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Open Access 01-12-2019 | Acute Respiratory Distress-Syndrome | Research

Lung fluid biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis

Authors: Yishan Wang, Huijuan Wang, Chunfang Zhang, Chao Zhang, Huqin Yang, Ruiyue Gao, Zhaohui Tong

Published in: Critical Care | Issue 1/2019

Abstract

Background

With the development of new techniques to easily obtain lower respiratory tract specimens, bronchoalveolar lavage fluid and other lung fluids are gaining importance in pulmonary disease diagnosis. We aimed to review and summarize lung fluid biomarkers associated with acute respiratory distress syndrome diagnosis and mortality.

Methods

After searching PubMed, Embase, Web of Science, and the Cochrane Library for articles published prior to January 11, 2018, we performed a meta-analysis on biomarkers for acute respiratory distress syndrome diagnosis in at-risk patients and those related to disease mortality. From the included studies, we then extracted the mean and standard deviation of the biomarker concentrations measured in the lung fluid, acute respiratory distress syndrome etiologies, sample size, demographic variables, diagnostic criteria, mortality, and protocol for obtaining the lung fluid. The effect size was measured by the ratio of means, which was then synthesized by the inverse-variance method using its natural logarithm form and transformed to obtain a pooled ratio and 95% confidence interval.

Results

In total, 1156 articles were identified, and 49 studies were included. Increases in total phospholipases A2 activity, total protein, albumin, plasminogen activator inhibitor-1, soluble receptor for advanced glycation end products, and platelet activating factor-acetyl choline were most strongly associated with acute respiratory distress syndrome diagnosis. As for biomarkers associated with acute respiratory distress syndrome mortality, interleukin-1β, interleukin-6, interleukin-8, Kerbs von Lungren-6, and plasminogen activator inhibitor-1 were significantly increased in the lung fluid of patients who died. Decreased levels of Club cell protein and matrix metalloproteinases-9 were associated with increased odds for acute respiratory distress syndrome diagnosis, whereas decreased levels of Club cell protein and interleukin-2 were associated with increased odds for acute respiratory distress syndrome mortality.

Conclusions

This meta-analysis provides a ranking system for lung fluid biomarkers, according to their association with diagnosis or mortality of acute respiratory distress syndrome. The performance of biomarkers among studies shown in this article may help to improve acute respiratory distress syndrome diagnosis and outcome prediction.

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Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–49.PubMedCrossRef

Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R: Report of the American-European Consensus Conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care 1994, 9(1):72–81.

Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin definition. Jama. 2012;307(23):2526–33.PubMed

Terpstra ML, Aman J, GPvN A, ABJ G. Plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med. 2014;42(3):691–700.PubMedCrossRef

Garcia-Laorden MI, Lorente JA, Flores C, Slutsky AS, Villar J. Biomarkers for the acute respiratory distress syndrome: how to make the diagnosis more precise. Ann Transl Med. 2017;5(14):283.PubMedPubMedCentralCrossRef

Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):529–36.PubMedCrossRef

Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med. 2005;142(7):510–24.PubMedCrossRef

Friedrich JO, Adhikari NK, Beyene J. The ratio of means method as an alternative to mean differences for analyzing continuous outcome variables in meta-analysis: a simulation study. BMC Med Res Methodol. 2008;8:32.PubMedPubMedCentralCrossRef

Friedrich JO, Adhikari NKJ, Beyene J. Ratio of means for analyzing continuous outcomes in meta-analysis performed as well as mean difference methods. J Clin Epidemiol. 2011;64(5):556–64.PubMedCrossRef

10.

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.PubMedPubMedCentralCrossRef

11.

Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–63.PubMedCrossRef

12.

Adamzik M, Broll J, Steinmann J, Westendorf AM, Rehfeld I, Kreissig C, Peters J. An increased alveolar CD4 + CD25 + Foxp3 + T-regulatory cell ratio in acute respiratory distress syndrome is associated with increased 30-day mortality. Intensive Care Med. 2013;39(10):1743–51.PubMedCrossRef

13.

