Clinical Utility of Midregional Proadrenomedullin in Patients With COVID-19

Bruna Lo Sasso, PhD; Caterina Maria Gambino, PhD; Nicola Scichilone, MD; Rosaria Vincenza Giglio, PhD; Giulia Bivona, MD; Concetta Scazzone, BS; Roberto Muratore, BS; Salvatore Milano, BS; Mario Barbagallo, MD; Luisa Agnello, PhD; Marcello Ciaccio, MD


Lab Med. 2021;52(5):493-498. 

In This Article

Abstract and Introduction


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.


COVID-19 is caused by SARS-CoV-2, which primarily infects the respiratory system in humans. It is characterized by a broad spectrum of clinical manifestations with varying degrees of severity, from asymptomatic form to pneumonia, which can evolve into acute respiratory distress syndrome and multiorgan failure syndrome, until death.[1–4]

SARS-CoV-2 internalization occurs by the viral spike glycoprotein that binds to angiotensin-converting enzyme 2 (ACE2), which is mainly expressed on type II alveolar epithelial cells, myocardial cells, proximal tubule cells of the kidney, bladder urothelial cells, and enterocytes.[5,6] This interaction results in the downregulation of ACE2 expression and excessive angiotensin production, enhancing an inflammatory response that contributes to acute organ injury.[7]

The clinical course of the disease is unpredictable, and there is an urgent need for biomarkers that could reliably stratify patients into different classes of risk. Early identification of hospitalized patients who are more vulnerable to clinical deterioration could guide clinicians for risk stratification and monitoring.

The hallmark of SARS-CoV-2 infection is the activation of the immune system, which can lead to an uncontrolled and generalized inflammatory response and to the so-called cytokine storm.[8] Indeed, patients with COVID-19 have significantly increased circulating levels of inflammatory biomarkers, such as interleukin (IL)-6, C-reactive protein (CRP), and procalcitonin (PCT). Moreover, several biochemical parameters, such as D-dimer, cardiac troponin, and homocysteine, are altered.[9–13] These biomarkers have been associated with disease severity and mortality.[2,14,15] However, there is ongoing research for biomarkers to better define the biochemical phenotype of COVID-19 patients to improve their management.

Midregional proadrenomedullin (MR-proADM) is a surrogate biomarker of adrenomedullin (ADM), a 52–amino acid peptide belonging to the Calc gene family. Under physiological conditions, ADM levels are very low. Several factors, including catecholamines, hypoxia, oxidative stress, inflammatory mediators, and cytokines, induce their increase.[16] Thus, it has been evaluated in several inflammatory conditions.[17,18] However, the measurement of ADM has several technical issues, such as a short half-life and rapid degradation by proteases. The more stable MR-proADM provides a solution to these problems. The latter is secreted in equimolar amounts with ADM and is more stable in vitro. Moreover, it can be easily measured on a fully automated platform.

Research has recently proposed MR-proADM as a biomarker of organ failure.[19–22] Specifically, increased MR-proADM levels have been associated with short- and long-term mortality in patients with community-acquired pneumonia and sepsis.[23–26] In addition, MR-proADM has emerged as a prognostic biomarker in critically ill patients admitted to the intensive care unit (ICU) independently by their underlying clinical conditions.[23,24] Considering that patients with COVID-19 are at high risk of developing organ failure, MR-proADM could represent a useful prognostic biomarker.

The aim of the present study was to evaluate the potential prognostic value of MR-proADM to predict in-hospital mortality in patients with COVID-19.