Acute respiratory distress syndrome

Nature Reviews Disease Primers

Volumn 5, Issue 1, 2018, Pages

  Matthay, Michael A ^a   Zemans, Rachel L ^b   Zimmerman, Guy A ^c   Arabi, Yaseen M ^d   Beitler, Jeremy R ^e   Mercat, Alain ^f   Herridge, Margaret ^g   Randolph, Adrienne G ^h   Calfee, Carolyn S ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

^d KING SAUD BIN ABDULAZIZ UNIVERSITY FOR HEALTH SCIENCES   (Saudi Arabia)

^e Och Spine at New York Presbyterian Hospitals   (United States)

^f UNIVERSITÉ D'ANGERS   (France)

^g UNIVERSITY HEALTH NETWORK   (Canada)

^h BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; BUDESONIDE; CISATRACURIUM; CORTICOSTEROID; FORMOTEROL; GLUCOCORTICOID; NITRIC OXIDE; PROSTAGLANDIN; VASCULAR ENDOTHELIAL CADHERIN; ANGIOPOIETIN 2; ANGPT2 PROTEIN, HUMAN; BIOLOGICAL MARKER; CADHERIN; CARBON DIOXIDE; INTERLEUKIN 8; LEUKOCYTE ANTIGEN; VASODILATOR AGENT; VON WILLEBRAND FACTOR;

ADULT; ADULT RESPIRATORY DISTRESS SYNDROME; ARTICLE; CHILD; CLINICAL STUDY; CORTICOSTEROID THERAPY; DIAGNOSTIC TEST; EARLY INTERVENTION; ENDOTHELIUM LESION; ENDOTRACHEAL INTUBATION; EXTRACORPOREAL CARBON DIOXIDE REMOVAL; EXTRACORPOREAL OXYGENATION; FLUID THERAPY; HUMAN; IMMUNOCOMPETENT CELL; LUNG ENDOTHELIUM; LUNG EPITHELIUM; NEUROMUSCULAR BLOCKING; NONINVASIVE VENTILATION; PATHOPHYSIOLOGY; POSITIVE END EXPIRATORY PRESSURE; PRIORITY JOURNAL; PRONE POSITION; PROPHYLAXIS; QUALITY OF LIFE; TIDAL VOLUME; VENO VENOUS EXTRACORPOREAL MEMBRANE OXYGENATION; ADVERSE EVENT; ARTIFICIAL VENTILATION; COMPLICATION; HIGH FREQUENCY VENTILATION; METABOLISM; PHYSIOLOGY; PROCEDURES; PSYCHOLOGY; RADIOGRAPHY; VENTILATOR INDUCED LUNG INJURY;

ANGIOPOIETIN-2; ANTIGENS, CD; BIOMARKERS; CADHERINS; CARBON DIOXIDE; GLUCOCORTICOIDS; HIGH-FREQUENCY VENTILATION; HUMANS; INTERLEUKIN-8; POSITIVE-PRESSURE RESPIRATION; QUALITY OF LIFE; RADIOGRAPHY; RESPIRATION, ARTIFICIAL; RESPIRATORY DISTRESS SYNDROME, ADULT; VASODILATOR AGENTS; VENTILATOR-INDUCED LUNG INJURY; VON WILLEBRAND FACTOR;

EID: 85062954577     PISSN: None     EISSN: 2056676X     Source Type: Journal    
DOI: 10.1038/s41572-019-0069-0     Document Type: Article

References (242)

1. Ashbaugh, D. G., Bigelow, D. B., Petty, T. L. & Levine, B. E. Acute respiratory distress in adults. Lancet 2, 319–323 (1967).
2. Bernard, G. R. et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am. J. Respir. Crit. Care Med. 149, 818–824 (1994).
3. Ranieri, V. M. et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 307, 2526–2533 (2012). This article describes the standard clinical definition for adult ARDS that was proposed in 2012 and has been widely adopted.
4. Rubenfeld, G. D. et al. Incidence and outcomes of acute lung injury. N. Engl. J. Med. 353, 1685–1693 (2005).
5. Bellani, G. et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315, 788–800 (2016).
6. Pham, T. & Rubenfeld, G. D. Fifty years of research in ARDS. The epidemiology of acute respiratory distress syndrome. A 50th birthday review. Am. J. Respir. Crit. Care Med. 195, 860–870 (2017).
7. Cortegiani, A. et al. Immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the LUNG SAFE database. Crit. Care 22, 157 (2018).
8. Moss, M., Bucher, B., Moore, F. A., Moore, E. E. & Parsons, P. E. The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 275, 50–54 (1996).
9. Calfee, C. S. et al. Active and passive cigarette smoking and acute lung injury after severe blunt trauma. Am. J. Respir. Crit. Care Med. 183, 1660–1665 (2011).
10. Calfee, C. S. et al. Cigarette smoke exposure and the acute respiratory distress syndrome. Crit. Care Med. 43, 1790–1797 (2015).
11. Ware, L. B. et al. Long-term ozone exposure increases the risk of developing the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 193, 1143–1150 (2016).
12. Reilly, J. P. et al. Low to moderate air pollutant exposure and acute respiratory distress syndrome after severe trauma. Am. J. Respir. Crit. Care Med. 199, 62–70 (2018).
13. Mangialardi, R. J. et al. Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen Sepsis Study Group. Crit. Care Med. 28, 3137–3145 (2000).
14. Moss, M. et al. Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit. Care Med. 28, 2187–2192 (2000).
15. Honiden, S. & Gong, M. N. Diabetes, insulin, and development of acute lung injury. Crit. Care Med. 37, 2455–2464 (2009).
16. Boyle, A. J. et al. Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database. Crit. Care 22, 268 (2018).
17. Toy, P. et al. Transfusion-related acute lung injury: incidence and risk factors. Blood 119, 1757–1767 (2012).
18. Robinson, B. R. et al. Application of the Berlin definition in PROMMTT patients: the impact of resuscitation on the incidence of hypoxemia. J. Trauma Acute Care Surg. 75, S61–S67 (2013).
19. Howard, B. M. et al. Differences in degree, differences in kind: characterizing lung injury in trauma. J. Trauma Acute Care Surg. 78, 735–741 (2015).
20. Erickson, S. E. et al. Racial and ethnic disparities in mortality from acute lung injury. Crit. Care Med. 37, 1–6 (2009).
21. Ryb, G. E. & Cooper, C. Race/ethnicity and acute respiratory distress syndrome: a National Trauma Data Bank study. J. Natl Med. Assoc. 102, 865–869 (2010).
22. Cochi, S. E., Kempker, J. A., Annangi, S., Kramer, M. R. & Martin, G. S. Mortality trends of acute respiratory distress syndrome in the United States from 1999 to 2013. Ann. Am. Thorac Soc. 13, 1742–1751 (2016).
23. Moss, M. & Mannino, D. M. Race and gender differences in acute respiratory distress syndrome deaths in the United States: an analysis of multiple-cause mortality data (1979–1996). Crit. Care Med. 30, 1679–1685 (2002).
24. Reilly, J. P., Christie, J. D. & Meyer, N. J. Fifty years of research in ARDS. Genomic contributions and opportunities. Am. J. Respir. Crit. Care Med. 196, 1113–1121 (2017).
25. Meyer, N. J. & Calfee, C. S. Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome. Lancet Respir. Med. 5, 512–523 (2017).
26. Reilly, J. P. et al. Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis. Intensive Care Med. 44, 1849–1858 (2018).
27. Schouten, L. R. et al. Incidence and mortality of acute respiratory distress syndrome in children: a systematic review and meta-analysis. Crit. Care Med. 44, 819–829 (2016).
28. Khemani, R. G. et al. Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study. Lancet Respir. Med. 7, 115–128 (2018).
29. Bindl, L. et al. Gender-based differences in children with sepsis and ARDS: the ESPNIC ARDS Database Group. Intensive Care Med. 29, 1770–1773 (2003).
30. Nye, S., Whitley, R. J. & Kong, M. Viral infection in the development and progression of pediatric acute respiratory distress syndrome. Front. Pediatr. 4, 128 (2016).
31. de Roulet, A. et al. Pediatric trauma-associated acute respiratory distress syndrome: incidence, risk factors, and outcomes. J. Pediatr. Surg. https://doi.org/10.1016/j.jpedsurg.2018.07.005 (2018).
32. Randolph, A. G. Management of acute lung injury and acute respiratory distress syndrome in children. Crit. Care Med. 37, 2448–2454 (2009).
33. Spicer, A. C. et al. A simple and robust bedside model for mortality risk in pediatric patients with acute respiratory distress syndrome. Pediatr. Crit. Care Med. 17, 907–916 (2016).
34. Bhattacharya, J. & Matthay, M. A. Regulation and repair of the alveolar-capillary barrier in acute lung injury. Annu. Rev. Physiol. 75, 593–615 (2013).
35. Matthay, M. A. Resolution of pulmonary edema. Thirty years of progress. Am. J. Respir. Crit. Care Med. 189, 1301–1308 (2014).
36. Matthay, M. A., Ware, L. B. & Zimmerman, G. A. The acute respiratory distress syndrome. J. Clin. Invest. 122, 2731–2740 (2012).
37. Bachofen, M. & Weibel, E. R. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin. Chest Med. 3, 35–56 (1982).
38. Fein, A. et al. The value of edema fluid protein measurement in patients with pulmonary edema. Am. J. Med. 67, 32–38 (1979).
39. Nuckton, T. J. et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N. Engl. J. Med. 346, 1281–1286 (2002).
40. Katzenstein, A. L., Bloor, C. M. & Leibow, A. A. Diffuse alveolar damage—the role of oxygen, shock, and related factors. A review. Am. J. Pathol. 85, 209–228 (1976).
41. Mendez, J. L. & Hubmayr, R. D. New insights into the pathology of acute respiratory failure. Curr. Opin. Crit. Care 11, 29–36 (2005).
