REVIEW URRENT C OPINION
Biomarkers in acute respiratory distress syndrome Alexandra Binnie a, Jennifer L.Y. Tsang b, and Claudia C. dos Santos c,d
Purpose of review The article provides an overview of efforts to identify and validate biomarkers in acute respiratory distress syndrome (ARDS) and a discussion of the challenges confronting researchers in this area. Recent findings Although various putative biomarkers have been investigated in ARDS, the data have been largely disappointing and the ‘troponin’ of ARDS remains elusive. Establishing a relationship between measurable biological processes and clinical outcomes is vital to advancing clinical trials in ARDS and expanding our arsenal of treatments for this complex syndrome. Summary This article summarizes the current status of ARDS biomarker research and provides a framework for future investigation. Keywords acute lung injury, acute respiratory distress syndrome, biomarkers, ventilator-induced/associated lung injury
INTRODUCTION Numerous proteins have been identified as potential markers of acute respiratory distress syndrome (ARDS). These include the inflammatory cytokines interleukin (IL)-1b, tumor necrosis factor (TNF)-a, IL-6, IL-8, soluble intercellular adhesion molecule (sICAM)-1, the coagulation proteins plasminogen activator inhibitor (PAI)-1 and protein C, the endothelial proteins von Willebrand factor (vWF) and angiopoietin (Ang)-2, and the epithelial proteins Krebs von den Lungen (KL)-6, Clara cell protein (CC)-16, soluble receptor for advanced glycation end product (sRAGE), the surfactant-associated proteins A, B, C, and D, and vascular endothelial growth factor (VEGF). The most compelling recent data come from studies of Ang-2, but there is also strong evidence for Il-8, sICAM-1, the surfactantassociated proteins, and VEGF as both diagnostic and prognostic tools in ARDS. None of these markers, however, has supplanted clinical criteria in the diagnosis and management of ARDS.
WHAT IS A BIOMARKER OF ACUTE RESPIRATORY DISTRESS SYNDROME? The term ‘biomarker’, or ‘biological marker’, refers to any medical or biological sign that provides an objective indication of medical state [1]. In principle, this characteristic(s) can be accurately measured and evaluated, with reproducible results,
and can ‘influence or predict the incidence of outcome of disease’ [2]. At best, biomarkers, including physical signs, laboratory measures, and radiological tests, are indirect measures. They are considered as replacement endpoints or ‘surrogates’ for clinically meaningful endpoints [3]. Although various putative biomarkers have been investigated in the context of ARDS (Table 1) [4–6,7 ,8–15,16 ,17,18,19 ,20 ,21–58], their correlation with disease development and disease outcome has been inconsistent. The syndromic nature of the ARDS definition, the paucity of acute lung injury (ALI)/ARDS tissues available for diagnostic and pathological studies, and the discrepancies between clinical and autopsy findings make identifying and validating an ARDS biomarker extremely challenging. Yet these same issues underlie the need for a reliable and validated biomarker that can be &
&
&
&
a
Department of Medicine, St Joseph’s Health Centre, Toronto, Department of Critical Care Medicine, McMaster University, Hamilton, c Keenan and Li Ka Shing Knowledge Institute of Saint Michael’s Hospital and dInstitute of Medical Sciences and Department of Medicine, University of Toronto, Toronto, Ontario, Canada b
Correspondence to Dr dos Santos, Critical Care Medicine and Clinician Scientist, Assistant Professor of Medicine, St. Michael’s Hospital/ University of Toronto, 30 Bond Street, Toronto, ON M5B 1WB, Canada. Tel: +1 416 946 0420; e-mail: [email protected] Curr Opin Crit Care 2014, 20:47–55 DOI:10.1097/MCC.0000000000000048
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-criticalcare.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system
KEY POINTS
transudation of proteinaceous fluid into the alveoli [65 ]. On autopsy and biopsy samples, ARDS is characterized by a pattern of ‘diffuse alveolar damage’ (DAD) [66]. Studies have shown, however, that not all patients meeting the clinical definition of ARDS have this pathological phenotype [67 ,68,69]. Estimates of the specificity of the ARDS definition for DAD range from 51 to 84% [67 ,68,69], with a recent review of the Berlin definition showing 63% specificity [70 ]. Similarly, some patients with pathological evidence of DAD do not have clinical ARDS; estimates of sensitivity range from 75 to 83% [67 ,69], with the Berlin definition achieving a sensitivity of 89% [70 ]. These discrepancies underlie the need for a definition of ARDS that has greater biological relevance and can identify a group of patients with similar underlying pathophysiology. Unfortunately, the search for a ‘biomarker’ of ARDS has been challenging and a winning candidate has yet to emerge. &
ARDS is a clinical syndrome representing a variety of pathophysiologic processes, which hugely complicates the search for a clinically useful biomarker.
&
Numerous candidate proteins, including inflammatory cytokines, endothelial proteins, epithelial proteins, and coagulation proteins, have been investigated as markers of ARDS. Angiopoietin-2, an endothelial protein, is currently the most promising ARDS biomarker; however, its validation is ongoing. Combinatorial approaches using multiple biomarkers to diagnose ARDS provide slightly higher sensitivity and specificity than do any individual biomarkers. Other approaches to ARDS biomarker discovery, such as RNA or DNA methylation screens or metabolomics studies, have not yet been attempted and may yield new insights into ARDS pathophysiology as well as new candidate markers.
used to diagnose ARDS and predict outcome. Moreover, an accurate diagnostic tool would enable researchers to select patient populations with similar pathophysiology on whom to test new therapies and interventions.
WHAT IS ACUTE RESPIRATORY DISTRESS SYNDROME? Acute respiratory distress syndrome is a syndrome characterized by acute bilateral pulmonary infiltrates and impaired oxygenation in the absence of elevated left atrial pressure. It is triggered by a wide range of predisposing conditions ranging from pneumonia, to sepsis, to trauma. It is a frequent cause of ICU admission and has a high rate of mortality and morbidity [59–61]. ARDS was first reported in 1967 [62 ] and subsequently defined by expert consensus in 1994 [63 ]. In 2012, the definition was updated in an effort to improve its diagnostic and predictive value [64 ]. In this study, in the interest of clarity, we may use the original term, ALI, when referring to data generated before the establishment of the Berlin criteria. For the most part, but not always, these studies will likely be referring to patients who under the new criteria can be considered as ‘mild ARDS’. Biologically, ARDS represents a noncardiogenic form of pulmonary edema. The mechanisms of its development include overwhelming immune activation accompanied by breakdown of epithelial and endothelial membranes in the lung with resultant &
&
&
48
www.co-criticalcare.com
&
&
&
&
THE SEARCH FOR AN ACUTE RESPIRATORY DISTRESS SYNDROME BIOMARKER The search for an ARDS biomarker has focused on proteins detectable in either serum or bronchoalveolar lavage fluid (BALF). Four broad anatomical categories of proteins have been studied: inflammatory cytokines, coagulation proteins, epithelial proteins, and endothelial proteins (Table 1). Most studies have compared results from ARDS patients with ‘at-risk’ patients comprising ventilated critically ill patients with similar illness severity scores. Some studies, however, have compared ARDS patients to patients with cardiogenic pulmonary edema, whereas others have used healthy nonventilated patients as their control group. For reasons of brevity, this review will focus only on those biomarkers that have a substantial body of evidence. As a result, we may be omitting promising biomarkers that have yet to be validated. We have also limited ourselves to a brief discussion of the diagnostic and prognostic value of each biomarker without providing significant background on their role in the pathogenesis of ARDS. For an excellent discussion of the underlying biology we refer you to a recent review on this topic [65 ]. &
THE INFLAMMATORY CYTOKINES The earliest work on ARDS biomarkers measured inflammatory cytokines in the BALF of ‘acute respiratory failure’ patients. The pro-inflammatory cytokines IL-1b and TNF-a were detected at increased levels in BALF from ‘ARDS-like’ patients when Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Clara cell protein-16
Interleukin-1b
Interleukin-6
Interleukin-8
Interleukin-10
Krebs von den Lungen-6
Plasminogen activator inhibitor-1
Protein C
Soluble intercellular adhesion molecule-1
Soluble receptor for advanced glycation end products
Surfactant protein A
Surfactant protein B
Surfactant protein C
Surfactant protein D
Tumor necrosis factor-a Plasma and BALF – decrease with LPV
Vascular endothelial growth receptor
von Willebrand factor
CC-16
IL-1b
IL-6
IL-8
IL-10
KL-6
PAI-1
Protein C
s-ICAM-1
s-RAGE
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
SP-A
SP-B
SP-C
SP-D
TNF-a
VEGF
vWF
www.co-criticalcare.com Endothelium
Epithelium (ATII); inflammatory cells (PMN, M1)
Epithelium (ATII); inflammatory cells (PMN, monocytes)
Epithelium (ATII, Clara cells)
Epithelium (ATII)
Epithelium (ATII)
Epithelium (ATII)
Epithelium (ATI)
Endothelium; epithelium (ATI and ATII); inflammatory cells
Liver
Endothelium; platelets
&
[15,16 ]
[10–14]
&
[4–6,7 ,8,9]
References
&
Anti-inflammatory by inhibition of cytokines production
Potent PMN chemotactic and activating factor
[15,17,18,36,37]
[15,21,22,34,35]
[31,33]
&
[20 ,28–32]
&
[15,19 ,21,23,24, 43,45–47, 49–51]
Acts as a marker of endothelial activation and injury
Increases endothelial barrier permeability; it is potentially protective
Acts as a chemotactic factors for fibroblasts; up-regulates expression of leukocytes and endothelial adhesion molecules; stimulates PMN functions
Directly modulates inflammatory cell functions
[4,9,35]
[53–58]
&
[18,19 ]
[10,11,17,22,24– 27,46,51,52]
Facilitates the adsorption of surfactant phospholipids to an [18,48] air–water interface and stabilizes the interfacial lipid layer during firm compression
Enhances spreading and stabilizes surfactant phospholipids at the air–liquid interface
&
Participates in innate defense and regulates the release of [15,17,18,20 ,21, 22,38–48] surfactants by ATII
Influences gene and protein expression via activated signal transduction pathways
Epithelial source activates inflammatory functions; endothelial source contributes to elevated edema fluid level
Plasma anticoagulant that promotes fibrinolysis and inhibits thrombosis and inflammation
Inhibits tissue plasminogen activator and urokinase, therefore inhibits fibrinolysis
[10,11,17,25–27]
[18]
&
[15,20 ,21,23,24]
Induces synthesis of acute phase protein by liver; activates [15,17,18,19 ,2& 0 ,21,22] T and B cells
Induces synthesis of endothelial adhesion molecules; induces PMN inflammatory functions; stimulates repair of alveolar epithelium
Impairs endothelial barrier function; increases adhesion and migration of inflammatory cells Suppresses PMN mediated lung damage; modulates dysregulated coagulation characteristics of ALI
Biological functions
Epithelium (ATII, bronchiolar cells) Acts as chemotactic factor that promotes migration, proliferation and survival of lung fibroblasts
Inflammatory cells (Th2 cells)
Endothelium; inflammatory cells (PMN, M1, T/B cells); fibroblasts
Endothelium; inflammatory cells (monocytes, T/B cells); fibroblasts
Inflammatory cells
Epithelium (Clara cells)
Endothelium
Source
ATI, alveolar epithelial type I cells; ATII, alveolar epithelial type II cells; BALF, bronchoalveolar lavage fluid; LPV, lung-protective ventilation; M1, macrophage; PMN, neutrophils; VT, tidal volume. Various biomarkers of ARDS, their source, location of detection, expression patterns, and biological functions are listed.
