Effectiveness of mid-regional pro-adrenomedullin, compared to other biomarkers (including lymphocyte subpopulations and immunoglobulins), as a prognostic biomarker in COVID-19 critically ill patients: New evidence from a 15-month observational prospective study

Abstract

Background: Mid-regional pro-adrenomedullin (MR-proADM), an endothelium-related peptide, is a predictor of death and multi-organ failure in respiratory infections and sepsis and seems to be effective in identifying COVID-19 severe forms. The study aims to evaluate the effectiveness of MR-proADM in comparison to routine inflammatory biomarkers, lymphocyte subpopulations, and immunoglobulin (Ig) at an intensive care unit (ICU) admission and over time in predicting mortality in patients with severe COVID-19.

Methods: All adult patients with COVID-19 pneumonia admitted between March 2020 and June 2021 in the ICUs of a university hospital in Italy were enrolled. MR-proADM, lymphocyte subpopulations, Ig, and routine laboratory tests were measured within 48 h and on days 3 and 7. The log-rank test was used to compare survival curves with MR-proADM cutoff value of >1.5 nmol/L. Predictive ability was compared using the area under the curve (AUC) and 95% confidence interval (CI) of different receiver-operating characteristic curves.

Results: A total of 209 patients, with high clinical severity [SOFA 7, IQR 4-9; SAPS II 52, IQR 41-59; median viral pneumonia mortality score (MuLBSTA)-11, IQR 9-13] were enrolled. ICU and overall mortality were 55.5 and 60.8%, respectively. Procalcitonin, lactate dehydrogenase, D-dimer, the N-terminal prohormone of brain natriuretic peptide, myoglobin, troponin, neutrophil count, lymphocyte count, and natural killer lymphocyte count were significantly different between survivors and non-survivors, while lymphocyte subpopulations and Ig were not different in the two groups. MR-proADM was significantly higher in non-survivors (1.17 ± 0.73 vs. 2.31 ± 2.63, p < 0.0001). A value of >1.5 nmol/L was an independent risk factor for mortality at day 28 [odds ratio of 1.9 (95% CI: 1.220-3.060)] after adjusting for age, lactate at admission, SOFA, MuLBSTA, superinfections, cardiovascular disease, and respiratory disease. On days 3 and 7 of the ICU stay, the MR-proADM trend evaluated within 48 h of admission maintained a correlation with mortality (p < 0.0001). Compared to all other biomarkers considered, the MR-proADM value within 48 h had the best accuracy in predicting mortality at day 28 [AUC = 0.695 (95% CI: 0.624-0.759)].

Conclusion: MR-proADM seems to be the best biomarker for the stratification of mortality risk in critically ill patients with COVID-19. The Ig levels and lymphocyte subpopulations (except for natural killers) seem not to be correlated with mortality. Larger, multicentric studies are needed to confirm these findings.

Keywords: COVID-19; MR-proADM; SARS-CoV-2; adrenomedullin; biomarkers; immunoglobulins; intensive care; lymphocyte subpopulations.

Figure 1

Kaplan–Meier survival curve. Stratification of patients with mid-regional pro-adrenomedullin (MR-proADM) levels greater or less than 1.5 nmol/L at an intensive care unit admission.

Figure 2

Boxplot representing the trend of MR-proADM over time in overall population (N = 209) (Tpred, predictive value; T0, first available value in 48 h; T3, value at day 3; T7, value at day 7). Outcome: survivors (gray); non-survivors (black). MR-proADM, mid-regional pro-adrenomedullin; Tpred (predictive value), first available value in 48 h; N, number.

Figure 3

ROC curves performance of MR-proADM (blue), LDH (brown), D-dimer (yellow), PCT (green), Ly (pink) predictive values, and their comparison for predicting 28-day mortality. MR-proADM, mid-regional pro-adrenomedullin; LDH, lactate dehydrogenase; PCT, procalcitonin; Ly, lymphocytes; AUC, area under the curve.

Figure 4

Boxplot representing the trend of Immunoglobulin (Ig) (subtypes IgM, IgG, and IgA) and lymphocytes (lymphocytes B, CD19, CD3, CD3/CD4, CD4/CD8, and CD16/CD56) predictive values over time in overall population (T0, first available value in 48 h; T3, value at day 3; T7, value at day 7). Outcome: survivors (gray); non-survivors (black).

Figure 5

Boxplot representing the trend of MR-proADM predictive values over time in extracorporeal membrane oxygenation (ECMO) population (N = 47) (Tpred, predictive value; T0, first available value in 48 h; T3, value at day 3; T7, value at day 7). Outcome: survivors (gray); non-survivors (black). MR-proADM, mid-regional pro-adrenomedullin; N, number.