ARDS Subphenotypes: Understanding a Heterogeneous Syndrome

  • J. G. Wilson
  • C. S. CalfeeEmail author
Part of the Annual Update in Intensive Care and Emergency Medicine book series (AUICEM)


Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome, presenting challenges to both frontline clinicians and researchers testing novel therapies. Identifying more homogeneous subgroups within the broader ARDS population could allow for more efficient testing of interventions in targeted cohorts of patients, as well as better-tailored therapy at the bedside. Over the past decade, various physiologic, clinical, and biologic characteristics have been used to identify ARDS patients at highest risk for poor clinical outcomes. Using those markers to select patients for enrollment in clinical trials is called prognostic enrichment. Similarly, some studies have shown that different subgroups of ARDS patients respond differently to a specific therapy. Selecting patients for trials based on a higher likelihood of responding to a therapy is called predictive enrichment. For example, a mix of clinical and biologic markers has been used to identify two distinct subphenotypes of ARDS—termed hypoinflammatory and hyperinflammatory—that not only are present in multiple different clinical trial populations, but have divergent clinical outcomes and may respond differently to several experimental therapies. The future of the field will involve developing more pragmatic methods to stratify ARDS patients, harnessing new ‘omics technology to improve subphenotyping, and using subphenotypes prospectively to guide enrollment in clinical trials of focused therapies for ARDS. Advances in our ability to discern subphenotypes within the general ARDS population could help us move from a one-size-fits-all approach to ARDS management to therapy tailored to the unique clinical and biologic profile of each ARDS patient.


