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Editorial |

Clinical, Radiographic, Physiologic, and Biologic Measurements to Facilitate Personalized Medicine for ARDS FREE TO VIEW

Michael A. Matthay, MD, FCCP; Jeremy R. Beitler, MD, MPH
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: M. A. M. declares no conflict of interest for this editorial commentary and discloses support for his research from the National Institutes of Health/National Heart, Lung, and Blood Institute, Amgen, and GlaxoSmithKline. M. A. M. does consulting work for Cerus Therapeutics, GlaxoSmithKline, Boerhinger-Ingleheim, Bayer, Biogen, Quark Pharmaceuticals, and Incardia. None declared (J. R. B.)

aDepartments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA

bDivision of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA

CORRESPONDENCE TO: Michael A. Matthay, MD, FCCP, University of California, San Francisco, 505 Parnassus Ave, Room M-917, San Francisco, CA 94143


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(5):989-990. doi:10.1016/j.chest.2016.05.013
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Diagnosis of ARDS requires that patients have a PaO2/FiO2 ≤ 300 mm Hg and bilateral infiltrates on chest radiograph that cannot be primarily attributed to cardiogenic edema or intravascular volume overload. ARDS, as clinically defined, includes patients with a wide range of underlying biologic processes. Identification of physiologic, clinical, and biologic characteristics that further classify patients with ARDS into more homogeneous subgroups or endotypes may add value in determining prognosis and predicting response to treatments.

FOR RELATED ARTICLE SEE PAGE 998

In this issue of CHEST, Mrozek et al report the results of a prospective study of 119 patients with ARDS to test the hypothesis that focal vs nonfocal patterns of parenchymal involvement on chest imaging might be associated with distinct profiles of plasma biomarkers. They measured plasminogen activator inhibitor-1, surfactant protein-D, soluble intercellular adhesion molecule-1, and soluble receptor for advanced glycation end-product (sRAGE) within 24 hours of ARDS onset and performed chest CT scan or frontal radiograph and lung ultrasound (when CT scan was infeasible) within 48 hours. Each of the included plasma biomarkers has been associated with higher mortality in observational studies and clinical trials of ARDS. In the current study, only plasma sRAGE and plasminogen activator inhibitor-1 were significantly higher in patients with nonfocal vs focal ARDS. Also, 90-day mortality was significantly higher in the nonfocal vs focal pattern (46% vs 21%). In multivariable analysis, elevated plasma sRAGE levels and Simplified Acute Physiology Score-II (SAPS II) were independently associated with risk of death.

These findings add to the growing literature demonstrating that plasma sRAGE levels correlate with lung injury severity and mortality in ARDS. In a murine model of hydrochloric acid-induced acute lung injury, elevated plasma and bronchoalveolar lavage levels of sRAGE correlated with the severity of lung injury. In that same study, sRAGE was significantly elevated in the pulmonary edema fluid and plasma from patients with ARDS in whom it was inversely associated with impaired alveolar fluid clearance. Although sRAGE can be released from several organs, in the lung sRAGE is primarily released by alveolar epithelial type 1 cells. Therefore, the working hypothesis has been that elevated plasma sRAGE levels in ARDS may reflect the severity of alveolar epithelial type 1 cell injury. This theory has been supported by subsequent studies, including evidence in the ex vivo human lung and in patients with ARDS that alveolar fluid clearance and the resolution of alveolar edema are impaired when sRAGE is elevated in the alveolar fluid or plasma.

The idea that alveolar epithelial injury is a major determinant of the severity of lung injury is well supported by several studies over the last four decades. The classic ultrastructural morphologic studies by Bachofen and Weibel in 1977 established the extent of pathologic injury to the alveolar epithelium in patients who died of ARDS. Several preclinical studies have demonstrated that injury to the alveolar epithelium is a major factor in pathogenesis and delayed resolution of lung injury in animal models of ARDS. Impaired alveolar fluid clearance, in large part attributed to alveolar epithelial barrier injury, also has been reported as a major factor predicting mortality in patients with ARDS. In addition, elevated plasma sRAGE predicted which patients benefited most from low tidal volume ventilation in the inaugural National Heart Lung and Blood Institute ARDS Network trial.

