# Decrease of the plasmatic endocan cleavage ratio is associated with the hyperinflammatory phenotype of acute respiratory distress syndrome

Alexandre Gaudet, Erika Parmentier, Nathalie de Freitas Caires, Lucie

Portier, Sylvain Dubucquoi, Julien Poissy, Thibault Duburcq, Maxence

Hureau, Philippe Lassalle, Daniel Mathieu

► To cite this version:

Alexandre Gaudet, Erika Parmentier, Nathalie de Freitas Caires, Lucie Portier, Sylvain Dubucquoi, et al. Decrease of the plasmatic endocan cleavage ratio is associated with the hyperinflammatory phenotype of acute respiratory distress syndrome. Critical care (London, England), 2019, Critical care (London, England), 23, pp.252. 10.1186/s13054-019-2537-z. http://hal-04465817

HAL Id: hal-04465817

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# Decrease of the plasmatic endocan cleavage ratio is associated with the hyperinflammatory phenotype of acute respiratory distress syndrome

Alexandre Gaudet, Erika Parmentier, Nathalie de Freitas Caires, Lucie

Portier, Sylvain Dubucquoi, Julien Poissy, Thibault Duburcq, Maxence

Hureau, Philippe Lassalle, Daniel Mathieu

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Alexandre Gaudet, Erika Parmentier, Nathalie de Freitas Caires, Lucie Portier, Sylvain Dubucquoi, et al. Decrease of the plasmatic endocan cleavage ratio is associated with the hyperinflammatory phenotype of acute respiratory distress syndrome. Critical Care, 2019, Critical care (London, England), 23, pp.252. 10.1186/s13054-019-2537-z. http://04465817v2

HAL Id: hal-04465817

https://lilloa.hal.science/hal-04465817v2

Submitted on 14 May 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>
LETTER

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<figure><img src="image_1.png" /></figure>

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# Decrease of the plasmatic endocan cleavage ratio is associated with the hyperinflammatory phenotype of acute respiratory distress syndrome

Alexandre Gaudet<sup>1,2,3,4*</sup> ID, Erika Parmentier<sup>1,2,3,4</sup>, Nathalie De Freitas Caires<sup>1,2,3,5</sup>, Lucie Portier<sup>1,2,3,5</sup>, Sylvain Dubucquoi<sup>6</sup>, Julien Poissy<sup>4</sup>, Thibault Duburcq<sup>4</sup>, Maxence Hureau<sup>1,2,3,4</sup>, Philippe Lassalle<sup>1,2,3</sup> and Daniel Mathieu<sup>1,2,3,4</sup>

Dear editor,

Several studies have reported the identification of pro-inflammatory subphenotypes of acute respiratory distress syndrome (ARDS) which seem to be the most likely to respond to targeted treatments, such as restrictive vascular filling, higher PEEP, or statins [1]. In these studies, vasopressor use, low platelets, and low bicarbonate appeared as routine markers of hyperinflammatory ARDS [1]. Endocan and its major catalolite p14 have been reported as novel biomarkers in ARDS [2], yet their potential utility in the characterization of ARDS phenotypes has never been explored.

We hereby present the results of a post hoc analysis based on the data from a previously published prospective cohort of severe septic patients [3]. Patients with a diagnosis of ARDS within 72 h following enrollment were included in this analysis. We considered ARDS as belonging to the HIP group when the 3 following criteria were present at the time of diagnosis: vasopressor use, platelets < 150 G/L, and bicarbonate < 22 mmol/L [1]. Measurements of endocan and p14 were performed at the time of diagnosis of ARDS and 24 h later if biological samples were available. Plasmatic endocan cleavage ratio (ECR) was

calculated as previously described [4]. The aim of this analysis was to assess if static measurements of blood endocan and ECR at time of diagnosis of ARDS, as well as their variations within 24 h, were different between the HIP and NHIP subgroups of ARDS.

Thirty-nine patients with a diagnosis of ARDS were included in this analysis. Plasmatic levels of endocan and ECR were measured at the time of ARDS in every patient and were repeated 24 h later in 29 patients. Patients' baseline characteristics are described in Additional file 1. ECR variation over 24 h was the only parameter to be found significantly different in the HIP group (−7% [−19%; −5%]) by comparison with the NHIP group (6% [−3%; 16%]) (*p* < 10⁻<fnref n="2" />) (Fig. 1) and to show clinically relevant diagnostic values according to ROC analysis (AUC = 0.84 (95% CI 0.69–0.94; *p* < 10⁻<fnref n="2" />)) (Fig. 2). A variation of ECR < −4.5% was found as the best cutoff for the diagnosis of HIP ARDS according to the Youden index, with a sensitivity at 0.86 and a specificity at 0.82.