Agouridakis P, Kyriakou D, Alexandrakis MG, Perisinakis K, Karkavitsas N, Bouros D. Association between increased levels of IL-2 and IL-15 and outcome in patients with early acute respiratory distress syndrome. Eur J Clin Investig. 2002;32(11):862–7.CrossRef

14.

Armstrong L, Thickett DR, Mansell JP, Ionescu M, Hoyle E, Billinghurst RC, Poole AR, Millar AB. Changes in collagen turnover in early acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160(6):1910–5.PubMedCrossRef

15.

Bersten AD, Doyle IR, Davidson KG, Barr HA, Nicholas TE, Kermeen F. Surfactant composition reflects lung overinflation and arterial oxygenation in patients with acute lung injury. Eur Respir J. 1998;12(2):301–8.PubMedCrossRef

16.

Calfee CS, Eisner MD, Parsons PE, Thompson BT, Conner ER Jr, Matthay MA, Ware LB, Network NARDSCT. Soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury. Intensive Care Med. 2009;35(2):248–57.PubMedCrossRef

17.

Chesnutt AN, Matthay MA, Tibayan FA, Clark JG. Early detection of type III procollagen peptide in acute lung injury. Pathogenetic and prognostic significance. Am J Respir Crit Care Med. 1997;156(3 Pt 1):840–5.PubMedCrossRef

18.

Chollet-Martin S, Jourdain B, Gibert C, Elbim C, Chastre J, Gougerot-Pocidalo MA. Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. In: American journal of respiratory and critical care medicine. Vol. 154; 1996. p. 594–601.

19.

Clark JG, Milberg JA, Steinberg KP, Hudson LD. Type III procollagen peptide in the adult respiratory distress syndrome. Association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death. Ann Intern Med. 1995;122(1):17–23.PubMedCrossRef

20.

Conner ER, Ware LB, Modin G, Matthay MA. Elevated pulmonary edema fluid concentrations of soluble intercellular adhesion molecule-1 in patients with acute lung injury: biological and clinical significance. Chest. 1999;116(1 Suppl):83s–4s.PubMedCrossRef

21.

Delclaux C, d’Ortho MP, Delacourt C, Lebargy F, Brun-Buisson C, Brochard L, Lemaire F, Lafuma C, Harf A. Gelatinases in epithelial lining fluid of patients with adult respiratory distress syndrome. Am J Phys. 1997;272(3 Pt 1):L442–51.

22.

El Solh AA, Bhora M, Pineda L, Aquilina A, Abbetessa L, Berbary E. Alveolar plasminogen activator inhibitor-1 predicts ARDS in aspiration pneumonitis. Intensive Care Med. 2006;32(1):110–5.PubMedCrossRef

23.

Farjanel J, Hartmann DJ, Guidet B, Luquel L, Offenstadt G. Four markers of collagen metabolism as possible indicators of disease in the adult respiratory distress syndrome. Am Rev Respir Dis. 1993;147(5):1091–9.PubMedCrossRef

24.

Frenzel J, Gessner C, Sandvoss T, Hammerschmidt S, Schellenberger W, Sack U, Eschrich K, Wirtz H. Outcome prediction in pneumonia induced ALI/ARDS by clinical features and peptide patterns of BALF determined by mass spectrometry. PLoS One. 2011;6(10):e25544.PubMedPubMedCentralCrossRef

25.

Geerts L, Jorens PG, Willems J, De Ley M, Slegers H. Natural inhibitors of neutrophil function in acute respiratory distress syndrome. Crit Care Med. 2001;29(10):1920–4.PubMedCrossRef

26.

González-López A, García-Prieto E, Batalla-Solís E, Amado-Rodríguez L, Avello N, Blanch L, Albaiceta GM. Lung strain and biological response in mechanically ventilated patients. Intensive Care Med. 2012;38(2):240–7.PubMedCrossRef

27.