Plasma and BALF – higher
Plasma – elevated; BALF and lung tissue – lower
BALF – elevated; plasma – mixed results
BALF – lower
Plasma – elevated; BALF – lower
BALF – lower; plasma – mixed results
Plasma and BALF – elevated
Plasma – elevated
Plasma – lower
Plasma and BALF – elevated
Plasma and BALF – elevated
Plasma – elevated
Plasma – elevated; plasma and BALF – lower in LPV
Plasma – elevated; plasma and BALF – lower in LPV
BALF – lower in LPV; plasma – elevated
Plasma and BALF – elevated
Plasma – elevated
Angiopoietin 2
Ang-2
Expression in ALI/ARDS
Full name
Biomarker
Table 1. Putative biomarkers of ARDS, their source, location of detection, expression patterns, and biological function(s)
Biomarkers in acute respiratory distress syndrome Binnie et al.
49
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system
Clara cell
CC–16
Inflammatory cell
Alveolar space
ATI
Fibroblast
IL–IB IL–6 TNF–α IL–6 vwf
VEGF SICAM–1
ATI S VE P G SIC F AM
Interstitial space
SR AG IL– E TN 6 F–α
II-6
M–1 SICA E SRAG
PAI–1 Ang2
Endothelial cell
Pulmonary capillary Red blood cells
Breakdown of epithelial and endothelial barrier
FIGURE 1. Putative biomarkers of ARDS. There is a breakdown of epithelial and endothelial barrier (shown in green double arrows) in ARDS. This breakdown of barrier allows the movement of molecules between the alveolar space (detected from BALF) and the pulmonary capillary (detected from plasma). Various cell types in the pulmonary unit (alveolar space, interstitial space, and capillary) contribute to the secretion of molecules that can act as biomarkers of ARDS. Epithelial markers are represented in green. They include CC-16 produced by Clara cells, VEGF produced by inflammatory cells and ATII, SP produced by ATII, and sRAGE produced by ATI and ATII. CC-16, VEGF, and SP are detected in plasma only, whereas sRAGE can be detected in BALF and plasma. Endothelial markers are represented in red. They include Ang-2 and vWF, both produced by endothelial cells. vWF can be detected in both BALF and plasma, whereas Ang-2 can only be detected in plasma. Inflammatory markers are represented in black. They include IL-1b produced by inflammatory cells, IL-6 produced by inflammatory cells, endothelial cells, fibroblasts and ATII, TNF-a produced by inflammatory cells and ATII, and sICAM-1 produced by ATI and ATII. IL-1b, IL-6, and TNF-a can be detected in BALF and plasma, whereas sICAM-1 is primarily detected in plasma. Coagulation marker PAI-1 is represented in blue. It is produced by endothelial cells and can be detected in plasma. ATI, type I epithelial cells; ATII, type II epithelial cells; Ang-2, angiopoietin 2; BALF, bronchoalveolar lavage fluid; CC-16, Clara cell protein-16; IL, interleukin; PAI-1, plasminogen activator inhibitor-1; sICAM-1, soluble intercellular adhesion molecule1; SP, surfactant proteins; sRAGE, soluble receptor for advanced glycation end produdct; TNF-a, tumor necrosis factor-a; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor.
compared to critically ill patients without evidence of ARDS, or healthy controls [71,72 ,73]. Serum levels of IL-1b and TNF-a do not correlate with ARDS development, but subsequent studies did show a correlation between serum cytokine levels and ARDS mortality [16 ,74]. The wider applicability of these findings is limited, however, as trauma patients with ARDS have undetectable serum levels of IL-1b and TNF-a [75,76]. Thus, serum IL-1b and TNF-a levels may be better markers of sepsis severity than ARDS (Fig. 1). Other pro-inflammatory cytokines, including IL-6, IL-8, and sICAM-1, have also been studied in ARDS. Plasma IL-6 levels correlate with ARDS development in mixed ICU patients [17,35], but have again shown variable results in trauma patients &
&
50
www.co-criticalcare.com
[75,76]. Better correlations have been noted between serum IL-6 levels and ventilator-induced lung injury, most notably in the ARDS Net study of high vs. low tidal volume ventilation where IL-6 levels decreased in the low-tidal-volume group [77 ], which also had better outcomes. Other studies have confirmed an inverse correlation between injurious ventilation and IL-6 levels [15,18,19 ]. Plasma IL-8 levels have been shown to correlate with ARDS development in medical ICU as well as trauma patients [7 ,35,75,76], and have shown a consistent inverse correlation with ARDS mortality [20 ,21,24]. Correlations with ventilation strategy have not been consistent [15,19 ,23,35]. Finally, plasma sICAM-1 levels appear to correlate with ARDS development [34,35] and ARDS &
&
&
&
&
Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Biomarkers in acute respiratory distress syndrome Binnie et al.
mortality [21,24,34]. It will be interesting to see whether these correlations carry over to traumainduced ARDS. sICAM-1 levels are low in trauma patients, when compared with septic patients [78 ], so an association with ARDS development in these patients would be very significant. &
THE COAGULATION PROTEINS ARDS is associated with intra-alveolar and intravascular fibrin deposition secondary to generalized activation of the coagulation cascade (Fig. 1). Several coagulation pathway proteins have shown promise as markers of ARDS. PAI-1, an inhibitor of fibrinolysis, is increased in both plasma [20 ,28,29] and BALF or ‘pulmonary edema fluid’ [29,32] from ARDS patients and shows some correlation with ARDS outcomes [20 ,31]. The only study to report sensitivities and specificities estimated an area under the receiver operating curve (ROC) of 0.75 for plasma PAI-1 as a marker of ARDS development, indicating a moderate predictive value. Another recent study did not confirm the association between PAI-1 levels and ARDS, but did show a correlation with overall mortality in critically ill patients [30]. Conversely, protein C, an inhibitor of the coagulation cascade, is decreased in the plasma of ARDS patients [31] and is lower in nonsurvivors than survivors [31,33], suggesting a link between hypercoagulability and mortality. These results are consistent with a recent clinical trial of activated protein C in ARDS, in which patients treated with activated protein C showed less evidence of hypercoagulability than patients treated with placebo [79]. Encouragingly, this correlated with decreased lung injury scores and decreased organ dysfunction [79]. &
&
THE EPITHELIAL MARKERS Several markers of pulmonary epithelial damage have come under scrutiny as possible markers of ARDS (Fig. 1). This approach makes intuitive sense, given that lung epithelial markers should be more specific to lung injury than are the inflammatory cytokines. The markers that have been most extensively studied include the surfactant-associated proteins, KL-6 protein, CC-16-kD protein, sRAGE, and VEGF (Table 1). The surfactant-associated proteins include SP-A, SP-B, SP-C, and SP-D. These apolipoproteins are produced by alveolar type II (ATII) cells in the alveolar epithelium and secreted into the alveolar space as part of pulmonary surfactant [80]. Multiple studies have shown decreased levels of surfactant proteins in BALF from ARDS patients relative to
‘at-risk’ or non-ARDS controls [39,40,42,43,45, 46,48]. Further investigation has revealed that surfactant expression is unchanged in ARDS [81]; however, degradation products of SP-A are detected in BALF samples from ARDS patients, suggesting enhanced degradation as the mechanism of depletion [82]. The use of exogenous surfactant has been studied as a possible therapy for ARDS with some evidence of benefit in pediatric patients [83], but not in adults [84]. In contrast to BALF levels, plasma levels of surfactant-associated proteins are generally increased in ARDS, particularly SP-B protein, which is small and can more easily cross the damaged alveo-capillary membrane [41,46,50]. Plasma levels of SP-D have also been shown to correlate with ARDS mortality [20 ,52]. Another ATII cell product that has been investigated as a marker of ARDS is the KL-6 protein, a secreted glycoprotein normally found in the alveolar space. Multiple studies have shown increased levels of KL-6 in both BALF and serum samples from ARDS patients relative to ‘at-risk’ and healthy controls [10,17,26,27]. The presence of KL-6 in the serum is presumed to indicate breakdown of the alveo-capillary barrier. Unfortunately, serum KL-6 levels are elevated in other respiratory diseases including interstitial pneumonitis, so may not be specific for ARDS in patients with underlying lung disease. Indeed, a study of critically ill patients with ventilator-associated pneumonia showed no difference in serum KL-6 levels between those who developed ARDS and those who did not [11]. Krebs von den Lungen-6 may be a more specific marker of ARDS mortality than ARDS development. Both BALF and serum levels have been shown to correlate with ARDS mortality [25–27]. There is also a correlation between serum KL-6 levels and injurious ventilation [10], suggesting that plasma KL-6 levels might be a biological correlate of the alveocapillary damage caused by overdistension of the lungs. Another epithelial protein that has been studied as an ARDS marker is the CC-16-kD protein, produced by Clara cells or ‘club cells’ which are located in the ciliated epithelium, proximal to the alveoli. Data have been mixed with that of some authors showing strong correlations between plasma CC-16 levels and ARDS development [10,11], whereas others have shown poor or inverse correlations [12,14]. This may relate, in part, to the choice of control population, as CC-16 levels are also elevated in heart failure patients [14]. Soluble receptor for advanced glycation end product, the secreted form of the epithelial RAGE membrane receptor, has been studied as a marker of
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-criticalcare.com
51
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system
ARDS. In animal models of ARDS, RAGE expression is up-regulated in the pulmonary epithelium and RAGE has been suggested as a therapeutic target for ARDS [85]. Its utility as a marker of ARDS in humans, however, is questionable and data have been very mixed. Some studies have shown an association between plasma sRAGE levels and ARDS development in mixed ICU patients [17,36,86] and trauma patients [87], but several robust studies have not shown any association [7 ,10,11] and it is likely that sRAGE is a marker of illness severity rather than ARDS. Finally, one of the most extensively studied epithelial markers in ARDS is VEGF, a protein that is highly expressed in ATII cells and may have a protective role in ARDS [88]. VEGF levels are decreased in BALF from ARDS patients [53,57,58] and show recovery in line with clinical improvement [53,58]. Moreover, VEGF expression is increased in the lung tissue of recovering ARDS patients [88]. Some authors have also reported an increase in plasma VEGF levels in ARDS [53,54] which then decreases with recovery [53]; however, this association has been inconsistent [4,8,57].
an important (and biologically plausible) association between endothelial dysfunction and extrapulmonary causes of ARDS. Indeed, there is genetic work indicating that certain angiopoietin variants are associated with a predisposition for the development of ARDS [96,97].
