Fatigue (physical)
However a 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.

Reduced brain connectivity: Fatigue has been correlated with reductions in structural and functional connectivity in the brain. This has included in post-stroke, MS, NMOSD and MOG, and ME/CFS. This was also found for fatigue after brain injury, including a significant linear correlation between self-reported fatigue and brain functional connectivity.
Areas of the brain for which there is evidence of relation to fatigue are the thalamus and middle frontal cortex, fronto-parietal and cingulo-opercular,  and default mode network, salience network, and thalamocortical loop areas.
A 2024 review found that structural connectivity changes may underlie fatigue in pwRRMS but that the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies. 
A small 2023 study found that infratentorial lesion volume (cerebellar and brainstem) was a relatively good predictor of RRMS fatigue severity.

Damage to brain white matter: Studies have found MS fatigue correlates with damage to NAWM (normal appearing white matter) (which will not show on normal MRI but will show on DTI (diffusion tensor imaging)). The correlation becomes unreliable in patients aged over 65 due to damage due to ageing.

Heat shock proteins: A small 2016 study found that primary Sjögren's syndrome patients with high fatigue, when compared with those with low fatigue, had significantly higher plasma concentrations of HSP90α, and a tendency to higher concentrations of HSP72. A small 2020 study of Crohn's disease patients found that higher fatigue visual analogue scale (fVAS) scores correlated with hgher HSP90α levels. A related small 2012 trial investigating if application of an IL-1 receptor antagonist (anakinra) would reduce fatigue in primary Sjögren's syndrome patients was inconclusive.

Diagnosis: Fatigue is currently measured by many different self-measurement surveys. Examples are the Fatigue Symptom Inventory (FSI) and the Fatigue Severity Scale. There is no consensus on best practice, and the existing surveys do not capture the intermittent nature of some forms of fatigue.
A 2023 guidance indicates the following

in the primary care setting, a medical or psychiatric diagnosis is found in at least two-thirds of patients;
the most common diagnoses are viral illness, upper respiratory infection, iron-deficiency anaemia, acute bronchitis, adverse effects of a medical agent in the proper dose, and depression or other mental disorder, such as panic disorder, and somatisation disorder;
the origin of fatigue may be central, brain-derived, or peripheral, usually of a neuromuscular origin—it may be attributed to physical illness, psychological (e.g., psychiatric disorder), social (e.g., family problems), and physiological factors (e.g., old age), occupational illness (e.g., workplace stress);
when unexplained, clinically evaluated chronic fatigue can be separated into ME/CFS and idiopathic chronic fatigue.
A 2016 German review found that

about 20% of people complaining of tiredness to a GP (general practitioner) suffered from a depressive disorder.
anaemia, malignancies and other serious somatic diseases were only very rarely found in fatigued primary care patients, with prevalence rates hardly differing from non-fatigued patients.
if fatigue occurred in primary care patients as an isolated symptom without additional abnormalities in the medical history and in the clinical examination, then extensive diagnostic testing rarely helped detect serious diseases. Such testing might also lead to false-positive tests.
A 2014 Australian review recommended that a period of watchful waiting may be appropriate if there are no major warning signs.
A 2009 study found that about 50% of people who had fatigue received a diagnosis that could explain the fatigue after a year with the condition. In those people who had a possible diagnosis, musculoskeletal (19.4%) and psychological problems (16.5%) were the most common. Definitive physical conditions were only found in 8.2% of cases.

Classification: 

By type: 

Uni- or multi-dimensional: Fatigue can be seen as a uni-dimensional phenomenon that influences different aspects of human life. It can be multi-faceted and broadly defined, making understanding the causes of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases.
A 2021 review considered that different "types/subsets" of fatigue may exist and that patients normally present with more than one such "type/subset". These different "types/subsets" of fatigue may be different dimensions of the same symptom, and the relative manifestations of each may depend on the relative contribution of different mechanisms. Inflammation may be the root causal mechanism in many cases.

