrine changes can amplify fatigue and cognitive symptoms and reduce the capacity to recover after exertion.

Metabolic and mitochondrial considerations

Metabolic studies indicate that some patients exhibit impaired cellular energy production, altered mitochondrial function, and disrupted metabolic responses to exertion. Research suggests that during and after activity these patients may fail to mount normal metabolic adaptations, producing prolonged malaise. Such findings support why graded increases in activity can worsen symptoms for many individuals and why objective testing sometimes reveals abnormal post-exertional physiological responses.

Consequences and contextual factors

The interaction of these biological mechanisms yields profound functional consequences: reduced work capacity, social isolation, and impaired quality of life. Cultural and territorial factors shape diagnosis and care—regions with limited specialist access or where fatigue carries stigma often under-recognize the condition, delaying supportive treatments. Nancy G. Klimas, University of Miami, highlights that patient outcomes depend not only on biology but on access to multidisciplinary care, social support, and validation of symptoms. Environmental factors such as concurrent infections, pollutants, or socioeconomic stressors may modify disease expression and recovery potential.

Understanding of myalgic encephalomyelitis/chronic fatigue syndrome continues to evolve. Current evidence supports a model in which infections, immune activation, autonomic and neuroendocrine dysregulation, and metabolic impairment interact to produce the characteristic symptoms. Recognizing these mechanisms helps guide research into targeted diagnostics and treatments and underscores the need for comprehensive clinical care that addresses biological, psychological, and social dimensions.