Increased Interleukin-6 is Associated with Long COVID-19: Evidence from a Systematic Review and Meta-analysis

Abstract

Abstract Background: Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, no correlation between IL-6 and long COVID-19 is known. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19. Methods: Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran's Q test and the Higgins I-squared (I2) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-post-acute sequelae of SARS-CoV-2 infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger's test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results. Results: An increase in IL-6 levels was observed after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30 – 32.54 pg/ml, I2 = 100%, p < 0.01) for long COVID-19. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75 – 13.75 pg/ml, I2 = 100%, p < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22 – 6.42 pg/ml, I2 = 88%, p = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups (long COVID-19 versus healthy controls, p = 0.24; long COVID-19 versus non-PASC, p = 0.31). Conclusions: This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on “early stage” of long COVID-19.