Background
Severe burn injury is associated with an early and profound hypovolemia followed by an intense systemic inflammatory response. Hemodynamic management, including fluid resuscitation, has long been recognized as the cornerstone of the early management and hemodynamic resuscitation of severely burned patients [
1‐
3]. However, a systemic inflammatory response may be associated with distributive shock and/or acute myocardial dysfunction [
4]. Dipeptidyl peptidase-3 (DPP3), also named enkephalinase B or red cell angiotensinase, is a predominantly intracellular, ubiquitously expressed, zinc-dependent metallopeptidase involved in the metabolism of peptides [
5] implicated in many different pathways (e.g., blood pressure regulation, inflammation). DPP3 cleaves bioactive peptides, notably angiotensin II, enkephalins, and endomorphins [
6‐
8]. We hypothesize that cleavage of angiotensin II by DPP3 may promote vasodilatation and circulatory failure. Severe burn patients are at high risk of developing vasodilatory shock with systemic inflammatory response after the early phase of hypovolemic shock. The main objective of this study was therefore to assess the association between DPP3 at admission (DPP3
admin) and day 3 (DPP3
Day3) with 90-day mortality in severely burned patients. The secondary objective was to evaluate the association between DPP3 and organ dysfunction (i.e., circulatory failure and acute kidney injury (AKI)).
Discussion
In this biomarker analysis of a prospective cohort, we observed that DPP3admin was strongly associated with 90-day mortality, circulatory failure, and AKI in severely burned patients. Furthermore, adding DPP3admin to SOFAadmin, lactateadmin, or ABSI outperformed these prognostic factors to predict 90-day mortality. Serial measurements of DPP3 have improved the prediction of outcome compared to DPP3admin alone.
While the prognosis of burn patients has improved, the mortality of most severe patients remains high with many patients dying from circulatory failure and multiple organ failure [
16,
17]. Initial hemodynamic management has long been considered critical in the treatment and prognosis of burn patients [
18]. Burn injury is characterized by an initial hypodynamic state with low cardiac output due to hypovolemia followed by a hyperdynamic state with high cardiac output and low vascular resistance developing 12 to 24 h after the injury [
1]. The severity of the distributive shock and occurrence of cardiac dysfunction may, however, vary greatly between patients. The association between DPP3 levels, circulatory failure, and AKI is consistent with the current understanding of AKI in the critically ill, associating hemodynamic factors and inflammation/immune response [
19,
20]. These results might also be expected in patients developing systemic inflammatory response from different causes (e.g., sepsis, post-cardiopulmonary bypass, post-cardiac arrest, pancreatitis), and it should be further explored.
In the current study, DPP3 was strongly associated with mortality and hemodynamic failure, even after adjustment for classic markers of severity and prognosis. Recently, Deniau et al. observed an association between high plasmatic levels of DPP3 and high mortality and organ dysfunction in severe heart failure patients. Furthermore, I.V. administration of DPP3 rapidly deteriorated cardiac contraction in mice [
21]. In an ancillary study of the OptimaCC study, Takagi et al. showed that high circulating DPP3 was associated with low cardiac index, refractory shock, and high mortality in patients with cardiogenic shock [
22].
The results of the present study have several potential implications for future research. First, the identification of patients with high plasma DPP3 may trigger cardiac function assessment. Second, high DPP3 levels at admission may help to select candidate patients for alternative vasopressor therapies, especially for infusion of angiotensin II [
23,
24]. Angiotensin II has been found to be downregulated in some forms of septic shock associated with poor prognosis [
25]. DPP3 cleaves angiotensin II and may, therefore, play a role in vasoplegic shock by reducing angiotensin II levels. Since angiotensin II is not easy to measure in clinical practice, DPP3 may represent a potential candidate biomarker for selecting patients most likely to respond to angiotensin II infusion. Third, pharmacological inhibition of DPP3 by a specific antibody has been shown to promptly restore and sustain cardiac contraction in mice [
21] and might be a therapeutic option in burn patients with high DPP3. All these strategies are hypothesis and require exploration and validation in well-designed prospective human studies.
Our study has several limitations. First, the observational design of the present study does not allow us to conclude on the causality between DPP3 and mortality or organ dysfunction. Second, the study contains a relatively low number of patients, even though this is one of the largest cohort studies among critically ill burn patients with sufficient power to identify an association between the biomarker levels and outcomes. Thirdly, factors influencing DPP3 metabolism are unknown and will need further exploration in critically ill burn patients. Finally, only half of our patients had an echocardiography at admission, limiting the interpretation of the association between DPP3 levels and cardiac dysfunction.
Conclusion
Plasma DPP3 concentration at admission was associated with an increased risk of death, circulatory failure, and AKI in severely burned patients. Whether DPP3 plasma levels could identify patients who would respond to alternative hemodynamic support strategies, such as intravenous angiotensin II, should be explored.
Competing interests
FD has received research grants from the French ministry of health, Société française d’anesthésie reanimation, European Society of Intensive Care Medicine, and lecture fees Sedana medical.
JA has no conflict of interest.
MCo has no conflict of interest.
MCh has no conflict of interest.
KS and OH are employed by 4TEEN4 Pharmaceuticals GmbH, a company which holds patent rights in and commercializes the DPP3 assay.
MJ has no conflict of interest.
AF has no conflict of interest.
HO has no conflict of interest.
AC has no conflict of interest.
MB has no conflict of interest.
LG has no conflict of interest.
BD received research grant from 4TEEN4 Pharmaceuticals GmbH.
AM has received speaker’s honoraria from Novartis, Orion, and Servier and fees as a member of the advisory board and/or steering committee from Cardiorentis, Adrenomed, sphingotec, Sanofi, Roche, Abbott, and Bristol-Myers Squibb.
BS has no conflict of interest.
JT is employed by Biomerieux.
ML has received research grants from the French ministry of health, lecture fees from Baxter, and Fresenius and research support from Sphingotec.
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