The study by Mrozek et al also suggests an important link between regional differences in lung mechanics and biologic evidence of clinically significant lung injury. Regional heterogeneity of CT scan attenuation signifies collapsed, consolidated, or flooded lung units adjacent to well-aerated regions. Mechanical stress is concentrated at the border zones between well and poorly aerated lung units, which is thought to predispose to mechanical lung injury in these regions during tidal ventilation. Recent work using PET-CT scans found increased [18F]fluorodeoxyglucose uptake at the border zones of parenchymal inhomogeneity in patients with ARDS, indicating localized inflammation. The extent of parenchymal inhomogeneity also has been associated with physiologic markers of lung injury (dead-space fraction and PaO2/FiO2) and risk of death in patients with ARDS. The results of the current study support this possibility that mechanical lung injury persists in regions of stress concentration during low tidal volume ventilation, contributing to higher mortality in nonfocal ARDS. The current study also provides additional evidence that a plasma biomarker, such as sRAGE, could improve our ability to endotype patients with ARDS, forecast prognosis, and identify subgroups for targeting of specific therapies early in the course of ARDS.

What is needed to move the field forward? First, practical, financial, safety (during patient transport), and generalizability concerns might preclude large-scale use of CT scan-derived parenchymal inhomogeneity assessment in multicenter trials and clinical practice. Use of standard chest radiographs and ultrasound to determine focal vs nonfocal patterns should be independently validated against CT scan, and their association with sRAGE reconfirmed, in subsequent studies. Second, we need to develop point-of-care testing for the most promising plasma biomarkers, such as sRAGE, IL-8, and soluble tumor necrosis factor receptor-1, to improve our ability to classify biologically similar subgroups of patients early in the course of ARDS. Third, we need to test prospectively the logistics of incorporating clinical, imaging, and biologic measurements to group patients with ARDS into subcategories or endotypes that can facilitate population enrichment in clinical trials. A similar approach could be used for patients at risk of developing ARDS, especially patients with sepsis. Fourth, performance of such bedside physiologic measures as lung stress and pulmonary dead-space fraction should be compared against clinical, radiographic, and biologic measures to identify the variable (or combination of variables) that best identifies subgroups for trial enrichment, balancing needs for feasibility and generalizability. These advancements will facilitate development and testing of a more specific and personalized approach to managing patients with ARDS.

References

Ranieri V.M. .Rubenfeld G.D. . ARDS Definition Task Forceet al Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526-2533 [PubMed]journal. [PubMed]
 
Calfee C.S. .Delucchi K. .Parsons P.E. .Thompson B.T. .Ware L.B. .Matthay M.A. . Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2:611-620 [PubMed]journal. [CrossRef] [PubMed]
 
Mrozek S. .Jabaudon M. .Jaber S. .et al Elevated plasma levels of sRAGE are associated with nonfocal CT-based lung imaging in patients with ARDS: a prospective multicenter study. Chest. 2016;150:998-1007 [PubMed]journal. [CrossRef]
 
Jabaudon M. .Blondonnet R. .Roszyk L. .et al Soluble RAGE predicts impaired alveolar fluid clearance in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2015;192:191-199 [PubMed]journal. [CrossRef] [PubMed]
 
Uchida T. .Shirasawa M. .Ware L.B. .et al Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med. 2006;173:1008-1015 [PubMed]journal. [CrossRef] [PubMed]
 
Briot R. .Frank J.A. .Uchida T. .Lee J.W. .Calfee C.S. .Matthay M.A. . Elevated levels of the receptor for advanced glycation end products, a marker of alveolar epithelial type I cell injury, predict impaired alveolar fluid clearance in isolated perfused human lungs. Chest. 2009;135:269-275 [PubMed]journal. [CrossRef] [PubMed]
 
Bachofen M. .Weibel E.R. . Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis. 1977;116:589-615 [PubMed]journal. [CrossRef] [PubMed]
 
Wiener-Kronish J.P. .Albertine K.H. .Matthay M.A. . Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest. 1991;88:864-875 [PubMed]journal. [CrossRef] [PubMed]
 
Ware L.B. .Matthay M.A. . Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:1376-1383 [PubMed]journal. [CrossRef] [PubMed]
 
Calfee C.S. .Ware L.B. .Eisner M.D. .et al Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax. 2008;63:1083-1089 [PubMed]journal. [CrossRef] [PubMed]
 
Mead J. .Takishima T. .Leith D. . Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol. 1970;28:596-608 [PubMed]journal. [PubMed]
 
Cressoni M. .Chiumello D. .Chiurazzi C. .et al Lung inhomogeneities, inflation and [18F]2-fluoro-2-deoxy-D-glucose uptake rate in acute respiratory distress syndrome. Eur Respir J. 2016;47:233-242 [PubMed]journal. [CrossRef] [PubMed]
 
