Identification of Parameters Representative of Immune Dysfunction in Patients with Severe and Fatal COVID-19 Infection: a Systematic Review and Meta-analysis

Abnormal immunological indicators associated with disease severity and mortality in patients with COVID-19 have been reported in several observational studies. However, there are marked heterogeneities in patient characteristics and research methodologies in these studies. We aimed to provide an updated synthesis of the association between immune-related indicators and COVID-19 prognosis. We conducted an electronic search of PubMed, Scopus, Ovid, Willey, Web of Science, Cochrane library, and CNKI for studies reporting immunological and/or immune-related parameters, including hematological, inflammatory, coagulation, and biochemical variables, tested on hospital admission of COVID-19 patients with different severities and outcomes. A total of 145 studies were included in the current meta-analysis, with 26 immunological, 11 hematological, 5 inflammatory, 4 coagulation, and 10 biochemical variables reported. Of them, levels of cytokines, including IL-1 beta, IL-1Ra, IL-2R, IL-4, IL-6, IL-8, IL-10, IL-18, TNF-alpha, IFN-gamma, IgA, IgG, and CD4(+) T/CD8(+) T cell ratio, WBC, neutrophil, platelet, ESR, CRP, ferritin, SAA, D-dimer, FIB, and LDH were significantly increased in severely ill patients or non-survivors. Moreover, non-severely ill patients or survivors presented significantly higher counts of lymphocytes, monocytes, lymphocyte/monocyte ratio, eosinophils, CD3(+) T,CD4(+)T and CD8(+)T cells, B cells, and NK cells. The currently updated meta-analysis primarily identified a hypercytokinemia profile with the severity and mortality of COVID-19 containing IL-1 beta, IL-1Ra, IL-2R, IL-4, IL-6, IL-8, IL-10, IL-18, TNF-alpha, and IFN-gamma. Impaired innate and adaptive immune responses, reflected by decreased eosinophils, lymphocytes, monocytes, B cells, NK cells, T cells, and their subtype CD4(+) and CD8(+) T cells, and augmented inflammation, coagulation dysfunction, and nonpulmonary organ injury, were marked features of patients with poor prognosis. Therefore, parameters of immune response dysfunction combined with inflammatory, coagulated, or nonpulmonary organ injury indicators may be more sensitive to predict severe patients and those non-survivors.

Automated summary

Abnormal immunological indicators are associated with disease severity and mortality in patients with COVID-19. This meta-analysis synthesized the findings of many studies and found that cytokine levels, white blood cell count, and inflammatory markers were significantly increased in severely ill patients or non-survivors. Conversely, lymphocyte count, monocyte count, and other indicators were significantly increased in non-severely ill patients or survivors. Impaired immune response and increased inflammation, coagulation dysfunction, and nonpulmonary organ injury were marked features of patients with poor prognosis. Parameters of immune response dysfunction combined with inflammatory, coagulated, or nonpulmonary organ injury indicators may be more sensitive to predict severe patients and non-survivors.