Is a “Cytokine Storm” Relevant to COVID-19?

In its most severe form, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), leads to a life-threatening pneumonia and acute respiratory distress syndrome (ARDS). The mortality rate from COVID-19 ARDS can approach 40% to 50%.1,2 Although the mechanisms of COVID-19–induced lung injury are still being elucidated, the term cytokine storm has become synonymous with its pathophysiology, both in scientific publications and the media. Absent convincing data of their effectiveness in COVID-19, drugs such as tocilizumab and sarilumab, which are monoclonal antibodies targeting interleukin (IL)-6 activity, are being used to treat patients; trials of these agents typically cite the cytokine storm as their rationale (NCT04306705, NCT04322773). A critical evaluation of the term cytokine storm and its relevance to COVID-19 is warranted. Cytokine storm has no definition. Broadly speaking, it denotes a hyperactive immune response characterized by the release of interferons, interleukins, tumor-necrosis factors, chemokines, and several other mediators. These mediators are part of a well-conserved innate immune response necessary for efficient clearance of infectious agents. Cytokine storm implies that the levels of released cytokines are injurious to host cells. Distinguishing an appropriate from a dysregulated inflammatory response in the pathophysiology of critical illness, however, has been a major challenge. To add further complexity, most mediators implicated in cytokine storm demonstrate pleotropic downstream effects and are frequently interdependent in their biological activity. The interactions of these mediators and the pathways they inform are neither linear nor uniform. Further, although their quantified levels may suggest severity of responses, they do not necessarily imply pathogenesis. This complex interplay illustrates the limitations of interfering in the acute inflammatory response based on single mediators and at indiscriminate time points. Whyhasthe“cytokinestorm”beensocloselyassociatedwith COVID-19? During the SARS epidemic caused by SARS-CoV-1, the termcytokinestormwasdescribedasafeatureandassociatedwith adverseoutcomes.3 SeveralearlycaseseriesinCOVID-19reported levelsofsomeplasmacytokineselevatedabovethenormalrange. In most cases, however, they are lower than plasma levels in previous cohorts of patients with ARDS. Interleukin-6, a proinflammatory cytokine, is a key mediator in the acute inflammatory response and the purported cytokine storm. The Table summarizes reported IL-6 levels in 5 cohorts of patients with COVID-19,1,2,4-6 each with more than 100 patients, and 3 cohorts of patients with ARDS.7-9 Although the median values are above the normal range in many (but not all) cases, they are lower than the median values typically reported in ARDS. The median values in random-