**2. Pathophysiology of post-COVID-19 fatigue**

Typically, across various infections, symptoms of fatigue persist long after the onset of the disease [18]. Although the characteristics of chronic fatigue commonly associated with post-infectious diseases such as post-COVID-19 remain controversial, the manifestations remain similar to other post-infectious diseases irrespective of the pathogen. According to Poenaru et al. [17], the proposed mechanism of chronic fatigue in post-infection is likely multifactorial.

#### **2.1 Immune/inflammatory mechanisms**

In post-infectious fatigue, the immune system appears to be impacted by the pathogen [13]. The process remains unclear and can involve multiple pathways. A proposed mechanism is that during acute infection by the COVID-19 virus, tissue damage is sustained which results in the activation of auto-reactive bystander cells and molecular mimicry [16]. For example, in patients with severe COVID-19, there has been a substantial production of anti-nuclear antibodies. Also, rheumatic factor was detected among such individuals suggesting that there is increased activation of auto-reactive B-cells [16]. However, in chronic fatigue syndromes, antibodies that work against muscarinic and adrenergic receptors have been the syndrome but no auto-antibody has been linked to chronic antibodies [16].

Another mechanism purports that the deregulation of cytokine networks may play a role in chronic fatigue [8, 22]. A study on encephalitis detected those increased levels of pro-inflammatory cytokines were observed from the acute phase and remained consistently elevated 30 days post-infection within the central nervous system [16, 17]. However, evidence found no significant association between cytokine levels and chronic fatigue. Better still, new evidence suggested that cytokine signaling was more significant [16].

#### **2.2 Mitochondrial function**

Within the muscle tissue, alterations in mitochondrial structure, metabolism, and energy production may be associated with chronic fatigue [8, 11, 17]. Mitochondrial degeneration, pleomorphic features, and structural abnormalities were found in muscles of individuals diagnosed with post-viral symptoms [16]. From the onset of symptoms, mitochondrial enzymes are involved in the inflammatory and antioxidant pathways due to their involvement in peripheral vasodilation and autonomic regulation of the cardiovascular system [16]. This mechanism has not been evidence enough to link post-infectious chronic fatigue with mitochondrial dysfunction [8]. Also, a clear logical way to explain the pathway of lasting mitochondrial abnormalities among post-infectious individuals is also lacking [8].

#### **2.3 Central nervous system involvement**

Mental health symptoms such as sleep disorders and post-anxiety stress disorders commonly with chronic fatigue may reflect impairment of the central nervous system [21]. *COVID-19 Pandemic, Mental Health and Neuroscience - New Scenarios for Understanding…*

Many viruses, including coronaviruses, have been shown to cause damage to the CNS tissue [11, 21]. For example, SARS-CoV1, as well as COVID-19, has been associated with edema, neuronal degeneration, demyelination, and necrosis resulting in an increased risk for cerebral ischemic events. In addition, a high proportion of rapid eye movements and alpha electroencephalographic sleep disorders were found among SARS survivors who had chronic fatigue [16]. This is a common mechanism behind sleep disorders in post-infectious fatigue. Although this mechanism has been defined, the causal relationship between the infection, altered CNS structure, and chronic fatigue still remain unclear (**Figure 1**) [16].
