Serum CK-MB, COVID-19 severity and mortality: An updated systematic review and meta-analysis with meta-regression

Abstract

Objectives: We conducted a systematic review and meta-analysis with meta-regression of creatine kinase-MB (CK-MB), a biomarker of myocardial injury, in COVID-19 patients.

Methods: We searched PubMed, Web of Science and Scopus, for studies published between January 2020 and January 2021 that reported CK-MB, COVID-19 severity and mortality (PROSPERO registration number: CRD42021239657).

Results: Fifty-five studies in 11,791 COVID-19 patients were included in the meta-analysis. The pooled results showed that CK-MB concentrations were significantly higher in patients with high disease severity or non-survivor status than patients with low severity or survivor status (standardized mean difference, SMD, 0.81, 95% CI 0.61 to 1.01, p<0.001). The rate of patients with CK-MB values above the normal range was also significantly higher in the former than the latter (60/350 vs 98/1,780; RR ​= ​2.84, 95%CI 1.89 to 4.27, p<0.001; I² ​= ​19.9, p ​= ​0.254). Extreme between-study heterogeneity was observed (I² ​= ​93.4%, p<0.001). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified (effect size range, 0.77 to 0.84). Begg's (p ​= ​0.50) and Egger's (p ​= ​0.86) t-tests did not show publication bias. In meta-regression analysis, the SMD was significantly and positively associated with the white blood count, aspartate aminotransferase, myoglobin, troponin, brain natriuretic peptide, lactate dehydrogenase, and D-dimer.

Conclusions: Higher CK-MB concentrations were significantly associated with severe disease and mortality in COVID-19 patients. This biomarker of myocardial injury might be useful for risk stratification in this group.

Keywords: COVID-19; Creatine kinase-MB; Creatine kinase-MB values Above the normal range; Disease severity; Mortality.

Fig. 1

Flow chart of study selection.

Fig. 2

Forest plot of studies reporting CK-MB concentrations in patients with COVID-19.

Fig. 3

Forest plot of studies reporting the proportion of patients with CK-MB concentrations above the normal range in COVID-19 patients with high severity or non-survivor status vs. those with low severity or survivor status during follow-up.

Fig. 4

Sensitivity analysis of the association between CK-MB and COVID-19 disease. The influence of individual studies on the overall standardized mean difference (SMD) is shown. The middle vertical axis indicates the overall SMD and the two vertical axes indicate the 95% confidence intervals (CIs). The hollow circles represent the pooled SMD when the remaining study is omitted from the meta-analysis. The two ends of each broken line represent the 95% CIs.

Fig. 5

Funnel plot of studies investigating disease severity of survival status after trimming and filling. Dummy studies and genuine studies are represented by enclosed circles and free circles, respectively.

Fig. 6

Bubble plot reporting univariate meta-regression analysis between the month of recruitment commencement and SMD. Each study is represented by a circle (bubble) with the size area proportional to the study precision (the inverse of its within-study variance).

Fig. 7

Forest plot of studies examining CK-MB concentrations in patients with COVID-19 according to disease severity or survival status. The diamond represents the point estimate and confidence intervals after combining and averaging all individual studies. The vertical line through the vertical points of the diamond represents the point estimate of the averaged studies.

Fig. 8

Funnel plot of a sub-group of 13 studies that were homogeneous for endpoint, country, study design and assay (A). Forest plot of CK-MB concentrations after removing the three studies that were outside the funnel plot (B).