Associations of elevated pro-inflammatory cytokines Interleukin-6, C-reactive protein and tumor necrosis factor alpha with neuropsychiatric symptoms of post-acute sequelae of COVID-19 (PASC)

Background: This cross-sectional study investigated the prevalence of clinically elevated interleukin 6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α), and explored their associations with sociodemographic, medical, and neuropsychiatric symptoms of Post-acute Sequelae of COVID-19 (PASC). Method: Participants were assessed for acute and current COVID-19 symptomatology, measures of distress and neuropsychological testing approximately 6 months (mean 183 days, SD 137 days, range 30–598 days) after acute infection. Serum IL-6, CRP and TNF-α levels were drawn from 80 participants concurrently. Laboratory cutoffs were used to determine elevated IL-6, CRP and TNF-α. Participants with elevated markers were compared to those in the normal range on demographic, medical, and neuropsychiatric measures. Results: Of those with available results, 34 % had elevated IL-6, 32 % had elevated CRP and 16 % had elevated TNF-α. Elevated IL-6 was associated with older age (p = 0.02), more medical comorbidities (p = 0.02), particularly obesity (p < 0.001), greater acute COVID-19 severity (p < 0.001), fatigue (p = 0.02), anxiety (p < 0.05) and post-traumatic stress symptoms (p = 0.04), and lower scores on tests of attention (p = 0.01), psychomotor speed (p < 0.05), and executive function (p = 0.02). Elevated IL-6 was more common in those seeking care for PASC (p < 0.01). Elevated CRP was associated with more medical comorbidities (p = 0.01), including obesity (p = 0.01), increased fatigue (p = 0.01) and depression symptoms (p = 0.01) and diminished quality of life (=0.05). Elevated TNF-α was associated with obesity (p = 0.02), less time since infection (p = 0.04) and lower vaccination rates (p = 0.04). Conclusion: Elevation of inflammatory cytokines IL-6 and CRP was present in over one-third of participants approximately 6 months after acute COVID-19. Elevated IL-6, and less frequently, CRP, was associated with multiple neuropsychiatric PASC symptoms. Findings support further research into these pro-inflammatory cytokines as clinical markers, and as potential targets for neuropsychiatric PASC treatment.