In October 2021, the World Health Organization (WHO) convened a multidisciplinary panel of experts to establish a consensus on the term "post-COVID-19 condition." This condition is defined as occurring in individuals who have a documented history of probable or confirmed SARS-CoV-2 infection, typically manifesting approximately 3 months after the onset of COVID-19 symptoms and persisting for a minimum of 2 months, with no other diagnosis explaining the symptoms [3].
Clinical and laboratory research on SARS-CoV-2 have made significant strides in contribution to our understanding of the pathophysiology underlying the infectious mechanisms, as well as its potential long-term sequelae [5]. Although COVID-19 is primarily a lung disease, evidence derived from pertinent literature underscores its impact on a broader array of body systems and organs, including but not limited to the cardiovascular system, central nervous system, thromboembolic incident, hemorrhagic incident, renal system, gastrointestinal tract, hepatic system, biliary system, pancreatic system etc. [6], [7].
PASC encompasses a spectrum of symptoms. Individuals experiencing Long COVID report persistent multisystem manifestations and notable disability. Many months post-infection, a considerable portion of patients have yet to achieve full recovery, particularly in relation to systemic and cognitive and neurological signs and symptoms, leading to prolonged impairment in work capacity and a continued burden of significant symptoms. The patient presented in this study exhibits such symptoms, which bring about obstacles that make him incapable of working, and partaking in routine and social activities [8], [9]. Furthermore, there are suggestions for a correlation between infection severity and the likelihood of developing long-term complications. In this case, the patient had a second reinfection which was more symptomatic and more severe than the first one [10].
Globally, a minimum of 65 million individuals are affected by long COVID, with this figure likely being an underestimate, extrapolated from over 651 million documented COVID-19 cases worldwide; the actual number may be higher than only 10% of all cases, as it is anticipated to be substantially higher due to numerous undocumented cases [11]. In some countries, there are medical institutions to identify and register PASC correctly, e.g. multidisciplinary long-COVID outpatient clinics in Germany, i.e. “Long-COVID-Ambulanz” [12].
The patient was admitted to the long-COVID outpatient clinic in April 2023 after strong indications and concrete evidence for his post-infectious symptoms. Although he never had any memory problems, he complains of trouble finding words, as well as poor memory and concentration which are unresolved and unimproved after many months [13]. Brain fog is a common long COVID complication which describes a range of symptoms, such as cognitive decline, inability to concentrate, and memory lapses affecting both short-term and long-term recall [14]. The patient scored a 24/30 in Montreal Cognitive Assessment (MoCA) [15] which indicated deficits in concentration and memory.
Moreover, he scored 11 points on the Hospital Anxiety and Depression Scale (HADS-D) for anxiety, indicating severe symptoms. and 12 points for depression, also indicating severe symptoms [16]. In addition, the Fatigue Scale for Motor and Cognitive Functions (FSMC) score of 82 suggests strong fatigue [17]. These findings collectively suggest a complex interplay of psychological distress, sleep disturbances, and fatigue in long-haulers, highlighting the need for comprehensive management strategies addressing both physical and mental health aspects [18]. It is also worth noting that the patient eventually found himself with Middle-of-the-night insomnia (MOTN), more need to sleep during the day, and feeling unpowered in the morning, as his Epworth Sleepiness Scale (ESS) score of 14 falls within mild to moderate sleep-related disorders [19].
Several crucial factors influence post-COVID depression. Among the identified biomarkers, the most frequently cited include heightened levels of interleukin 6 (IL-6), soluble interleukin 6 receptor (sIL-6R), interleukin 1 β (IL-1β), tumor necrosis factor α (TNF-α), interferon gamma (IFN-γ), interleukin 10 (IL-10), interleukin 2 (IL-2), soluble interleukin 2 receptor (sIL-2R), C-reactive protein (CRP), Monocyte Chemoattractant Protein-1 (MCP-1), serum amyloid a (SAA1), metabolites of the kynurenine pathway, in addition to reduced brain derived neurotrophic factor (BDNF) and tryptophan (TRP) levels. These biomarkers identified by us suggest a similar etiopathogenesis of post-COVID depression akin to the leading inflammatory hypothesis of Major Depressive Disorder (MDD) [20] [21].
Apart from the impact of inflammatory markers and cytokines, the neurobiology of post-COVID depression involves the central nervous system (CNS) damage mediated by indirect immune-inflammatory responses and potential direct viral neuroinvasion. The virus binds to ACE2 receptors, entering host cells and triggering an immune response characterized by increased production of pro-inflammatory cytokines. This systemic inflammation, coupled with potential disruption of the blood-brain barrier, allows peripheral inflammatory factors to enter the CNS, inducing neuroinflammation. Additionally, the psychological stressors associated with COVID-19, such as social isolation and uncertainty, can activate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, further contributing to depressive symptoms through immune modulation in the CNS. Therefore, a combination of immune-neuroendocrine mechanisms and psychological stressors likely underlies post-COVID depression [22].
Studies and reports on various intensity and duration in the long haulers are essential in the research. The patient in our case still suffers from 2 of the most common post-COVID conditions, namely fatigue along with myalgia which are still peculiarly unresolved and unimproved after many months [23], [24]. There are postulations and ongoing investigations about potential mechanisms for long COVID, e.g. on mitochondrial dysfunction induced by SARS-CoV-2. Patients recovering from COVID-19 may experience chronic fatigue during exercise despite no apparent heart or lung issues, posing a challenge in managing long COVID due to the lack of effective treatments. Mitochondrial dysfunction, triggered by SARS-CoV-2 infection, increases oxidative stress and leads to cell death, potentially contributing to long COVID symptoms. Additionally, viral proteins disrupt mitochondrial function, causing immune cell overreaction and inflammation. Although the exact roles of mitochondrial damage and inflammatory responses in long COVID are still being explored, targeting mitochondrial function emerges as a promising therapeutic approach. Compounds like antioxidants and mitochondrion-targeting peptides show potential in pre-clinical studies, but further research is necessary to assess their safety and efficacy in treating mitochondrial dysfunction in long COVID. Managing long COVID remains challenging, highlighting the importance of understanding mitochondrial dysfunction in developing effective treatments for this condition [25].
Viral open reading frames (ORFs), e.g. ORF-9b and ORF-6 are pivotal in disrupting the mitochondrial regulation of the immune response during SARS-CoV-2 infection, antagonizing the RIG-I-MAVS antiviral type I interferon response [26]. Additionally, mitochondrial reactive oxygen species (mtROS) contribute to cellular dynamics by exacerbating the inflammatory response, a critical aspect in COVID-19 pathogenesis [25]. SARS-CoV-2 hijacks mitochondria to form double-membrane vesicles, compromising mitochondrial membrane integrity and releasing mtDNA and mitochondrial cardiolipin into the cytosol, serving as damage-associated molecular patterns (DAMPs) [27]. These circulating DAMPs contribute to cytokine storm (Fig. 1).
Further insights into the pathophysiology of post-exertional malaise in long COVID patients reveal skeletal muscle impairments as key contributors. These impairments include severe exercise-induced myopathy, metabolic disturbances, and tissue infiltration of amyloid-containing deposits in skeletal muscles. Post-exertional malaise, characterized by symptom exacerbation following physical or mental exertion, poses a significant challenge in managing post-COVID fatigue. This phenomenon limits exercise capacity and available rehabilitation options while diminishing their effectiveness [28], [29].