Table 2.

Evidence for and against severe COVID-19 involving a cytokine storm

	FOR	AGAINST
Cytokine levels	Cytokine levels (e.g IL-6, GM-CSF) are elevated in severe COVID-19 and increasing levels are strongly associated with worsening outcomes There are increased frequencies of circulating activated CD4+ and CD8+ T cells and plasmablasts in severe COVID-19	The elevated cytokines and activated immune cells in severe COVID-19 may be necessary for controlling SARS-CoV-2 infection The levels of several cytokines are only modestly elevated in COVID-19, relative to ARDS, sepsis, CART-CRS, and influenza
Clinical and Laboratory features	Clinical and lab abnormalities, such as elevated CRP and d-dimer levels, hypoalbuminemia, renal dysfunction, and effusions, are observed in COVID-19, as they are in other cytokine storms	These clinical and laboratory abnormalities can appear in an appropriate robust immune response to a pathogen Lymphopenia is not often found in cytokine storm disorders, but it is a hallmark of severe COVID-19
Classification criteria	Severe COVID-19 patients demonstrate all three features of cytokine storm (13): elevated circulating cytokines, acute inflammatory symptoms, and organ dysfunction secondary to hyperinflammation New classification criteria have been proposed that are associated with hyperinflammation and worsening outcomes: Temple (28), COVID-19-associated hyperinflammatory syndrome (cHIS)(29), and COVID-19-associated hyperinflammation (COV-HI) (30)	Conventional criteria for cytokine storm observed in HLH perform poorly in COVID-19 (e.g. H score)
Treatment	Immunomodulation (Corticosteroids and IL-6 inhibition) can reduce mortality in severe COVID-19, suggesting that excess inflammation is a modifiable pathogenic component of severe COVID-19 Additional immunomodulators including JAK1/2 inhibitors have demonstrated a potential role in severe COVID-19	Cytokine removal with CytoSorb led to worsening outcomes in critically ill patients on extracorporeal membrane oxygenation (ECMO)
Other host factors	Increased SARS-CoV-2 specific antibodies and decreased viral loads are found in patients with severe COVID-19 Longitudinal immunological correlates of disease outcomes have demonstrated distinct signatures of ‘immunological misfiring’ in COVID-19	Other host factors also have significant contribution to poor outcomes in severe COVID-19, including chronic illness comorbidities, thromboembolic events, genetic polymorphisms and auto-autoantibodies directed against interferons and other proteins.

SARS-CoV-2, severe acute respiratory coronavirus 2.