Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic diseases that severely impact a person’s ability to function at home and work. Together, these diseases affect hundreds of millions of people worldwide. The incidence of chronic fatigue in the year after acute COVID-19 infection is 4 to 5 times higher than in comparable non-COVID controls or individuals with influenza. Risk factors for long COVID include old age, being female, lower socioeconomic status, and a more severe acute infection. The estimated worldwide prevalence of long COVID varies between 60 and 400 million people, resulting in a significant societal burden because of decreased quality of life.
ME/CFS often begins with an acute, infectious-like disease in previously healthy young people. It affects 3.1 million individuals in the United States alone. It is associated with indirect and direct costs estimated at $36 to $51 billion annually.
Several biological abnormalities have been implicated in both ME/CFS and long COVID, including residual viral antigens, endothelial dysfunction, serotonin deficiency, and autonomic dysfunction. These abnormalities can cause cognitive impairment, social withdrawal, and fatigue. One observed behavioural response is sickness behaviour, which results from immune activation, specifically through the release of inflammatory molecules like cytokines. This reaction triggers behaviour and physiological changes such as decreased brain metabolism and rupture of the blood-brain barrier, specifically in regions like the hippocampus and cortex.
Neuroinflammation plays an important role in sickness behaviour. It stimulates the innate immune cells in the brain, like astrocytes and microglia, in response to injury, inflammation, or infection. Neuroinflammation can be initiated within the brain or triggered by systemic signals, which reach the brain via nerve and chemical-based pathways. Cytokines in the blood can act on areas that lack the blood-brain barrier or cross into the brain where the barrier has been compromised by inflammation. Additionally, peripheral inflammation may stimulate sensory nerves like the vagus nerve, transmitting inflammatory signs to the brainstem and initiating a neuroimmune response.
Individuals with ME/CFS and long COVID often exhibit a cerebral and systemic hypometabolic state, reduced brain energy production, and altered blood metabolites. These metabolic changes are regulated by two main signaling pathways: mTOR and AMPK. AMPK supports energy-efficient catabolic activity, while mTOR promotes anabolic activity. Under stress conditions, AMPK suppresses mTOR to preserve energy balance.Â
Beyond metabolic abnormalities, the duration and nature of symptoms may differ between diseases due to distinct underlying mechanisms. The ongoing existence of infectious agents and/or molecular residues is linked with both long-term COVID and severe acute infection. Some chronic RNA viruses, such as Ebola virus, Zika virus, hepatitis C virus, and retrovirus, are known to persist in the body for years. Similarly, SARS-CoV-2 may leave tissue reservoirs that remain for extended periods after the acute phase of COVID-19.
In contrast, there is limited evidence that a novel, single infectious agent can cause ME/CFS. ME/CFS is considered a post-acute infection syndrome (PAIS) that can be triggered by multiple infectious agents. Diagnostic tools for ME/CFS may help assess both metabolic and immune responses to a variety of pathogens.
Both ME/CFS and long COVID are affecting millions of individuals and imposing enormous economic and societal costs. It is evident that multiple underlying biological abnormalities contribute to the symptoms and their persistence in these debilitating diseases.
Reference: Komaroff AL, Dantzer R. Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Cell Rep Med. 2025;6(8):102259. doi:10.1016/j.xcrm.2025.102259
