Long-term COVID syndrome (the post-acute sequelae of SARS-CoV2 infection) is a growing public health problem. There is increasing evidence that a significant proportion of COVID-19 survivors develop a chronic and debilitating set of multisystem signs and symptoms [22]. It has a negative impact on society, the economy, and patients' quality of life, physical functioning, work participation, care dependency, and activities of daily living [23]. Long COVID has been associated with over 60 physical and psychological symptoms [24]. Profound fatigue is one of the most commonly reported symptoms in post-acute COVID-19 patients, with a prevalence of 52% within 3 weeks of hospital discharge [25]. The persistence of fatigue following an acute COVID infection is also associated with episodes of overwhelming exhaustion, depressive symptoms, poor sleep quality, memory impairment and low energy levels, all of which influence quality of life [26]. There is currently no specific pharmacotherapy available for the treatment of long COVID. Recently, efforts have been made to understand the cause, epidemiological burden, and potential biomarkers of long COVID [27].
This study aimed to evaluate the efficacy of the CelWel product in improving long COVID symptoms, particularly persistent fatigue in COVID-19 survivors. The findings revealed that all patients experienced clinically significant fatigue prior to CelWel treatment, as evidenced by a higher FSSQ score (≥ 4) for each question as well as an overall FSSQ score (> 40). After 14 days of treatment, CelWel significantly reduced FSSQ scores. The C19-YRS test was also used in this study to assess the effect of CelWel on post-COVID symptoms. Results showed that CelWel significantly improved some symptoms related to the body's functions and structures, including fatigue and limitations in activities. Therefore, CelWel was found to be an effective health supplement to ameliorate long COVID symptoms, including persistent fatigue in COVID-19 survivors. However, its exact mechanism for reducing persistent fatigue and other long COVID symptoms is unknown.
It has recently been suggested that an ongoing low-grade pro-inflammatory response may be linked to the development of post-COVID symptoms [28]. As mentioned in the introduction, long COVID and ME/CFS share some clinical manifestations. ME/CFS pathophysiology has been linked to immune function dysregulation, hyperinflammation, oxidative stress, and autoimmunity [29]. Furthermore, ME/CFS-associated post-infectious fatigue syndrome has been linked to other acute viral and bacterial infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), Epstein-Barr virus (EBV), human parvovirus (HPV)-B19, and Q fever [23, 30]. Moreover, neuroimmunological involvement is a crucial precondition for long-term fatigue [31, 32]. IFN-α and other cytokines of the innate immune response have been shown to promote behavioural changes in medically ill patients, including fatigue-related symptoms, by acting on the basal ganglia nuclei [33]. Evidence from studies with neuroimmunological disorders suggests strong connections between structural brain abnormalities and fatigue severity, such as changes in the basal ganglia [34, 35] and frontoparietal white matter [36] associated with fatigue in multiple sclerosis. New structural images of the brain in patients with post-COVID syndrome revealed abnormalities in the thalamus and basal ganglia, which are associated with post-COVID fatigue [26].
With these similarities between long-term COVID and ME/CFS, as well as the neuroimmunological disorders associated with fatigue, it is plausible that SARS-CoV-2 infection may promote long-term COVID-19 symptoms, particularly fatigue, by inducing an inflammatory state and a dysregulated immune response. We measured plasma levels of IL-2, IFN-γ, and CCL4 (MIP-1β) to see if CelWel treatment affected patients' immunogenic profiles. CelWel had no effect on the proinflammatory cytokine IL-2, but it did downregulate IFN-γ and CCL4 (MIP-1β). In addition to that, after CelWel treatment, the PASC score decreased in 11 patients, indicating a reduction of the inflammatory state by preventing the production of proinflammatory cytokines in patients with prolonged COVID-19. However, four patients had the opposite trend in PASC score and would have required a large or very prolonged dose of CelWel to improve their PASC score. During the study period, no patients reported adverse events or abnormal clinical findings in laboratory parameters.
The limitations of the present study are the inability to measure other inflammatory cytokines, the non-randomized, small sample size, and the fact that the study was conducted in a single center. A future study should require comparing the effects of CelWel with placebos or standard NSAIDs on a large cohort for an extended period.