In this study, we examined the link between the immune response during the acute phase of COVID-19 and the severity of subjective fatigue observed 6–9 months later. We found inverse correlations between plasma levels of TNFα and IL-1RA during the acute phase and the overall fatigue scores measured 6–9 months post-infection. Additionally, TNFα plasma levels during the acute phase of COVID-19 were inversely associated with physical fatigue scores 6–9 months post-infection, and the percentage of blood monocyte among white blood cells during the acute phase of COVID-19 was inversely associated with cognitive fatigue scores. Our analysis further revealed that IL-1RA and IFNγ plasma levels during the acute phase of COVID-19 predicted total fatigue scores 6–9 months post-infection. IFNγ plasma level measured during the acute phase of COVID-19 predicting physical fatigue 6–9 months post-infection. Notably, higher TNFα concentrations during the acute phase of COVID-19 were associated with a higher lack of awareness of cognitive fatigue 6–9 months post-infection and IL-1RA predicted fatigue awareness scores.
These results, suggest that inflammation reactions during the acute phase of COVID-19 may influence different long-term cognitive and fatigue profiles 12,17. On the one hand, people with high levels of inflammation during the acute phase would develop more significant cognitive sequelae in the long term, observable via problems with awareness of deficits, memory impairment 12 and executive impairment 3,19. On the other hand, people with a low level of inflammation in the acute phase would develop an increased subjective sensitivity in the long term to the sensation of fatigue and symptoms of depression 3,19. Our observations therefore do not fully corroborate the results observed in the literature describing a linear relationship between fatigue and inflammation levels. We observe here acute inflammatory mechanisms that could follow an inverted-U curve, with an over- or under-optimal acute reaction generating distinct sequelae. These observations are made possible by the prism of awareness of cognitive disorders/fatigue measured via the discrepancy between subjective complaints and objective measurements. This discrepancy between subjective complaint and objective measurement has already been mentioned in Ceban et al,8 where it was shown that a greater proportion of patients appeared to have cognitive difficulties when using objective measures compared with subjective measures. At the immune level in animals, McAfoose et al 20, established an inverted-U relationship between inflammatory cytokine markers and cognitive performance in memory and appraisal. According to these authors, a basal level of inflammatory cytokines is necessary for good cognitive function, but an excess or a low level would have neurotoxic consequences. Thus, contrary to the prediction that a high inflammatory state in the acute phase would be associated with high subjective chronic fatigue, we observe that a hypo-inflammatory state in the acute phase is associated with high subjective chronic fatigue and hyper-inflammation with cognitive difficulties in fatigue awareness. In this way, an optimised acute phase immune response to SARS-CoV-2 would produce few or no symptoms of long COVID 21. This interpretation is in line with Hartung, et al. 15 who suggested the possibility of 2 observable phenotypes in the post-COVID condition. First, a phenotype of patients displaying high fatigue and a phenotype of patients displaying cognitive disorders. We showed here that awareness of disorders observed 6–9 months post-infection and inflammatory levels measured in the acute phase of infection may be markers that could allow phenotyping patient trajectories in the context of COVID-19.
On this continuum of awareness of disorders, we had previously shown that levels of TNFα and monocytes measured during the acute phase of COVID-19 were associated with memory disorders and awareness of these disorders 6–9 months post-infection 22. This anosognosia of memory impairment was accompanied by hypoconnectivity of subcortical, cerebellar and hippocampal regions 6–9 months post-infection 12. In the context of post-COVID fatigue, Heine, et al. 4 also demonstrated morphometric changes in the basal ganglia 7–8 months post-infection. Other studies are currently showing the implication of TNFα plasma levels on the increased risk of developing a post-COVID condition in the longer term 23. Furthermore, it would appear that the persistence of high levels of TNFα, IL-6 and IL-1β seems to persist beyond the acute phase of COVID-19, in some cases two years after infection 21. This post-COVID trajectory could be associated with accelerated brain ageing 24 and the emergence of neurodegenerative pathologies 25.
