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.

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.

Procalcitonin and Adrenomedullin in Infectious Diseases

Calcitonin (CT) and adrenomedullin (ADM) are members of the CT family. Procalcitonin (PCT) is a prohormone of CT. Elevations in serum PCT and ADM levels are associated with severe sepsis and coronavirus disease 2019 (COVID-19). PCT enhances sepsis mortality and it binds to the CGRP receptor, which is a heterodimer of CT receptor-like receptor and receptor activity-modifying protein 1. The N-terminal truncated form of PCT, PCT3-116, is produced by the cleavage of PCT by dipeptidyl peptidase 4 (DPP-4) and is the main form of PCT in serum during sepsis, inducing microvascular permeability. Mid-regional pro-adrenomedullin (MR-proADM) is used instead of ADM as a biological indicator because ADM is rapidly degraded, and MR-proADM is released at the same rate as ADM. ADM reduces endothelial permeability and promotes endothelial stability. Endothelial dysfunction is responsible for multiple organ failure in sepsis and COVID-19 patients. Therefore, ADM may be an important molecule for improving the severity associated with sepsis and COVID-19. This review focuses on the current knowledge of PCT and ADM in sepsis and COVID-19.Copyright © 2023 by the authors.

Plasma bioactive adrenomedullin on intensive care unit admission is associated with acute respiratory distress syndrome: an observational study.

BACKGROUND: Bioactive adrenomedullin (bio-ADM) is a vasoactive peptide with a key role in reducing vascular hyperpermeability and improving endothelial stability during infection, but it also has vasodilatory properties. Bioactive ADM has not been studied in conjunction with acute respiratory distress syndrome (ARDS), but it has recently been shown to correlate with outcomes after severe COVID-19. Therefore, this study investigated the association between circulating bio-ADM on intensive care unit (ICU) admission and ARDS. The secondary aim was the association between bio-ADM and ARDS mortality. METHODS: We analysed bio-ADM levels and assessed the presence of ARDS in adult patients admitted to two general intensive care units in southern Sweden. Medical records were manually screened for the ARDS Berlin criteria. The association between bio-ADM levels and ARDS and mortality in ARDS patients was analysed using logistic regression and receiver-operating characteristics analysis. The primary outcome was an ARDS diagnosis within 72 h of ICU admission, and the secondary outcome was 30-day mortality. RESULTS: Out of 1224 admissions, 11% (n = 132) developed ARDS within 72 h. We found that elevated admission bio-ADM level was associated with ARDS independently of sepsis status and of organ dysfunction as measured by the Sequential organ failure assessment (SOFA) score. Both lower levels (< 38 pg/L) and high (> 90 pg/L) levels of bio-ADM were independently (of the Simplified acute physiology score, SAPS-3) predictive of mortality. Patients with indirect mechanisms of lung injury had higher bio-ADM levels than those with a direct mechanism of injury, and bio-ADM increased with increasing ARDS severity. CONCLUSIONS: High levels of bio-ADM on admission are associated with ARDS, and bio-ADM levels significantly differ depending on the injury mechanism. In contrast, both high and low levels of bio-ADM are associated with mortality, possibly due to the dual action of bio-ADM in stabilising the endothelial barrier and causing vasodilation. These findings could lead to improved diagnostic accuracy of ARDS and potentially lead to new therapeutic strategies.

Systematic review with meta-analysis of mid-regional pro-adrenomedullin (MR-proadm) as a prognostic marker in Covid-19-hospitalized patients.

BACKGROUND: Mid-regional pro-adrenomedullin (MR-proADM) is useful for risk stratification in patients with sepsis and respiratory infections. The study's purpose was to assess the available data and determine the association between MR-proADM levels and mortality in COVID-19 participants. METHODS: A comprehensive literature search of medical electronic databases was performed including PubMed, Web of Science, Scopus, Cochrane, and grey literature for relevant data published from 1 January 2020, to 20 November 2022. Mean differences (MD) with 95% confidence intervals (CI) were calculated. RESULTS: Fourteen studies reported MR-proADM levels in survivors vs. non-survivors of COVID-19 patients. Pooled analysis showed that MR-proADM level in the survivor group was 0.841 ± 0.295 nmol/L for patients who survive COVID-19, compared to 1.692 ± 0.761 nmol/L for non-survivors (MD = -0.78; 95%CI: -0.92 to -0.64; p < 0.001). CONCLUSIONS: The main finding of this study is that mortality of COVID-19 is linked to MR-proADM levels, according to this meta-analysis. The use of MR-proADM might be extremely beneficial in triaging, assessing probable therapy escalation, predicting potential complications during therapy or significant clinical deterioration of patients, and avoiding admission which may not be necessary. Nevertheless, in order to confirm the obtained data, it is necessary to conduct large prospective studies that will address the potential diagnostic role of MR-proADM as a marker of COVID-19 severity.KEY MESSAGESSeverity of COVID-19 seems to be linked to MR-proADM levels and can be used as a potential marker for predicting a patient's clinical course.The use of MR-proADM might be beneficial in triaging, assessing probable therapy escalation, predicting potential complications during therapy or significant clinical deterioration of patients, and avoiding admission which may not be necessary.For patients with COVID-19, MR-proADM may be an excellent prognostic indicator because it is a marker of endothelial function that may predict the precise impact on the equilibrium between vascular relaxation and contraction and lowers platelet aggregation inhibitors, coagulation inhibitors, and fibrinolysis activators in favor of clotting factors.

