The Behaviour of IL-6 and Its Soluble Receptor Complex during Different Waves of the COVID-19 Pandemic

In late December 2019, SARS-CoV-2 was identified as the cause of a new pneumonia (COVID-19), leading to a global pandemic declared by the WHO on 11 March 2020, with significant human, economic, and social costs. Although most COVID-19 cases are asymptomatic or mild, 14% progress to severe disease, and 5% develop critical illness with complications such as interstitial pneumonia, acute respiratory distress syndrome (ARDS), and multiple organ dysfunction syndrome (MODS). SARS-CoV-2 primarily targets the respiratory system but can affect multiple organs due to the widespread presence of angiotensin-converting enzyme 2 (ACE2) receptors, which the virus uses to enter cells. This broad distribution of ACE2 receptors means that SARS-CoV-2 infection can lead to cardiovascular, gastrointestinal, renal, hepatic, central nervous system, and ocular damage. The virus triggers the innate and adaptive immune systems, resulting in a massive cytokine release, known as a "cytokine storm", which is linked to tissue damage and poor outcomes in severe lung disease. Interleukin-6 (IL-6) is particularly important in this cytokine release, with elevated levels serving as a marker of severe COVID-19. IL-6 is a multifunctional cytokine with both anti-inflammatory and pro-inflammatory properties, acting through two main pathways: classical signalling and trans-signalling. Classical signalling involves IL-6 binding to its membrane-bound receptor IL-6R and then to the gp130 protein, while trans-signalling occurs when IL-6 binds to the soluble form of IL-6R (sIL-6R) and then to membrane-bound gp130 on cells that do not express IL-6R. The soluble form of gp130 (sgp130) can inhibit IL-6 trans-signalling by binding to sIL-6R, thereby preventing it from interacting with membrane-bound gp130. Given the central role of IL-6 in COVID-19 inflammation and its association with severe disease, we aimed to analyse the behaviour of IL-6 and its soluble receptor complex during different waves of the pandemic. This analysis could help determine whether IL-6 levels can serve as prognostic markers of disease severity.