5.2  IL-6 and IL-1 blockers
As already described, ARDS occurring in most severe case of COVID-19 infection is mainly produced by the massive release of pro-inflammatory mediators (CRS) associated with viral replication and lung injury, leading to multiorgan failure [22]. Moreover, the high levels of these cytokines have been reported to be inversely related to the absolute lymphocytes count, with surviving T-cells functionally exhausted [94]. Since an effective immune response against viral infections depends on the activation of cytotoxic T cells, CRS might be associated with a decreased viral clearance, contributing to COVID-19 worsening. IL-6 and IL-1 play a pivotal role in this hyperinflammatory condition, suggesting the potential use of their blockers as treatment option for SARS-CoV2 related interstitial pneumonia. Data from a phase 3 RCT of IL-1 blockade (anakinra) in sepsis showed significant survival benefit in patients with hyperinflammation, without increased adverse events [95]. A small retrospective study on 21 patients affected by severe COVID-19 demonstrated that tocilizumab improved CT scan abnormalities and oxygen saturation, and normalized CRP levels and lymphocytes count in most of the patients [96]. A multicentre RCT of tocilizumab (IL-6 receptor blocker licensed for both RA and cytokine release syndrome) has been approved in China and is currently ongoing in patients with COVID-19 pneumonia and elevated IL-6 levels (ChiCTR2000029765) and a phase II study has been approved by the Italian Regulatory Drug Agency (AIFA) and will enrol 330 patients with pneumonia and early respiratory failure, with 1-month mortality reduction as primary outcome (TOCIVID-19). Moreover, the company that produces the second marketed IL-6 inhibitor sarilumab recently announced its intention to undertake a study with a similar design [97].
The identification of a unique definition of CRS during COVID-19 infection is crucial to better customize the management of critical patients. The presence of a large area of lung injury (≥50%) with decreased levels of CD4 and CD8 T-lymphocytes (lower than 50% of minimum normal range), and increased levels of IL-6 in peripheral blood have been recognized as the greatest risk factors of CRS in a retrospective analysis of 11 critically pneumonia Chinese patients infected with COVID-19 [98]. Increasing ferritin level and erythrocyte sedimentation rate or decreasing platelet counts would be additional parameters potentially useful to discriminate patients requiring immunosuppressive treatment [22].