The present prospective observational study evidenced that MR-proADM measured within 48 hours from admission was significantly higher in patients with worse outcome and that a higher mortality characterized patients presenting a predictive value of MR-proADM exceeding the cut-off of 1.8 nmol/L [23–26]. A result maintaining its statistical significance even in a multivariate logistic regression model including age, gender, cardiovascular disease, diabetes mellitus and PCT values at admission as possible confounding. Moreover, its ability to discriminate surviving patients was found to be better than all other biomarkers usually measured in ICU.
Finding a biomarker able to identify patients with worst outcome has always been a challenge, especially in ICU, but emerged as a priority in the context of the pandemic induced by COVID-19 leading even the most advanced health systems to face the problem of the limited health resources available.
MR-proADM appears to be a biomarker with a strong prognostic value. This finding even is supported by a series of experimental evidences attributing to ADM a major role in the regulation of vascular permeability and endothelial barrier , on inflammation mediators and microcirculation . All mechanisms certainly playing a role in the development of organ failures characterizing the pathology induced by SARS-CoV2.
To the best of our knowledge, none previously compared sequential measurements of conventional biomarkers such as PCT, C-RP, and other laboratory tests such as lymphocytes, NT-pro-BNP, LDH with MR-proADM values in a cohort of COVID-19 critically ill patients admitted in ICU.
The choice to study the progress of some biomarkers already in use in clinical practice in our patients was taken in accordance with the evidences from the existing literature at the beginning of the pandemic. It is in fact known that a number of laboratory parameters are altered in COVID-19 patients and that some of these alterations, such as the decrease in lymphocyte count  and increase in LDH, D-dimer, CRP [30, 31] could be considered predictors of adverse clinical outcomes.
In the population we studied, we observed lymphopenia and an increase in CRP and LDH, while NT-proBNP and D-dimer did not increase significantly.
Although serum procalcitonin levels are generally normal in patients with viral infections, we observed that these increased in about half of our cases and continued to remain higher than normal during ICU stay. It is reasonable that this increase reflects the occurrence of bacterial superinfection possibly contributing to unfavorable outcomes .
MR-proADM ROC analysis showed that this biomarker has significantly greater prediction skill. It is therefore reasonable to hypothesize that MR-proADM is the best biomarker to predict outcome of patients either at admission or during ICU stay. It follows that, as found in sepsis and septic shock [10, 16], the inclusion of MR-proADM monitoring into an early clinical management protocol may support diagnostic intervention and facilitate the choice of the most appropriate treatment in case of organ dysfunctions.
The rise of MR-proADM, resulting from a dose-response mechanism induced by the host-pathogen interaction, appears to occur in the initial phase of pathogen recognition which means, in the case of COVID-19, at the time of hospital admission or even before. However, it is interesting to note that the increase tends to persist over the days in line with the persistence of the disease, underlying the additional value of this biomarker in predicting patient’s outcome. Low values, on the other hand, seems to characterize patients with a shorter ICU length of stay and a lower mortality. It follows that MR-proADM seems particularly interesting biomarker even to monitor the disease progression.
So far, a predictive value of individual MR-proADM measurements has been found in ischemic and congestive heart disease [33–34], after cardiac surgery , in sepsis , in pneumoniae [13, 36] and in other ARDS-related conditions . Despite the low number of cases affected by serious viral pathologies included in previous studies [14, 38], we believe that a similar effect can be hypothesized in the context of cohorts of COVID-19 patients. It is hence possible, as already proposed in the context of sepsis , that the use of this biomarker could help either to anticipate the escalation of therapy in patients at risk of treatment failure or to suggest a faster discharge of patients with a low risk of unfavorable evolution.
Particularly interesting is the observation that our small subpopulation of patients treated with ECMO exhibit a significant difference between surviving and non-surviving patients. This in spite of the typical inflammatory response proved to be associated with the use of extracorporeal circulation . This observation certainly deserves further investigation in larger cohorts of patients treated with extracorporeal circulation and monitored by MR-proADM.
A further aspect of discussion is the identification of an appropriate cut-off of MR-proADM. Although Krintus et al. reported normality values ranging between 0.21 (0.19–0.23) and 0.57 nmol/L , the literature is not univocal in defining a single pathological cut-off. There are evidences, mainly related to sepsis, septic shock, and community-acquired pneumonia (CAP) proposing values ranging between 0.9 and 5.19 nmol/L [36, 40] or more. Considering COVID 19 as a severe community pneumonia, we chose the cut-off 1.8 mn/l, suggested by important studies on pneumonia [23–26]. The same cut-off is suggested concerning the role of MR-proADM in predicting mortality in patients with sepsis or septic shock [41–43]. Of course, the complexity of this new and only partially known infection makes it difficult to classify, and probably different values (as proposed in the context of septic shock or multi-organ failure) could be adequate, considering that the cut-off may change accordingly to the outcome investigated .
We included a population with clinical characteristics that are comparable with others Italian experience [19, 44]: a high proportion required mechanical ventilation at ICU admission (66.7%); a median age of 64 years, with a high preponderance of the male sex (87.7%), and at least one comorbidity in the 77.2%. Cardiovascular disease (other than hypertension) represented the most important comorbidity, with a statistically significant impact on outcome (p value 0.008) even confirmed by the multivariate analysis (OR 22.2, IC 1.556–316.960). This in line with a large-scale study reporting that cardiovascular disease was a major risk factor for fatality of COVID-19 patients .
We even observed that 22.8% of our patients presented superinfection at arrival and 54.4% within 21 days in ICU. This aspect deserves particular attention. Bacterial and fungal infections are in fact common complications of viral pneumonia, especially in critically ill patients. But even among a wide number of articles reporting on COVID-19 clinical data, only a few have reported secondary infection, mostly without detailed pathogens. Some reported a low proportion of superinfections in hospitalized patients (7–8%) that rose to 14% in ICU, less than in previous influenza pandemics . According to other data, secondary infections were identified in 5%-44% of ICU patients with COVID-19, being bacterial or fungal pneumonia and bloodstream the most frequent infections  (23a), as in our cohort (VAP 38.6% and BSI 36.8%), where the total number of superinfections is higher overall. Interestingly, we found that 33.3% of our patients developed septic shock due to superinfections. These data appear more representative of a population of critically ill patients, with the need for invasive support, prolonged hospitalization, and subjected to repeated, broad-spectrum antibiotic therapies.
Concerning mortality, our data are slightly higher than the values reported in the literature (54.4%). In fact, in a recent metanalysis on 24 observational studies, in patients with completed ICU admissions with COVID-19 infection, combined ICU mortality (95%CI) was 41.6% (34.0–49.7%) . To note, the in‐ICU mortality from COVID‐19 is far higher than usually seen in ICU admissions with other viral pneumonias. Importantly, the mortality from completed episodes of ICU differs considerably from the crude mortality rates in some early reports. For instance, in the Lombardy experience, ICU mortality was 26% as of March 25, 2020  but rose to 48.7% in ICU and 53.4% in hospital as of May 30, 2020 .
Our population certainly had particularly severity conditions at admission, as confirmed by the high percentage of patients transferred from other hospitals (59.6%); of patients undergoing VV-ECMO (15.8%) or suffering from superinfection (54.4%) and septic shock (33.3%).