Subphenotypes Heterogeneity Prognostic enrichment Predictive enrichment 


  1. 1.
    ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526–33.Google Scholar
  2. 2.
    Bellani G, Laffey JG, Pham T, et al., LUNG SAFE Investigators, ESICM Trials Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315:788–800.CrossRefGoogle Scholar
  3. 3.
    Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med. 2017;377:562–72.PubMedCrossRefGoogle Scholar
  4. 4.
    FDA. Draft guidance: enrichment strategies for clinical trials to support approval of human drugs and biological products. Available from Accessed 27 Aug 2019.
  5. 5.
    Papazian L, Forel JM, Gacouin A, et al., ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Guerin C, Reignier J, Richard JC, et al., PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–68.PubMedCrossRefGoogle Scholar
  7. 7.
    Moss M, Huang DT, Brower RG, et al. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med. 2019;380:1997–2008.PubMedCrossRefGoogle Scholar
  8. 8.
    Nuckton TJ, Alonso JA, Kallet RH, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med. 2002;346:1281–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Sinha P, Calfee CS, Beitler JR, et al. Physiological analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2019;199:333–41.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747–55.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Calfee CS, Eisner MD, Ware LB, et al., Acute Respiratory Distress Syndrome Network, National Heart, Lung, and Blood Institute. Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders. Crit Care Med. 2007;35:2243–50.Google Scholar
  12. 12.
    Luo L, Shaver CM, Zhao Z, et al. Clinical predictors of hospital mortality differ between direct and indirect ARDS. Chest. 2017;151:755–63.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Liu KD, Glidden DV, Eisner MD, et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med. 2007;35(12):2755–61.PubMedPubMedCentralGoogle Scholar
  14. 14.
    McNicholas BA, Rezoagli E, Pham T, et al. Impact of early acute kidney injury on management and outcome in patients with acute respiratory distress syndrome: a secondary analysis of a multicenter observational study. Crit Care Med. 2019;47:1216–25.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Liao KM, Chen CW, Hsiue TR, Lin WC. Timing of acute respiratory distress syndrome onset is related to patient outcome. J Formos Med Assoc. 2009;108:694–703.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Zhang R, Wang Z, Tejera P, et al. Late-onset moderate to severe acute respiratory distress syndrome is associated with shorter survival and higher mortality: a two-stage association study. Intensive Care Med. 2017;43:399–407.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Schenck EJ, Oromendia C, Torres LK, Berlin DA, Choi AMK, Siempos II. Rapidly improving ARDS in therapeutic randomized controlled trials. Chest. 2019;155:474–82.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Mrozek S, Jabaudon M, Jaber S, et al., Azurea Network. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–3.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374:1351–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Warren MA, Zhao Z, Koyama T, et al. Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS. Thorax. 2018;73:840–6.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Constantin JM, Jabaudon M, Lefrant JY, et al. Personalised mechanical ventilation tailored to lung morphology versus low positive end-expiratory pressure for patients with acute respiratory distress syndrome in France (the LIVE study): a multicentre, single-blind, randomised controlled trial. Lancet Respir Med. 2019;7:870–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Thille AW, Richard JC, Maggiore SM, et al. Alveolar recruitment in pulmonary and extrapulmonary acute respiratory distress syndrome: comparison using pressure-volume curve or static compliance. Anesthesiology. 2007;106:212–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Walter JM, Wilson J, Ware LB. Biomarkers in acute respiratory distress syndrome: from pathobiology to improving patient care. Expert Rev Respir Med. 2014;8:573–86.PubMedCrossRefGoogle Scholar
  25. 25.
    Jabaudon M, Blondonnet R, Pereira B, et al. Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data. Intensive Care Med. 2018;44:1388–99.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Rogers AJ, Guan J, Trtchounian A, et al. Association of elevated plasma interleukin-18 level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome. Crit Care Med. 2019;47:1089–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Calfee CS, Delucchi K, Parsons PE, et al., NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2:611–20.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Delucchi K, Famous KR, Ware LB, et al. Stability of ARDS subphenotypes over time in two randomised controlled trials. Thorax. 2018;73:439–45.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Famous KR, Delucchi K, Ware LB, et al., ARDS Network. Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med. 2017;195:331–8.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Bos LD, Schouten LR, van Vught LA, et al., MARS Consortium. Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis. Thorax. 2017;72:876–83.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Meyer NJ, Feng R, Li M, et al. IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. Am J Respir Crit Care Med. 2013;187:950–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Zhu Z, Liang L, Zhang R, et al. Whole blood microRNA markers are associated with acute respiratory distress syndrome. Intensive Care Med Exp. 2017;5:38–50.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Rogers AJ, Contrepois K, Wu M, et al. Profiling of ARDS pulmonary edema fluid identifies a metabolically distinct subset. Am J Physiol Lung Cell Mol Physiol. 2017;312:L703–9.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Sinha P, Delucchi KL, McAuley DF, O’Kane CM, Matthay MA, Calfee CS. Development and validation of parsimonious algorithms to classify ARDS phenotypes. Lancet Respir Med. 2020. [Epub ahead of print].
  35. 35.
    Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX. Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design. Am J Respir Crit Care Med. 2016;194:147–55.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Calfee CS, Janz DR, Bernard GR, et al. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest. 2015;147:1539–48.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gattinoni L, Pelosi P, Suter PM, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med. 1998;158:3–11.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Riva DR, Oliveira MB, Rzezinski AF, et al. Recruitment maneuver in pulmonary and extrapulmonary experimental acute lung injury. Crit Care Med. 2008;36:1900–8.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Leite-Junior JH, Garcia CS, Souza-Fernandes AB, et al. Methylprednisolone improves lung mechanics and reduces the inflammatory response in pulmonary but not in extrapulmonary mild acute lung injury in mice. Crit Care Med. 2008;36:2621–8.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Calfee CS, Delucchi KL, Sinha P, et al., Irish Critical Care Trials Group. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. 2018;6:691–8.Google Scholar
  41. 41.
    Sinha P, Delucchi KL, Thompson BT, et al., NHLBI ARDS Network. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 2018;44:1859–69.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Bos LDJ, Scicluna BP, Ong DSY, et al., MARS Consortium. Understanding heterogeneity in biological phenotypes of acute respiratory distress syndrome by leukocyte expression profiles. Am J Respir Crit Care Med. 2019;200:42–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Meyer NJ, Reilly JP, Anderson BJ, et al. Mortality benefit of recombinant human interleukin-1 receptor antagonist for sepsis varies by initial interleukin-1 receptor antagonist plasma concentration. Crit Care Med. 2018;46:21–8.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Silva IP, Long GV. Systemic therapy in advanced melanoma: integrating targeted therapy and immunotherapy into clinical practice. Curr Opin Oncol. 2017;29:484–92.PubMedCrossRefGoogle Scholar
  45. 45.
    FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an antiinterleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128–41.PubMedCrossRefGoogle Scholar
  46. 46.
    Wong HR, Atkinson SJ, Cvijanovich NZ, et al. Combining prognostic and predictive enrichment strategies to identify children with septic shock responsive to corticosteroids. Crit Care Med. 2016;44:e1000–3.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Gårdlund B, Dmitrieva NO, Pieper CF, Finfer S, Marshall JC, Thompson BT. Six subphenotypes in septic shock: latent class analysis of the PROWESS shock study. J Crit Care. 2018;47:70–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321:2003–17.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al. Systemic inflammatory response and potential prognostic implications after out-of-hospital cardiac arrest: a substudy of the Target Temperature Management Trial. Crit Care Med. 2015;43:1223–32.PubMedCrossRefGoogle Scholar
  50. 50.
    Anderson RJ, Jinadasa SP, Hsu L, et al. Shock subtypes by left ventricular ejection fraction following out-of-hospital cardiac arrest. Crit Care. 2018;22:162.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Emergency MedicineStanford UniversityPalo AltoUSA
  2. 2.Department of MedicineUniversity of California, San FranciscoSan FranciscoUSA
  3. 3.Department of AnesthesiaUniversity of California, San FranciscoSan FranciscoUSA

Personalised recommendations