Contrary to anosognosia, at the other end of the awareness continuum for disorders are individuals with severe, non-objectified complaints who exhibit a sub-optimal acute inflammatory response at the onset of infection. This idea of under-optimisation of the immune response is in line with the observations of Kervevan, et al. 26 who distinguished between patients with reduced immune responses and patients with increased immune responses in the post-COVID condition. It would also seem judicious to take into account that the pandemic, socio-economic conditions and pre-existing vulnerabilities could contribute to the appearance of an exacerbated awareness of cognitive disorders and post-COVID fatigue, whatever the severity of the disease in the acute phase of COVID-19 27. As shown by Miller and Maner 28 in other infectious contexts, pre-existing cognitive biases could make part of the population vulnerable to over-interpreting the danger represented by the contagiousness of the environment and the disease and activate parallel behavioural and immune reactions. Finally, between these two conditions of patients, there would exist a third category of people presenting subjective complaints which are objectified by the corroboration of processing speed capacities (defining a form of objective fatigue) 29.
Finally, the results of this study reveal the importance of distinguishing subtypes of fatigue because each fatigue dimension maintains specific links with immune markers 16,30. Dimensions of fatigue could explain variance in fatigue and cognitive symptoms between post-COVID individuals 31. The common denominator able to predict physical and total fatigue is IFNγ. The associations suggest that specific mechanisms are at work between IL-1RA and total fatigue; monocyte percentage and cognitive fatigue. Curiously, TNFα levels are associated with both total and physical fatigue. IFNγ levels may be related to subjective awareness of physical state while IL-1RA to a more global measure of fatigue dimensions. This raises several questions, such as how the different dimensions of fatigue evolve over time in parallel with individuals' socio-economic status and intrinsic vulnerabilities. Numerous synergies between fatigue, cognitive disorders, and the trajectory of neurodegenerative pathologies or myalgic encephalomyelitis remain to be investigated.
From the point of view of hospitalization subgroups, we observed that the blood monocyte percentage of patients hospitalised in intermediate care were associated with total and physical fatigue measured 6–9 months post-infection. Inflammatory responses measured in the acute phase were not predictive of chronic fatigue scores in this subsample. Among those hospitalised in intensive care, TNFα plasma levels were associated with total, cognitive and social fatigue scores measured 6–9 months post-infection. Curiously, IFNγ and IL-1RA plasma levels measured in the acute phase predicted total, cognitive, and social chronic fatigue scores. Interestingly, IFNγ was the only marker to predict chronic physical fatigue. These results suggest that the viral load has long-term repercussions, although the severity of the acute respiratory form does not fully explain the long-term cognitive and fatigue repercussions after infection.
This study has limitations, primarily the relatively small sample size for which we have applied statistical corrections. Although we have shown that our statistical power was sufficient we are aware of the limitations of our sample size. We suggest that studies with larger sample sizes should be carried out in the field of research investigated here in order to make this information more generalizable. In line with this limitation, the restriction of the analyses to hospitalized patients also limits the generalisation of the study to the general population. A second limitation relates, of course, to the discrepancy between subjective and objective fatigue, which must be a normal process up to a certain stage of difference. The first difficulty lies in the lack of definition of objective fatigue and, in fact, its measurement. A second difficulty lies in the quantification and categorisation of the normal process of discrepancy between subjective and objective complaints. Furthermore, although the French-language measure of subjective fatigue EMIF-SEP (MFIS in English) was initially validated on a population with multiple sclerosis, its use has already been extended to the COVID-19 study 32. Finally, the retrospective nature of the analyses could give rise to variance linked to confounding factors concerning the time between the acute phase and the 6–9 months post-infection measurements. This limitation is also a strength, as it allows us to visualise the effects of baseline immunity without SARS-CoV-2 treatment and its impact on long-term cognition.
In summary, fatigue is a clinical entity present in the majority of cases of post-COVID conditions. Circulating blood monocytes and certain cytokines secreted during the acute phase of COVID-19 are associated with different dimensions of fatigue, in particular physical and cognitive fatigue 6–9 months post-infection. In addition, fatigue awareness, defined as the difference between subjective and objective cognitive fatigue, appears to be associated with TNFα concentration and predicted by IL-1RA concentrations measured in the acute phase of SARS-CoV-2 infection. The evolution of immunity and dimensions of fatigue over time will need to be investigated in the future.