Utility of Measuring Circulating Bio-Adrenomedullin and Proenkephalin for 30-Day Mortality Risk Prediction in Patients with COVID-19 and Non-COVID-19 Interstitial Pneumonia in the Emergency Department.

Background and Objectives: In order to accelerate the risk stratification of patients referred to the Emergency Department (ED) with interstitial pneumonia, it could be useful to provide new and effective laboratory tests for use. The aim of our study was to evaluate the prognostic role of two biomarkers, bio-adrenomedullin (Bio-ADM) and proenkephalin (penKid), in patients with interstitial pneumonia (IP) at ED admission. Materials and Methods: In 153 consecutive patients with IP, both from COVID-19 or non-COVID-19 etiology, we measured, in a prospective observational manner, penKid and Bio-ADM at ED admission and after 24 h. In order to evaluate patient outcomes, 30-day follow-ups were also performed. The endpoints were 24 h, 10-day, and 30-day mortality. Results: Both biomarkers were shown to be good predictors of adverse events at 30 days, with Bio-ADM outperforming penKid. Bio-ADM was linked with 24 h and 10-day patient mortality. Moreover, PenKid was related to parameters defining worsening kidney function. Conclusions: Both in patients with COVID-19 or non-COVID-19 interstitial pneumonia at ED admission, Bio-ADM and penKid were good predictors of patient mortality. To evaluate these two biomarkers could be considered to be useful during the first evaluation in the ED when integrated with clinical scores.

Mid-regional proadrenomedullin, C-terminal proendothelin-1 values, and disease course are not different in critically ill SARS-CoV-2 pneumonia patients with obesity.

BACKGROUND/OBJECTIVES: Patients affected by obesity and Coronavirus disease 2019, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appear to have a higher risk for intensive care (ICU) admission. A state of low-grade chronic inflammation in obesity has been suggested as one of the underlying mechanisms. We investigated whether obesity is associated with differences in new inflammatory biomarkers mid-regional proadrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), and clinical outcomes in critically ill patients with SARS-CoV-2 pneumonia. SUBJECTS/METHODS: A total of 105 critically ill patients with SARS-CoV-2 pneumonia were divided in patients with obesity (body mass index (BMI) ≥ 30 kg/m2, n = 42) and patients without obesity (BMI < 30 kg/m2, n = 63) and studied in a retrospective observational cohort study. MR-proADM, CT-proET-1 concentrations, and conventional markers of white blood count (WBC), C-reactive protein (CRP), and procalcitonin (PCT) were collected during the first 7 days. RESULTS: BMI was 33.5 (32-36.1) and 26.2 (24.7-27.8) kg/m2 in the group with and without obesity. There were no significant differences in concentrations MR-proADM, CT-proET-1, WBC, CRP, and PCT at baseline and the next 6 days between patients with and without obesity. Only MR-proADM changed significantly over time (p = 0.039). Also, BMI did not correlate with inflammatory biomarkers (MR-proADM rho = 0.150, p = 0.125, CT-proET-1 rho = 0.179, p = 0.067, WBC rho = -0.044, p = 0.654, CRP rho = 0.057, p = 0.564, PCT rho = 0.022, p = 0.842). Finally, no significant differences in time on a ventilator, ICU length of stay, and 28-day mortality between patients with or without obesity were observed. CONCLUSIONS: In critically ill patients with confirmed SARS-CoV-2 pneumonia, obesity was not associated with differences in MR-proADM, and CT-proET-1, or impaired outcome. TRIAL REGISTRATION: Netherlands Trial Register, NL8460.

Clinical Utility of Midregional Proadrenomedullin in Patients with COVID-19.

OBJECTIVE: The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19. METHODS: We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated. RESULTS: Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3-2.95 vs median, 0.82 nmol/L; interquartile range, 0.57-1.03; P <.0001). Receiver operating characteristic curve analysis showed good accuracy of MR-proADM for predicting mortality. A MR-proADM value of 1.73 nmol/L was established as the best cutoff value, with 90% sensitivity and 95% specificity (P <.0001). CONCLUSION: We found that MR-proADM could represent a prognostic biomarker of COVID-19.

Endothelial dysfunction and Mid-Regional proAdrenomedullin: What role in SARS-CoV-2 infected Patients?

