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. 2024 Feb 9;25(1):88.
doi: 10.1186/s12931-024-02707-3.

Blood MMP-9 measured at 2 years after lung transplantation as a prognostic biomarker of chronic lung allograft dysfunction

Adrien Tissot  1 , Eugénie Durand  2 , Thomas Goronflot  3 , Benjamin Coiffard  4 , Benjamin Renaud-Picard  5 , Antoine Roux  6 , Xavier Demant  7 , Jean-François Mornex  8 , Loïc Falque  9 , Mathilde Salpin  10 , Jérôme Le Pavec  11 , Thomas Villeneuve  12 , Véronique Boussaud  13 , Christiane Knoop  14 , Antoine Magnan  6 , David Lair  15 , Laureline Berthelot  2 , Richard Danger  2 , Sophie Brouard  2 ; COLT consortium
Collaborators, Affiliations

Blood MMP-9 measured at 2 years after lung transplantation as a prognostic biomarker of chronic lung allograft dysfunction

Adrien Tissot et al. Respir Res. .

Abstract

Background: Long-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development.

Methods: Participants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after.

Results: MMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0-253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%.

Conclusion: Plasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD.

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Conflict of interest statement

AT and BC declare competing interests with Biotest. tSB and RD have ownership interests in the BioMAdvanced Diagnostics company. TV declares competing interests with Boeringer Ingelheim and Mauna Kea. The other authors declare no competing interests. All authors have completed the ICMJE uniform disclosure form.

Figures

Fig. 1
Fig. 1
Year 1 sample analysis flowchart. Selection of COLT lung transplant recipients with CLAD or a stable phenotype. Other phenotypes included death before 3 months, death without CLAD and an inconclusive phenotype (insufficient data or cofounding factors affecting adjudication). “No phenotype” refers to recipients awaiting adjudication
Fig. 2
Fig. 2
Year 2 sample flowchart. Selection of COLT lung transplant recipients with CLAD or a stable phenotype. Other phenotypes included death before 3 months, death without CLAD and an inconclusive phenotype (insufficient data or cofounding factors affecting the adjudication). “No phenotypes” refer to recipients awaiting adjudication.* One recipient was initially classified as having azithromycin-responsive allograft dysfunction and was not included in the stable group for the year 1 sample analysis but later developed CLAD and was included in the CLAD group for the year 2 sample analysis
Fig. 3
Fig. 3
Blood MMP-9 value at Y1. A Comparison of the MMP-9 plasmatic concentration at Y1 between recipients who then developed CLAD and those who remained stable in the next 2 years (p = 0.2). B Comparison of samples close to CLAD and distant from CLAD. Comparison of the MMP-9 plasmatic concentration at Y1 between recipients who developed CLAD within 1 year of measurement, those who developed CLAD at least 1 year after measurement and those who remained stable at least 2 years after measurement. No significant difference was observed. Boxplot interpretation: thick horizontal bars correspond to the median, notches to the upper and lower limits of the confidence interval and top and bottom of the box to the first and third interquartile of MMP-9 values
Fig. 4
Fig. 4
Blood MMP-9 value at Y2. A Comparison of the MMP-9 plasmatic concentration at Y2 between recipients who then developed CLAD and those who remained stable in the next 2 years (p = 0.003). B Blood MMP-9 value at Y2 with comparison of samples close to the CLAD and distant from the CLAD. Comparison of the MMP-9 plasmatic concentration at Y2 between recipients who developed CLAD within 1 year of measurement, those who developed CLAD at least 1 year after measurement and those who remained stable at least 2 years after measurement with a significant difference between the stable and CLAD groups within 1 year (p = 0.003). Boxplot interpretation: thick horizontal bars correspond to the median, notches to the upper and lower limits of the confidence interval and top and bottom of the box to the first and third interquartile of MMP-9 values. * corresponds to p value < 0.05
Fig. 5
Fig. 5
Precision-Recall (A) and ROC (B) curves for the Y1 MMP-9 analysis. The precision-recall curve represents, for each available value of MMP-9, the positive predictive value and sensitivity for CLAD onset within the next 2 years
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