Which interleukin (IL) is most commonly associated with COVID-19?

Interleukin-6 (IL-6) is the Primary Interleukin Associated with COVID-19

IL-6 is the most clinically significant interleukin in COVID-19, serving as both a key driver of cytokine storm and a predictor of disease severity and mortality. 1

Role of IL-6 in COVID-19 Pathophysiology

IL-6 elevation is central to the cytokine release syndrome ("cytokine storm") that characterizes severe COVID-19. 1 The pathophysiologic sequence involves:

• SARS-CoV-2 binds to ACE2 receptors in respiratory epithelium, triggering immune cell activation (T cells, B cells, macrophages) that produce pro-inflammatory cytokines 1
• IL-6 levels increase discrepantly with D-dimer elevations—IL-6 appears elevated around day 13 of disease onset, while D-dimer levels are already 10-fold increased by that time 1
• Higher IL-6 expression levels are found in ICU patients compared to non-ICU patients 1
• Monocyte and macrophage hyperactivation contributes to increased circulating IL-6, particularly in patients with ARDS 1

IL-6 as a Prognostic Biomarker

Peak IL-6 levels are independent predictors of in-hospital mortality and disease severity. 2, 3

• Peak IL-6 demonstrated superior predictability of in-hospital mortality (AUC 0.875) compared to IL-6 at admission (AUC 0.794) or D-dimer levels 2
• Non-survivors had significantly higher maximal IL-6 values compared to survivors (720 vs 336 pg/mL, p=0.01) 3
• IL-6 maximal value had significant predictive value for ICU mortality (AUROC 0.73, p=0.01) 3
• Repeated IL-6 measurements over time show significant differences between survivors and non-survivors (p=0.001) 3

Other Interleukins in COVID-19

While IL-6 is predominant, multiple other interleukins are elevated in COVID-19 patients:

• IL-1β, IL-2, IL-7, IL-8, IL-9, and IL-10 are all increased in COVID-19 patients, with higher levels in ICU patients 1
• IL-1 induces IL-6 and assists in acute phase CRP synthesis 4
• However, IL-6 levels are significantly higher in severe versus mild COVID-19 and serve as the independent predictor of illness severity 4, 5

Therapeutic Implications

Tocilizumab, an IL-6 receptor antagonist, is FDA-approved for hospitalized COVID-19 patients receiving systemic corticosteroids and requiring supplemental oxygen or mechanical ventilation. 6

• The NHC guidelines recommend tocilizumab in severe COVID-19 with extensive bilateral lung disease and elevated IL-6 1
• Tocilizumab blocks IL-6 signal transduction, potentially interrupting cytokine storm progression 5, 7
• However, evidence shows tocilizumab did not decrease in-hospital mortality after adjustment for IL-6 levels (OR 1.00, p=0.998), and was associated with significantly higher fungal infections (13.0% vs 1.1%, p<0.001) 2
• Current evidence remains insufficient to support tocilizumab use outside clinical trials according to some guidelines 1

Clinical Monitoring Recommendations

For hospitalized COVID-19 patients, IL-6 should be measured at admission and serially monitored in severe cases to identify high-risk patients. 3

• Assess IL-6 alongside D-dimer, CRP, ferritin, LDH, and lymphocyte count 1, 3
• Peak IL-6 values >336 pg/mL indicate significantly increased mortality risk 3
• Rising IL-6 trends over time correlate with poor prognosis and should prompt escalation of care 3

Common pitfall: IL-6 elevation alone should not drive treatment decisions without considering the complete clinical picture, including respiratory status, other inflammatory markers, and timing of disease course 1, 4