Hallgren R, Samuelsson T, Laurent TC, Modig J. Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome. Am Rev Respir Dis. 1989;139(3):682–7.PubMedCrossRef

28.

Hamacher J, Lucas R, Lijnen HR, Buschke S, Dunant Y, Wendel A, Grau GE, Suter PM, Ricou B. Tumor necrosis factor-a and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar lavages of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;166(5):651–6.PubMedCrossRef

29.

Idell S, Thrall RS, Maunder R, Martin TR, McLarty J, Scott M, Starcher BC. Bronchoalveolar lavage desmosine in bleomycin-induced lung injury in marmosets and patients with adult respiratory distress syndrome. Exp Lung Res. 1989;15(5):739–53.PubMedCrossRef

30.

Ishizaka A, Matsuda T, Albertine KH, Koh H, Tasaka S, Hasegawa N, Kohno N, Kotani T, Morisaki H, Takeda J, et al. Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Phys Lung Cell Mol Phys. 2004;286(6):L1088–94.

31.

Jorens PG, Sibille Y, Goulding NJ, van Overveld FJ, Herman AG, Bossaert L, De Backer WA, Lauwerys R, Flower RJ, Bernard A. Potential role of Clara cell protein, an endogenous phospholipase A2 inhibitor, in acute lung injury. Eur Respir J. 1995;8(10):1647–53.PubMedCrossRef

32.

Karagiorga G, Nakos G, Galiatsou E, Lekka ME. Biochemical parameters of bronchoalveolar lavage fluid in fat embolism. Intensive Care Med. 2006;32(1):116–23.PubMedCrossRef

33.

Keane MP, Donnelly SC, Belperio JA, Goodman RB, Dy M, Burdick MD, Fishbein MC, Strieter RM. Imbalance in the expression of CXC chemokines correlates with bronchoalveolar lavage fluid angiogenic activity and procollagen levels in acute respiratory distress syndrome. J Immunol. 2002;169(11):6515–21.PubMedCrossRef

34.

Kondo T, Hattori N, Ishikawa N, Murai H, Haruta Y, Hirohashi N, Tanigawa K, Kohno N. KL-6 concentration in pulmonary epithelial lining fluid is a useful prognostic indicator in patients with acute respiratory distress syndrome. Respir Res. 2011;12:32.PubMedPubMedCentralCrossRef

35.

Kropski JA, Fremont RD, Calfee CS, Ware LB. Clara cell protein (CC16), a marker of lung epithelial injury, is decreased in plasma and pulmonary edema fluid from patients with acute lung injury. Chest. 2009;135(6):1440–7.PubMedPubMedCentralCrossRef

36.

Kurdowska A, Noble JM, Grant IS, Robertson CR, Haslett C, Donnelly SC. Anti-interleukin-8 autoantibodies in patients at risk for acute respiratory distress syndrome. Crit Care Med. 2002;30(10):2335–7.PubMedCrossRef

37.

Lanchou J, Corbel M, Tanguy M, Germain N, Boichot E, Theret N, Clement B, Lagente V, Malledant Y. Imbalance between matrix metalloproteinases (MMP-9 and MMP-2) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in acute respiratory distress syndrome patients. Crit Care Med. 2003;31(2):536–42.PubMedCrossRef

38.

Lee KS, Choi YH, Kim YS, Baik SH, Oh YJ, Sheen SS, Park JH, Hwang SC, Park KJ. Evaluation of bronchoalveolar lavage fluid from ARDS patients with regard to apoptosis. Respir Med. 2008;102(3):464–9.PubMedCrossRef

39.

Lee YL, Chen W, Chen LY, Chen CH, Lin YC, Liang SJ, Shih CM. Systemic and bronchoalveolar cytokines as predictors of in-hospital mortality in severe community-acquired pneumonia. J Crit Care. 2010;25(1):176 e177–113.PubMedCrossRef

40.

