Deciphering the COVID‐19 cytokine storm: Systematic review and meta‐analysis

Abstract

Introduction The coronavirus pandemic has affected more than 20 million people so far. Elevated cytokines and suppressed immune responses have been hypothesized to set off a cytokine storm, contributing to ARDS, multiple‐organ failure and, in the most severe cases, death. We aimed to quantify the differences in the circulating levels of major inflammatory and immunological markers between severe and nonsevere COVID‐19 patients. Methods Relevant studies were identified from PubMed, EMBASE, Web of Science, SCOPUS and preprint servers. Risk of bias was assessed for each study, using appropriate checklists. All studies were described qualitatively and a subset was included in the meta‐analysis, using forest plots. Results Based on 23 studies, mean cytokine levels were significantly higher (IL‐6: MD, 19.55 pg/mL; CI, 14.80, 24.30; IL‐8: MD, 19.18 pg/mL; CI, 2.94, 35.43; IL‐10: MD, 3.66 pg/mL; CI, 2.41, 4.92; IL‐2R: MD, 521.36 U/mL; CI, 87.15, 955.57; and TNF‐alpha: MD, 1.11 pg/mL; CI, 0.07, 2.15) and T‐lymphocyte levels were significantly lower (CD4+ T cells: MD, −165.28 cells/µL; CI, −207.58, −122.97; CD8+ T cells: MD, −106.51 cells/µL; CI, −128.59, −84.43) among severe cases as compared to nonsevere ones. There was heterogeneity across studies due to small sample sizes and nonuniformity in outcome assessment and varied definitions of disease severity. The overall quality of studies was sub‐optimal. Conclusion Severe COVID‐19 is characterized by significantly increased levels of pro‐inflammatory cytokines and reduced T lymphocytes. Well‐designed and adequately powered prospective studies are needed to amplify the current evidence and provide definitive answers to dilemmas regarding timing and type of anti‐COVID‐19 therapy particularly in severe patients.

Macrophage Migration Inhibitory Factor (MIF) Plasma Concentration in Critically Ill COVID-19 Patients: A Prospective Observational Study

“…However, our data did not include the whole data set of the biomarker-based predicted model of Bime et al except for IL- 6 and MIF. In contrast to the ARDS studies, using inflammatory biomarkers for sub-classification of ARDS [ 27 ], as well as the most recent COVID-19 studies [ 28 , 29 ], demonstrating that IL-6 correlates with severe and fatal ARDS/COVID-19, we found no differences in serum IL-6 concentrations between Responder and Non-Responder groups. Furthermore, the concentration of the acute phase proteins PCT and CRP were not significantly different between Responder and Non-Responder groups at any time during the 14 days.…”

Presentation and management of anxiety in individuals with acute symptomatic or asymptomatic COVID-19 infection, and in the post-COVID-19 recovery phase

“…In COVID-19, pathological activation of monocytes/macrophages and lymphocytes may cause a cytokine storm, which may result in lung injury, ARDS, and further release of pro-inflammatory cytokines (Hojyo et al 2020;Mulchandani et al 2020). They may cause anxiety through an IL-17 mechanism and additionally through ARDS and oxygen insufficiency (Bienvenu et al 2018;Shibabaw 2020).…”

The Immunopathological and Histological Landscape of COVID-19-Mediated Lung Injury

“…Leaving aside the dispute on whether a “cytokine storm” occurs or is just a simplistic assumption to describe a more complex process, many studies suggest that there is a kind of direct proportionality between proinflammatory cytokines levels and the severity of symptoms caused by COVID-19. In particular, higher levels of cytokines have been documented in COVID-19 patients with severe illness compared to those with a moderate one [ 54 , 55 , 56 , 57 , 58 ]; furthermore, the enhanced level of cytokines seems to be associated with a lowered T lymphocytes count [ 59 ]. Another fact that somewhat supports the occurrence of a cytokine storm as a true entity is that patients with increased levels of cytokines have been found to have a poorer prognosis [ 50 ].…”