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

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.

Allergic diseases as risk factors for Long‐COVID symptoms: Systematic review of prospective cohort studies

“…In the context of viral respiratory infections, innate immune responses activate innate lymphocytic cells of a type‐2 phenotype (ILC‐2) which release a range of cytokines associated with allergic diseases 55 . This process has been observed in COVID‐19 patients and linked with more favourable outcomes.…”

“…Other immunological (dys) regulation processes are also suspected to influence the development of LC, e.g., Th-17 or cytokine activity, in particular interleukin (IL) 6 53,54. In a recent systematic review and meta-analysis of 16 studies, Yin et al even postulate that increased IL-6 levels might predict LC 55.…”

Immune activation and immune-associated neurotoxicity in Long-COVID: A systematic review and meta-analysis of 82 studies comprising 58 cytokines/chemokines/growth factors

“…In addition, there was an observed elevation in lymphocytes and IL-6 in these patients (Yong, Halim et al 2023). Yin et al (2023) also reported a significant increase in IL-6 levels in LC patients compared to healthy controls (Yin, Agbana et al 2023).…”

“…However, the two meta-analyses that examined immune functions in LC did not provide a comprehensive examination of the immune profiles, including the neurotoxicity profile (Yin, Agbana et al 2023, Yong, Halim et al 2023. Therefore, a more extensive examination of cytokines/chemokines/growth factor profiles in LC would be instrumental in elucidating the mechanisms of this illness.…”

Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

“…6 Persistent inflammation, signposted by elevated blood concentrations of C-reactive protein and proinflammatory cytokines, has also been reported in people with long COVID. 7,8 The underlying causes of this inflammatory process nonetheless remain obscure. Dysregulation of the complement cascade has been implicated as a driver of inflammation in many diseases, including acute COVID-19.…”