BACKGROUND: Endothelial dysfunction, a major complication of SARS-CoV-2 infectionplaying a key-role in multi-organ damage, carries high risk of mortality. AIM: To investigate the potential role of Mid-Regional pro-Adrenomedullin (MR-proADM) in detecting endothelial damage with a view to stratifying the risk of adverse events (length of stay, death, admission in Intensive Care Unit) and/or disease resolution. MATERIALS AND METHODS: In 135 consecutive patients with SARS-CoV-2 infection, MR-proADM was measured in EDTA-K2 plasma samples using B.R.A.H.M.S. KRYPTOR® COMPACT Plus method (Thermo Fisher Scientific, Hennigsdorf, Germany) RESULTS: Patients were subdivided into three groups based on their MR-proADM value (nmol/L): 1 (n = 20, MR-proADM ≤ 0.55); 2 (n = 82, 0.55 < MR-proADM ≤ 1.50); 3 (n = 33, MR-proADM > 1.50). The higher the MR-proADM value, the greater the patients' age, the more frequent the occurrence of pneumonia, the requiring of more aggressive treatment, the longer the hospitalization and the more frequent a fatal event. Significant differences were found between the three groups for MR-proADM, White-blood cell count, Neutrophil count, D-dimer, C-reactive Protein, Procalcitonin and hs-Troponin I. At logistic regression,it was found that MR-proADM and Log10D-dimer were the most significant predictors of adverse events. CONCLUSION: The findings made in the present study highlight the relevance of MR-proADM values in providing clinically useful information, particularly for stratifying COVID-19 patients according to the risk of a more severe form of disease and to the development of adverse events.

Mid-regional pro-adrenomedullin as a supplementary tool to clinical parameters in cases of suspicion of infection in the emergency department.

INTRODUCTION: Mid-regional proadrenomedullin (MR-proADM), a novel biomarker, has recently gained interest particularly with regards to its potential in assisting clinicians' decision making in patients with suspicion of infection in the emergency department (ED). A group of international experts, with research and experience in MR-proADM applications, produced this review based on their own experience and the currently available literature. AREAS COVERED: The review provides evidence related to MR-proADM as a triaging tool in avoiding unnecessary admissions to hospital and/or inadequate discharge, and identifying patients most at risk of deterioration. It also covers the use of MR-proADM in the context of COVID-19. Moreover, the authors provide a proposal on how to incorporate MR-proADM into patients' clinical pathways in an ED setting. EXPERT OPINION: The data we have so far on the application of MR-proADM in the ED is promising. Incorporating it into clinical scoring systems may aid the clinician's decision making and recognizing the 'ill looking well' and the 'well looking ill' sooner. However there are still many gaps in our knowledge especially during the ongoing COVID-19 waves. There is also a need for cost-effectiveness analysis studies especially in the era of increasing cost pressures on health systems globally.

MR-proADM as prognostic factor of outcome in COVID-19 patients.

Mid Regional pro-ADM (MR-proADM) is a promising novel biomarker in the evaluation of deteriorating patients and an emergent prognosis factor in patients with sepsis, septic shock and organ failure. It can be induced by bacteria, fungi or viruses. We hypothesized that the assessment of MR-proADM, with or without other inflammatory cytokines, as part of a clinical assessment of COVID-19 patients at hospital admission, may assist in identifying those likely to develop severe disease. A pragmatic retrospective analysis was performed on a complete data set from 111 patients admitted to Udine University Hospital, in northern Italy, from 25th March to 15th May 2020, affected by SARS-CoV-2 pneumonia. Clinical scoring systems (SOFA score, WHO disease severity class, SIMEU clinical phenotype), cytokines (IL-6, IL-1b, IL-8, TNF-α), and MR-proADM were measured. Demographic, clinical and outcome data were collected for analysis. At multivariate analysis, high MR-proADM levels were significantly associated with negative outcome (death or orotracheal intubation, IOT), with an odds ratio of 4.284 [1.893-11.413], together with increased neutrophil count (OR = 1.029 [1.011-1.049]) and WHO disease severity class (OR = 7.632 [5.871-19.496]). AUROC analysis showed a good discriminative performance of MR-proADM (AUROC: 0.849 [95% Cl 0.771-0.730]; p < 0.0001). The optimal value of MR-proADM to discriminate combined event of death or IOT is 0.895 nmol/l, with a sensitivity of 0.857 [95% Cl 0.728-0.987] and a specificity of 0.687 [95% Cl 0.587-0.787]. This study shows an association between MR-proADM levels and the severity of COVID-19. The assessment of MR-proADM combined with clinical scoring systems could be of great value in triaging, evaluating possible escalation of therapies, and admission avoidance or inclusion into trials. Larger prospective and controlled studies are needed to confirm these findings.

