C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis

Abstract

Background: Patients critically ill with coronavirus disease-2019 (COVID-19) feature hyperinflammation, and the associated biomarkers may be beneficial for risk stratification. We aimed to investigate the association between several biomarkers, including serum C-reactive protein (CRP), procalcitonin (PCT), D-dimer, and serum ferritin, and COVID-19 severity.

Methods: We performed a comprehensive systematic literature search through electronic databases. The outcome of interest for this study was the composite poor outcome, which comprises mortality, acute respiratory distress syndrome, need for care in an intensive care unit, and severe COVID-19.

Results: A total of 5350 patients were pooled from 25 studies. Elevated CRP was associated with an increased composite poor outcome [risk ratio (RR) 1.84 (1.45, 2.33), p < 0.001; I²: 96%] and its severe COVID-19 (RR 1.41; I²: 93%) subgroup. A CRP ⩾10 mg/L has a 51% sensitivity, 88% specificity, likelihood ratio (LR) + of 4.1, LR- of 0.5, and an area under curve (AUC) of 0.84. An elevated PCT was associated with an increased composite poor outcome [RR 3.92 (2.42, 6.35), p < 0.001; I²: 85%] and its mortality (RR 6.26; I²: 96%) and severe COVID-19 (RR 3.93; I²: 63%) subgroups. A PCT ⩾0.5 ng/ml has an 88% sensitivity, 68% specificity, LR+ of 2.7, LR- of 0.2, and an AUC of 0.88. An elevated D-dimer was associated with an increased composite poor outcome [RR 2.93 (2.14, 4.01), p < 0.001; I²: 77%], including its mortality (RR 4.15; I²: 83%) and severe COVID-19 (RR 2.42; I²: 58%) subgroups. A D-dimer >0.5 mg/L has a 58% sensitivity, 69% specificity, LR+ of 1.8, LR- of 0.6, and an AUC of 0.69. Patients with a composite poor outcome had a higher serum ferritin with a standardized mean difference of 0.90 (0.64, 1.15), p < 0.0001; I²: 76%.

Conclusion: This meta-analysis showed that an elevated serum CRP, PCT, D-dimer, and ferritin were associated with a poor outcome in COVID-19. The reviews of this paper are available via the supplemental material section.

Keywords: COVID-19; SARS-CoV-2; biomarker; coronavirus; inflammatory.

Figure 1.

Study flow diagram. ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease-2019; CRP, C-reactive protein; ICU, intensive care unit; PCT, procalcitonin.

Figure 2.

Elevated CRP and composite poor outcome. (a) Patients with a composite poor outcome comprising mortality, ARDS, need for ICU care, and severe COVID-19 have an elevated serum CRP. (b) SROC analysis (with prediction and confidence contours) of an elevated CRP and a composite poor outcome. ⁽¹⁾Cao et al., ⁽²⁾Guan et al., ⁽³⁾Tabata et al., ⁽⁴⁾Zhao et al., ⁽⁵⁾Liu et al. ARDS, acute respiratory distress syndrome; AUC, area under curve; CI, confidence interval; COVID-19, coronavirus disease-2019; CRP, C-reactive protein; df, degrees of freedom; ICU, intensive care unit. SROC, summary receiver operating characteristic.

Figure 3.

Elevated PCT and composite poor outcome. (a) Patients with a composite poor outcome comprising mortality, ARDS, need for ICU care, and severe COVID-19 have an elevated serum PCT. (b) SROC analysis (with prediction and confidence contours) of elevated PCT and composite poor outcome. ⁽¹⁾Chen et al., ⁽²⁾Luo et al., ⁽³⁾Zhou et al., ⁽⁴⁾Guan et al., ⁽⁵⁾Wang et al., ⁽⁶⁾Liu et al., ⁽⁷⁾Chen et al. ARDS, acute respiratory distress syndrome; AUC, area under curve; CI, confidence interval; COVID-19, coronavirus disease-2019; df, degrees of freedom; ICU, intensive care unit; PCT, procalcitonin; SROC, summary receiver operating characteristic. Pooled analysis of a single cutoff point of ⩾0.5 ng/ml resulted in a sensitivity of 88% (70–96%) and a specificity of 68% (47–84%). SROC curve analysis demonstrated an AUC of 0.88 (0.84–0.90) (Figure 3(b)). PCT ⩾0.5 ng/ml has an LR+ of 2.7 and an LR- of 0.2.

Figure 4.

Elevated D-dimer and composite poor outcome. (a) Patients with a composite poor outcome comprising mortality, ARDS, need for ICU care, and severe COVID-19 have an elevated serum PCT. (b) SROC analysis (with prediction and confidence contours) of elevated D-dimer and a composite poor outcome. ⁽¹⁾Cai et al., ⁽²⁾ Guan et al., ⁽³⁾Hu et al., ⁽⁴⁾Liu et al., ⁽⁵⁾Cao et al. ARDS, acute respiratory distress syndrome; AUC, area under curve; CI, confidence interval; COVID-19, coronavirus disease-2019; df, degrees of freedom; ICU, intensive care unit; PCT, procalcitonin; SROC, summary receiver operating characteristic. Pooled analysis of a single cutoff point of >0.5 mg/L resulted in a sensitivity of 58% (18–90%) and a specificity of 69% (43–86%). SROC curve analysis (with prediction and confidence contours) demonstrated an AUC of 0.69 (0.65–0.73) (Figure 4(b)). A D-dimer >0.5 mg/L has an LR+ of 1.8 and an LR- of 0.6.

Figure 5.

Higher serum ferritin and a composite poor outcome. Patients with a composite poor outcome comprising mortality, ARDS, need for ICU care, and severe COVID-19 have a higher serum ferritin level. ARDS, acute respiratory distress syndrome; CI, confidence interval; COVID-19, coronavirus disease-2019; df, degrees of freedom; ICU, intensive care unit.