42. Cardinal-Fernandez, P., Lorente, J. A., Ballen-Barragan, A. & Matute-Bello, G. Acute respiratory distress syndrome and diffuse alveolar damage. New insights on a complex relationship. Ann. Am. Thorac Soc. 14, 844–850 (2017).
43. Thille, A. W. et al. Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies. Lancet Respir. Med. 1, 395–401 (2013).
44. Thille, A. W. et al. Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy. Am. J. Respir. Crit. Care Med. 187, 761–767 (2013). This study provides 20 years of post-mortem pathology data from patients with ARDS, including a reduction in the frequency of DAD in the low tidal volume era (2000–2010).
45. Cardinal-Fernandez, P. et al. The presence of diffuse alveolar damage on open lung biopsy is associated with mortality in patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Chest 149, 1155–1164 (2016).
46. Bachofen, M. & Weibel, E. R. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am. Rev. Respir. Dis. 116, 589–615 (1977).
47. Tomashefski, J. F. Jr Pulmonary pathology of acute respiratory distress syndrome. Clin. Chest Med. 21, 435–466 (2000).
48. Albertine, K. H. et al. Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am. J. Pathol. 161, 1783–1796 (2002).
49. Wang, L. et al. Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation. Am. J. Respir. Cell Mol. Biol. 36, 497–503 (2007).
50. Bastarache, J. A., Fremont, R. D., Kropski, J. A., Bossert, F. R. & Ware, L. B. Procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L1035–L1041 (2009).
51. Cheng, K. T. et al. Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J. Clin. Invest. 127, 4124–4135 (2017).
52. Brigham, K. L., Woolverton, W. C., Blake, L. H. & Staub, N. C. Increased sheep lung vascular permeability caused by pseudomonas bacteremia. J. Clin. Invest. 54, 792–804 (1974).
53. 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. 88, 864–875 (1991).
54. Gotts, J. E., Abbott, J. & Matthay, M. A. Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy. Am. J. Physiol. Lung Cell. Mol. Physiol. 307, L395–L406 (2014).
55. Frye, M. et al. Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. J. Exp. Med. 212, 2267–2287 (2015).
56. Giannotta, M., Trani, M. & Dejana, E. VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev. Cell 26, 441–454 (2013).
57. Broermann, A. et al. Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo. J. Exp. Med. 208, 2393–2401 (2011).
58. Corada, M. et al. Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc. Natl Acad. Sci. USA 96, 9815–9820 (1999).
59. Schulte, D. et al. Stabilizing the VE-cadherin-catenin complex blocks leukocyte extravasation and vascular permeability. EMBO J. 30, 4157–4170 (2011).
60. Williams, A. E. et al. Evidence for chemokine synergy during neutrophil migration in ARDS. Thorax 72, 66–73 (2017).
61. Lefrancais, E., Mallavia, B., Zhuo, H., Calfee, C. S. & Looney, M. R. Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight 3, 98178 (2018).
62. Abdulnour, R. E. et al. Early intravascular events are associated with development of acute respiratory distress syndrome. A substudy of the LIPS-A clinical trial. Am. J. Respir. Crit. Care Med. 197, 1575–1585 (2018).
63. Short, K. R. et al. Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions. Eur. Respir. J. 47, 954–966 (2016).
64. Schlingmann, B. et al. Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions. Nat. Commun. 7, 12276 (2016).
65. Shaver, C. M. et al. Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury. JCI Insight 3, 98546 (2018).
66. Budinger, G. R. et al. Epithelial cell death is an important contributor to oxidant-mediated acute lung injury. Am. J. Respir. Crit. Care Med. 183, 1043–1054 (2011).
67. Hogner, K. et al. Macrophage-expressed IFN-beta contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. PLOS Pathog. 9, e1003188 (2013).
68. Vaughan, A. E. et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517, 621–625 (2015).
69. Imai, Y. et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289, 2104–2112 (2003).
70. Herrero, R. et al. The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk region. J. Clin. Invest. 121, 1174–1190 (2011).
71. Saffarzadeh, M. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLOS ONE 7, e32366 (2012).
72. Brauer, R. et al. Syndecan-1 attenuates lung injury during influenza infection by potentiating c-Met signaling to suppress epithelial apoptosis. Am. J. Respir. Crit. Care Med. 194, 333–344 (2016).
73. Hook, J. L. et al. Disruption of staphylococcal aggregation protects against lethal lung injury. J. Clin. Invest. 128, 1074–1086 (2018).
74. Vohwinkel, C. U. et al. Elevated CO(2) levels cause mitochondrial dysfunction and impair cell proliferation. J. Biol. Chem. 286, 37067 (2011).
75. 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. 163, 1376–1383 (2001). This study establishes the critical contribution of alveolar epithelial injury to higher mortality in ARDS by impaired alveolar oedema fluid clearance early in the clinical course of acute respiratory failure.
76. Hogan, B. L. et al. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15, 123–138 (2014).
77. Ray, S. et al. Rare SOX2(+) airway progenitor cells generate KRT5(+) cells that repopulate damaged alveolar parenchyma following influenza virus infection. Stem Cell Rep. 7, 817–825 (2016).
78. Quantius, J. et al. Influenza virus infects epithelial stem/progenitor cells of the distal lung: impact on Fgfr2b-driven epithelial repair. PLOS Pathog. 12, e1005544 (2016).
79. Xi, Y. et al. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat. Cell Biol. 19, 904–914 (2017).
80. Nabhan, A. N., Brownfield, D. G., Harbury, P. B., Krasnow, M. A. & Desai, T. J. Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 359, 1118–1123 (2018).
81. Dial, C. F., Tune, M. K., Doerschuk, C. M. & Mock, J. R. Foxp3+regulatory T cell expression of keratinocyte growth factor enhances lung epithelial proliferation. Am. J. Respir. Cell Mol. Biol. 57, 162–173 (2017).
82. Zemans, R. L. et al. Neutrophil transmigration triggers repair of the lung epithelium via beta-catenin signaling. Proc. Natl Acad. Sci. USA 108, 15990–15995 (2011).
83. Cong, X., Hubmayr, R. D., Li, C. & Zhao, X. Plasma membrane wounding and repair in pulmonary diseases. Am. J. Physiol. Lung Cell. Mol. Physiol. 312, L371–L391 (2017).
84. Schumacker, P. T. et al. Mitochondria in lung biology and pathology: more than just a powerhouse. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L962–L974 (2014).
85. Fang, X., Neyrinck, A. P., Matthay, M. A. & Lee, J. W. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J. Biol. Chem. 285, 26211–26222 (2010).
86. Koval, M. et al. Extracellular matrix influences alveolar epithelial claudin expression and barrier function. Am. J. Respir. Cell Mol. Biol. 42, 172–180 (2010).
87. Gwozdzinska, P. et al. Hypercapnia impairs ENaC cell surface stability by promoting phosphorylation, polyubiquitination and endocytosis of beta-ENaC in a human alveolar epithelial cell line. Front. Immunol. 8, 591 (2017).
88. Vadasz, I. & Sznajder, J. I. Gas exchange disturbances regulate alveolar fluid clearance during acute lung injury. Front. Immunol. 8, 757 (2017).
89. Nikolaidis, N. M. et al. Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection. Proc. Natl Acad. Sci. USA 114, E6613–E6622 (2017).
90. Albert, R. K. The role of ventilation-induced surfactant dysfunction and atelectasis in causing acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 185, 702–708 (2012).
91. Webb, H. H. & Tierney, D. F. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure. Am. Rev. Respir. Dis. 110, 556–565 (1974).
92. Parker, J. C., Townsley, M. I., Rippe, B., Taylor, A. E. & Thigpen, J. Increased microvascular permeability in dog lungs due to high peak airway pressures. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 57, 1809–1816 (1984).
93. Dreyfuss, D., Soler, P., Basset, G. & Saumon, G. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am. Rev. Respir. Dis. 137, 1159–1164 (1988).
94. Brower, R. G. et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N. Engl. J. Med. 342, 1301–1308 (2000).
95. Tremblay, L., Valenza, F., Ribeiro, S. P., Li, J. & Slutsky, A. S. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J. Clin. Invest. 99, 944–952 (1997).
96. Frank, J. A. et al. Low tidal volume reduces epithelial and endothelial injury in acid-injured rat lungs. Am. J. Respir. Crit. Care Med. 165, 242–249 (2002).
97. Thompson, B. T., Chambers, R. C. & Liu, K. D. Acute respiratory distress syndrome. N. Engl. J. Med. 377, 562–572 (2017).
98. Sprung, C. L., Rackow, E. C., Fein, I. A., Jacob, A. I. & Isikoff, S. K. The spectrum of pulmonary edema: differentiation of cardiogenic, intermediate, and noncardiogenic forms of pulmonary edema. Am. Rev. Respir. Dis. 124, 718–722 (1981).
99. Idell, S. et al. Angiotensin converting enzyme in bronchoalveolar lavage in ARDS. Chest 91, 52–56 (1987).
100. Rubin, D. B. et al. Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J. Clin. Invest. 86, 474–480 (1990).
101. Donnelly, S. C. et al. Role of selectins in development of adult respiratory distress syndrome. Lancet 344, 215–219 (1994).
102. Parsons, P. E., Matthay, M. A., Ware, L. B. & Eisner, M. D. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 288, L426–L431 (2005).
103. Meduri, G. U. et al. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 108, 1303–1314 (1995).
104. Agrawal, A. et al. Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am. J. Respir. Crit. Care Med. 187, 736–742 (2013).
105. Eisner, M. D. et al. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 58, 983–988 (2003).
106. Uchida, T. 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. 173, 1008–1015 (2006).
107. Ware, L. B. et al. Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest 137, 288–296 (2010).
108. Parsons, P. E. et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit. Care Med. 33, 1–6; discussion 230–232 (2005).
109. Calfee, C. S. et al. Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax 63, 1083–1089 (2008).
110. Ranieri, V. M. et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 282, 54–61 (1999).
111. Calfee, C. S. et al. Distinct molecular phenotypes of direct versus indirect ARDS in single-center and multicenter studies. Chest 147, 1539–1548 (2015).
112. Calfee, C. S. et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir. Med. 2, 611–620 (2014).
113. Famous, K. R. et al. Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am. J. Respir. Crit. Care Med. 195, 331–338 (2017).
114. Calfee, C. S. et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir. Med. 6, 691–698 (2018).
115. Sinha, P. et al. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 44, 1859–1869 (2018).
116. McAuley, D. F. et al. Simvastatin in the acute respiratory distress syndrome. N. Engl. J. Med. 371, 1695–1703 (2014).
117. Bos, L. D. et al. Understanding heterogeneity in biological phenotypes of ARDS by leukocyte expression profiles. Am. J. Respir. Crit. Care Med. https://doi.org/10.1164/rccm.201809-1808OC (2019).
118. Morrell, E. D. et al. Peripheral and alveolar cell transcriptional programs are distinct in acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 197, 528–532 (2018).
119. Kangelaris, K. N. et al. Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L1102–L1113 (2015).
120. Rubenfeld, G. D., Caldwell, E., Granton, J., Hudson, L. D. & Matthay, M. A. Interobserver variability in applying a radiographic definition for ARDS. Chest 116, 1347–1353 (1999).
121. Wheeler, A. P. et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N. Engl. J. Med. 354, 2213–2224 (2006).
122. Ware, L. B., Fremont, R. D., Bastarache, J. A., Calfee, C. S. & Matthay, M. A. Determining the aetiology of pulmonary oedema by the oedema fluid-to-plasma protein ratio. Eur. Respir. J. 35, 331–337 (2010).
123. Rice, T. W. et al. Vascular pedicle width in acute lung injury: correlation with intravascular pressures and ability to discriminate fluid status. Crit. Care 15, R86 (2011).
124. Riviello, E. D. et al. Hospital incidence and outcomes of the acute respiratory distress syndrome using the Kigali Modification of the Berlin Definition. Am. J. Respir. Crit. Care Med. 193, 52–59 (2016).
125. Palakshappa, J. A. & Meyer, N. J. Which patients with ARDS benefit from lung biopsy? Chest 148, 1073–1082 (2015).
126. Khemani, R. G., Smith, L. S., Zimmerman, J. J. & Erickson, S. Pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr. Crit. Care Med. 16, S23–S40 (2015).
127. De Luca, D. et al. The Montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity. Lancet Respir. Med. 5, 657–666 (2017).
128. Kao, K. C. et al. Coinfection and mortality in pneumonia-related acute respiratory distress syndrome patients with bronchoalveolar lavage: a prospective observational study. Shock 47, 615–620 (2017).
129. Hong, D. K. et al. Liquid biopsy for infectious diseases: sequencing of cell-free plasma to detect pathogen DNA in patients with invasive fungal disease. Diagn. Microbiol. Infect. Dis. 92, 210–213 (2018).
130. Fischer, N. et al. Rapid metagenomic diagnostics for suspected outbreak of severe pneumonia. Emerg. Infect. Dis. 20, 1072–1075 (2014).
131. Hasvold, J., Sjoding, M., Pohl, K., Cooke, C. & Hyzy, R. C. The role of human metapneumovirus in the critically ill adult patient. J. Crit. Care 31, 233–237 (2016).
132. Robert, D. et al. A series of five adult cases of respiratory syncytial virus-related acute respiratory distress syndrome. Anaesth. Intensive Care 36, 230–234 (2008).
133. Ferguson, N. D. et al. Clinical risk conditions for acute lung injury in the intensive care unit and hospital ward: a prospective observational study. Crit. Care 11, R96 (2007).
134. Matthay, M. A. Challenges in predicting which patients will develop ARDS. Lancet Respir. Med. 4, 847–848 (2016).
135. Levitt, J. E., Calfee, C. S., Goldstein, B. A., Vojnik, R. & Matthay, M. A. Early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation*. Crit. Care Med. 41, 1929–1937 (2013).
136. Gajic, O. et al. Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am. J. Respir. Crit. Care Med. 183, 462–470 (2011).
137. Kor, D. J. et al. Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department: the LIPS-A randomized clinical trial. JAMA 315, 2406–2414 (2016).
138. Levitt, J. E., Bedi, H., Calfee, C. S., Gould, M. K. & Matthay, M. A. Identification of early acute lung injury at initial evaluation in an acute care setting prior to the onset of respiratory failure. Chest 135, 936–943 (2009).
139. Levitt, J. E. & Matthay, M. A. Clinical review: early treatment of acute lung injury—paradigm shift toward prevention and treatment prior to respiratory failure. Crit. Care 16, 223 (2012).
140. Afshar, M. et al. Injury characteristics and von Willebrand Factor for the prediction of acute respiratory distress syndrome in patients with burn injury: development and internal validation. Ann. Surg. https://doi.org/10.1097/SLA.0000000000002795 (2018).
141. Liu, X. et al. Plasma sRAGE enables prediction of acute lung injury after cardiac surgery in children. Crit. Care 16, R91 (2012).
