ABSTRACT
An increasing number of young and previously fit and healthy people who did not require hospitalisation continue to have symptoms months after mild cases of COVID-19. Rehabilitation clinics are already offering cognitive behavioural therapy (CBT) as an effective treatment for long COVID and post-COVID-19 fatigue syndrome based on the claims that it is effective for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-the most common post-infectious syndrome-as no study into the efficacy of CBT for post-COVID-19 fatigue syndrome has been published. Re-analyses of these studies, however, showed that CBT did not lead to objective improvements in heterogeneous groups of ME/CFS patients, nor did it restore the ability to work. The group of patients with long COVID and post-COVID-19 fatigue syndrome, on the other hand, is homogeneous. We therefore analysed the Dutch Qure study, as it studied the efficacy of CBT in a homogeneous group of patients who developed Q-fever fatigue syndrome-which affects up to 30% of patients-after the largest reported outbreak of Q-fever, to see if CBT might potentially be an effective treatment for long-haulers after COVID-19 infection. Our reanalysis found that the Qure study suffered from many serious methodological problems, which included relying on one subjective primary outcome in a study without a control group for the non-blinded CBT treatment group, using a post hoc definition of improvement, waiting 2 years before publishing their objective actometer results and ignoring the null effect of said results. Moreover, only 10% of participants achieved a clinically meaningful subjective improvement in fatigue as a result of CBT according to the study's own figures. Consequently, CBT has no subjective clinically meaningful effect in nine out of every ten patients that are treated with it. Additionally, the subjective improvement in fatigue was not matched by an improvement in disability, even though the disability was fatigue related according to the researchers. On top of this, CBT did not lead to an objective improvement in physical performance. Therefore, it cannot be said that CBT is an effective treatment for Q-fever fatigue syndrome either. It seems therefore unlikely that CBT will reduce disability or lead to objective improvement in long COVID or in post-COVID-19 fatigue syndrome.
ABSTRACT
There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.