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Matrix metalloproteinase-8: a useful biomarker to refine the diagnosis of community-acquired pneumonia upon intensive care unit admission?

The optimal management of severe community-acquired pneumonia (CAP) requires a prompt and accurate diagnosis [1]. Since clinical, radiological, and biological findings are poorly sensitive or specific, microbiological documentation often slow and unavailing, biomarkers could help to safely withhold antibiotics when the risk of bacterial infection is minimal and steer the diagnostic process towards non-infectious causes of respiratory failure [2]. In our previous study deriving the FAIM3:PLAC8 molecular biomarker, we noticed that MMP8, encoding matrix metalloproteinase-8 (MMP-8), was the most overexpressed gene in confirmed CAP relative to non-infectious differential diagnoses (no-CAP) [3]. We investigated in the same cohort if plasma levels of MMP-8 could be a valuable candidate biomarker for the diagnosis of CAP.

Similar to MMP8 whole blood gene expression (Fig. 1a), plasma MMP-8 (measured by Luminex assay [BioRad, Hercules, CA, USA]) was increased in patients with a suspicion of CAP compared to healthy volunteers and further increased in patients with confirmed CAP (median 3.45 ng/mL; interquartile range [IQR], 0.93–15.40 ng/mL, n = 86) compared to no-CAP (0.76 ng/mL; IQR, 0.35–2.64 ng/mL, p < 0.001, n = 31, Fig. 1b). MMP8 expression correlated with plasma levels of MMP-8 (rho = 0.73, p < 0.001, Fig. 1c). The receiver operating characteristic area under the curve (AUC) of plasma MMP-8 for the prediction of infection was 0.71 (95% CI 0.59–0.81) (Fig. 1d). A numerical threshold set at 0.25 ng/mL to minimize the risk of false-negative diagnosis allowed the identification of infection with a 97% sensitivity at the expense of a low specificity (19%). AUCs for plasma MMP-8, MMP8 expression, and procalcitonin (widely used for the diagnosis of CAP [4]) were not statistically different (Fig. 1d). In the independent validation cohort comprising 57 CAP and 26 no-CAP patients, the AUC for MMP-8 was 0.83 (95% CI 0.73–0.91, Fig. 1e). A numerical threshold of 0.30 ng/mL favoring a > 97% sensitivity yielded a specificity of 15%. The combination of MMP-8 (cutoff 0.25 ng/mL) with a reference model including variables routinely used for the diagnosis of infection (body temperature ≥ 37.5 °C and procalcitonin > 1.0 ng/mL [5]) significantly but modestly improved the prediction of infection (net reclassification improvement 0.36 [95% CI 0.03–0.70], p = 0.033).

Fig. 1
figure1

Comparison of MMP8 expression, MMP-8 plasma levels, and procalcitonin in consecutively enrolled patients treated for suspected community-acquired pneumonia (CAP) upon intensive care unit admission. a Box-and-whisker and dot plots depicting MMP8 expression in CAP (n = 86) and no-CAP patients (non-infectious control, n = 31). The dotted line represents MMP8 median expression in age-matched healthy volunteers (n = 42). b Box-and-whisker and dot plots depicting MMP-8 plasma levels in CAP and no-CAP patients. The dotted lines indicate median values obtained in 27 age-matched healthy subjects. c Correlation between MMP8 expression and MMP8 plasma levels in patients admitted for a suspected CAP. d Comparison of MMP8 expression or plasma levels with procalcitonin in patients consecutively admitted to the ICU for a suspicion of CAP (cohort A). Receiver operating characteristic analysis. AUC, area under the curve. e Assessment of the MMP8 plasma biomarker in an independent cohort (Validation cohort) of CAP (n = 57) and no-CAP patients (n = 26). Receiver operating characteristic analysis AUC

In conclusion, MMP-8 slightly improved patient classification compared to a routine care reference strategy. However, its poor specificity precludes its use as a stand-alone diagnostic biomarker to safely withhold antibiotics in this critically ill population. Further studies are needed to establish the potential add-on value of plasma MMP-8 in diagnostic tests including multiple biomarkers.