Cressoni M. .Cadringher P. .Chiurazzi C. .et al Lung inhomogeneity in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2014;189:149-158 [PubMed]journal. [PubMed]
 
Beitler J.R. .Goligher E.C. .Schmidt M. .et al Personalized medicine for ARDS: the 2035 research agenda. Intensive Care Med. 2016;42:756-767 [PubMed]journal. [CrossRef] [PubMed]
 
Agrawal A. .Matthay M.A. .Kangelaris K.N. .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 [PubMed]journal. [CrossRef] [PubMed]
 
Beitler J.R. .Majumdar R. .Hubmayr R.D. .et al Volume delivered during recruitment maneuver predicts lung stress in acute respiratory distress syndrome. Crit Care Med. 2016;44:91-99 [PubMed]journal. [CrossRef] [PubMed]
 
Nuckton T.J. .Alonso J.A. .Kallet R.H. .et al Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med. 2002;346:1281-1286 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Ranieri V.M. .Rubenfeld G.D. . ARDS Definition Task Forceet al Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526-2533 [PubMed]journal. [PubMed]
 
Calfee C.S. .Delucchi K. .Parsons P.E. .Thompson B.T. .Ware L.B. .Matthay M.A. . Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2:611-620 [PubMed]journal. [CrossRef] [PubMed]
 
Mrozek S. .Jabaudon M. .Jaber S. .et al Elevated plasma levels of sRAGE are associated with nonfocal CT-based lung imaging in patients with ARDS: a prospective multicenter study. Chest. 2016;150:998-1007 [PubMed]journal. [CrossRef]
 
Jabaudon M. .Blondonnet R. .Roszyk L. .et al Soluble RAGE predicts impaired alveolar fluid clearance in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2015;192:191-199 [PubMed]journal. [CrossRef] [PubMed]
 
Uchida T. .Shirasawa M. .Ware L.B. .et al Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med. 2006;173:1008-1015 [PubMed]journal. [CrossRef] [PubMed]
 
Briot R. .Frank J.A. .Uchida T. .Lee J.W. .Calfee C.S. .Matthay M.A. . Elevated levels of the receptor for advanced glycation end products, a marker of alveolar epithelial type I cell injury, predict impaired alveolar fluid clearance in isolated perfused human lungs. Chest. 2009;135:269-275 [PubMed]journal. [CrossRef] [PubMed]
 
Bachofen M. .Weibel E.R. . Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis. 1977;116:589-615 [PubMed]journal. [CrossRef] [PubMed]
 
Wiener-Kronish J.P. .Albertine K.H. .Matthay M.A. . Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest. 1991;88:864-875 [PubMed]journal. [CrossRef] [PubMed]
 
Ware L.B. .Matthay M.A. . Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:1376-1383 [PubMed]journal. [CrossRef] [PubMed]
 
Calfee C.S. .Ware L.B. .Eisner M.D. .et al Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax. 2008;63:1083-1089 [PubMed]journal. [CrossRef] [PubMed]
 
Mead J. .Takishima T. .Leith D. . Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol. 1970;28:596-608 [PubMed]journal. [PubMed]
 
Cressoni M. .Chiumello D. .Chiurazzi C. .et al Lung inhomogeneities, inflation and [18F]2-fluoro-2-deoxy-D-glucose uptake rate in acute respiratory distress syndrome. Eur Respir J. 2016;47:233-242 [PubMed]journal. [CrossRef] [PubMed]
 
Cressoni M. .Cadringher P. .Chiurazzi C. .et al Lung inhomogeneity in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2014;189:149-158 [PubMed]journal. [PubMed]
 
Beitler J.R. .Goligher E.C. .Schmidt M. .et al Personalized medicine for ARDS: the 2035 research agenda. Intensive Care Med. 2016;42:756-767 [PubMed]journal. [CrossRef] [PubMed]
 
Agrawal A. .Matthay M.A. .Kangelaris K.N. .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 [PubMed]journal. [CrossRef] [PubMed]
 
Beitler J.R. .Majumdar R. .Hubmayr R.D. .et al Volume delivered during recruitment maneuver predicts lung stress in acute respiratory distress syndrome. Crit Care Med. 2016;44:91-99 [PubMed]journal. [CrossRef] [PubMed]
 
Nuckton T.J. .Alonso J.A. .Kallet R.H. .et al Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med. 2002;346:1281-1286 [PubMed]journal. [CrossRef] [PubMed]
 
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