Key symptoms Persistent, debilitating symptoms that include extreme fatigue or lack of energy, assessed by the impairment in the ability to work, study, or undertake domestic tasks, leisure activities, and social interactions. Persistent exhaustion or unusually high levels of fatigue, aggravated by low levels of exertion, still, upright position, and stress (physical or emotional, such as infections or raised anxiety levels). Post-exertional malaise, or post-exertional exacerbation of symptoms: any or all symptoms can get worse following physical or mental efforts and stress—this can happen immediately or more typically delayed after a period following the exertion, e.g., which may be longer than 24 h; recovery to previous levels of functioning and symptom severity may last long (typically from a day to weeks). Sleep dysfunction with unrefreshing sleep, i.e., waking up not feeling rested as one would expect following a good night’s sleep. Complaints of cognitive impairment, such as poor memory, attention, and concentration, slow thinking, reasoning difficulties, sense of disorientation, or “brain fog”. Pain: muscle and joint pains, which may affect multiple sites and be migratory, but without local signs of inflammation; headaches (tension or migraine type); existing musculoskeletal symptoms may worsen. Additional symptoms Orthostatic intolerance, defined by symptoms occurring only or worsened in the upright position (particularly when not associated with movement—i.e., in the still position), and improved by lying down, e.g., palpitations, tremors, light-headedness, dizziness, weakness, nausea. Over-sensitivity to stresses and sensory stimuli such as light, noise, temperature changes, or touch. Intolerance to dietary and environmental factors, such as to alcohol, selected or multiple food intolerances and medications, new allergies. Infection-like immune symptoms, e.g., frequent and prolonged symptoms of upper respiratory tract infections, such as flu-like symptoms, tender cervical lymph nodes, sore throat, congested nose, shortness of breath. Symptoms of irritable bowel syndrome. Weight loss or gain. Sicca-symptoms (dry eyes, mouth, or the opposite: hypersalivation). Emotional instability, anxiety, and depression. Symptoms’ characteristics • Symptoms may start following infectious or other insults or insidiously. These are persistent, but they may fluctuate from day to day or during the day. Some people experience temporary partial remission of symptoms, which is followed by recurrence and may occur after physical or mental exertion beyond their tolerance level. Although specific symptoms vary in presentation and severity, the symptoms tend to follow a typical pattern of inter-relatedness. This means that patients may have difficulties in distinguishing whether their symptoms arise from lack of energy, pain, or sleep deprivation, for example. Fatigue and intolerance to efforts are key symptoms which are not always easy to interpret Fatigue is a main symptom, but its description and interpretation are variable. It usually represents a feeling of intense lack of physical energy or stamina and mental tiredness (reduced mental clarity with slowness in thinking and difficulty in understanding and processing information, focusing attention and forgetfulness), which restricts the ability to undertake physical and mental activities. Intolerance to efforts is a key symptom, which relates to disease severity and previous levels of functioning. The most severely affected may be limited in simple movements in bed, speaking or engaging in conversation, eating, and activities of daily living such as going to bathroom, bathing, showering, or dressing), milder cases who were previously very active (e.g., athletes) may remain active, though much less than previously.