Analytical performance evaluation of bioactive adrenomedullin on point-of-care platform

For matrix comparison, EDTA whole blood samples (freshly collected and stored at 2-8 °C until the testing) from ten healthy donors were spiked with synthetic bio-ADM to achieve two bio-ADM levels per donor spanning the measuring range. The analytical performance evaluation was mainly conducted using frozen and contrived plasma samples and to validate bio-ADM measurements with IB10 sphingotest SP ® sp bio-ADM SP ® sp . Keywords: acute care;bioactive adrenomedullin;critical care biomarker;endothelial function;Nexus IB10;point-of-care platform EN acute care bioactive adrenomedullin critical care biomarker endothelial function Nexus IB10 point-of-care platform e13 e16 4 11/28/22 20230101 NES 230101 To the Editor, Biologically active adrenomedullin (bio-ADM) is a peptide hormone that regulates the endothelial barrier function [[1]], [[2]], [[3]]. [Extracted from the article]

Mid-regional pro-adrenomedullin as a predictor of in-hospital mortality in adult patients with COVID-19: a single-centre prospective study.

BACKGROUND: To determine the predictive value of mid-regional pro-adrenomedullin (MR-proADM) compared to routine clinical and laboratory parameters in patients with COVID-19. METHODS: A total of 135 adult patients hospitalized with COVID-19 were included in a prospective single-centre study. In addition to routine parameters, the levels of MR-proADM in blood plasma were measured on the day of hospitalization. The patients were divided into 2 groups: those who survived and were discharged (n = 115, 85%) and those who did not survive (n = 20, 15%). Data are presented as median and interquartile range. RESULTS: The non-survivors had a statistically significantly greater age (73.4 [63.5-84.8] vs. 62.2 [50.3-71.4] years, P = 0.001), a lower level of haemoglobin oxygen saturation (91 [87-92] vs. 92 [92-93]%, P < 0.001), lower lymphocyte level (13 [7-30] vs. 21 [15-27]%, P = 0.03), higher lactate dehydrogenase (338 [273-480] vs. 280 [233-383] EU L-1, P = 0.04) and aspartate aminotransferase levels (49 [28-72] vs. 33 [23-47] EU L-1, P = 0.03), a higher National Early Warning (NEWS) score (7 [7- 8] vs. 6 [5-7] points, P < 0.001), and higher procalcitonin (0.16 [0.11-0.32] vs. 0.1 [0.07-0.18] ng mL-1, P = 0.006) and MR-proADM levels (1.288 [0.886-1.847] vs. 0.769 [0.6-0.955] nmol L-1, P < 0.001). MR-proADM had the highest predictive value for death during hospital stay (cut-off: 0.895 nmol L-1, AUC ROC 0.78 [95% CI: 0.66-0.90], sensitivity 75%, specificity 69%, OR 6.58 [95% CI: 2.22-19.51]). CONCLUSIONS: Compared with other indicators, MR-proADM has the highest predictive value for in-hospital mortality in patients with COVID-19.

Mid-Regional Pro-Adrenomedullin as a Prognostic Factor for Severe COVID-19 ARDS.