These results suggest that the variation of ECR 24 h after the diagnosis of ARDS seems to be a discriminant biomarker to identify hyperinflammatory subphenotypes of ARDS. New studies are warranted to comfort these preliminary observations.

<footnote>* Correspondence: alexandre.gaudet@chru-lille.fr</footnote>

<footnote n="1">¹Center for Infection and Immunity of Lille, University of Lille, U1019, UMR 8204, CIIIL, F-59000 Lille, France</footnote>

<footnote n="2">²CNRS, UMR 8204, F-59000 Lille, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
<figure><img src="image_3.png" /></figure>

Check for
updates

# Decrease of the plasmatic endocan cleavage ratio is associated with the hyperinflammatory phenotype of acute respiratory distress syndrome

Alexandre Gaudet<sup>1,2,3,4*</sup> ID, Erika Parmentier<sup>1,2,3,4</sup>, Nathalie De Freitas Caires<sup>1,2,3,5</sup>, Lucie Portier<sup>1,2,3,5</sup>, Sylvain Dubucquoi<sup>6</sup>, Julien Poissy<sup>4</sup>, Thibault Duburcq<sup>4</sup>, Maxence Hureau<sup>1,2,3,4</sup>, Philippe Lassalle<sup>1,2,3</sup> and Daniel Mathieu<sup>1,2,3,4</sup>

Dear editor,

Several studies have reported the identification of pro-inflammatory subphenotypes of acute respiratory distress syndrome (ARDS) which seem to be the most likely to respond to targeted treatments, such as restrictive vascular filling, higher PEEP, or statins [1]. In these studies, vasopressor use, low platelets, and low bicarbonate appeared as routine markers of hyperinflammatory ARDS [1]. Endocan and its major catalolite p14 have been reported as novel biomarkers in ARDS [2], yet their potential utility in the characterization of ARDS phenotypes has never been explored.

We hereby present the results of a post hoc analysis based on the data from a previously published prospective cohort of severe septic patients [3]. Patients with a diagnosis of ARDS within 72 h following enrollment were included in this analysis. We considered ARDS as belonging to the HIP group when the 3 following criteria were present at the time of diagnosis: vasopressor use, platelets < 150 G/L, and bicarbonate < 22 mmol/L [1]. Measurements of endocan and p14 were performed at the time of diagnosis of ARDS and 24 h later if biological samples were available. Plasmatic endocan cleavage ratio (ECR) was

calculated as previously described [4]. The aim of this analysis was to assess if static measurements of blood endocan and ECR at time of diagnosis of ARDS, as well as their variations within 24 h, were different between the HIP and NHIP subgroups of ARDS.

Thirty-nine patients with a diagnosis of ARDS were included in this analysis. Plasmatic levels of endocan and ECR were measured at the time of ARDS in every patient and were repeated 24 h later in 29 patients. Patients' baseline characteristics are described in Additional file 1. ECR variation over 24 h was the only parameter to be found significantly different in the HIP group (−7% [−19%; −5%]) by comparison with the NHIP group (6% [−3%; 16%]) (*p* < 10⁻<fnref n="2" />) (Fig. 1) and to show clinically relevant diagnostic values according to ROC analysis (AUC = 0.84 (95% CI 0.69–0.94; *p* < 10⁻<fnref n="2" />)) (Fig. 2). A variation of ECR < −4.5% was found as the best cutoff for the diagnosis of HIP ARDS according to the Youden index, with a sensitivity at 0.86 and a specificity at 0.82.

These results suggest that the variation of ECR 24 h after the diagnosis of ARDS seems to be a discriminant biomarker to identify hyperinflammatory subphenotypes of ARDS. New studies are warranted to comfort these preliminary observations.