142. Jabaudon, M. et al. Receptor for advanced glycation end-products and ARDS prediction: a multicentre observational study. Sci. Rep. 8, 2603 (2018).
143. Luce, J. M. et al. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am. Rev. Respir. Dis. 138, 62–68 (1988).
144. Weigelt, J. A., Norcross, J. F., Borman, K. R. & Snyder, W. H. 3rd. Early steroid therapy for respiratory failure. Arch. Surg. 120, 536–540 (1985).
145. Festic, E. et al. Randomized clinical trial of a combination of an inhaled corticosteroid and beta agonist in patients at risk of developing the acute respiratory distress syndrome. Crit. Care Med. 45, 798–805 (2017).
146. Determann, R. M. et al. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit. Care 14, R1 (2010).
147. Neto, A. S. & Jaber, S. What’s new in mechanical ventilation in patients without ARDS: lessons from the ARDS literature. Intensive Care Med. 42, 787–789 (2016).
148. Writing Group for the, P. I. et al. Effect of a low versus intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: a randomized clinical trial. JAMA 320, 1872–1880 (2018).
149. Li, G. et al. Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am. J. Respir. Crit. Care Med. 183, 59–66 (2011).
150. Ahmed, A. H. et al. The role of potentially preventable hospital exposures in the development of acute respiratory distress syndrome: a population-based study. Crit. Care Med. 42, 31–39 (2014).
151. 2 was OpenSPILessThanSPI200mmHg) to reduce overall mortality, providing evidence that patients at high risk of developing ARDS (by Berlin criteria) could be identified early in the their clinical course and enrolled in a randomized clinical trial to test new therapies.
152. Azoulay, E. et al. Effect of high-flow nasal oxygen versus standard oxygen on 28-day mortality in immunocompromised patients with acute respiratory failure: the HIGH randomized clinical trial. JAMA 320, 2099–2107 (2018).
153. Drusano, G. L. What are the properties that make an antibiotic acceptable for therapy of community-acquired pneumonia? J. Antimicrob. Chemother. 66 (Suppl. 3), 61–67 (2011).
154. Roberts, J. A. et al. Continuous versus intermittent beta-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am. J. Respir. Crit. Care Med. 194, 681–691 (2016).
155. Ross, J. T., Matthay, M. A. & Harris, H. W. Secondary peritonitis: principles of diagnosis and intervention. BMJ 361, k1407 (2018).
156. Gattinoni, L. et al. Lung recruitment in patients with the acute respiratory distress syndrome. N. Engl. J. Med. 354, 1775–1786 (2006).
157. Gattinoni, L. & Pesenti, A. The concept of “baby lung”. Intensive Care Med. 31, 776–784 (2005).
158. Beitler, J. R. et al. Volume delivered during recruitment maneuver predicts lung stress in acute respiratory distress syndrome. Crit. Care Med. 44, 91–99 (2016).
159. Amato, M. B. et al. Driving pressure and survival in the acute respiratory distress syndrome. N. Engl. J. Med. 372, 747–755 (2015).
160. Talmor, D. et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N. Engl. J. Med. 359, 2095–2104 (2008).
161. Beitler, J. R. et al. EPVent-2 Study Group. Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure-guided strategy versus an empiric high PEEP-FiO2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA (in the press).
162. Brower, R. G. et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N. Engl. J. Med. 351, 327–336 (2004).
163. Meade, M. O. et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299, 637–645 (2008).
164. Mercat, A. et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299, 646–655 (2008).
165. Briel, M. et al. Higher versus lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 303, 865–873 (2010).
166. Cavalcanti, A. B. et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA 318, 1335–1345 (2017).
167. Sahetya, S. K. & Brower, R. G. Lung recruitment and titrated PEEP in moderate to severe ARDS: is the door closing on the open lung? JAMA 318, 1327–1329 (2017).
168. Goligher, E. C. et al. Lung recruitment maneuvers for adult patients with acute respiratory distress syndrome. A systematic review and meta-analysis. Ann. Am. Thorac Soc. 14, S304–S311 (2017).
169. Gattinoni, L., Taccone, P., Carlesso, E. & Marini, J. J. Prone position in acute respiratory distress syndrome. Rationale, indications, and limits. Am. J. Respir. Crit. Care Med. 188, 1286–1293 (2013).
170. 2 OpenSPILessThanSPI150mmHg) reduced mortality compared with the standard practice of ventilating patients with ARDS in the supine position.
171. Beitler, J. R. et al. Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis. Intensive Care Med. 40, 332–341 (2014).
172. Fan, E. et al. An Official American Thoracic Society/ European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 195, 1253–1263 (2017).
173. Brochard, L., Slutsky, A. & Pesenti, A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am. J. Respir. Crit. Care Med. 195, 438–442 (2017).
174. Beitler, J. R. et al. Quantifying unintended exposure to high tidal volumes from breath stacking dyssynchrony in ARDS: the BREATHE criteria. Intensive Care Med. 42, 1427–1436 (2016).
175. Papazian, L. et al. Neuromuscular blockers in early acute respiratory distress syndrome. N. Engl. J. Med. 363, 1107–1116 (2010).