Availability of data and materials

Gene expression datasets are available at the Gene Expression Omnibus public repository of NCBI under accession number GSE65682. Other data generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AUC:

Area under the curve

CAP:

Community-acquired pneumonia

IQR:

Interquartile range

MMP-8:

Matrix metalloproteinase-8

ROC:

Receiver operating characteristic

References

  1. 1.

    Prina E, Ceccato A, Torres A. New aspects in the management of pneumonia. Crit Care. 2016;20:267.

    Article  Google Scholar 

  2. 2.

    Christ-Crain M, Opal SM. Clinical review: the role of biomarkers in the diagnosis and management of community-acquired pneumonia. Crit Care. 2010;14:203.

    Article  Google Scholar 

  3. 3.

    Scicluna BP, Klein Klouwenberg PMC, van Vught LA, Wiewel MA, Ong DSY, Zwinderman AH, et al. A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission. Am J Respir Crit Care Med. 2015;192:826–35.

    CAS  Article  Google Scholar 

  4. 4.

    Schuetz P, Wirz Y, Mueller B. Procalcitonin testing to guide antibiotic therapy in acute upper and lower respiratory tract infections. JAMA. 2018;319:925–6.

    Article  Google Scholar 

  5. 5.

    Musher DM, Roig IL, Cazares G, Stager CE, Logan N, Safar H. Can an etiologic agent be identified in adults who are hospitalized for community-acquired pneumonia: results of a one-year study. J Infect. 2013;67:11–8.

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge all the members of the Molecular Diagnosis and Risk Stratification of Sepsis consortium for the participation in the data collection and especially acknowledge Friso M. de Beer, M.D.; Lieuwe D. J. Bos, Ph.D.; Gerie J. Glas, M.D.; Roosmarijn T. M. van Hooijdonk, M.D., Ph.D.; Janneke Horn, M.D., Ph.D.; Laura R. A. Schouten, M.D.; Marleen Straat, M.D.; Luuk Wieske, M.D., Ph.D.; Esther Witteveen, M.D. (Department of Intensive Care, Academic Medical Center, University of Amsterdam, The Netherlands), Arie J. Hoogendijk, Ph.D.; Mischa A. Huson, M.D.; Maryse A. Wiewel, M.D. (Center for Experimental and Molecular Medicine, and Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands), Peter M.C. Klein Klouwenberg, M.D., Ph.D; David S.Y. Ong, M.D., Ph.D. (Department of Medical Microbiology, Department of Intensive Care Medicine, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands), Jos F. Frencken, M.D.; Maria E. Koster-Brouwer, MSc; Kirsten van de Groep, M.D.; and Diana M. Verboom, M.D. (Department of Intensive Care Medicine and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands).

Funding

This research was performed within the framework of the Center for Translational Molecular Medicine (CTMM) (www.ctmm.nl) project Molecular Diagnosis and Risk Stratification of Sepsis (grant 04I-201). The sponsor CTMM was not involved in the design and conduction of the study nor was the sponsor involved in the collection, management, analysis, and interpretation of the data or preparation, review, or approval of the article. The decision to submit the article was not dependent on the sponsor.

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FU, BPS, and TvdP designed the paper and wrote the manuscript. All authors participated in collecting and analyzing the data. All authors read and approved the final version of the manuscript.

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Correspondence to Fabrice Uhel.

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Patients were included via an opt-out consent method approved by the institutional review boards of both hospitals (Academic Medical Center, Amsterdam; University Medical Center Utrecht, Utrecht, IRB No. 10-056C).

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Uhel, F., Scicluna, B.P., van Vught, L.A. et al. Matrix metalloproteinase-8: a useful biomarker to refine the diagnosis of community-acquired pneumonia upon intensive care unit admission?. Crit Care 23, 226 (2019). https://doi.org/10.1186/s13054-019-2513-7

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Keywords

  • Sepsis
  • Pneumonia
  • Biomarker
  • Matrix metalloproteinase-8
  • Procalcitonin
  • Infection