Is severe COVID-19 a cytokine storm syndrome: a hyperinflammatory debate

Abstract

The COVID-19 pandemic is a global public health crisis with considerable mortality and morbidity. A role for cytokine storm and therapeutic immunomodulation in a subgroup of patients with severe COVID-19 was proposed early in the pandemic. The concept of cytokine storm in COVID-19 has been criticised, given the lack of clear definition and relatively modest cytokinaemia (which may be necessary for viral clearance) compared with acute respiratory distress syndrome and bacterial sepsis.Here we consider the argument for and against the concept of cytokine storm in COVID-19. Recent findings:Several criteria have been proposed to identify the subgroup of COVID-19 patients exhibiting a cytokine storm. The beneficial effect of corticosteroids and interleukin (IL)-6 inhibition suggest that inflammation is a modifiable pathogenic component of severe COVID-19. The presence of genetic polymorphisms and pathogenic auto-autoantibodies in severe COVID-19 also suggests a significant contribution of immune dysregulation to poor outcomes.

Endogenous Regulation and Pharmacological Modulation of Sepsis-Induced HMGB1 Release and Action: An Updated Review

“…Furthermore, these TN/RBM-reactive mAbs competitively inhibited RBM-ACE2 interactions in vitro [ 176 ], and selectively impaired the RBM-induced secretion of the granulocyte macrophage colony-stimulating factor (GM-CSF) [ 176 ]. Our findings fully supported the emerging notion that GM-CSF might be a key biomarker for SARS-CoV-2-induced cytokine storm in a subset of COVID-19 patients with more severe pneumonia often escalating to respiratory failure and death [ 178 , 179 , 180 , 181 , 182 ] ( Figure 5 ), although the possible roles of GM-CSF and other cytokines in the pathogenesis COVID-19 remain a subject of ongoing debate [ 56 , 57 ]. Nevertheless, it is possible that these TN/RBM-reactive mAbs might selectively prevent its interaction with a receptor involved in the GM-CSF induction, but did not interfere with its engagement with other pattern recognition receptors responsible for the induction of other cytokines or chemokines [ 183 ].…”

“…Thus, various cell death pathways can potentially lead to the passive release of HMGB1 following traumatic injuries or microbial infections. However, the possible roles of HMGB1 and various other cytokines in the pathogenesis of lethal infections such as COVID-19 remain controversial, because there is still a lack of clear association between many cytokine biomarkers and the severity of viral infections [ 56 , 57 ].…”

Clinical and prognostic significance of C-reactive protein to albumin ratio in hospitalized coronavirus disease 2019 (COVID-19) patients

“…Pneumonia and subsequent respiratory insufficiency caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2) infection are leading reasons for hospitalization and high morbidity and mortality observed in coronavirus disease 2019 (COVID-19) patients [ 1 , 2 ]. Due to strong inflammatory response mediated through interleukin (IL)-6, a subset of patients develop severe or critical symptoms and experience unfavorable clinical outcomes [ 3 ]. Severe or critical disease and hospitalization rates may vary depending on the dominant circulating virus strain, number of tested individuals and vaccination status of the population [ 4 ] and were reported to be 15–20% in the large cohort of patients at the start of the pandemic [ 2 ].…”

Autoinflammatory Diseases and Cytokine Storms—Imbalances of Innate and Adaptative Immunity

“…Of note, the selective inhibition of specific cytokines, during viral infections or other diseases characterized by hyperinflammation, is, however, always evaluated with great caution, as it also inhibits physiological responses of the immune system. In fact, too strict inhibition of several cytokines in some cases could produce the opposite effect, as it could cause the organism not to respond to pathogens [ 166 , 167 ].…”