Mid-regional proadrenomedullin (MR-proADM) protects against endothelial permeability and has been associated with prognosis in bacterial sepsis. As endothelial dysfunction is central in the pathophysiology of severe SARS-CoV-2 infection, we sought to evaluate MR-proADM both as a prognostic biomarker and as a marker of bacterial superinfection. Consecutive patients admitted to the ICU for severe SARS-CoV-2 pneumonia were prospectively included and serum was bio-banked on days 1, 3, and 7. MR-proADM levels were measured blindly from clinical outcomes in batches at the end of follow-up. Among the 135 patients included between April 2020 and May 2021, 46 (34.1%) had died at day 60. MR-proADM levels on days 1, 3, and 7 were significantly higher in day-60 non-survivors. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve (0.744, p < 0.001) of day-1 MR-proADM compared favorably with the AUC ROC curve of day-1 procalcitonin (0.691, p < 0.001). Serial MR-proADM measurements on days 3 and 7 may add prognostic information. After adjusting for CRP, LDH, and lymphocyte values, day-1 MR-proADM remained significantly associated with day-60 mortality. MR-proADM concentrations were significantly higher in patients with respiratory superinfections (on days 3 and 7) and bloodstream infections (on days 1, 3, and 7) than in patients without infection. Our results suggest that MR-proADM is a good predictor of outcome in severe SARS-CoV-2 infection and could be a useful tool to assess bacterial superinfection in COVID-19 patients.

Soluble Signals to Improve Endothelial Integrity in the Lung

Disorders in pulmonary vascular integrity are a prominent feature in many lung diseases, including acute respiratory distress syndrome (ARDS), capillary leak syndrome, and COVID19. Paracrine signals are enriched in the lung and are critically important in regulating the homeostasis of the functional pulmonary microvasculature. Here, we employed single-cell RNA-sequencing (scRNAseq) to study ligand and receptor interactions in the native human lung microvascular niche, and identified soluble factors that are critical in endothelial integrity. The scRNAseq data reveals a total of 47 cell populations consisting of five vascular endothelial subtypes in human lungs, including general capillary EC, aerocyte capillary EC (EC aCap), arterial EC, pulmonary venous EC, and systemic venous EC. Using EC aCap as a signal receiving core (Receptors) and the putative adjacent cell types (alveolar fibroblast, ATI, ATII, pericyte, plasma cell, etc.) in the EC aCap niche as senders (Ligands), we identified that SLIT2-ROBO4, ANGPT1-TIE1, ADM-RAMP2, VEGFD-KDR, and BMP5-BMPR2 are the top specific and abundant pairs in the niche. Immunostaining and ELISA assays confirmed their spatial information and secretion level. Furthermore, upon treatment with these ligands, real-time resistance recorded using an electric cell-substrate impedance sensing (ECIS) system revealed that VEGFD, ANGPT1 (angiopoietin 1), and ADM (adrenomedullin) could markedly increase the electrical resistance of human lung microvascular, arterial, and venous endothelial cells, suggesting their strong impact on the endothelial barrier function. Deciphering the cell-cell soluble signals that improve endothelial integrity in human lungs lays the foundation for uncovering the pathogenesis of pulmonary vascular disorders and the development of ex vivo functional lung vasculature.

Adrenomedullin Therapy in Moderate to Severe COVID-19.

The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study.

Prognostic Value of Bioactive Adrenomedullin in Critically Ill Patients with COVID-19 in Germany: An Observational Cohort Study.

The coronavirus disease 2019 (COVID-19) pandemic has placed a significant burden on hospitals worldwide. Objective biomarkers for early risk stratification and clinical management are still lacking. The aim of this work was to determine whether bioactive adrenomedullin can assist in the risk stratification and clinical management of critically ill COVID-19 patients. Fifty-three patients with confirmed COVID-19 were included in this prospective observational cohort study between March and April 2020. Bioactive adrenomedullin (bio-ADM) plasma concentration was measured daily for seven days after admission. The prognostic value and clinical significance of bio-ADM plasma levels were evaluated for the severity of respiratory failure, the need for extracorporeal organ support and outcome (28-day mortality). Bio-ADM levels increased with the severity of acute respiratory distress syndrome (ARDS; p < 0.001) and were significantly elevated in invasively ventilated patients (p = 0.006) and patients in need of extracorporeal membrane oxygenation (p = 0.040) or renal replacement therapy (RRT; p < 0.001) compared to patients without these conditions. Non-survivors showed significantly higher bio-ADM levels than survivors (p = 0.010). Bio-ADM levels predicted 28-day mortality (C-index 0.72, 95% confidence interval 0.56-0.87, p < 0.001). Bio-ADM plasma levels correlate with disease severity, the need for extracorporeal organ assistance, and outcome, and highlight the promising value of bio-ADM in the early risk stratification and management of patients with COVID-19.

