Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Abstract

Background The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown. Methods We measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)–attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods. Results During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor–α (1.14-fold higher mean ratio [95% confidence interval {CI}, 1.01–1.28]; P = .028) and interferon-γ–induced protein 10 (1.28-fold higher mean ratio [95% CI, 1.01–1.62]; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio [95% CI, .98–1.70]; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio [95% CI, 1.11–1.86]; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms. Conclusions Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.

Plasma markers of neurologic injury and systemic inflammation in individuals with self-reported neurologic post-acute sequelae of SARS-CoV-2 infection (PASC)

“…We log-transformed all biomarkers to reduce influence of outliers and to permit interpretation of fold-changes. As in prior work, 38 we compared the ratio of the mean transformed values for each biomarker between those with and without persistent neurologic symptoms using linear mixed effects models with terms for PASC, time period (early versus late recovery), and their interaction. This approach permits comparison of the values at early and late time points as well as assessment of whether trajectories in marker values differ between those with and without persistent symptoms.…”

“…32–37 Recent work has suggested that immune activation might play a role in PASC. 13,38 Inflammatory markers such as interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and interferon-gamma induced protein (IP)-10 have been associated with ongoing symptoms. 38 These markers, particularly IL-6, may correlate with long-term neuropsychiatric manifestations of COVID-19.…”

“…13,38 Inflammatory markers such as interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and interferon-gamma induced protein (IP)-10 have been associated with ongoing symptoms. 38 These markers, particularly IL-6, may correlate with long-term neuropsychiatric manifestations of COVID-19. 14 However, there are limited data on the relationship between biomarkers of inflammation, neurologic injury, and neurologic symptoms during the post-acute period.…”

“…In a prior analysis utilizing a broad case definition of PASC (i.e., presence of any 1 of 32 COVID-19-attributed symptoms), we found that differences in levels of inflammatory markers predicted the presence of symptoms >90 days following COVID-19. 38 In the current report, we investigated a more specific outcome defined by 5 self-reported neurologic symptoms. We evaluated markers of CNS injury and systemic inflammation among those with and without this more specific phenotype.…”

Long-term immunologic effects of SARS-CoV-2 infection: leveraging translational research methodology to address emerging questions

“…Studies that have evaluated persistent inflammation have suggested potential elevations in biomarkers, 116,127 although no clear immunologic pathways have yet to be consistently implicated. We recently demonstrated that during early recovery (i.e.…”