176. Huang, D. T. et al. Design and rationale of the reevaluation of systemic early neuromuscular blockade trial for acute respiratory distress syndrome. Ann. Am. Thorac Soc. 14, 124–133 (2017).
177. Ely, E. W. et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 291, 1753–1762 (2004).
178. Schweickert, W. D. et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 373, 1874–1882 (2009).
179. Antonelli, M. et al. A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N. Engl. J. Med. 339, 429–435 (1998).
180. Bellani, G. et al. Noninvasive ventilation of patients with acute respiratory distress syndrome. Insights from the LUNG SAFE Study. Am. J. Respir. Crit. Care Med. 195, 67–77 (2017).
181. Patel, B. K., Wolfe, K. S., Pohlman, A. S., Hall, J. B. & Kress, J. P. Effect of noninvasive ventilation delivered by helmet versus face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA 315, 2435–2441 (2016).
182. Beitler, J. R., Owens, R. L. & Malhotra, A. Unmasking a role for noninvasive ventilation in early acute respiratory distress syndrome. JAMA 315, 2401–2403 (2016).
183. Matthay, M. A. Saving lives with high-flow nasal oxygen. N. Engl. J. Med. 372, 2225–2226 (2015).
184. Calfee, C. S. & Matthay, M. A. Nonventilatory treatments for acute lung injury and ARDS. Chest 131, 913–920 (2007).
185. Wiedemann, H. P. et al. Comparison of two fluid-management strategies in acute lung injury. N. Engl. J. Med. 354, 2564–2575 (2006). This clinical trial demonstrates a significant increase in ventilator-free days in patients with ARDS randomly assigned to a fluid-conservative treatment strategy compared with a liberal fluid strategy.
186. Mikkelsen, M. E. et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am. J. Respir. Crit. Care Med. 185, 1307–1315 (2012).
187. Zinter, M. S. et al. Positive cumulative fluid balance is associated with mortality in pediatric acute respiratory distress syndrome in the setting of acute kidney injury. Pediatr. Crit. Care Med. https://doi.org/10.1097/PCC.0000000000001845 (2019).
188. Fielding-Singh, V., Matthay, M. A. & Calfee, C. S. Beyond low tidal volume ventilation: treatment adjuncts for severe respiratory failure in acute respiratory distress syndrome. Crit. Care Med. 46, 1820–1831 (2018).
189. Combes, A. et al. Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am. J. Respir. Crit. Care Med. 190, 488–496 (2014).
190. Davies, A. et al. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA 302, 1888–1895 (2009).
191. Combes, A. et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N. Engl. J. Med. 378, 1965–1975 (2018).
192. Mi, M. Y., Matthay, M. A. & Morris, A. H. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N. Engl. J. Med. 379, 884–887 (2018).
193. Fanelli, V. et al. Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome. Crit. Care 20, 36 (2016).
194. Terragni, P. P. et al. Tidal volume lower than 6ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology 111, 826–835 (2009).
195. 2 removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Med. 39, 847–856 (2013).
196. Meduri, G. U. et al. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. 42, 829–840 (2016).
197. Steinberg, K. P. et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N. Engl. J. Med. 354, 1671–1684 (2006).
198. Ewald, H. et al. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection. Cochrane Database Syst. Rev. 4, CD006150 (2015).
199. Griffiths, M. J. & Evans, T. W. Inhaled nitric oxide therapy in adults. N. Engl. J. Med. 353, 2683–2695 (2005).
200. Taylor, R. W. et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 291, 1603–1609 (2004).
201. Repesse, X., Charron, C. & Vieillard-Baron, A. Acute cor pulmonale in ARDS: rationale for protecting the right ventricle. Chest 147, 259–265 (2015).
202. Young, D. et al. High-frequency oscillation for acute respiratory distress syndrome. N. Engl. J. Med. 368, 806–813 (2013).
203. Ferguson, N. D. et al. High-frequency oscillation in early acute respiratory distress syndrome. N. Engl. J. Med. 368, 795–805 (2013).
204. Bateman, S. T. et al. Early high-frequency oscillatory ventilation in pediatric acute respiratory failure. A propensity score analysis. Am. J. Respir. Crit. Care Med. 193, 495–503 (2016).
205. Putensen, C. et al. Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am. J. Respir. Crit. Care Med. 164, 43–49 (2001).
206. Putensen, C., Mutz, N. J., Putensen-Himmer, G. & Zinserling, J. Spontaneous breathing during ventilatory support improves ventilation-perfusion distributions in patients with acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 159, 1241–1248 (1999).
207. Lalgudi Ganesan, S., Jayashree, M., Singhi, S. C. & Bansal, A. Airway pressure release ventilation in pediatric acute respiratory distress syndrome: a randomized controlled trial. Am. J. Respir. Crit. Care Med. 198, 1199–1207 (2018).
208. Matthay, M. A., McAuley, D. F. & Ware, L. B. Clinical trials in acute respiratory distress syndrome: challenges and opportunities. Lancet Respir. Med. 5, 524–534 (2017).
209. Downs, J. B. & Olsen, G. N. Pulmonary function following adult respiratory distress syndrome. Chest 65, 92–93 (1974).
210. Lakshminarayan, S., Stanford, R. E. & Petty, T. L. Prognosis after recovery from adult respiratory distress syndrome. Am. Rev. Respir. Dis. 113, 7–16 (1976).
211. Klein, J. J., van Haeringen, J. R., Sluiter, H. J., Holloway, R. & Peset, R. Pulmonary function after recovery from the adult respiratory distress syndrome. Chest 69, 350–355 (1976).
212. Weinert, C. R., Gross, C. R., Kangas, J. R., Bury, C. L. & Marinelli, W. A. Health-related quality of life after acute lung injury. Am. J. Respir. Crit. Care Med. 156, 1120–1128 (1997).
213. Schelling, G. et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit. Care Med. 26, 651–659 (1998).
214. Davidson, T. A., Caldwell, E. S., Curtis, J. R., Hudson, L. D. & Steinberg, K. P. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients. JAMA 281, 354–360 (1999).
215. McHugh, L. G. et al. Recovery of function in survivors of the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 150, 90–94 (1994).
216. Angus, D. C. et al. Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 163, 1389–1394 (2001).
217. Herridge, M. S. et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N. Engl. J. Med. 348, 683–693 (2003). This study reports functional impairments in survivors of ARDS at 3 months, 6 months and 12 months, including muscle wasting and weakness, thereby establishing a new field of ARDS research focusing on long-term clinical outcomes and QOL.
218. Herridge, M. S. et al. Functional disability 5 years after acute respiratory distress syndrome. N. Engl. J. Med. 364, 1293–1304 (2011).
219. Fan, E. et al. Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. Crit. Care Med. 42, 849–859 (2014).
220. Needham, D. M. et al. Risk factors for physical impairment after acute lung injury in a national, multicenter study. Am. J. Respir. Crit. Care Med. 189, 1214–1224 (2014).
221. Pfoh, E. R. et al. Physical declines occurring after hospital discharge in ARDS survivors: a 5-year longitudinal study. Intensive Care Med. 42, 1557–1566 (2016).
222. Hopkins, R. O. et al. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 160, 50–56 (1999).
223. Hopkins, R. O. et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 171, 340–347 (2005).
224. Dowdy, D. W. et al. Intensive care unit hypoglycemia predicts depression during early recovery from acute lung injury. Crit. Care Med. 36, 2726–2733 (2008).
225. Pandharipande, P. P. et al. Long-term cognitive impairment after critical illness. N. Engl. J. Med. 369, 1306–1316 (2013).
226. Ferrante, L. E. et al. Functional trajectories among older persons before and after critical illness. JAMA Intern. Med. 175, 523–529 (2015).
227. Kress, J. P. & Hall, J. B. ICU-acquired weakness and recovery from critical illness. N. Engl. J. Med. 371, 287–288 (2014).
228. Levine, S. et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N. Engl. J. Med. 358, 1327–1335 (2008).
229. Puthucheary, Z. A. et al. Acute skeletal muscle wasting in critical illness. JAMA 310, 1591–1600 (2013).
230. Dos Santos, C. et al. Mechanisms of chronic muscle wasting and dysfunction after an intensive care unit stay. A pilot study. Am. J. Respir. Crit. Care Med. 194, 821–830 (2016).
231. Warren, M. A. et al. Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS. Thorax 73, 840–846 (2018).
232. Sinha, P. et al. Physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 199, 333–341 (2019).
233. Langelier, C. et al. Integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults. Proc. Natl Acad. Sci. USA 115, E12353–E12362 (2018).
234. Boyle, A. J. et al. Extracorporeal carbon dioxide removal for lowering the risk of mechanical ventilation: research questions and clinical potential for the future. Lancet Respir. Med. 6, 874–884 (2018).
235. Laffey, J. G. & Matthay, M. A. Fifty years of research in ARDS. Cell-based therapy for acute respiratory distress syndrome. Biology and potential therapeutic value. Am. J. Respir. Crit. Care Med. 196, 266–273 (2017).
236. Matthay, M. A. et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir. Med. 7, P154–P162 (2018).
237. Azoulay, E. et al. Recovery after critical illness: putting the puzzle together-a consensus of 29. Crit. Care 21, 296 (2017).
238. Jansing, N. L. et al. Unbiased quantitation of alveolar type II to alveolar type I cell transdifferentiation during repair after lung injury in mice. Am. J. Respir. Cell Mol. Biol. 57, 519–526 (2017).
239. Zacharias, W. J. et al. Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555, 251–255 (2018).
240. Liu, Y. et al. FoxM1 mediates the progenitor function of type II epithelial cells in repairing alveolar injury induced by Pseudomonas aeruginosa. J. Exp. Med. 208, 1473–1484 (2011).
241. Liang, J. et al. Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nat. Med. 22, 1285–1293 (2016).
242. Rafii, S. et al. Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. Nat. Cell Biol. 17, 123–136 (2015).