Lesur O, Kokis A, Hermans C, Fulop T, Bernard A, Lane D. Interleukin-2 involvement in early acute respiratory distress syndrome: relationship with polymorphonuclear neutrophil apoptosis and patient survival. Crit Care Med. 2000;28(12):3814–22.PubMedCrossRef

41.

Lin W-C, Lin C-F, Chen C-L, Chen C-W, Lin Y-S. Prediction of outcome in patients with acute respiratory distress syndrome by bronchoalveolar lavage inflammatory mediators. Exp Biol Med. 2010;235(1):57–65.CrossRef

42.

Marshall RP, Bellingan G, Webb S, Puddicombe A, Goldsack N, McAnulty RJ, Laurent GJ. Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome. Am J Respir Crit Care Med. 2000;162(5):1783–8.PubMedCrossRef

43.

Martin R, Martin GS, Harris F, Brown L, Esper AM. The rage signaling pathway in sepsis induced ARDS: role of HMGB1 and MMPS. Am J Respir Crit Care Med. 2015;191:A2372.

44.

Martin TR, Rubenfeld GD, Ruzinski JT, Goodman RB, Steinberg KP, Leturcq DJ, Moriarty AM, Raghu G, Baughman RP, Hudson LD. Relationship between soluble CD14, lipopolysaccharide binding protein, and the alveolar inflammatory response in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155(3):937–44.PubMedCrossRef

45.

Medford ARL, Godinho SIH, Keen LJ, Bidwell JL, Millar AB. Relationship between vascular endothelial growth factor + 936 genotype and plasma/epithelial lining fluid vascular endothelial growth factor protein levels in patients with and at risk for ARDS. Chest. 2009;136(2):457–64.PubMedCrossRef

46.

Miller EJ, Cohen AB, Matthay MA. Increased interleukin-8 concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis. Crit Care Med. 1996;24(9):1448–54.PubMedCrossRef

47.

Nakos G, Kitsiouli E, Hatzidaki E, Koulouras V, Touqui L, Lekka ME. Phospholipases A2 and platelet-activating-factor acetylhydrolase in patients with acute respiratory distress syndrome. Crit Care Med. 2005;33(4):772–9.PubMedCrossRef

48.

Nakos G, Kitsiouli EI, Tsangaris I, Lekka ME. Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS - alterations in leukocytes, proteins, PAF and surfactant components. Intensive Care Med. 1998;24(4):296–303.PubMedCrossRef

49.

Nakos G, Pneumatikos J, Tsangaris I, Tellis C, Lekka M. Proteins and phospholipids in BAL from patients with hydrostatic pulmonary edema. Am J Respir Crit Care Med. 1997;155(3):945–51.PubMedCrossRef

50.

Nathani N, Perkins GD, Tunnicliffe W, Murphy N, Manji M, Thickett DR. Kerbs von Lungren 6 antigen is a marker of alveolar inflammation but not of infection in patients with acute respiratory distress syndrome. Crit Care. 2008;12(1):R12.PubMedPubMedCentralCrossRef

51.

Park WY, Goodman RB, Steinberg KP, Ruzinski JT, Radella F 2nd, Park DR, Pugin J, Skerrett SJ, Hudson LD, Martin TR. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1896–903.PubMedCrossRef

52.

Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Phys Lung Cell Mol Phys. 2003;285(1):L20–8.

53.

Pugin J, Verghese G, Widmer MC, Matthay MA. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med. 1999;27(2):304–12.PubMedCrossRef

54.

Quesnel C, Piednoir P, Gelly J, Nardelli L, Garnier M, Lecon V, Lasocki S, Bouadma L, Philip I, Elbim C, et al. Alveolar fibrocyte percentage is an independent predictor of poor outcome in patients with acute lung injury. Crit Care Med. 2012;40(1):21–8.PubMedCrossRef

55.

