Table 1 Characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior

Physiosomatic symptoms

Disabling fatigue

Fatigue, lethargy, behavioral inhibition

Mental fatigue

Reduction of exploration

'Pacing' as an energy-conservation strategy

Reduced locomotor activity

Post-exertion malaise following mental/physical activities

Fatigability

A flu-like malaise

Malaise, flu-like symptoms

Hyperalgesia

Hyperalgesia

Muscle tension and pain

Muscle pain

Sleep disorders

Sleepiness

High incidence of autonomic symptoms

Probably yes, but not well documented

Failure to concentrate

Failure to concentrate

Memory disturbances

Memory disturbances

Gastrointestinal symptoms

-

Depressive symptoms

May occur when comorbid depression is present

Disinterest in social interactions

Anhedonia may occur when depression co-occurs

Anhedonia, or reduced intake of sweetened milk in rodent models

Sadness

Sadness

Anorexia/weight loss

May occur when comorbid depression is present

Anorexia and weight loss

Pyrexia

Slightly increased body temperature in a few patients

Pyrexia

Onset

Acute onset or insidious

Acute onset

Course

Waxing and waning or progressive course

Acute adaptive response

Chronic course (>6 months)

Maximal 19 to 43 days

Energy metabolism

Mitochondrial dysfunction, lowered ATP, abnormally high lactate levels

Is an adaptive behavioral response aiming to conserve energy and to redirect energy to immune cells to combat the pathogens

Is an adaptive response to counteract negative energy balance

Impaired oxidative phosphorylation

Sickness behavior plays a key role in the resolution of acute inflammation

When the energy stores are depleted and the acute inflammation is not resolved, chronic inflammation ensues

Structural mitochondrial abnormalities

Accelerated glycolysis; decreased phosphocreatine synthesis rates following exercise

Pathways

(Sub)chronic inflammation with increased proinflammatory cytokines

Acute inflammation with increased proinflammatory cytokines

Cell-mediated immune (CMI) activation

Probably activated

Simultaneous T helper (Th)1 and Th2 responses

-

Multiple immune dysfunctions

-

Lowered antioxidant levels

-

Reactive oxygen species (ROS)/reactive nitrogen species (RNS)

Probably yes

Damage by oxidative and nitrosative stress (O&NS) to lipids, DNA, proteins

-

Autoimmune responses to O&NS modified neoepitopes

-

Autoimmunity

-

Reduced hypothalamic-pituitary-adrenal (HPA) axis function in some patients

Enhanced HPA axis activity (part of compensatory (anti)-inflammatory reflex system (CIRS))

Triggers

Multiple, not well defined

Acute, highly defined

Long-term effects of acute infection

Acute pathogens and tissue injury

Disease exacerbated by infections

-

Disease exacerbated by psychological stress

-

Chronic medical inflammatory illness

-

Chronic neuroinflammatory disorders

-

Autoimmune disorders

-

Sometimes no trigger factor is observed

Is always a response to a defined trigger

Risk factors

IgG, IgG1 and IgG3 deficiencies

-

Immune gene polymorphisms

-

Reduced ω3/ω6 ratio

-

General

Inflammation, O&NS and mitochondrial-related chronic progressive disorder

Inflammation-induced adaptive behavioral and CIRS response that is conserved through evolution

Janus face

Bad 'chronic' side: a chronic disorder with positive feedback loops between inflammatory responses and autoimmune processes

Beneficial 'acute' side: supports inflammation, redirects energy to immune cells, conserves energy and prevents negative energy balance, helps eradicating the trigger, and has anti-inflammatory effects