Effectiveness of mid-regional pro-adrenomedullin (MR-proADM) as prognostic marker in COVID-19 critically ill patients: An observational prospective study.

OBJECTIVE: To test the effectiveness of mid-regional pro-adrenomedullin (MR-proADM) in comparison to C-reactive protein (CRP), procalcitonin (PCT), D-dimer, lactate dehydrogenase (LDH) in predicting mortality in COVID-19-ICU-patients. METHODS: All consecutive COVID-19 adult patients admitted between March and June 2020 to the ICU of a referral, university hospital in Northern-Italy were enrolled. MR-proADM and routine laboratory test were measured within 48 hours from ICU admission, on day 3, 7 and 14. Survival curves difference with MR-proADM cut-off set to 1.8 nmol/L were tested using log-rank test. Predictive ability was compared using area under the curve and 95% confidence interval of different receiver-operating characteristics curves. RESULTS: 57 patients were enrolled. ICU and overall mortality were 54.4%. At admission, lymphocytopenia was present in 86% of patients; increased D-dimer and CRP levels were found in 84.2% and 87.7% of patients respectively, while PCT values > 0.5 µg/L were observed in 47.4% of patients. MR-proADM, CRP and LDH were significantly different between surviving and non-surviving patients and over time, while PCT, D-dimer and NT-pro-BNP did not show any difference between the groups and over time; lymphocytes were different between surviving and non-surviving patients only. MR-proADM was higher in dying patients (2.65±2.33vs1.18±0.47, p<0.001) and a higher mortality characterized patients with MR-proADM >1.8 nmol/L (p = 0.016). The logistic regression model adjusted for age, gender, cardiovascular disease, diabetes mellitus and PCT values confirmed an odds ratio = 10.3 [95%CI:1.9-53.6] (p = 0.006) for MR-proADM >1.8 nmol/L and = 22.2 [95%CI:1.6-316.9] (p = 0.022) for cardiovascular disease. Overall, MR-proADM had the best predictive ability (AUC = 0.85 [95%CI:0.78-0.90]). CONCLUSIONS: In COVID-19 ICU-patients, MR-proADM seems to have constantly higher values in non-survivor patients and predict mortality more precisely than other biomarkers. Repeated MR-proADM measurement may support a rapid and effective decision-making. Further studies are needed to better explain the mechanisms responsible of the increase in MR-proADM in COVID-19 patients.

High levels of mid-regional proadrenomedullin in ARDS COVID-19 patients: the experience of a single, Italian Center.

OBJECTIVE: This study evaluated the ability of mid-regional proadrenomedullin (MR-proADM) to identify disease severity in Coronavirus disease 2019 (COVID-19) patients in comparison to conventional inflammatory biomarkers and clinical scores. PATIENTS AND METHODS: In an observational trial, COVID-19 acute respiratory distress syndrome (ARDS) patients were enrolled. MR-proADM, C-reactive protein (CRP), procalcitonin (PCT) and lactic acid (LA) were measured in all patients at admission (T0), at 24 hours (T1) and in the third (T3) and fifth day (T5) of hospitalization. The aims of this study were to determine the role of MR-proADM to detect patients with high risk of mortality and compare the prognostic value of MR-proADM with commonly used clinical scores (Sequential Organ Failure Assessment score - SOFA score, Acute Physiologic Assessment and Chronic Health Evaluation II score - APACHE II score, and Simplified Acute Physiological score II - SAPS II score). RESULTS: Twenty-one COVID-19 ARDS patients admitted to the Intermediate Care Unit (IMCU) were enrolled. The median MR-proADM values were 2.28, 2.41, 1.96 and 1.89 nmol/L at T0, T1, T3 and T5, respectively. The 30-day all-cause mortality rate was 52.4%. Mean MR-proADM T0 value was significantly higher in non-survivors compared with survivors (3.5 vs. 1.1 nmol/L, p < 0.05). No significant differences were found for the other inflammatory biomarkers. In terms of the area under the receiver-operating characteristic curve (AUC), MR-proADM showed a similar discriminatory power compared with APACHE II, SOFA and SAPS II score (0.81, 0.91, 0.70 and 0.78, respectively). The optimal MR-proADM cut-point cut-off point was 1.07 nmol/L, which corresponds to a sensitivity of 91% and a specificity of 71%. CONCLUSIONS: MR-proADM, in addition to the clinical scores, could be useful to predict outcome in COVID-19 ARDS patients.