<figure><img src="image_4.png" /></figure>

<footnote>* Correspondence: alexandre.gaudet@chru-lille.fr</footnote>

<footnote n="1">¹Center for Infection and Immunity of Lille, University of Lille, U1019, UMR 8204, CIIIL, F-59000 Lille, France</footnote>

<footnote n="2">²CNRS, UMR 8204, F-59000 Lille, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

**Fig. 1** Endocan and ECR plasmatic levels at time of ARDS and variations over 24 h in HIP and NHIP ARDS. We found no difference between HIP and NHIP groups for blood concentrations of endocan (a), variations of endocan within 24 h (b), and ECR (c). ECR variation over 24 h in the HIP group was significantly different to that of the NHIP group (d). Box plot shows the median (horizontal line) and IQR (25th–75th percentile) (box). The whiskers show the lowest data within 1.5 IQR of the lower quartile and highest data within 1.5 IQR of the upper quartile. We used the Mann-Whitney test for comparisons of two groups of continuous variables and the chi-square test for comparisons of categorical variables. ARDS: acute respiratory distress syndrome; ECR: endocan cleavage ratio; HIP: hyperinflammatory phenotype; NHIP: non-hyperinflammatory phenotype
a

p = 0.59

<figure><img src="image_5.png" /></figure>

b

p = 0.66

<figure><img src="image_6.png" /></figure>

c

p = 0.99

<figure><img src="image_7.png" /></figure>

d

p < 10⁻²

<figure><img src="image_8.png" /></figure>

**Fig. 1** Endocan and ECR plasmatic levels at time of ARDS and variations over 24 h in HIP and NHIP ARDS. We found no difference between HIP and NHIP groups for blood concentrations of endocan (a), variations of endocan within 24 h (b), and ECR (c). ECR variation over 24 h in the HIP group was significantly different to that of the NHIP group (d). Box plot shows the median (horizontal line) and IQR (25th–75th percentile) (box). The whiskers show the lowest data within 1.5 IQR of the lower quartile and highest data within 1.5 IQR of the upper quartile. We used the Mann-Whitney test for comparisons of two groups of continuous variables and the chi-square test for comparisons of categorical variables. ARDS: acute respiratory distress syndrome; ECR: endocan cleavage ratio; HIP: hyperinflammatory phenotype; NHIP: non-hyperinflammatory phenotype
<figure><img src="image_6.png" /><figcaption>**Fig. 2** ROC analysis of endocan plasmatic levels at time of ARDS (a) and their variations over 24 h (b), as well as ECR plasmatic levels a time of ARDS (c) and their variations over 24 h (d) for the diagnosis of hyperinflammatory subphenotypes of ARDS. ARDS: acute respiratory distress syndrome; ECR: endocan cleavage ratio; HIP: hyperinflammatory phenotype; NHIP: non-hyperinflammatory phenotype</figcaption></figure>

## Additional file

**Additional file 1:** Cohort baseline characteristics. Continuous and categorical variables are described as median [interquartile range] and number (percentage), respectively. COPD chronic obstructive pulmonary disease SOFA Sequential Organ Failure Assessment ICU intensive care unit SAPS 2 Simplified Acute Physiology Score 2 LIPS Lung Injury Prediction Score. (DOC 45 kb)

### Abbreviations

ARDS: Acute respiratory distress syndrome; ECR: Endocan cleavage ratio; HIP: Hyperinflammatory phenotype; NHIP: Non-hyperinflammatory phenotype

### Acknowledgements

Not applicable

### Authors' contributions

AG and EP conducted data analyses and drafted the manuscript. ND, LP, and SD performed the biological measurements. DM supervised the whole project. All authors read, critically revised, and approved the final manuscript.

### Funding

The original study was supported by BPI France (grant number BPI 2012-05-336). This funding was attributed to D.M., representing Lille University Hospital. There

was no role of the funding body in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

### Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

### Ethics approval and consent to participate

The original study has been approved by the ethics committee of Lille University Hospital (approval number CP03/07). All the participants to this study gave their informed consent prior to enrollment.

### Consent for publication

Not applicable

### Competing interests

The Endomark H1 and DIYEK C1 ELISA kits used in this study were provided by Lunginnov. P.L. is the cofounder of Lunginnov. N.D. and L.P. are staff members of Lunginnov. The remaining authors declare that they have no competing interests.

### Author details

<footnote n="1">¹Center for Infection and Immunity of Lille, University of Lille, U1019, UMR 8204, CIIL, F-59000 Lille, France. ²CNRS, UMR 8204, F-59000 Lille, France.</footnote>

<footnote n="3">³INSERM, U1019, F-59000 Lille, France. ⁴CHU Lille, Pôle de Réanimation, Hôpital Roger Salengro, F-59000 Lille, France. ⁵Lunginnov, 1 rue du Pr</footnote>
<figure><img src="image_9.png" /><figcaption>**Fig. 2** ROC analysis of endocan plasmatic levels at time of ARDS (a) and their variations over 24 h (b), as well as ECR plasmatic levels a time of ARDS (c) and their variations over 24 h (d) for the diagnosis of hyperinflammatory subphenotypes of ARDS. ARDS: acute respiratory distress syndrome; ECR: endocan cleavage ratio; HIP: hyperinflammatory phenotype; NHIP: non-hyperinflammatory phenotype</figcaption></figure>

## Additional file

**Additional file 1:** Cohort baseline characteristics. Continuous and categorical variables are described as median [interquartile range] and number (percentage), respectively. COPD chronic obstructive pulmonary disease SOFA Sequential Organ Failure Assessment ICU intensive care unit SAPS 2 Simplified Acute Physiology Score 2 LIPS Lung Injury Prediction Score. (DOC 45 kb)

### Abbreviations

ARDS: Acute respiratory distress syndrome; ECR: Endocan cleavage ratio; HIP: Hyperinflammatory phenotype; NHIP: Non-hyperinflammatory phenotype

### Acknowledgements

Not applicable

### Authors' contributions

AG and EP conducted data analyses and drafted the manuscript. ND, LP, and SD performed the biological measurements. DM supervised the whole project. All authors read, critically revised, and approved the final manuscript.

### Funding

The original study was supported by BPI France (grant number BPI 2012-05-336). This funding was attributed to D.M., representing Lille University Hospital. There

was no role of the funding body in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

### Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

### Ethics approval and consent to participate

The original study has been approved by the ethics committee of Lille University Hospital (approval number CP03/07). All the participants to this study gave their informed consent prior to enrollment.

### Consent for publication

Not applicable

### Competing interests

The Endomark H1 and DIYEK C1 ELISA kits used in this study were provided by Lunginnov. P.L. is the cofounder of Lunginnov. N.D. and L.P. are staff members of Lunginnov. The remaining authors declare that they have no competing interests.

### Author details

<footnote n="1">¹Center for Infection and Immunity of Lille, University of Lille, U1019, UMR 8204, CIIL, F-59000 Lille, France. ²CNRS, UMR 8204, F-59000 Lille, France.</footnote>

<footnote n="3">³INSERM, U1019, F-59000 Lille, France. ⁴CHU Lille, Pôle de Réanimation, Hôpital Roger Salengro, F-59000 Lille, France. ⁵Lunginnov, 1 rue du Pr</footnote>
Calmette, F-59000 Lille, France. ¤CHU Lille, Institut d'Immunologie, Centre de Biologie Pathologie Génétique, F-59000 Lille, France.

Received: 13 June 2019 Accepted: 4 July 2019

Published online: 11 July 2019

References

1. Shankar-Hari M, Fan E, Ferguson ND. Acute respiratory distress syndrome (ARDS) phenotyping. Intensive Care Med. 2019;45:516-9.

2. De Freitas CN, Gaudet A, Portier L, Tsicopoulos A, Mathieu D, Lassalle P. Endocan, sepsis, pneumonia, and acute respiratory distress syndrome. Crit Care Lond Engl. 2018;22:280.

3. Gaudet A, Parmentier E, Dubucquoi S, Poissy J, Duburcq T, Lassalle P, et al. Low endocan levels are predictive of acute respiratory distress syndrome in severe sepsis and septic shock. J Crit Care. 2018;47:121-6.

4. Gaudet A, Parmentier E, De Freitas CN, Portier L, Dubucquoi S, Poissy J, et al. Impact of acute renal failure on plasmatic levels of cleaved endocan. Crit Care Lond Engl. 2019;23:55.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Calmette, F-59000 Lille, France. ¤CHU Lille, Institut d'Immunologie, Centre de Biologie Pathologie Génétique, F-59000 Lille, France.

Received: 13 June 2019 Accepted: 4 July 2019

Published online: 11 July 2019

## References

1. Shankar-Hari M, Fan E, Ferguson ND. Acute respiratory distress syndrome (ARDS) phenotyping. Intensive Care Med. 2019;45:516-9.

2. De Freitas CN, Gaudet A, Portier L, Tsicopoulos A, Mathieu D, Lassalle P. Endocan, sepsis, pneumonia, and acute respiratory distress syndrome. Crit Care Lond Engl. 2018;22:280.

3. Gaudet A, Parmentier E, Dubucquoi S, Poissy J, Duburcq T, Lassalle P, et al. Low endocan levels are predictive of acute respiratory distress syndrome in severe sepsis and septic shock. J Crit Care. 2018;47:121-6.

4. Gaudet A, Parmentier E, De Freitas CN, Portier L, Dubucquoi S, Poissy J, et al. Impact of acute renal failure on plasmatic levels of cleaved endocan. Crit Care Lond Engl. 2019;23:55.

## Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.