THE ENDOTHELIAL MARKERS
CHALLENGES IN IDENTIFYING ACUTE RESPIRATORY DISTRESS SYNDROME BIOMARKERS
&
Early studies of endothelial markers focused on vWF, a protein that is released from the endothelium in response to endothelial damage and is a key initiator of the coagulation cascade. The data have been very mixed: initial studies indicated an association between serum vWF levels and ‘acute respiratory failure’, particularly in patients with extra-pulmonary causes for their lung injury [89–91]; however, recent studies have shown this association to be modest or nonexistent [4,7 ,92]. There is reasonable evidence, however, that vWF levels correlate with mortality in ARDS, perhaps indicating a higher degree of endothelial dysfunction in these patients [20 ,24,93]. The most encouraging recent data come from studies of Ang-2, an endothelial protein that has been studied extensively in sepsis [94,95]. Serum Ang-2 is a marker (and driver) of endothelial dysfunction, whereas Ang-1 is a marker of endothelial ‘health’. Increases in Ang-2, or in the Ang-2/Ang-1 ratio, correlate with endothelial dysfunction in sepsis, and are predictive of mortality [78 ]. Studies in ARDS reveal elevated levels of Ang-2 both in patients with ARDS and in ‘at-risk’ patients who go on to develop ARDS [4,5,7 ,8]. Furthermore, there is a reproducible correlation between Ang-2 levels and ARDS mortality [5,9]. The association between Ang-2 levels and ARDS development has been confirmed in trauma patients [87], suggesting &
&
&
&
52
www.co-criticalcare.com
COMBINATORIAL APPROACHES The lack of a single, reliable biomarker of ARDS has led to attempts to identify combinations of biomarkers that might better predict ARDS development and mortality. In a study of trauma patients, the combination of Ang-2, sRAGE, procollagen peptide III, IL-10, TNF-a, and IL-8 serum levels had good predictive value for ALI/ARDS development with an area under the ROC of 0.86 [87]. Another study from the same group looked at markers to predict ARDS mortality and found that the addition of eight serum biomarkers (IL-6, IL-8, TNFR, protein C, PAI-1, ICAM, SP-D, and vWF) to a range of clinical indicators increased the area under the ROC from 0.82 to 0.85 [20 ]. Of these, the highest prognostic value came from IL-8 and SP-D. &
Efforts to identify an ARDS biomarker have been hampered by a number of significant challenges. The largest single challenge is that ARDS is a syndrome, not a disease. Autopsy studies reveal that 51–84% of patients diagnosed with ARDS have DAD on lung pathology, whereas the remainder do not [67 ,69,70 ]. Thus, ARDS represents a grab bag of pathophysiological processes, hugely complicating the search for a reliable biomarker. This challenge, however, underscores the urgent need for a marker (or markers) that can identify patients with similar pathophysiology in order to tailor their therapy. Is there a subgroup of adult ARDS patients that might benefit from exogenous surfactant treatment? Only the identification of clear-cut cohorts amongst ARDS patients will enable us to answer this question. The second challenge is the difficulty of validating a diagnostic biomarker of ARDS. The ideal marker is one that can predict the development of ARDS in ‘at-risk’ patients and also distinguish patients with true noncardiogenic pulmonary edema from those with congestive heart failure, bilateral pneumonia, lymphangitic carcinomatosis, and all other causes of bilateral lung infiltrates and hypoxemia. Thus, at a minimum, a biomarker identified in medical-surgical ICU patients ‘at risk’ of ARDS needs to be validated in ‘at-risk’ trauma &
&
Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Biomarkers in acute respiratory distress syndrome Binnie et al.
patients and also in patients with non-ARDS causes of respiratory failure. The ideal biomarker should also correlate with pathology findings on autopsy, a step that has not yet been attempted. Several biomarkers that appeared promising in early studies, such as IL-6, KL-6, and CC-16, have not proven useful upon further validation [11,14,75,76]. Other promising biomarkers, including sICAM-1, have yet to be properly validated. The third challenge is obtaining access to appropriate patient samples. Conducting human biomarker studies requires the recruitment of large numbers of patients and carefully selected controls with excellent clinical documentation. Given the cost and effort involved, it is not surprising that many of the most robust biomarker studies have been substudies of large-scale ARDS clinical trials. The ARDS Network has been particularly successful in this regard. The integration of a biomarker study into a clinical trial can be undertaken with relatively little disruption and minimal costs. The benefit to the clinical trial is the addition of biological insight into clinical outcomes. A prime example would be the integration of IL-6 measurements into the ARDS Net study of high vs. low tidal volume ventilation [77 ]. &
THE FUTURE OF ACUTE RESPIRATORY DISTRESS SYNDROME BIOMARKERS RESEARCH Studies to date have focused on candidate proteins detectable in serum/plasma or BALF as biomarkers of ARDS. The disadvantage of this approach is that it entails laborious investigation of small numbers of candidate proteins (Fig. 1). The likelihood of identifying the best possible biomarker is dependent on our knowledge of ARDS physiology and a substantial dose of good luck. Other types of markers including metabolic markers, RNA markers, and DNA methylation markers have not yet been investigated. Unlike serum proteins, these types of markers are amenable to broad screening approaches that might generate high-probability candidate markers, which could then be validated. Not only would this yield potential candidate markers, it might also provide further insight into ARDS pathogenesis by identifying genes with altered expression levels or altered physiology. The future of ARDS biomarker research is wide open and we hope to see new and novel ways of approaching this challenge emerge over the coming years.
CONCLUSION The search for a reliable biomarker of ARDS is ongoing. The most encouraging data come from
studies of Ang-2, but there are also compelling data for the IL-8, sICAM-1, the surfactant-associated proteins, and VEGF. To date, however, no marker has supplanted clinical criteria in the diagnosis of ARDS. Acknowledgements None. Conflicts of interest The work is supported by the Canadian Institutes of Health Sciences, The Physicians’ Services Incorporate, and the Ministry of Research and Innovation of Ontario, Canada.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69:89–95. 2. World Health Organization. Biomarkers in risk assessment: validity and validation (EHC 222, 2001) [Internet]. inchem.org [no date], [no volume]. 3. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Statist Med 2012; 31:2973–2984. 4. van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, et al. Angiopoietin2, permeability oedema, occurrence and severity of ALI/ARDS in septic and nonseptic critically ill patients. Thorax 2008; 63:903–909. 5. Gallagher DC, Parikh SM, Balonov K, et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock 2008; 29:656–661. 6. Kranidioti H, Orfanos SE, Vaki I, et al. Angiopoietin-2 is increased in septic shock: evidence for the existence of a circulating factor stimulating its release from human monocytes. Immunol Lett 2009; 125:65–71. 7. Agrawal A, Matthay MA, Kangelaris KN, et al. Plasma angiopoietin-2 predicts & the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med 2013; 187:736–742. A recent study showing that Ang-2 may be useful in predicting the onset of ARDS in critically ill patients. 8. Wada T, Jesmin S, Gando S, et al. The role of angiogenic factors and their soluble receptors in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with critical illness. J Inflamm 2013; 10:1–11. 9. Calfee CS, Gallagher D, Abbott J, et al., the NHLBI ARDS Network. Plasma angiopoietin-2 in clinical acute lung injury: prognostic and pathogenetic significance. Crit Care Med 2012; 40:1731–1737. 10. Determann RM, Royakkers AANM, Haitsma JJ, et al. Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients. BMC Pulm Med 2010; 10:6. 11. Determann RM, Millo JL, Waddy S, et al. Plasma CC16 levels are associated with development of ALI/ARDS in patients with ventilator-associated pneumonia: a retrospective observational study. BMC Pulm Med 2009; 9:49. 12. Geerts L, Jorens PG, Willems J, et al. Natural inhibitors of neutrophil function in acute respiratory distress syndrome. Crit Care Med 2001; 29:1920–1924. 13. Lesur O, Langevin S, Berthiaume Y, et al. Outcome value of Clara cell protein in serum of patients with acute respiratory distress syndrome. Intensive Care Med 2006; 32:1167–1174. 14. Kropski JA. 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; 135:1440. 15. Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology 2009; 111:826–835. 16. Meduri GU, Headley S, Kohler G, et al. Persistent elevation of inflammatory & cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995; 107:1062–1073. An early study looking at correlations between ARDS biomarker levels and ARDS outcomes. 17. Nakamura T, Sato E, Fujiwara N, et al. Increased levels of soluble receptor for advanced glycation end products (sRAGE) and high mobility group box 1 (HMGB1) are associated with death in patients with acute respiratory distress syndrome. Clin Biochem 2011; 44:601–604.
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-criticalcare.com
53
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system 18. Stuber F, Wrigge H, Schroeder S, et al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intensive Care Med 2002; 28:834–841. 19. Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on & inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. J Am Med Assoc 1999; 282:54–61. A very detailed study that predated the ARDS Net trial of high vs. low tidal volume ventilation looking at the effects of high tidal volume ventilation on biomarkers of ARDS and ventilator-induced lung injury. 20. Ware LB, Koyama T, Billheimer DD, et al. Prognostic and pathogenetic value & of combining clinical and biochemical indices in patients with acute lung injury. Chest 2010; 137:288–296. The first study to look at groups of biomarkers as predictors of ARDS development and outcome. 21. McClintock D, Zhuo H, Wickersham N, et al. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care 2008; 12:R41. 22. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351:327. 23. Diehl JL, Coolen N, Faisy C, et al. Growth-arrest-specific 6 (GAS6) protein in ARDS patients: determination of plasma levels and influence of PEEP setting. Respir Care 2013; 58:1886–1891. 24. Calfee CS, Ware LB, Glidden DV, et al. National Heart, Blood, and Lung Institute Acute Respiratory Distress Syndrome Network: use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury. Crit Care Med 2011; 39:711–717. 25. Kondo T, Hattori N, Ishikawa N, et al. 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. 26. Nathani N, Perkins GD, Tunnicliffe W, et al. 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:R12. 27. Sato H, Callister MEJ, Mumby S, et al. KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome. Eur Respir J 2004; 23:142–145. 28. Moalli R, Doyle JM, Tahhan HR, et al. Fibrinolysis in critically ill patients. Am Rev Respir Dis 1989; 140:287–293. 29. Prabhakaran P, Ware LB, White KE, et al. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285:L20–L28. 30. Jalkanen V, Yang R, Linko R, et al. FINNALI Study Group: SuPAR and PAI-1 in critically ill, mechanically ventilated patients. Intensive Care Med 2013; 39:489–496. 31. Ware LB, Matthay MA, Parsons PE, et al. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007; 35:1821–1828. 32. Bertozzi P, Astedt B, Zenzius L, et al. Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 1990; 322:890–897. 33. Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285:L514–L521. 34. Calfee CS, Eisner MD, Parsons PE, et al. NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network: soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury. Intensive Care Med 2009; 35:248–257. 35. Cepkova M, Brady S, Sapru A, et al. Biological markers of lung injury before and after the institution of positive pressure ventilation in patients with acute lung injury. Crit Care 2006; 10:R126. 36. Uchida T, Shirasawa M, Ware LB, et al. Receptor for advanced glycation endproducts is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 2006; 173:1008–1015. 37. Mauri T, Masson S, Pradella A, et al. Elevated plasma and alveolar levels of soluble receptor for advanced glycation endproducts are associated with severity of lung dysfunction in ARDS patients. Tohoku J Exp Med 2010; 222:105–112. 38. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366:2055–2064. 39. Bowler RP. Proteomic analysis of pulmonary edema fluid and plasma in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 2004; 286:L1095–L1104. 40. Pison U, Obertacke U, Seeger W, Hawgood S. Surfactant protein A (SP-A) is decreased in acute parenchymal lung injury associated with polytrauma. Eur J Clin Invest 1992; 22:712–718. 41. Doyle IR, Nicholas TE, Bersten AD. Serum surfactant protein-A levels in patients with acute cardiogenic pulmonary edema and adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152:307–317. 42. Veldhuizen RA, McCaig LA, Akino T, Lewis JF. Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152:1867–1871. 43. Gu¨nther A, Siebert C, Schmidt R, et al. Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit Care Med 1996; 153:176–184.
54
www.co-criticalcare.com
44. Shimura S, Masuda T, Takishima T, Shirato K. Surfactant apoprotein-A concentration in airway secretions for the detection of pulmonary oedema. Eur Respir J 1996; 9:2525–2530. 45. Gregory TJ, Longmore WJ, Moxley MA, et al. Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J Clin Invest 1991; 88:1976–1981. 46. Greene KE, Wright JR, Steinberg KP, et al. Serial changes in surfactantassociated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 1999; 160:1843–1850. 47. Bersten AD, Hunt T, Nicholas TE, Doyle IR. Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure. Am J Respir Crit Care Med 2001; 164:648–652. 48. Schmidt R, Steinhilber W, Ruppert C, et al. An ELISA technique for quantification of surfactant apoprotein (SP)-C in bronchoalveolar lavage fluid. Am J Respir Crit Care Med 2002; 165:470–474. 49. Abadie Y, Bregeon F, Papazian L, et al. Decreased VEGF concentration in lung tissue and vascular injury during ARDS. Eur Respir J 2005; 25:139– 146. 50. Doyle IR, Bersten AD, Nicholas TE. Surfactant proteins-A and -B are elevated in plasma of patients with acute respiratory failure. Am J Respir Crit Care Med 1997; 156:1217–1229. 51. Schmidt R, Markart P, Ruppert C, et al. Time-dependent changes in pulmonary surfactant function and composition in acute respiratory distress syndrome due to pneumonia or aspiration. Respir Res 2007; 8:55. 52. Eisner MD, Parsons P, Matthay MA, et al. Acute Respiratory Distress Syndrome Network: plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003; 58:983–988. 53. Azamfirei L, Gurzu S, Solomon R, et al. Vascular endothelial growth factor: a possible mediator of endothelial activation in acute respiratory distress syndrome. Minerva Anestesiol 2010; 76:609–616. 54. Thickett DR, Armstrong L, Christie SJ, Millar AB. Vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 164:1601– 1605. 55. Medford ARL, Douglas SK, Godinho SIH, et al. Vascular endothelial growth factor (VEGF) isoform expression and activity in human and murine lung injury. Respir Res 2009; 10:27. 56. Koh H, Tasaka S, Hasegawa A, et al. Vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome. Respirology 2008; 13:281–284. 57. Maitre B, Boussat S, Jean D, et al. Vascular endothelial growth factor synthesis in the acute phase of experimental and clinical lung injury. Eur Respir J 2001; 18:100–106. 58. Thickett DR, Armstrong L, Millar AB. A role for vascular endothelial growth factor in acute and resolving lung injury. Am J Respir Crit Care Med 2002; 166:1332–1337. 59. Phua J, Badia JR, Adhikari NKJ, et al. Has mortality from acute respiratory distress syndrome decreased over time? Am J Respir Crit Care Med 2009; 179:220–227. 60. Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007; 131:554–562. 61. Herridge MS, Tansey CM, Matte A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364:1293–1304. 62. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in & adults. Lancet 1967; 2:319–323. The first published report of a patient with ARDS. 63. Bernard GR, Artigas A, Brigham KL, et al. The American-European Con& sensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818– 824. The publication of the American-European Consensus Conference definition of ARDS. 64. The ARDS Definition Task Force. Ranieri VM, Rubenfeld GD, et al. Acute & respiratory distress syndrome: the Berlin definition. JAMA 2012; 307:2526– 2533. The publication of the updated ‘Berlin definition’ of ARDS. 65. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress & syndrome. J Clin Invest 2012; 122:2731–2740. An excellent and up-to-date review of the pathophysiology of ARDS. 66. Pen˜uelas O, Aramburu JA, Frutos-Vivar F, Esteban A. Pathology of acute lung injury and acute respiratory distress syndrome: a clinical-pathological correlation. Clin Chest Med 2006; 27:; 571-8– abstract vii–viii. 67. Esteban A, Fernandez-Segoviano P, Frutos-Vivar F, et al. Comparison of & clinical criteria for the acute respiratory distress syndrome with autopsy findings. Ann Intern Med 2004; 141:440–445. The first study to compare the new AECC clinical definition of ARDS to pathology samples in order to determine its sensitivity and specificity for the pathological finding of DAD. 68. Sarmiento X, Guardiola JJ, Almirall J, et al. Discrepancy between clinical criteria for diagnosing acute respiratory distress syndrome secondary to community acquired pneumonia with autopsy findings of diffuse alveolar damage. Respir Med 2011; 105:1170–1175.
Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Biomarkers in acute respiratory distress syndrome Binnie et al. 69. Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005; 33:2228–2234. 70. Thille AW, Esteban A, Fernandez-Segoviano P, et al. Comparison of the Berlin & definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med 2013; 187:761–767. A revision of earlier autopsy studies looking at the sensitivity and specificity of the Berlin definition of ARDS for the pathological finding of DAD. 71. Suter PM, Suter S, Girardin E, et al. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis 1992; 145:1016–1022. 72. Siler TM, Swierkosz JE, Hyers TM, et al. Immunoreactive interleukin-1 in & bronchoalveolar lavage fluid of high-risk patients and patients with the adult respiratory distress syndrome. Exp Lung Res 1989; 15:881–894. One of the first studies to examine cytokine levels in BALF from patients with ARDS. 73. Makabe H, Kojika M, Takahashi G, et al. Interleukin-18 levels reflect the longterm prognosis of acute lung injury and acute respiratory distress syndrome. J Anesth 2012; 26:658–663. 74. Roumen RM, Hendriks T, van der Ven-Jongekrijg J, et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Ann Surg 1993; 218:769–776. 75. Meade P, Shoemaker WC, Donnelly TJ, et al. Temporal patterns of hemodynamics, oxygen transport, cytokine activity, and complement activity in the development of adult respiratory distress syndrome after severe injury. J Trauma Acute Care Surg 1994; 36:651–657. 76. Donnelly TJ, Meade P, Jagels M, et al. Cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury. Crit Care Med 1994; 22:768– 776. 77. ARDS Net. Ventilation with lower tidal volumes as compared with traditional & tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301–1308. The landmark ARDS Net trial of low vs. high tidal volume ventilation in ARDS. This study established IL-6 as an important biomarker of ARDS and ventilator-induced lung injury and is a model for how biomarkers can be integrated into large clinical trials thereby enriching the results of the trial. 78. Xing K, Murthy S, Liles WC, Singh JM. Clinical utility of biomarkers of & endothelial activation in sepsis-a systematic review. Crit Care 2012; 16:R7. An excellent review of biomarkers in sepsis, including Ang-2. 79. Cornet AD, Hofstra JJ, Vlaar AP, et al. Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome. J Thromb Haemost 2013; 11:894–901. 80. Perez-Gil J, Weaver TE. Pulmonary surfactant pathophysiology: current models and open questions. Physiology 2010; 25:132–141.
81. Pires-Neto RC, Morales MMB, Lancas T, et al. Expression of acute-phase cytokines, surfactant proteins, and epithelial apoptosis in small airways of human acute respiratory distress syndrome. J Crit Care 2013; 28:111; e9-111.e15. 82. Baker CS, Evans TW, Randle BJ, Haslam PL. Damage to surfactant-specific protein in acute respiratory distress syndrome. Lancet 1999; 353:1232–1237. 83. Duffett M, Choong K, Ng V, et al. Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis. Crit Care 2007; 11:R66. 84. Davidson WJ, Dorscheid D, Spragg R, et al. Exogenous pulmonary surfactant for the treatment of adult patients with acute respiratory distress syndrome: results of a meta-analysis. Crit Care 2006; 10:R41. 85. Guo WA, Knight PR, Raghavendran K. The receptor for advanced glycation end products and acute lung injury/acute respiratory distress syndrome. Intensive Care Med 2012; 38:1588–1598. 86. Narvaez-Rivera RM, Rendon A, Salinas-Carmona MC, Rosas-Taraco AG. Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis. BMC Infect Dis 2012; 12:15. 87. Fremont RD, Koyama T, Calfee CS, et al. Acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma 2010; 68:1121–1127. 88. Medford ARL, Godinho SIH, Keen LJ, et al. Relationship between vascular endothelial growth factor þ 936 genotype and plasma/epithelial lining fluid vascular endothelial growth factor protein levels in patients with and at risk for ARDS. Chest 2009; 136:457–464. 89. Modig J, Bagge L. Specific coagulation and fibrinolysis tests as biochemical markers in traumatic-induced adult respiratory distress syndrome. Resuscitation 1986; 13:87–95. 90. Rubin DB, Wiener-Kronish JP, Murray JF, et al. Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 1990; 86:474–480. 91. Carvalho AC, Bellman SM, Saullo VJ, et al. Altered factor VIII in acute respiratory failure. N Engl J Med 1982; 307:1113–1119. 92. Moss M, Ackerson L, Gillespie MK, et al. von Willebrand factor antigen levels are not predictive for the adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151:15–20. 93. Ware LB, Eisner MD, Thompson BT, et al. Significance of Von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004; 170:766–772. 94. van der Heijden M, van Nieuw Amerongen GP, Chedamni S, et al. The angiopoietin-Tie2 system as a therapeutic target in sepsis and acute lung injury. Expert Opin Ther Targets 2009; 13:39–53. 95. Liles WC. Is angiopoietin-2 the key piece in the sepsis puzzle?. Crit Care Med 2012; 40:3100–3101. 96. Su L, Zhai R, Sheu C-C, et al. Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS. Intensive Care Med 2009; 35:1024–1030. 97. Meyer NJ, Li M, Feng R, et al. ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. Am J Respir Crit Care Med 2011; 183:1344–1353.
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-criticalcare.com
55
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Biomarkers in acute respiratory distress syndrome Alexandra Binnie a, Jennifer L.Y. Tsang b, and Claudia C. dos Santos c,d
Purpose of review The article provides an overview of efforts to identify and validate biomarkers in acute respiratory distress syndrome (ARDS) and a discussion of the challenges confronting researchers in this area. Recent findings Although various putative biomarkers have been investigated in ARDS, the data have been largely disappointing and the ‘troponin’ of ARDS remains elusive. Establishing a relationship between measurable biological processes and clinical outcomes is vital to advancing clinical trials in ARDS and expanding our arsenal of treatments for this complex syndrome. Summary This article summarizes the current status of ARDS biomarker research and provides a framework for future investigation. Keywords acute lung injury, acute respiratory distress syndrome, biomarkers, ventilator-induced/associated lung injury
INTRODUCTION Numerous proteins have been identified as potential markers of acute respiratory distress syndrome (ARDS). These include the inflammatory cytokines interleukin (IL)-1b, tumor necrosis factor (TNF)-a, IL-6, IL-8, soluble intercellular adhesion molecule (sICAM)-1, the coagulation proteins plasminogen activator inhibitor (PAI)-1 and protein C, the endothelial proteins von Willebrand factor (vWF) and angiopoietin (Ang)-2, and the epithelial proteins Krebs von den Lungen (KL)-6, Clara cell protein (CC)-16, soluble receptor for advanced glycation end product (sRAGE), the surfactant-associated proteins A, B, C, and D, and vascular endothelial growth factor (VEGF). The most compelling recent data come from studies of Ang-2, but there is also strong evidence for Il-8, sICAM-1, the surfactantassociated proteins, and VEGF as both diagnostic and prognostic tools in ARDS. None of these markers, however, has supplanted clinical criteria in the diagnosis and management of ARDS.
WHAT IS A BIOMARKER OF ACUTE RESPIRATORY DISTRESS SYNDROME? The term ‘biomarker’, or ‘biological marker’, refers to any medical or biological sign that provides an objective indication of medical state [1]. In principle, this characteristic(s) can be accurately measured and evaluated, with reproducible results,
and can ‘influence or predict the incidence of outcome of disease’ [2]. At best, biomarkers, including physical signs, laboratory measures, and radiological tests, are indirect measures. They are considered as replacement endpoints or ‘surrogates’ for clinically meaningful endpoints [3]. Although various putative biomarkers have been investigated in the context of ARDS (Table 1) [4–6,7 ,8–15,16 ,17,18,19 ,20 ,21–58], their correlation with disease development and disease outcome has been inconsistent. The syndromic nature of the ARDS definition, the paucity of acute lung injury (ALI)/ARDS tissues available for diagnostic and pathological studies, and the discrepancies between clinical and autopsy findings make identifying and validating an ARDS biomarker extremely challenging. Yet these same issues underlie the need for a reliable and validated biomarker that can be &
&
&
&
a
Department of Medicine, St Joseph’s Health Centre, Toronto, Department of Critical Care Medicine, McMaster University, Hamilton, c Keenan and Li Ka Shing Knowledge Institute of Saint Michael’s Hospital and dInstitute of Medical Sciences and Department of Medicine, University of Toronto, Toronto, Ontario, Canada b
Correspondence to Dr dos Santos, Critical Care Medicine and Clinician Scientist, Assistant Professor of Medicine, St. Michael’s Hospital/ University of Toronto, 30 Bond Street, Toronto, ON M5B 1WB, Canada. Tel: +1 416 946 0420; e-mail: [email protected] Curr Opin Crit Care 2014, 20:47–55 DOI:10.1097/MCC.0000000000000048
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-criticalcare.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system
KEY POINTS
transudation of proteinaceous fluid into the alveoli [65 ]. On autopsy and biopsy samples, ARDS is characterized by a pattern of ‘diffuse alveolar damage’ (DAD) [66]. Studies have shown, however, that not all patients meeting the clinical definition of ARDS have this pathological phenotype [67 ,68,69]. Estimates of the specificity of the ARDS definition for DAD range from 51 to 84% [67 ,68,69], with a recent review of the Berlin definition showing 63% specificity [70 ]. Similarly, some patients with pathological evidence of DAD do not have clinical ARDS; estimates of sensitivity range from 75 to 83% [67 ,69], with the Berlin definition achieving a sensitivity of 89% [70 ]. These discrepancies underlie the need for a definition of ARDS that has greater biological relevance and can identify a group of patients with similar underlying pathophysiology. Unfortunately, the search for a ‘biomarker’ of ARDS has been challenging and a winning candidate has yet to emerge. &
ARDS is a clinical syndrome representing a variety of pathophysiologic processes, which hugely complicates the search for a clinically useful biomarker.
&
Numerous candidate proteins, including inflammatory cytokines, endothelial proteins, epithelial proteins, and coagulation proteins, have been investigated as markers of ARDS. Angiopoietin-2, an endothelial protein, is currently the most promising ARDS biomarker; however, its validation is ongoing. Combinatorial approaches using multiple biomarkers to diagnose ARDS provide slightly higher sensitivity and specificity than do any individual biomarkers. Other approaches to ARDS biomarker discovery, such as RNA or DNA methylation screens or metabolomics studies, have not yet been attempted and may yield new insights into ARDS pathophysiology as well as new candidate markers.
used to diagnose ARDS and predict outcome. Moreover, an accurate diagnostic tool would enable researchers to select patient populations with similar pathophysiology on whom to test new therapies and interventions.
WHAT IS ACUTE RESPIRATORY DISTRESS SYNDROME? Acute respiratory distress syndrome is a syndrome characterized by acute bilateral pulmonary infiltrates and impaired oxygenation in the absence of elevated left atrial pressure. It is triggered by a wide range of predisposing conditions ranging from pneumonia, to sepsis, to trauma. It is a frequent cause of ICU admission and has a high rate of mortality and morbidity [59–61]. ARDS was first reported in 1967 [62 ] and subsequently defined by expert consensus in 1994 [63 ]. In 2012, the definition was updated in an effort to improve its diagnostic and predictive value [64 ]. In this study, in the interest of clarity, we may use the original term, ALI, when referring to data generated before the establishment of the Berlin criteria. For the most part, but not always, these studies will likely be referring to patients who under the new criteria can be considered as ‘mild ARDS’. Biologically, ARDS represents a noncardiogenic form of pulmonary edema. The mechanisms of its development include overwhelming immune activation accompanied by breakdown of epithelial and endothelial membranes in the lung with resultant &
&
&
48
www.co-criticalcare.com
&
&
&
&
THE SEARCH FOR AN ACUTE RESPIRATORY DISTRESS SYNDROME BIOMARKER The search for an ARDS biomarker has focused on proteins detectable in either serum or bronchoalveolar lavage fluid (BALF). Four broad anatomical categories of proteins have been studied: inflammatory cytokines, coagulation proteins, epithelial proteins, and endothelial proteins (Table 1). Most studies have compared results from ARDS patients with ‘at-risk’ patients comprising ventilated critically ill patients with similar illness severity scores. Some studies, however, have compared ARDS patients to patients with cardiogenic pulmonary edema, whereas others have used healthy nonventilated patients as their control group. For reasons of brevity, this review will focus only on those biomarkers that have a substantial body of evidence. As a result, we may be omitting promising biomarkers that have yet to be validated. We have also limited ourselves to a brief discussion of the diagnostic and prognostic value of each biomarker without providing significant background on their role in the pathogenesis of ARDS. For an excellent discussion of the underlying biology we refer you to a recent review on this topic [65 ]. &
THE INFLAMMATORY CYTOKINES The earliest work on ARDS biomarkers measured inflammatory cytokines in the BALF of ‘acute respiratory failure’ patients. The pro-inflammatory cytokines IL-1b and TNF-a were detected at increased levels in BALF from ‘ARDS-like’ patients when Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Clara cell protein-16
Interleukin-1b
Interleukin-6
Interleukin-8
Interleukin-10
Krebs von den Lungen-6
Plasminogen activator inhibitor-1
Protein C
Soluble intercellular adhesion molecule-1
Soluble receptor for advanced glycation end products
Surfactant protein A
Surfactant protein B
Surfactant protein C
Surfactant protein D
Tumor necrosis factor-a Plasma and BALF – decrease with LPV
Vascular endothelial growth receptor
von Willebrand factor
CC-16
IL-1b
IL-6
IL-8
IL-10
KL-6
PAI-1
Protein C
s-ICAM-1
s-RAGE
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
SP-A
SP-B
SP-C
SP-D
TNF-a
VEGF
vWF
www.co-criticalcare.com Endothelium
Epithelium (ATII); inflammatory cells (PMN, M1)
Epithelium (ATII); inflammatory cells (PMN, monocytes)
Epithelium (ATII, Clara cells)
Epithelium (ATII)
Epithelium (ATII)
Epithelium (ATII)
Epithelium (ATI)
Endothelium; epithelium (ATI and ATII); inflammatory cells
Liver
Endothelium; platelets
&
[15,16 ]
[10–14]
&
[4–6,7 ,8,9]
References
&
Anti-inflammatory by inhibition of cytokines production
Potent PMN chemotactic and activating factor
[15,17,18,36,37]
[15,21,22,34,35]
[31,33]
&
[20 ,28–32]
&
[15,19 ,21,23,24, 43,45–47, 49–51]
Acts as a marker of endothelial activation and injury
Increases endothelial barrier permeability; it is potentially protective
Acts as a chemotactic factors for fibroblasts; up-regulates expression of leukocytes and endothelial adhesion molecules; stimulates PMN functions
Directly modulates inflammatory cell functions
[4,9,35]
[53–58]
&
[18,19 ]
[10,11,17,22,24– 27,46,51,52]
Facilitates the adsorption of surfactant phospholipids to an [18,48] air–water interface and stabilizes the interfacial lipid layer during firm compression
Enhances spreading and stabilizes surfactant phospholipids at the air–liquid interface
&
Participates in innate defense and regulates the release of [15,17,18,20 ,21, 22,38–48] surfactants by ATII
Influences gene and protein expression via activated signal transduction pathways
Epithelial source activates inflammatory functions; endothelial source contributes to elevated edema fluid level
Plasma anticoagulant that promotes fibrinolysis and inhibits thrombosis and inflammation
Inhibits tissue plasminogen activator and urokinase, therefore inhibits fibrinolysis
[10,11,17,25–27]
[18]
&
[15,20 ,21,23,24]
Induces synthesis of acute phase protein by liver; activates [15,17,18,19 ,2& 0 ,21,22] T and B cells
Induces synthesis of endothelial adhesion molecules; induces PMN inflammatory functions; stimulates repair of alveolar epithelium
Impairs endothelial barrier function; increases adhesion and migration of inflammatory cells Suppresses PMN mediated lung damage; modulates dysregulated coagulation characteristics of ALI
Biological functions
Epithelium (ATII, bronchiolar cells) Acts as chemotactic factor that promotes migration, proliferation and survival of lung fibroblasts
Inflammatory cells (Th2 cells)
Endothelium; inflammatory cells (PMN, M1, T/B cells); fibroblasts
Endothelium; inflammatory cells (monocytes, T/B cells); fibroblasts
Inflammatory cells
Epithelium (Clara cells)
Endothelium
Source
ATI, alveolar epithelial type I cells; ATII, alveolar epithelial type II cells; BALF, bronchoalveolar lavage fluid; LPV, lung-protective ventilation; M1, macrophage; PMN, neutrophils; VT, tidal volume. Various biomarkers of ARDS, their source, location of detection, expression patterns, and biological functions are listed.
Plasma and BALF – higher
Plasma – elevated; BALF and lung tissue – lower
BALF – elevated; plasma – mixed results
BALF – lower
Plasma – elevated; BALF – lower
BALF – lower; plasma – mixed results
Plasma and BALF – elevated
Plasma – elevated
Plasma – lower
Plasma and BALF – elevated
Plasma and BALF – elevated
Plasma – elevated
Plasma – elevated; plasma and BALF – lower in LPV
Plasma – elevated; plasma and BALF – lower in LPV
BALF – lower in LPV; plasma – elevated
Plasma and BALF – elevated
Plasma – elevated
Angiopoietin 2
Ang-2
Expression in ALI/ARDS
Full name
Biomarker
Table 1. Putative biomarkers of ARDS, their source, location of detection, expression patterns, and biological function(s)
Biomarkers in acute respiratory distress syndrome Binnie et al.
49
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system
Clara cell
CC–16
Inflammatory cell
Alveolar space
ATI
Fibroblast
IL–IB IL–6 TNF–α IL–6 vwf
VEGF SICAM–1
ATI S VE P G SIC F AM
Interstitial space
SR AG IL– E TN 6 F–α
II-6
M–1 SICA E SRAG
PAI–1 Ang2
Endothelial cell
Pulmonary capillary Red blood cells
Breakdown of epithelial and endothelial barrier
FIGURE 1. Putative biomarkers of ARDS. There is a breakdown of epithelial and endothelial barrier (shown in green double arrows) in ARDS. This breakdown of barrier allows the movement of molecules between the alveolar space (detected from BALF) and the pulmonary capillary (detected from plasma). Various cell types in the pulmonary unit (alveolar space, interstitial space, and capillary) contribute to the secretion of molecules that can act as biomarkers of ARDS. Epithelial markers are represented in green. They include CC-16 produced by Clara cells, VEGF produced by inflammatory cells and ATII, SP produced by ATII, and sRAGE produced by ATI and ATII. CC-16, VEGF, and SP are detected in plasma only, whereas sRAGE can be detected in BALF and plasma. Endothelial markers are represented in red. They include Ang-2 and vWF, both produced by endothelial cells. vWF can be detected in both BALF and plasma, whereas Ang-2 can only be detected in plasma. Inflammatory markers are represented in black. They include IL-1b produced by inflammatory cells, IL-6 produced by inflammatory cells, endothelial cells, fibroblasts and ATII, TNF-a produced by inflammatory cells and ATII, and sICAM-1 produced by ATI and ATII. IL-1b, IL-6, and TNF-a can be detected in BALF and plasma, whereas sICAM-1 is primarily detected in plasma. Coagulation marker PAI-1 is represented in blue. It is produced by endothelial cells and can be detected in plasma. ATI, type I epithelial cells; ATII, type II epithelial cells; Ang-2, angiopoietin 2; BALF, bronchoalveolar lavage fluid; CC-16, Clara cell protein-16; IL, interleukin; PAI-1, plasminogen activator inhibitor-1; sICAM-1, soluble intercellular adhesion molecule1; SP, surfactant proteins; sRAGE, soluble receptor for advanced glycation end produdct; TNF-a, tumor necrosis factor-a; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor.
compared to critically ill patients without evidence of ARDS, or healthy controls [71,72 ,73]. Serum levels of IL-1b and TNF-a do not correlate with ARDS development, but subsequent studies did show a correlation between serum cytokine levels and ARDS mortality [16 ,74]. The wider applicability of these findings is limited, however, as trauma patients with ARDS have undetectable serum levels of IL-1b and TNF-a [75,76]. Thus, serum IL-1b and TNF-a levels may be better markers of sepsis severity than ARDS (Fig. 1). Other pro-inflammatory cytokines, including IL-6, IL-8, and sICAM-1, have also been studied in ARDS. Plasma IL-6 levels correlate with ARDS development in mixed ICU patients [17,35], but have again shown variable results in trauma patients &
&
50
www.co-criticalcare.com
[75,76]. Better correlations have been noted between serum IL-6 levels and ventilator-induced lung injury, most notably in the ARDS Net study of high vs. low tidal volume ventilation where IL-6 levels decreased in the low-tidal-volume group [77 ], which also had better outcomes. Other studies have confirmed an inverse correlation between injurious ventilation and IL-6 levels [15,18,19 ]. Plasma IL-8 levels have been shown to correlate with ARDS development in medical ICU as well as trauma patients [7 ,35,75,76], and have shown a consistent inverse correlation with ARDS mortality [20 ,21,24]. Correlations with ventilation strategy have not been consistent [15,19 ,23,35]. Finally, plasma sICAM-1 levels appear to correlate with ARDS development [34,35] and ARDS &
&
&
&
&
Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Biomarkers in acute respiratory distress syndrome Binnie et al.
mortality [21,24,34]. It will be interesting to see whether these correlations carry over to traumainduced ARDS. sICAM-1 levels are low in trauma patients, when compared with septic patients [78 ], so an association with ARDS development in these patients would be very significant. &
THE COAGULATION PROTEINS ARDS is associated with intra-alveolar and intravascular fibrin deposition secondary to generalized activation of the coagulation cascade (Fig. 1). Several coagulation pathway proteins have shown promise as markers of ARDS. PAI-1, an inhibitor of fibrinolysis, is increased in both plasma [20 ,28,29] and BALF or ‘pulmonary edema fluid’ [29,32] from ARDS patients and shows some correlation with ARDS outcomes [20 ,31]. The only study to report sensitivities and specificities estimated an area under the receiver operating curve (ROC) of 0.75 for plasma PAI-1 as a marker of ARDS development, indicating a moderate predictive value. Another recent study did not confirm the association between PAI-1 levels and ARDS, but did show a correlation with overall mortality in critically ill patients [30]. Conversely, protein C, an inhibitor of the coagulation cascade, is decreased in the plasma of ARDS patients [31] and is lower in nonsurvivors than survivors [31,33], suggesting a link between hypercoagulability and mortality. These results are consistent with a recent clinical trial of activated protein C in ARDS, in which patients treated with activated protein C showed less evidence of hypercoagulability than patients treated with placebo [79]. Encouragingly, this correlated with decreased lung injury scores and decreased organ dysfunction [79]. &
&
THE EPITHELIAL MARKERS Several markers of pulmonary epithelial damage have come under scrutiny as possible markers of ARDS (Fig. 1). This approach makes intuitive sense, given that lung epithelial markers should be more specific to lung injury than are the inflammatory cytokines. The markers that have been most extensively studied include the surfactant-associated proteins, KL-6 protein, CC-16-kD protein, sRAGE, and VEGF (Table 1). The surfactant-associated proteins include SP-A, SP-B, SP-C, and SP-D. These apolipoproteins are produced by alveolar type II (ATII) cells in the alveolar epithelium and secreted into the alveolar space as part of pulmonary surfactant [80]. Multiple studies have shown decreased levels of surfactant proteins in BALF from ARDS patients relative to
‘at-risk’ or non-ARDS controls [39,40,42,43,45, 46,48]. Further investigation has revealed that surfactant expression is unchanged in ARDS [81]; however, degradation products of SP-A are detected in BALF samples from ARDS patients, suggesting enhanced degradation as the mechanism of depletion [82]. The use of exogenous surfactant has been studied as a possible therapy for ARDS with some evidence of benefit in pediatric patients [83], but not in adults [84]. In contrast to BALF levels, plasma levels of surfactant-associated proteins are generally increased in ARDS, particularly SP-B protein, which is small and can more easily cross the damaged alveo-capillary membrane [41,46,50]. Plasma levels of SP-D have also been shown to correlate with ARDS mortality [20 ,52]. Another ATII cell product that has been investigated as a marker of ARDS is the KL-6 protein, a secreted glycoprotein normally found in the alveolar space. Multiple studies have shown increased levels of KL-6 in both BALF and serum samples from ARDS patients relative to ‘at-risk’ and healthy controls [10,17,26,27]. The presence of KL-6 in the serum is presumed to indicate breakdown of the alveo-capillary barrier. Unfortunately, serum KL-6 levels are elevated in other respiratory diseases including interstitial pneumonitis, so may not be specific for ARDS in patients with underlying lung disease. Indeed, a study of critically ill patients with ventilator-associated pneumonia showed no difference in serum KL-6 levels between those who developed ARDS and those who did not [11]. Krebs von den Lungen-6 may be a more specific marker of ARDS mortality than ARDS development. Both BALF and serum levels have been shown to correlate with ARDS mortality [25–27]. There is also a correlation between serum KL-6 levels and injurious ventilation [10], suggesting that plasma KL-6 levels might be a biological correlate of the alveocapillary damage caused by overdistension of the lungs. Another epithelial protein that has been studied as an ARDS marker is the CC-16-kD protein, produced by Clara cells or ‘club cells’ which are located in the ciliated epithelium, proximal to the alveoli. Data have been mixed with that of some authors showing strong correlations between plasma CC-16 levels and ARDS development [10,11], whereas others have shown poor or inverse correlations [12,14]. This may relate, in part, to the choice of control population, as CC-16 levels are also elevated in heart failure patients [14]. Soluble receptor for advanced glycation end product, the secreted form of the epithelial RAGE membrane receptor, has been studied as a marker of
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-criticalcare.com
51
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system
ARDS. In animal models of ARDS, RAGE expression is up-regulated in the pulmonary epithelium and RAGE has been suggested as a therapeutic target for ARDS [85]. Its utility as a marker of ARDS in humans, however, is questionable and data have been very mixed. Some studies have shown an association between plasma sRAGE levels and ARDS development in mixed ICU patients [17,36,86] and trauma patients [87], but several robust studies have not shown any association [7 ,10,11] and it is likely that sRAGE is a marker of illness severity rather than ARDS. Finally, one of the most extensively studied epithelial markers in ARDS is VEGF, a protein that is highly expressed in ATII cells and may have a protective role in ARDS [88]. VEGF levels are decreased in BALF from ARDS patients [53,57,58] and show recovery in line with clinical improvement [53,58]. Moreover, VEGF expression is increased in the lung tissue of recovering ARDS patients [88]. Some authors have also reported an increase in plasma VEGF levels in ARDS [53,54] which then decreases with recovery [53]; however, this association has been inconsistent [4,8,57].
an important (and biologically plausible) association between endothelial dysfunction and extrapulmonary causes of ARDS. Indeed, there is genetic work indicating that certain angiopoietin variants are associated with a predisposition for the development of ARDS [96,97].
THE ENDOTHELIAL MARKERS
CHALLENGES IN IDENTIFYING ACUTE RESPIRATORY DISTRESS SYNDROME BIOMARKERS
&
Early studies of endothelial markers focused on vWF, a protein that is released from the endothelium in response to endothelial damage and is a key initiator of the coagulation cascade. The data have been very mixed: initial studies indicated an association between serum vWF levels and ‘acute respiratory failure’, particularly in patients with extra-pulmonary causes for their lung injury [89–91]; however, recent studies have shown this association to be modest or nonexistent [4,7 ,92]. There is reasonable evidence, however, that vWF levels correlate with mortality in ARDS, perhaps indicating a higher degree of endothelial dysfunction in these patients [20 ,24,93]. The most encouraging recent data come from studies of Ang-2, an endothelial protein that has been studied extensively in sepsis [94,95]. Serum Ang-2 is a marker (and driver) of endothelial dysfunction, whereas Ang-1 is a marker of endothelial ‘health’. Increases in Ang-2, or in the Ang-2/Ang-1 ratio, correlate with endothelial dysfunction in sepsis, and are predictive of mortality [78 ]. Studies in ARDS reveal elevated levels of Ang-2 both in patients with ARDS and in ‘at-risk’ patients who go on to develop ARDS [4,5,7 ,8]. Furthermore, there is a reproducible correlation between Ang-2 levels and ARDS mortality [5,9]. The association between Ang-2 levels and ARDS development has been confirmed in trauma patients [87], suggesting &
&
&
&
52
www.co-criticalcare.com
COMBINATORIAL APPROACHES The lack of a single, reliable biomarker of ARDS has led to attempts to identify combinations of biomarkers that might better predict ARDS development and mortality. In a study of trauma patients, the combination of Ang-2, sRAGE, procollagen peptide III, IL-10, TNF-a, and IL-8 serum levels had good predictive value for ALI/ARDS development with an area under the ROC of 0.86 [87]. Another study from the same group looked at markers to predict ARDS mortality and found that the addition of eight serum biomarkers (IL-6, IL-8, TNFR, protein C, PAI-1, ICAM, SP-D, and vWF) to a range of clinical indicators increased the area under the ROC from 0.82 to 0.85 [20 ]. Of these, the highest prognostic value came from IL-8 and SP-D. &
Efforts to identify an ARDS biomarker have been hampered by a number of significant challenges. The largest single challenge is that ARDS is a syndrome, not a disease. Autopsy studies reveal that 51–84% of patients diagnosed with ARDS have DAD on lung pathology, whereas the remainder do not [67 ,69,70 ]. Thus, ARDS represents a grab bag of pathophysiological processes, hugely complicating the search for a reliable biomarker. This challenge, however, underscores the urgent need for a marker (or markers) that can identify patients with similar pathophysiology in order to tailor their therapy. Is there a subgroup of adult ARDS patients that might benefit from exogenous surfactant treatment? Only the identification of clear-cut cohorts amongst ARDS patients will enable us to answer this question. The second challenge is the difficulty of validating a diagnostic biomarker of ARDS. The ideal marker is one that can predict the development of ARDS in ‘at-risk’ patients and also distinguish patients with true noncardiogenic pulmonary edema from those with congestive heart failure, bilateral pneumonia, lymphangitic carcinomatosis, and all other causes of bilateral lung infiltrates and hypoxemia. Thus, at a minimum, a biomarker identified in medical-surgical ICU patients ‘at risk’ of ARDS needs to be validated in ‘at-risk’ trauma &
&
Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Biomarkers in acute respiratory distress syndrome Binnie et al.
patients and also in patients with non-ARDS causes of respiratory failure. The ideal biomarker should also correlate with pathology findings on autopsy, a step that has not yet been attempted. Several biomarkers that appeared promising in early studies, such as IL-6, KL-6, and CC-16, have not proven useful upon further validation [11,14,75,76]. Other promising biomarkers, including sICAM-1, have yet to be properly validated. The third challenge is obtaining access to appropriate patient samples. Conducting human biomarker studies requires the recruitment of large numbers of patients and carefully selected controls with excellent clinical documentation. Given the cost and effort involved, it is not surprising that many of the most robust biomarker studies have been substudies of large-scale ARDS clinical trials. The ARDS Network has been particularly successful in this regard. The integration of a biomarker study into a clinical trial can be undertaken with relatively little disruption and minimal costs. The benefit to the clinical trial is the addition of biological insight into clinical outcomes. A prime example would be the integration of IL-6 measurements into the ARDS Net study of high vs. low tidal volume ventilation [77 ]. &
THE FUTURE OF ACUTE RESPIRATORY DISTRESS SYNDROME BIOMARKERS RESEARCH Studies to date have focused on candidate proteins detectable in serum/plasma or BALF as biomarkers of ARDS. The disadvantage of this approach is that it entails laborious investigation of small numbers of candidate proteins (Fig. 1). The likelihood of identifying the best possible biomarker is dependent on our knowledge of ARDS physiology and a substantial dose of good luck. Other types of markers including metabolic markers, RNA markers, and DNA methylation markers have not yet been investigated. Unlike serum proteins, these types of markers are amenable to broad screening approaches that might generate high-probability candidate markers, which could then be validated. Not only would this yield potential candidate markers, it might also provide further insight into ARDS pathogenesis by identifying genes with altered expression levels or altered physiology. The future of ARDS biomarker research is wide open and we hope to see new and novel ways of approaching this challenge emerge over the coming years.
CONCLUSION The search for a reliable biomarker of ARDS is ongoing. The most encouraging data come from
studies of Ang-2, but there are also compelling data for the IL-8, sICAM-1, the surfactant-associated proteins, and VEGF. To date, however, no marker has supplanted clinical criteria in the diagnosis of ARDS. Acknowledgements None. Conflicts of interest The work is supported by the Canadian Institutes of Health Sciences, The Physicians’ Services Incorporate, and the Ministry of Research and Innovation of Ontario, Canada.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69:89–95. 2. World Health Organization. Biomarkers in risk assessment: validity and validation (EHC 222, 2001) [Internet]. inchem.org [no date], [no volume]. 3. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Statist Med 2012; 31:2973–2984. 4. van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, et al. Angiopoietin2, permeability oedema, occurrence and severity of ALI/ARDS in septic and nonseptic critically ill patients. Thorax 2008; 63:903–909. 5. Gallagher DC, Parikh SM, Balonov K, et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock 2008; 29:656–661. 6. Kranidioti H, Orfanos SE, Vaki I, et al. Angiopoietin-2 is increased in septic shock: evidence for the existence of a circulating factor stimulating its release from human monocytes. Immunol Lett 2009; 125:65–71. 7. Agrawal A, Matthay MA, Kangelaris KN, et al. Plasma angiopoietin-2 predicts & the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med 2013; 187:736–742. A recent study showing that Ang-2 may be useful in predicting the onset of ARDS in critically ill patients. 8. Wada T, Jesmin S, Gando S, et al. The role of angiogenic factors and their soluble receptors in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with critical illness. J Inflamm 2013; 10:1–11. 9. Calfee CS, Gallagher D, Abbott J, et al., the NHLBI ARDS Network. Plasma angiopoietin-2 in clinical acute lung injury: prognostic and pathogenetic significance. Crit Care Med 2012; 40:1731–1737. 10. Determann RM, Royakkers AANM, Haitsma JJ, et al. Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients. BMC Pulm Med 2010; 10:6. 11. Determann RM, Millo JL, Waddy S, et al. Plasma CC16 levels are associated with development of ALI/ARDS in patients with ventilator-associated pneumonia: a retrospective observational study. BMC Pulm Med 2009; 9:49. 12. Geerts L, Jorens PG, Willems J, et al. Natural inhibitors of neutrophil function in acute respiratory distress syndrome. Crit Care Med 2001; 29:1920–1924. 13. Lesur O, Langevin S, Berthiaume Y, et al. Outcome value of Clara cell protein in serum of patients with acute respiratory distress syndrome. Intensive Care Med 2006; 32:1167–1174. 14. Kropski JA. 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; 135:1440. 15. Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology 2009; 111:826–835. 16. Meduri GU, Headley S, Kohler G, et al. Persistent elevation of inflammatory & cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995; 107:1062–1073. An early study looking at correlations between ARDS biomarker levels and ARDS outcomes. 17. Nakamura T, Sato E, Fujiwara N, et al. Increased levels of soluble receptor for advanced glycation end products (sRAGE) and high mobility group box 1 (HMGB1) are associated with death in patients with acute respiratory distress syndrome. Clin Biochem 2011; 44:601–604.
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-criticalcare.com
53
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Respiratory system 18. Stuber F, Wrigge H, Schroeder S, et al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intensive Care Med 2002; 28:834–841. 19. Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on & inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. J Am Med Assoc 1999; 282:54–61. A very detailed study that predated the ARDS Net trial of high vs. low tidal volume ventilation looking at the effects of high tidal volume ventilation on biomarkers of ARDS and ventilator-induced lung injury. 20. Ware LB, Koyama T, Billheimer DD, et al. Prognostic and pathogenetic value & of combining clinical and biochemical indices in patients with acute lung injury. Chest 2010; 137:288–296. The first study to look at groups of biomarkers as predictors of ARDS development and outcome. 21. McClintock D, Zhuo H, Wickersham N, et al. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care 2008; 12:R41. 22. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351:327. 23. Diehl JL, Coolen N, Faisy C, et al. Growth-arrest-specific 6 (GAS6) protein in ARDS patients: determination of plasma levels and influence of PEEP setting. Respir Care 2013; 58:1886–1891. 24. Calfee CS, Ware LB, Glidden DV, et al. National Heart, Blood, and Lung Institute Acute Respiratory Distress Syndrome Network: use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury. Crit Care Med 2011; 39:711–717. 25. Kondo T, Hattori N, Ishikawa N, et al. 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. 26. Nathani N, Perkins GD, Tunnicliffe W, et al. 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:R12. 27. Sato H, Callister MEJ, Mumby S, et al. KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome. Eur Respir J 2004; 23:142–145. 28. Moalli R, Doyle JM, Tahhan HR, et al. Fibrinolysis in critically ill patients. Am Rev Respir Dis 1989; 140:287–293. 29. Prabhakaran P, Ware LB, White KE, et al. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285:L20–L28. 30. Jalkanen V, Yang R, Linko R, et al. FINNALI Study Group: SuPAR and PAI-1 in critically ill, mechanically ventilated patients. Intensive Care Med 2013; 39:489–496. 31. Ware LB, Matthay MA, Parsons PE, et al. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007; 35:1821–1828. 32. Bertozzi P, Astedt B, Zenzius L, et al. Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 1990; 322:890–897. 33. Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285:L514–L521. 34. Calfee CS, Eisner MD, Parsons PE, et al. NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network: soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury. Intensive Care Med 2009; 35:248–257. 35. Cepkova M, Brady S, Sapru A, et al. Biological markers of lung injury before and after the institution of positive pressure ventilation in patients with acute lung injury. Crit Care 2006; 10:R126. 36. Uchida T, Shirasawa M, Ware LB, et al. Receptor for advanced glycation endproducts is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 2006; 173:1008–1015. 37. Mauri T, Masson S, Pradella A, et al. Elevated plasma and alveolar levels of soluble receptor for advanced glycation endproducts are associated with severity of lung dysfunction in ARDS patients. Tohoku J Exp Med 2010; 222:105–112. 38. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366:2055–2064. 39. Bowler RP. Proteomic analysis of pulmonary edema fluid and plasma in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 2004; 286:L1095–L1104. 40. Pison U, Obertacke U, Seeger W, Hawgood S. Surfactant protein A (SP-A) is decreased in acute parenchymal lung injury associated with polytrauma. Eur J Clin Invest 1992; 22:712–718. 41. Doyle IR, Nicholas TE, Bersten AD. Serum surfactant protein-A levels in patients with acute cardiogenic pulmonary edema and adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152:307–317. 42. Veldhuizen RA, McCaig LA, Akino T, Lewis JF. Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152:1867–1871. 43. Gu¨nther A, Siebert C, Schmidt R, et al. Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit Care Med 1996; 153:176–184.
54
www.co-criticalcare.com
44. Shimura S, Masuda T, Takishima T, Shirato K. Surfactant apoprotein-A concentration in airway secretions for the detection of pulmonary oedema. Eur Respir J 1996; 9:2525–2530. 45. Gregory TJ, Longmore WJ, Moxley MA, et al. Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J Clin Invest 1991; 88:1976–1981. 46. Greene KE, Wright JR, Steinberg KP, et al. Serial changes in surfactantassociated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 1999; 160:1843–1850. 47. Bersten AD, Hunt T, Nicholas TE, Doyle IR. Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure. Am J Respir Crit Care Med 2001; 164:648–652. 48. Schmidt R, Steinhilber W, Ruppert C, et al. An ELISA technique for quantification of surfactant apoprotein (SP)-C in bronchoalveolar lavage fluid. Am J Respir Crit Care Med 2002; 165:470–474. 49. Abadie Y, Bregeon F, Papazian L, et al. Decreased VEGF concentration in lung tissue and vascular injury during ARDS. Eur Respir J 2005; 25:139– 146. 50. Doyle IR, Bersten AD, Nicholas TE. Surfactant proteins-A and -B are elevated in plasma of patients with acute respiratory failure. Am J Respir Crit Care Med 1997; 156:1217–1229. 51. Schmidt R, Markart P, Ruppert C, et al. Time-dependent changes in pulmonary surfactant function and composition in acute respiratory distress syndrome due to pneumonia or aspiration. Respir Res 2007; 8:55. 52. Eisner MD, Parsons P, Matthay MA, et al. Acute Respiratory Distress Syndrome Network: plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003; 58:983–988. 53. Azamfirei L, Gurzu S, Solomon R, et al. Vascular endothelial growth factor: a possible mediator of endothelial activation in acute respiratory distress syndrome. Minerva Anestesiol 2010; 76:609–616. 54. Thickett DR, Armstrong L, Christie SJ, Millar AB. Vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 164:1601– 1605. 55. Medford ARL, Douglas SK, Godinho SIH, et al. Vascular endothelial growth factor (VEGF) isoform expression and activity in human and murine lung injury. Respir Res 2009; 10:27. 56. Koh H, Tasaka S, Hasegawa A, et al. Vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome. Respirology 2008; 13:281–284. 57. Maitre B, Boussat S, Jean D, et al. Vascular endothelial growth factor synthesis in the acute phase of experimental and clinical lung injury. Eur Respir J 2001; 18:100–106. 58. Thickett DR, Armstrong L, Millar AB. A role for vascular endothelial growth factor in acute and resolving lung injury. Am J Respir Crit Care Med 2002; 166:1332–1337. 59. Phua J, Badia JR, Adhikari NKJ, et al. Has mortality from acute respiratory distress syndrome decreased over time? Am J Respir Crit Care Med 2009; 179:220–227. 60. Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007; 131:554–562. 61. Herridge MS, Tansey CM, Matte A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364:1293–1304. 62. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in & adults. Lancet 1967; 2:319–323. The first published report of a patient with ARDS. 63. Bernard GR, Artigas A, Brigham KL, et al. The American-European Con& sensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818– 824. The publication of the American-European Consensus Conference definition of ARDS. 64. The ARDS Definition Task Force. Ranieri VM, Rubenfeld GD, et al. Acute & respiratory distress syndrome: the Berlin definition. JAMA 2012; 307:2526– 2533. The publication of the updated ‘Berlin definition’ of ARDS. 65. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress & syndrome. J Clin Invest 2012; 122:2731–2740. An excellent and up-to-date review of the pathophysiology of ARDS. 66. Pen˜uelas O, Aramburu JA, Frutos-Vivar F, Esteban A. Pathology of acute lung injury and acute respiratory distress syndrome: a clinical-pathological correlation. Clin Chest Med 2006; 27:; 571-8– abstract vii–viii. 67. Esteban A, Fernandez-Segoviano P, Frutos-Vivar F, et al. Comparison of & clinical criteria for the acute respiratory distress syndrome with autopsy findings. Ann Intern Med 2004; 141:440–445. The first study to compare the new AECC clinical definition of ARDS to pathology samples in order to determine its sensitivity and specificity for the pathological finding of DAD. 68. Sarmiento X, Guardiola JJ, Almirall J, et al. Discrepancy between clinical criteria for diagnosing acute respiratory distress syndrome secondary to community acquired pneumonia with autopsy findings of diffuse alveolar damage. Respir Med 2011; 105:1170–1175.
Volume 20 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Biomarkers in acute respiratory distress syndrome Binnie et al. 69. Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005; 33:2228–2234. 70. Thille AW, Esteban A, Fernandez-Segoviano P, et al. Comparison of the Berlin & definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med 2013; 187:761–767. A revision of earlier autopsy studies looking at the sensitivity and specificity of the Berlin definition of ARDS for the pathological finding of DAD. 71. Suter PM, Suter S, Girardin E, et al. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis 1992; 145:1016–1022. 72. Siler TM, Swierkosz JE, Hyers TM, et al. Immunoreactive interleukin-1 in & bronchoalveolar lavage fluid of high-risk patients and patients with the adult respiratory distress syndrome. Exp Lung Res 1989; 15:881–894. One of the first studies to examine cytokine levels in BALF from patients with ARDS. 73. Makabe H, Kojika M, Takahashi G, et al. Interleukin-18 levels reflect the longterm prognosis of acute lung injury and acute respiratory distress syndrome. J Anesth 2012; 26:658–663. 74. Roumen RM, Hendriks T, van der Ven-Jongekrijg J, et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Ann Surg 1993; 218:769–776. 75. Meade P, Shoemaker WC, Donnelly TJ, et al. Temporal patterns of hemodynamics, oxygen transport, cytokine activity, and complement activity in the development of adult respiratory distress syndrome after severe injury. J Trauma Acute Care Surg 1994; 36:651–657. 76. Donnelly TJ, Meade P, Jagels M, et al. Cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury. Crit Care Med 1994; 22:768– 776. 77. ARDS Net. Ventilation with lower tidal volumes as compared with traditional & tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301–1308. The landmark ARDS Net trial of low vs. high tidal volume ventilation in ARDS. This study established IL-6 as an important biomarker of ARDS and ventilator-induced lung injury and is a model for how biomarkers can be integrated into large clinical trials thereby enriching the results of the trial. 78. Xing K, Murthy S, Liles WC, Singh JM. Clinical utility of biomarkers of & endothelial activation in sepsis-a systematic review. Crit Care 2012; 16:R7. An excellent review of biomarkers in sepsis, including Ang-2. 79. Cornet AD, Hofstra JJ, Vlaar AP, et al. Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome. J Thromb Haemost 2013; 11:894–901. 80. Perez-Gil J, Weaver TE. Pulmonary surfactant pathophysiology: current models and open questions. Physiology 2010; 25:132–141.
81. Pires-Neto RC, Morales MMB, Lancas T, et al. Expression of acute-phase cytokines, surfactant proteins, and epithelial apoptosis in small airways of human acute respiratory distress syndrome. J Crit Care 2013; 28:111; e9-111.e15. 82. Baker CS, Evans TW, Randle BJ, Haslam PL. Damage to surfactant-specific protein in acute respiratory distress syndrome. Lancet 1999; 353:1232–1237. 83. Duffett M, Choong K, Ng V, et al. Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis. Crit Care 2007; 11:R66. 84. Davidson WJ, Dorscheid D, Spragg R, et al. Exogenous pulmonary surfactant for the treatment of adult patients with acute respiratory distress syndrome: results of a meta-analysis. Crit Care 2006; 10:R41. 85. Guo WA, Knight PR, Raghavendran K. The receptor for advanced glycation end products and acute lung injury/acute respiratory distress syndrome. Intensive Care Med 2012; 38:1588–1598. 86. Narvaez-Rivera RM, Rendon A, Salinas-Carmona MC, Rosas-Taraco AG. Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis. BMC Infect Dis 2012; 12:15. 87. Fremont RD, Koyama T, Calfee CS, et al. Acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma 2010; 68:1121–1127. 88. Medford ARL, Godinho SIH, Keen LJ, et al. Relationship between vascular endothelial growth factor þ 936 genotype and plasma/epithelial lining fluid vascular endothelial growth factor protein levels in patients with and at risk for ARDS. Chest 2009; 136:457–464. 89. Modig J, Bagge L. Specific coagulation and fibrinolysis tests as biochemical markers in traumatic-induced adult respiratory distress syndrome. Resuscitation 1986; 13:87–95. 90. Rubin DB, Wiener-Kronish JP, Murray JF, et al. Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 1990; 86:474–480. 91. Carvalho AC, Bellman SM, Saullo VJ, et al. Altered factor VIII in acute respiratory failure. N Engl J Med 1982; 307:1113–1119. 92. Moss M, Ackerson L, Gillespie MK, et al. von Willebrand factor antigen levels are not predictive for the adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151:15–20. 93. Ware LB, Eisner MD, Thompson BT, et al. Significance of Von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004; 170:766–772. 94. van der Heijden M, van Nieuw Amerongen GP, Chedamni S, et al. The angiopoietin-Tie2 system as a therapeutic target in sepsis and acute lung injury. Expert Opin Ther Targets 2009; 13:39–53. 95. Liles WC. Is angiopoietin-2 the key piece in the sepsis puzzle?. Crit Care Med 2012; 40:3100–3101. 96. Su L, Zhai R, Sheu C-C, et al. Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS. Intensive Care Med 2009; 35:1024–1030. 97. Meyer NJ, Li M, Feng R, et al. ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. Am J Respir Crit Care Med 2011; 183:1344–1353.
1070-5295 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-criticalcare.com
55
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