Physical: Physical fatigue, or muscle fatigue, is the temporary physical inability of muscles to perform optimally. The onset of muscle fatigue during physical activity is gradual, and depends upon an individual's level of physical fitness – other factors include sleep deprivation and overall health. Physical fatigue can be caused by a lack of energy in the muscle, by a decrease of the efficiency of the neuromuscular junction or by a reduction of the drive originating from the central nervous system, and can be reversed by rest. The central component of fatigue is triggered by an increase of the level of serotonin in the central nervous system. During motor activity, serotonin released in synapses that contact motor neurons promotes muscle contraction. During high level of motor activity, the amount of serotonin released increases and a spillover occurs. Serotonin binds to extrasynaptic receptors located on the axonal initial segment of motor neurons with the result that nerve impulse initiation and thereby muscle contraction are inhibited.
Muscle strength testing can be used to determine the presence of a neuromuscular disease, but cannot determine its cause. Additional testing, such as electromyography, can provide diagnostic information, but information gained from muscle strength testing alone is not enough to diagnose most neuromuscular disorders.

Mental: Mental fatigue is a temporary inability to maintain optimal cognitive performance. The onset of mental fatigue during any cognitive activity is gradual, and depends upon an individual's cognitive ability, and also upon other factors, such as sleep deprivation and overall health.
Mental fatigue has also been shown to decrease physical performance. It can manifest as somnolence, lethargy, directed attention fatigue, or disengagement. Research also suggests that mental fatigue is closely linked to the concept of ego depletion, though the validity of the concept is disputed. For example, one pre-registered study of 686 participants found that after exerting mental effort, people are likely to disengage and become less interested in exerting further effort.
Decreased attention can also be described as a more or less decreased level of consciousness. In any case, this can be dangerous when performing tasks that require constant concentration, such as operating large vehicles. For instance, a person who is sufficiently somnolent may experience microsleep. However, objective cognitive testing can be used to differentiate the neurocognitive deficits of brain disease from those attributable to tiredness.
The perception of mental fatigue is believed to be modulated by the brain's reticular activating system (RAS).
Fatigue impacts a driver's reaction time, awareness of hazards around them and their attention. Drowsy drivers are three times more likely to be involved in a car crash, and being awake over 20 hours is the equivalent of driving with a blood-alcohol concentration level of 0.08%.

Neurological fatigue: People with multiple sclerosis experience a form of overwhelming tiredness that can occur at any time of the day, for any duration, and that does not necessarily recur in a recognizable pattern for any given patient, referred to as "neurological fatigue", and often as "multiple sclerosis fatigue" or "lassitude". People with autoimmune diseases including inflammatory rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and primary Sjögren's syndrome, experience similar fatigue.
Attempts have been made to isolate causes of central nervous system fatigue.

By timescale: 

Acute: Acute fatigue is that which is temporary and self-limited. Acute fatigue is most often caused by an infection such as the common cold and can be cognized as one part of the sickness behavior response occurring when the immune system fights an infection. Other common causes of acute fatigue include depression and chemical causes, such as dehydration, poisoning, low blood sugar, or mineral or vitamin deficiencies.

Prolonged: Prolonged fatigue is a self-reported, persistent (constant) fatigue lasting at least one month.

Chronic: Chronic fatigue is a self-reported fatigue lasting at least 6 consecutive months. Chronic fatigue may be either persistent or relapsing. Chronic fatigue is a symptom of many chronic illnesses and of idiopathic chronic fatigue.

By effect: Fatigue can have significant negative impacts on quality of life. Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, Myalgic Encephalomyelitis/chronic fatigue syndrome, and rheumatoid arthritis. Fatigue has been described by sufferers as 'incomprehensible' due to its unpredictable occurrence, lack of relationship to physical effort and different character as compared to tiredness. Fatigue that dissociates by quantum with disease activity represents a large health economic burden and unmet need to patients and to society.