MR-proADM as marker of endotheliitis predicts COVID-19 severity.

BACKGROUND: Early identification of patients at high risk of progression to severe COVID-19 constituted an unsolved challenge. Although growing evidence demonstrates a direct association between endotheliitis and severe COVID-19, the role of endothelial damage biomarkers has been scarcely studied. We investigated the relationship between circulating mid-regional proadrenomedullin (MR-proADM) levels, a biomarker of endothelial dysfunction, and prognosis of SARS-CoV-2-infected patients. METHODS: Prospective observational study enrolling adult patients with confirmed COVID-19. On admission to emergency department, a blood sample was drawn for laboratory test analysis. Primary and secondary endpoints were 28-day all-cause mortality and severe COVID-19 progression. Area under the curve (AUC) and multivariate regression analysis were employed to assess the association of the biomarker with the established endpoints. RESULTS: A total of 99 patients were enrolled. During hospitalization, 25 (25.3%) cases progressed to severe disease and the 28-day mortality rate was of 14.1%. MR-proADM showed the highest AUC to predict 28-day mortality (0.905; [CI] 95%: 0.829-0.955; P < .001) and progression to severe disease (0.829; [CI] 95%: 0.740-0.897; P < .001), respectively. MR-proADM plasma levels above optimal cut-off (1.01 nmol/L) showed the strongest independent association with 28-day mortality risk (hazard ratio [HR]: 10.470, 95% CI: 2.066-53.049; P < .005) and with progression to severe disease (HR: 6.803, 95% CI: 1.458-31.750; P = .015). CONCLUSION: Mid-regional proadrenomedullin was the biomarker with highest performance for prognosis of death and progression to severe disease in COVID-19 patients and represents a promising predictor for both outcomes, which might constitute a potential tool in the assessment of prognosis in early stages of this disease.

The vasoactive peptide MR-pro-adrenomedullin in COVID-19 patients: an observational study.

OBJECTIVES: Midregional pro-adrenomedullin (MR-proADM) is a vasoactive peptide with key roles in reducing vascular hyperpermeability and thereby improving endothelial stability during infection. While MR-proADM is useful for risk stratification in patients with sepsis, clinical data about prediction accuracy in patients with severe acute respiratory syndrome coronavirus 2 disease (COVID-19) is currently missing. METHODS: We included consecutively adult patients hospitalized for confirmed COVID-19 at a tertiary care center in Switzerland between February and April 2020. We investigated the association of MR-proADM levels with in-hospital mortality in logistic regression and discrimination analyses. RESULTS: Of 89 included COVID-19 patients, 19% (n=17) died while in the hospital. Median admission MR-proADM levels (nmol/L) were increased almost 1.5-fold increased in non-survivors compared to survivors (1.3 [interquartile range IQR 1.1-2.3]) vs. 0.8 [IQR 0.7-1.1]) and showed good discrimination (area under the curve 0.78). An increase of 1 nmol/L of admission MR-proADM was independently associated with a more than fivefold increase in in-hospital mortality (adjusted odds ratio of 5.5, 95% confidence interval 1.4-21.4, p=0.015). An admission MR-proADM threshold of 0.93 nmol/L showed the best prognostic accuracy for in-hospital mortality with a sensitivity of 93%, a specificity of 60% and a negative predictive value of 97%. Kinetics of follow-up MR-proADM provided further prognostic information for in-hospital treatment. CONCLUSIONS: Increased levels of MR-proADM on admission and during hospital stay were independently associated with in-hospital mortality and may allow a better risk stratification, and particularly rule-out of fatal outcome, in COVID-19 patients.