Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19

Abstract

Objective and design: Fatigue is a prominent symptom in the general population and may follow viral infection, including SARS-CoV2 infection which causes COVID-19. Chronic fatigue lasting more than three months is the major symptom of the post-COVID syndrome (known colloquially as long-COVID). The mechanisms underlying long-COVID fatigue are unknown. We hypothesized that the development of long-COVID chronic fatigue is driven by the pro-inflammatory immune status of an individual prior to COVID-19.

Subjects and methods: We analyzed pre-pandemic plasma levels of IL-6, which plays a key role in persistent fatigue, in N = 1274 community dwelling adults from TwinsUK. Subsequent COVID-19-positive and -negative participants were categorized based on SARS-CoV-2 antigen and antibody testing. Chronic fatigue was assessed using the Chalder Fatigue Scale.

Results: COVID-19-positive participants exhibited mild disease. Chronic fatigue was a prevalent symptom among this population and significantly higher in positive vs. negative participants (17% vs 11%, respectively; p = 0.001). The qualitative nature of chronic fatigue as determined by individual questionnaire responses was similar in positive and negative participants. Pre-pandemic plasma IL-6 levels were positively associated with chronic fatigue in negative, but not positive individuals. Raised BMI was associated with chronic fatigue in positive participants.

Conclusions: Pre-existing increased IL-6 levels may contribute to chronic fatigue symptoms, but there was no increased risk in individuals with mild COVID-19 compared with uninfected individuals. Elevated BMI also increased the risk of chronic fatigue in mild COVID-19, consistent with previous reports.

Keywords: BMI; Chronic fatigue; IL-6; Inflammation; Long-COVID.

Fig. 1

Participant flow diagram. CoPE COVID-19 Personal Experience Questionnaire CFQ Chadler Fatigue Scale

Fig. 2

Association between fatigue and pre-pandemic levels of IL-6 and current levels of BMI. First panel shows unadjusted IL-6 values, second panel shows values undusted for age, sex, BMI, and COVID-19 status (via residuals). IL-6 values or the residuals have been transformed to achieve normal distribution

Fig. 3

Prevalence of different BMI classes among COVID-19-positive participants with and without chronic fatigue. BMI groups have been defined as the following: underweight (BMI < 18.5; n = 6), normal weight (BMI > 18.5 and < 25; n = 115), overweight (BMI > 25 and < 30; n = 102), and obesity (BMI ≥ 30; n = 59). The difference in the prevalence of the BMI groups is statistically significant (χ² = 8.3, df = 3, p value = 0.040)