Correspondence
Early and accurate risk stratification of critically ill patients in the Emergency Department (ED) remains a cornerstone of modern acute care medicine. Timely decisions regarding resource allocation, Intensive Care Unit (ICU) admission, and targeted therapies rely on tools that can identify patients at risk of rapid deterioration, preferably before overt clinical signs emerge.
Traditional clinical scoring systems, such as the Modified Early Warning Score (MEWS), the quick Sequential Organ Failure Assessment (qSOFA), and the Shock Index (SI), are widely used for initial triage and prognosis [1]. However, these scores often detect deterioration only after organ damage has already begun.
Recent literature has identified circulating dipeptidyl peptidase 3 (cDPP3), a cytosolic metalloprotease released into the bloodstream during cellular injury, as a promising biomarker associated with poor outcomes in patients with septic, cardiogenic, or vasoplegic shock admitted to the ICU [2–5]. By degrading angiotensin II and enkephalins, cDPP3 may directly contribute to hemodynamic instability, myocardial depression, and multi-organ failure. Despite these insights, the utility of cDPP3 as an early biomarker in the ED setting has not been fully explored.
We conducted a prospective observational study at the ED of San Giovanni Addolorata Hospital in Rome, Italy. A total of 336 consecutive patients classified as triage code 1 (critical) and presenting with at least one abnormal clinical score (MEWS > 3, qSOFA ≥ 2, or SI > 1) were enrolled. Exclusion criteria included pre-hospital cardiac arrest, trauma, and refusal of consent.
Following informed consent, all patients underwent point-of-care (POC) testing for cDPP3 on ED admission using the IB10 sphingotest® cDPP3 in the Nexus IB10 POC system (4TEEN4 Pharmaceuticals GmbH, Hennigsdorf-Berlin, Germany). The primary endpoint was in-hospital and 28-day all-cause mortality.
The median age in our cohort was 77 (61–86) years, with a slight male prevalence (60.4%). A total of 9 patients (2.7%) died in the ED within the first 24 h, with increasing mortality over the following days to a 28-day mortality of 15.8% (n = 53). No patient was lost at the 28-day follow-up.
Our findings suggest that elevated cDPP3 levels on arrival are significantly associated with short-term mortality. Median cDPP3 concentrations were higher in non-survivors compared to survivors (43.96 [31.95–70.66] ng/mL vs. 35.18 [21.74–58.32] ng/mL, p < 0.006). Using a cutoff of 40 ng/mL, consistent with thresholds identified in previous ICU studies, patients with a cDPP3 above this level had a twofold increased risk of 28-day mortality (HR 2.06, 95% CI 1.19–3.56). Importantly, cDPP3 demonstrated stronger predictive power for early mortality, with an AUC of 0.83 for 24-hour mortality and a C-index of 0.618 (95% CI: 0.547–0.689) for 28-day mortality.
The MEWS had the highest overall C-index for 28-day mortality (0.789), outperforming both qSOFA (0.682) and SI (0.570). However, cDPP3 demonstrated an additional prognostic value when combined with MEWS (Fig. 1). This combination slightly, yet significantly, improved the predictive capacity for 28-day mortality (C-index 0.791 vs. 0.789, p = 0.037), suggesting that cDPP3 may capture aspects of pathophysiological deterioration not yet reflected in clinical parameters.
Fig. 1.
Kaplan-Meier for 28-day mortality stratified for baseline cDPP3 and MEWS score
Another noteworthy finding was the interaction between cDPP3 levels and prior use of angiotensin-converting enzyme inhibitors (ACE-I). Patients with both cDPP3 > 40 ng/mL and ACE-I use had the highest mortality rates in our cohort (37.1% vs. 15.8% of the overall cohort). While still an observational result, this raises the hypothesis that cumulative interference with the renin-angiotensin system, via both pharmacologic blockade and enzymatic degradation, may amplify vulnerability to hemodynamic collapse. Further pathophysiological studies are warranted to explore this relationship.
This pilot study has several strengths. It is, to our knowledge, the first to evaluate cDPP3 prospectively as a biomarker in ED patients at the moment of first medical contact, bridging the gap between pre-ICU evaluation and intensive care management. Furthermore, we included every patient, regardless of the underlying pathology, which is key for ED physicians, when the diagnosis is still unknown. Additionally, the use of a rapid POC platform for cDPP3 measurement demonstrated the potential for timely bedside risk stratification.
Nevertheless, limitations include the single-center design and relatively short-term follow-up period. While our cohort was representative of a high-acuity urban ED population, external validation is necessary to generalize these findings. Furthermore, we did not perform serial cDPP3 measurements, which might provide additional prognostic information, as prior ICU studies suggest a dynamic association with patient outcomes [5].
In conclusion, our results support the role of cDPP3 as a valuable early biomarker in emergency care. When used alongside clinical scoring systems such as MEWS, this biomarker could enhance prognostic accuracy and identify patients at high risk of early deterioration. This may inform decisions on prompt ICU/HDU admission and encourage the development of targeted therapies to mitigate cDPP3-related pathophysiology. We believe these findings underscore the potential of cDPP3 to become part of an integrated approach to precision medicine in the acute care setting.
Acknowledgements
We are indebted to the patients who participated in the study and to the emergency department staff, as well as the laboratory technicians of all participating sites for their most valuable efforts.
Abbreviations
- ACE-I
Angiotensin Converting Enzyme Inhibitors
- AUC
Area Under Curve
- cDPP3
Circulating Dipeptidyl Peptidase 3
- CI
Confidence Interval
- ED
Emergency Department
- HDU
High Dependency Unit
- HR
Hazard Ratio
- ICU
Intensive Care Unit
- IQR
Interquartile range
- MEWS
Modified Early Warning Score
- POC
Point of Care
- qSOFA
quick Sequential Organ Failure Assessment
- SI
Shock Index
- SOFA
Sequential Organ Failure Assessment
Author contributions
GF: conceptualization, methodology, writing– original draft; MPR: conceptualization, methodology, supervision, funding, writing– review & editing; LC: methodology, formal analysis, writing– original draft; GV: methodology, formal analysis, writing– original draft; FDM: conceptualization, methodology; AB: writing– review & editing; KS: writing– review & editing; OH: formal analysis, writing– review & editing; SDS: conceptualization, methodology, writing– review & editing. All authors have read and approved the final version of the manuscript.
Funding
This study was self-promoted by the Department of Emergency Medicine of the Azienda Ospedaliera San Giovanni-Addolorata.
Data availability
The data, code, and study material that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The study protocol was approved by our local ethics committee (Lazio 1 Ethical Committee, protocol number 0945/2024) and conducted in agreement with the Declaration of Helsinki and its successive amendments. Before enrolment, informed consent was obtained from each patient (or their legal representatives).
Consent for publication
Not Applicable.
Competing interests
Oliver Hartmann, Karine Santos and Andreas Bergmann are employees of 4TEEN4 Pharmaceuticals GmbH. 4TEEN4 Pharmaceuticals GmbH holds patents related to the DPP3 biomarker and the anti-DPP3 therapy (procizumab).
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
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Associated Data
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Data Availability Statement
The data, code, and study material that support the findings of this study are available from the corresponding author upon reasonable request.