Soluble Angiotensin Converting Enzyme 2 (ACE2) Is Upregulated and Soluble Endothelial Nitric Oxide Synthase (eNOS) Is Downregulated in COVID-19-induced Acute Respiratory Distress Syndrome (ARDS).

A damaged endothelium is an underlying condition of the many complications of COVID-19 patients. The increased mortality risk associated with diseases that have underlying endothelial dysfunction, such as acute respiratory distress syndrome (ARDS), suggests that endothelial (e) nitric oxide synthase (NOS)-derived nitric oxide could be an important defense mechanism. Additionally, intravenous recombinant angiotensin converting enzyme 2 (ACE2) was recently reported as an effective therapy in severe COVID-19, by blocking viral entry, and thus reducing lung injury. Very few studies exist on the prognostic value of endothelium-related protective molecules in severe COVID-19 disease. To this end, serum levels of eNOS, inducible (i) NOS, adrenomedullin (ADM), soluble (s) ACE2 levels, and serum (s) ACE activity were measured on hospital admission in 89 COVID-19 patients, hospitalized either in a ward or ICU, of whom 68 had ARDS, while 21 did not. In our cohort, the COVID-19-ARDS patients had considerably lower eNOS levels compared to the COVID-19 non-ARDS patients. On the other hand, sACE2 was significantly higher in the ARDS patients. iNOS, ADM and sACE activity did not differ. Our results might support the notion of two distinct defense mechanisms in COVID-19-derived ARDS; eNOS-derived nitric oxide could be one of them, while the dramatic rise in sACE2 may also represent an endogenous mechanism involved in severe COVID-19 complications, such as ARDS. These results could provide insight to therapeutical applications in COVID-19.

Adrenomedullin: A vasoactive agent for sporadic and hereditary vascular cognitive impairment.

Adrenomedullin (AM) is an endogenous peptide mainly secreted from endothelial cells, which has multiple physiological actions such as anti-inflammation, vasodilation, vascular permeability regulation and angiogenesis. Blood AM levels are upregulated in a variety of pathological states including sepsis, severe COVID-19, acute ischemic stroke and vascular cognitive impairment with white matter changes, likely serving as a compensatory biological defense response against infection and ischemia. AM is currently being tested in clinical trials for ulcerative colitis, Crohn's disease, severe COVID-19 for its anti-inflammatory properties and in ischemic stroke for its additional angiogenic action. AM has been proposed as a therapeutic option for vascular cognitive impairment as its arteriogenic and angiogenic properties are thought to contribute to a slowing of cognitive decline in mice after chronic cerebral hypoperfusion. As AM promotes differentiation of oligodendrocyte precursor cells into mature oligodendrocytes under hypoxic conditions, AM could also be used in the treatment of CADASIL, where reduced oxygen delivery is thought to lead to the death of hypoxia-prone oligodendrocytes. AM therefore holds potential as an innovative therapeutic drug, which may regenerate blood vessels, while controlling inflammation in cerebrovascular diseases.

The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.

High value of mid-regional proadrenomedullin in COVID-19: A marker of widespread endothelial damage, disease severity, and mortality.

The widespread endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to a disruption of the adrenomedullin (ADM) system responsible for vascular leakage, increased inflammatory status, and microvascular alteration with multi-organs dysfunction. The aim of this study was to evaluate the role of mid-regional proadrenomedullin (MR-proADM) as a marker of SARS-CoV2 related widespread endothelial damage, clinically identified by organs damage, disease severity and mortality. Patients with SARS-CoV-2 infection has been prospectively enrolled and demographic characteristic, clinical and laboratory data has been evaluated. In the overall population, 58% developed acute respiratory distress syndrome (ARDS), 23.3% of patients died, 6.5% acute cardiac injury, 1.4% of patients developed acute ischemic stroke, 21.2% acute kidney injury, 11.8% acute liver damage, and 5.4% septic shock. The best MR-proADM cut-off values for ARDS development and mortality prediction were 3.04 and 2 nmol/L, respectively. Patients presenting with MR-proADM values ≥2 nmol/L showed a significantly higher mortality risk. In conclusion, MR-proADM values ≥2 nmol/L identify those patients with high mortality risk related to a multiorgan dysfunction syndrome. These patients must be carefully evaluated and considered for an intensive therapeutic approach.

Targeting Endothelial Dysfunction in Eight Extreme-Critically Ill Patients with COVID-19 Using the Anti-Adrenomedullin Antibody Adrecizumab (HAM8101).

Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a "treatment on a named-patient basis" approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0-16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging.