Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes

Abstract

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

“…In fact, hyperinflammation and hyperferritinemia are hallmarks of severe over moderate COVID-19 23 , 24 . Moreover, hypercoagulability causing thrombosis, a classical feature of secondary HLH, has been observed amongst around 30% of severe COVID-19 patients 12 . And more recent evidence suggests, that this hyperinflammation can replicate different facets of both sHLH and viral CRS in different patient groups and different timepoints of disease courses 12 , 23 .…”

“…Moreover, hypercoagulability causing thrombosis, a classical feature of secondary HLH, has been observed amongst around 30% of severe COVID-19 patients 12 . And more recent evidence suggests, that this hyperinflammation can replicate different facets of both sHLH and viral CRS in different patient groups and different timepoints of disease courses 12 , 23 . These observations gave rise to the idea, that “virus associated” CRS or even sHLH might drive severe COVID-19 7 , 25 .…”

“…Application of tocilizumab usually resolves symptoms 10 , 11 . In the sense of an exuberant anti-viral innate immune response, elevated cytokine levels, fever and CRS-like symptoms, including organ injury have been reported in the context of viral infections, such as H5N1, SARS-CoV-1 and SARS-CoV-2 14 , 1213 . To avoid confusion, we will refer to this with the term “virus-associated CRS”.…”

Retinal involvement and ocular findings in COVID‐19 pneumonia patients 

“…[9][10][11][12][13] Recent clinical and anatomopathological reports have described endothelial damage as one of the most prominent causes of the systemic vascular thromboembolic and/or in ammatory manifestations of COVID-19. [32][33][34] In this setting, the retina, as a privileged district for noninvasive and in vivo evaluation of systemic diseases, may reveal alterations such as vascular occlusion related to thrombotic susceptibility and chorioretinitis or vasculitis directly mediated by the virus. Hence, as reported in the brain, we considered the possibility of a direct ocular spread of SARS-CoV-2 through the two blood-retinal barriers (BRBs).…”

Ocular findings and retinal involvement in COVID-19 pneumonia patients: A cross-sectional study in an Italian referral centre

“…[9][10][11][12][13] Recent clinical and anatomopathological reports have described the endothelial damage as one of the most prominent causes of the systemic vascular thromboembolic and/or in ammatory manifestations of COVID-19. [32][33][34] In this setting, the retina as a privileged district for non-invasive and in vivo evaluation of systemic diseases, may reveal alterations such as vascular occlusion related to the thrombotic susceptibility and chorioretinitis or vasculitis directly mediated by the virus. Hence, as reported in the brain, we considered the possibility of a direct ocular spread of SARS-CoV-2 through the two blood-retinal barriers (BRBs).…”