Chronic Fatigue Syndrome, Long Coronavirus Disease 2019, and Cognition: A Complex Conundrum

Dear Editor, Chronic fatigue syndrome (CFS, also known as myalgic encephalomyelitis) is a neuropsychiatric condition characterized by profound fatigue despite adequate rest. There is a hidden but rising burden of CFS worldwide, especially in the wake of coronavirus disease 2019 (COVID-19), in the form of Long COVID-19.[1] Although the underlying pathophysiology for CFS is still unknown, theories have been proposed highlighting the emergence of CFS in the wake of a viral infection. The number of patients with CFS, which had been rising gradually over the years, saw a recent spike following the COVID-19 pandemic. Some estimates report that the worldwide burden of CFS, of around 50 million people, will be added to by 100 million more from Long COVID-19.[2] Recent reviews have reported that CFS is seen in almost half of all Long COVID-19 patients (patients with symptoms persisting 3 months after the acute infection).[1] Long COVID-19 is seen in 10%-50% of all patients with acute COVID-19 infection and commonly includes symptoms of fatigue, exacerbation of pain, breathlessness, cognitive dysfunction (brain fog), etc., with a drastic impact on functioning.[3] Literature reports significant neurocognitive symptoms in both CFS and Long COVID-19. Cognition stands at the crossroads of pain and fatigue on one end, and domains of functional impairment on the other hand. Investigations into its impact on functioning as a direct causative factor or as a moderator are still sparse. An interesting recent study has explored this caveat. The study aimed to untangle the complex interactions between various symptoms and their impact on cognitive functioning in individuals with CFS (Oosterman et al., 2025). The authors used categorical linear regression and moderation analysis to find independent influences of fatigue and pain on cognitive functions, along with potential moderating effects of age and symptom duration. In a large sample, they measured the variables by using daily recordings capturing real-time fluctuations, added elements of practical relevance via functioning assessment, and used objective neuropsychological tests for cognitive function assessment.[4] However, their findings should be interpreted in the light of some limitations. These include doubts about the quality of the data collection, limitations in assessment tools used, missing out on potential confounders (e.g., psychotropics), and significant multicollinearity between variables used for regression analysis. In light of the rising burden of CFS and Long COVID-19, further investigations into factors influencing the functioning of these individuals are of great importance. With ever-evolving definitions of these conditions and a limited understanding of the pathophysiological mechanisms, looking at some clinically relevant targets could help shape future treatment focus. The prominent role of cognition in these conditions, along with its impact on day-to-day functioning, makes it one such target for future research. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.