Ricou B, Nicod L, Lacraz S, Welgus HG, Suter PM, Dayer JM. Matrix metalloproteinases and TIMP in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;154(2 Pt 1):346–52.PubMedCrossRef

56.

Song Y, Lynch SV, Flanagan J, Zhuo H, Tom W, Glidden D, Brown R, Garcia O, Wiener-Kronish JP, Dotson RH, et al. Increased plasminogen activator inhibitor-1 concentrations in bronchoalveolar lavage fluids are associated with increased mortality in a cohort of patients with Pseudomonas aeruginosa. Anesthesiology. 2007;106(2):252–61.PubMedCrossRef

57.

Stern JB, Fierobe L, Paugam C, Rolland C, Dehoux M, Petiet A, Dombret MC, Mantz J, Aubier M, Crestani B. Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients. Crit Care Med. 2000;28(7):2326–33.PubMedCrossRef

58.

Uchida T, Shirasawa M, Ware LB, Kojima K, Hata Y, Makita K, Mednick G, Matthay ZA, Matthay MA. Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med. 2006;173(9):1008–15.PubMedPubMedCentralCrossRef

59.

Ware LB, Kaner RJ, Crystal RG, Schane R, Trivedi NN, McAuley D, Matthay MA. VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J. 2005;26(1):101–5.PubMedPubMedCentralCrossRef

60.

Jabaudon M, Blondonnet R, Roszyk L, Pereira B, Guerin R, Perbet S, Cayot S, Bouvier D, Blanchon L, Sapin V, et al. Soluble forms and ligands of the receptor for advanced glycation end-products in patients with acute respiratory distress syndrome: an observational prospective study. PLoS One. 2015;10(8):e0135857.PubMedPubMedCentralCrossRef

61.

Ware LB, Fremont RD, Bastarache JA, Calfee CS, Matthay MA. Determining the aetiology of pulmonary oedema by the oedema fluid-to-plasma protein ratio. Eur Respir J. 2010;35(2):331–7.PubMedCrossRef

62.

Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138(3):720–3.PubMedCrossRef

63.

Fowler AA, Hamman RF, Zerbe GO, Benson KN, Hyers TM. Adult respiratory distress syndrome. Prognosis after onset. Am Rev Respir Dis. 1985;132(3):472–8.PubMed

64.

Martin C, Papazian L, Payan MJ, Saux P, Gouin F. Pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. A study in mechanically ventilated patients. Chest. 1995;107(1):196–200.PubMedCrossRef

65.

Hill JD, Ratliff JL, Parrott JC, Lamy M, Fallat RJ, Koeniger E, Yaeger EM, Whitmer G. Pulmonary pathology in acute respiratory insufficiency: lung biopsy as a diagnostic tool. J Thorac Cardiovasc Surg. 1976;71(1):64–71.PubMed

66.

Friedrich JO, Adhikari NKJ, Beyene J. Ratio of geometric means to analyze continuous outcomes in meta-analysis: comparison to mean differences and ratio of arithmetic means using empiric data and simulation. Stat Med. 2012;31(17):1857–86.PubMedCrossRef

67.

Sun WJ, Grosser S, Tsong Y. Ratio of means vs. difference of means as measures of superiority, noninferiority, and average bioequivalence. J Biopharm Stat. 2017;27(2):338–55.PubMedCrossRef

68.

Meyer NJ, Calfee CS. Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome. Lancet Respir Med. 2017;5(6):512–23.PubMedCrossRef

Title: Lung fluid biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis
Authors: Yishan Wang
Huijuan Wang
Chunfang Zhang
Chao Zhang
Huqin Yang
Ruiyue Gao
Zhaohui Tong
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Acute Respiratory Distress-Syndrome
Biomarkers
Published in: Critical Care / Issue 1/2019
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/s13054-019-2336-6

At a glance: The STEP trials

Springer Medicine

Lung fluid biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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