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

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 non-severe COVID-19 patients.

METHODS: Relevant studies were identified from PubMed, Embase, Web of Science, SCOPUS and pre-print 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 non-severe ones. There was heterogeneity across studies due to small sample sizes and non-uniformity 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 proinflammatory 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.