Increased interleukin-6 is associated with long COVID-19: 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, the correlation between IL-6 and long COVID-19 is unknown. 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-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (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 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 patients. 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. 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 the “early stage” of long COVID-19.

Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism in SARS-CoV-2

“…Notably, subsegmental emboli had the lowest rate of persistence, while central emboli showed the highest rate of persistence; a higher rate of persistence of central emboli has already been described [35]. The higher level of IL-6 in patients with persistent thrombotic defects may instead be related to the persistence of symptoms in COVID-19 patients, which would be consistent with previous studies [36].…”

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

“…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 …”

“…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.…”

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.…”