Precision Medicine and Heterogeneity of Treatment Effect in Therapies for ARDS

ARDS is a clinically heterogeneous syndrome, rather than a distinct disease. This heterogeneity at least partially explains the difficulty in studying treatments for these patients and contributes to the numerous trials of therapies for the syndrome that have not shown benefit. Recent studies have identified different subphenotypes within the heterogeneous patient population. These different subphenotypes likely have variable clinical responses to specific therapies, a concept known as heterogeneity of treatment effect. Recognizing different subphenotypes and heterogeneity of treatment effect has important implications for the clinical management of patients with ARDS. This review presents studies that have identified different subphenotypes and discusses how they can modify the effects of therapies evaluated in trials that are commonly considered to have shown no overall benefit in patients with ARDS. ARDS is a clinically heterogeneous syndrome, rather than a distinct disease. This heterogeneity at least partially explains the difficulty in studying treatments for these patients and contributes to the numerous trials of therapies for the syndrome that have not shown benefit. Recent studies have identified different subphenotypes within the heterogeneous patient population. These different subphenotypes likely have variable clinical responses to specific therapies, a concept known as heterogeneity of treatment effect. Recognizing different subphenotypes and heterogeneity of treatment effect has important implications for the clinical management of patients with ARDS. This review presents studies that have identified different subphenotypes and discusses how they can modify the effects of therapies evaluated in trials that are commonly considered to have shown no overall benefit in patients with ARDS. ARDS is a severe, life-threatening inflammatory condition of the lung that can be caused by a wide variety of pulmonary and nonpulmonary insults, including both infectious and noninfectious causes.1Thompson B.T. Chambers R.C. Liu K.D. Acute respiratory distress syndrome.N Engl J Med. 2017; 377: 562-572Crossref PubMed Scopus (1033) Google Scholar The Berlin Definition for ARDS requires the acute onset of hypoxemia, defined as a ratio of Pao2 to Fio2 ≤ 300 mm Hg with bilateral airspace disease on chest imaging not primarily due to hydrostatic edema.2Ranieri V.M. Rubenfeld G.D. Thompson B.T. et al.Acute respiratory distress syndrome: the Berlin definition.JAMA. 2012; 307: 2526-2533Crossref PubMed Scopus (7793) Google Scholar The multiple potential causes and the broad definition for ARDS lend to the clinical heterogeneity of this syndrome and contribute to the difficulty in effectively studying treatments for these patients.3Villar J. Kacmarek R.M. Guérin C. Clinical trials in patients with the acute respiratory distress syndrome: burn after reading.Intensive Care Med. 2014; 40: 900-902Crossref PubMed Scopus (27) Google Scholar,4Rubenfeld G.D. Confronting the frustrations of negative clinical trials in acute respiratory distress syndrome.Ann Am Thorac Soc. 2015; 12: S58-S63Crossref PubMed Scopus (37) Google Scholar Table 15Brower R.G. Matthay M.A. Morris A. 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. 2000; 342: 1301-1308Crossref PubMed Scopus (10801) Google Scholar, 6Petrucci N. De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome.Cochrane Database Syst Rev. 2013; : CD003844PubMed Google Scholar, 7Eisner M.D. Thompson T. Hudson L.D. et al.Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.Am J Respir Crit Care Med. 2001; 164: 231-236Crossref PubMed Scopus (273) Google Scholar, 8Brower R.G. Lanken P.N. MacIntyre N. et al.Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.N Engl J Med. 2004; 351: 327-336Crossref PubMed Scopus (2015) Google Scholar, 9Mercat A. Richard J.C. Vielle B. et al.Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.JAMA. 2008; 299: 646-655Crossref PubMed Scopus (1094) Google Scholar, 10Meade M.O. Cook D.J. Guyatt G.H. 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. 2008; 299: 637-645Crossref PubMed Scopus (1156) Google Scholar, 11Cavalcanti A.B. Suzumura É. Laranjeira L.N. 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. 2017; 318: 1335-1345Crossref PubMed Scopus (669) Google Scholar, 12Briel M. Meade M. Mercat A. et al.Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis.JAMA. 2010; 303: 865-873Crossref PubMed Scopus (1157) Google Scholar, 13Goligher E.C. Kavanagh B.P. Rubenfeld G.D. et al.Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials.Am J Respir Crit Care Med. 2014; 190: 70-76Crossref PubMed Scopus (152) Google Scholar, 14Guo L. Xie J. Huang Y. et al.Higher PEEP improves outcomes in ARDS patients with clinically objective positive oxygenation response to PEEP: a systematic review and meta-analysis.BMC Anesthesiol. 2018; 18: 172Crossref PubMed Scopus (39) Google Scholar, 15Yehya N. Hodgson C.L. Amato M.B.P. et al.Response to ventilator adjustments for predicting acute respiratory distress syndrome mortality. Driving pressure versus oxygenation.Ann Am Thorac Soc. 2021; 18: 857-864Crossref PubMed Scopus (21) Google Scholar, 16Calfee C.S. Delucchi K. Parsons P.E. et al.Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials.Lancet Respir Med. 2014; 2: 611-620Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar, 17Zampieri F.G. Costa E.L. Iwashyna T.J. et al.Heterogeneous effects of alveolar recruitment in acute respiratory distress syndrome: a machine learning reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial.Br J Anaesth. 2019; 123: 88-95Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 18Ferguson N.D. Cook D.J. Guyatt G.H. et al.High-frequency oscillation in early acute respiratory distress syndrome.N Engl J Med. 2013; 368: 795-805Crossref PubMed Scopus (679) Google Scholar, 19Young D. Lamb S.E. Shah S. et al.High-frequency oscillation for acute respiratory distress syndrome.N Engl J Med. 2013; 368: 806-813Crossref PubMed Scopus (499) Google Scholar, 20Meade M.O. Young D. Hanna S. et al.Severity of hypoxemia and effect of high-frequency oscillatory ventilation in acute respiratory distress syndrome.Am J Respir Crit Care Med. 2017; 196: 727-733Crossref PubMed Scopus (67) Google Scholar, 21Guérin C. Reignier J. Richard J.C. et al.Prone positioning in severe acute respiratory distress syndrome.N Engl J Med. 2013; 368: 2159-2168Crossref PubMed Scopus (2746) Google Scholar, 22Papazian L. Forel J.M. Gacouin A. et al.Neuromuscular blockers in early acute respiratory distress syndrome.N Engl J Med. 2010; 363: 1107-1116Crossref PubMed Scopus (1842) Google Scholar, 23Moss M. Huang D.T. Brower R.G. et al.Early neuromuscular blockade in the acute respiratory distress syndrome.N Engl J Med. 2019; 380: 1997-2008Crossref PubMed Scopus (553) Google Scholar, 24Wiedemann H.P. Wheeler A.P. Bernard G.R. et al.Comparison of two fluid-management strategies in acute lung injury.N Engl J Med. 2006; 354: 2564-2575Crossref PubMed Scopus (2864) Google Scholar, 25Famous K.R. Delucchi K. Ware L.B. et al.Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy.Am J Respir Crit Care Med. 2017; 195: 331-338Crossref PubMed Scopus (516) Google Scholar, 26McAuley D.F. Laffey J.G. O'Kane C.M. et al.Simvastatin in the acute respiratory distress syndrome.N Engl J Med. 2014; 371: 1695-1703Crossref PubMed Scopus (357) Google Scholar, 27Truwit J.D. Bernard G.R. Steingrub J. et al.Rosuvastatin for sepsis-associated acute respiratory distress syndrome.N Engl J Med. 2014; 370: 2191-2200Crossref PubMed Scopus (416) Google Scholar, 28Calfee C.S. Delucchi K.L. Sinha P. et al.Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial.Lancet Respir Med. 2018; 6: 691-698Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar, 29Santhakumaran S. Gordon A. Prevost A.T. O'Kane C. McAuley D.F. Shankar-Hari M. Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials.Crit Care. 2019; 23: 156Crossref PubMed Scopus (23) Google Scholar, 30Mansur A. Steinau M. Popov A.F. et al.Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study.BMC Med. 2015; 13: 128Crossref PubMed Scopus (58) Google Scholar, 31Sinha P. Delucchi K.L. Thompson B.T. 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. 2018; 44: 1859-1869Crossref PubMed Scopus (205) Google Scholar presents a summary of randomized controlled trials of therapies for ARDS; although there are a few notable exceptions, the ARDS literature is rife with randomized trials that have not shown a mortality benefit.32Matthay M.A. McAuley D.F. Ware L.B. Clinical trials in acute respiratory distress syndrome: challenges and opportunities.Lancet Respir Med. 2017; 5: 524-534Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar One factor that may contribute to these many indeterminate results is heterogeneity of treatment effect (HTE).Table 1Summary of Randomized Controlled Trials of Therapies for ARDS and Corresponding Heterogeneity of Treatment EffectsTherapyNoteworthy Trial FindingsHeterogeneity of Treatment EffectLung-protective ventilationARMA: Lower mortality with LPV5Brower R.G. Matthay M.A. Morris A. 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. 2000; 342: 1301-1308Crossref PubMed Scopus (10801) Google ScholarNone identified6Petrucci N. De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome.Cochrane Database Syst Rev. 2013; : CD003844PubMed Google Scholar,7Eisner M.D. Thompson T. Hudson L.D. et al.Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.Am J Respir Crit Care Med. 2001; 164: 231-236Crossref PubMed Scopus (273) Google ScholarOpen lung ventilationALVEOLI: No difference in hospital mortality8Brower R.G. Lanken P.N. MacIntyre N. et al.Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.N Engl J Med. 2004; 351: 327-336Crossref PubMed Scopus (2015) Google ScholarExPress: No difference in 28-d mortality9Mercat A. Richard J.C. Vielle B. et al.Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.JAMA. 2008; 299: 646-655Crossref PubMed Scopus (1094) Google ScholarLOVS: No difference in 28-d hospital mortality10Meade M.O. Cook D.J. Guyatt G.H. 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. 2008; 299: 637-645Crossref PubMed Scopus (1156) Google ScholarART: Higher 28-d mortality with open lung ventilation11Cavalcanti A.B. Suzumura É. Laranjeira L.N. 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. 2017; 318: 1335-1345Crossref PubMed Scopus (669) Google ScholarOpen lung ventilation associated with lower mortality in:Pao2/Fio2 ratio ≤ 200 mm Hg12Briel M. Meade M. Mercat A. et al.Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis.JAMA. 2010; 303: 865-873Crossref PubMed Scopus (1157) Google ScholarPEEP responders with improved Pao2/Fio2 ratio13Goligher E.C. Kavanagh B.P. Rubenfeld G.D. et al.Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials.Am J Respir Crit Care Med. 2014; 190: 70-76Crossref PubMed Scopus (152) Google Scholar,14Guo L. Xie J. Huang Y. et al.Higher PEEP improves outcomes in ARDS patients with clinically objective positive oxygenation response to PEEP: a systematic review and meta-analysis.BMC Anesthesiol. 2018; 18: 172Crossref PubMed Scopus (39) Google ScholarPEEP responders with lower driving pressure15Yehya N. Hodgson C.L. Amato M.B.P. et al.Response to ventilator adjustments for predicting acute respiratory distress syndrome mortality. Driving pressure versus oxygenation.Ann Am Thorac Soc. 2021; 18: 857-864Crossref PubMed Scopus (21) Google ScholarHyperinflammatory phenotype16Calfee C.S. Delucchi K. Parsons P.E. et al.Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials.Lancet Respir Med. 2014; 2: 611-620Abstract Full Text Full Text PDF PubMed Scopus (912) Google ScholarOpen lung ventilation associated with higher mortality in patients with pneumonia requiring vasopressors17Zampieri F.G. Costa E.L. Iwashyna T.J. et al.Heterogeneous effects of alveolar recruitment in acute respiratory distress syndrome: a machine learning reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial.Br J Anaesth. 2019; 123: 88-95Abstract Full Text Full Text PDF PubMed Scopus (38) Google ScholarHFOVOSCILLATE: Higher hospital mortality with HFOV18Ferguson N.D. Cook D.J. Guyatt G.H. et al.High-frequency oscillation in early acute respiratory distress syndrome.N Engl J Med. 2013; 368: 795-805Crossref PubMed Scopus (679) Google ScholarOSCAR: No difference in 30-d mortality19Young D. Lamb S.E. Shah S. et al.High-frequency oscillation for acute respiratory distress syndrome.N Engl J Med. 2013; 368: 806-813Crossref PubMed Scopus (499) Google ScholarHFOV associated with lower mortality in patients with a Pao2/Fio2 ratio < 100 mm Hg (or < 64 mm Hg)20Meade M.O. Young D. Hanna S. et al.Severity of hypoxemia and effect of high-frequency oscillatory ventilation in acute respiratory distress syndrome.Am J Respir Crit Care Med. 2017; 196: 727-733Crossref PubMed Scopus (67) Google ScholarProne positioningPROSEVA: Lower 28-d mortality with prone positioning21Guérin C. Reignier J. Richard J.C. et al.Prone positioning in severe acute respiratory distress syndrome.N Engl J Med. 2013; 368: 2159-2168Crossref PubMed Scopus (2746) Google ScholarMortality benefit limited to a Pao2/Fio2 ratio < 150 mm Hg21Guérin C. Reignier J. Richard J.C. et al.Prone positioning in severe acute respiratory distress syndrome.N Engl J Med. 2013; 368: 2159-2168Crossref PubMed Scopus (2746) Google ScholarNMBAACURASYS: Lower adjusted 90-d mortality with NMBA22Papazian L. Forel J.M. Gacouin A. et al.Neuromuscular blockers in early acute respiratory distress syndrome.N Engl J Med. 2010; 363: 1107-1116Crossref PubMed Scopus (1842) Google ScholarROSE: No difference in 90-d mortality23Moss M. Huang D.T. Brower R.G. et al.Early neuromuscular blockade in the acute respiratory distress syndrome.N Engl J Med. 2019; 380: 1997-2008Crossref PubMed Scopus (553) Google ScholarNMBA associated with lower mortality in: Pao2/Fio2 ratio <150 mm Hg22Papazian L. Forel J.M. Gacouin A. et al.Neuromuscular blockers in early acute respiratory distress syndrome.N Engl J Med. 2010; 363: 1107-1116Crossref PubMed Scopus (1842) Google ScholarFluid therapyFACTT: No difference in mortality; more VFDs with conservative fluid strategy24Wiedemann H.P. Wheeler A.P. Bernard G.R. et al.Comparison of two fluid-management strategies in acute lung injury.N Engl J Med. 2006; 354: 2564-2575Crossref PubMed Scopus (2864) Google ScholarLiberal fluid strategy associated with higher mortality in hyperinflammatory phenotype25Famous K.R. Delucchi K. Ware L.B. et al.Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy.Am J Respir Crit Care Med. 2017; 195: 331-338Crossref PubMed Scopus (516) Google ScholarLiberal fluid strategy associated with lower mortality in less inflammatory phenotypeStatinsHARP-2: No difference in 28-d mortality with simvastatin26McAuley D.F. Laffey J.G. O'Kane C.M. et al.Simvastatin in the acute respiratory distress syndrome.N Engl J Med. 2014; 371: 1695-1703Crossref PubMed Scopus (357) Google ScholarSAILS: No difference in 60-d or hospital mortality with rosuvastatin27Truwit J.D. Bernard G.R. Steingrub J. et al.Rosuvastatin for sepsis-associated acute respiratory distress syndrome.N Engl J Med. 2014; 370: 2191-2200Crossref PubMed Scopus (416) Google ScholarSimvastatin associated with lower mortality in:Hyperinflammatory phenotype28Calfee C.S. Delucchi K.L. Sinha P. et al.Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial.Lancet Respir Med. 2018; 6: 691-698Abstract Full Text Full Text PDF PubMed Scopus (431) Google ScholarLower APACHE II score29Santhakumaran S. Gordon A. Prevost A.T. O'Kane C. McAuley D.F. Shankar-Hari M. Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials.Crit Care. 2019; 23: 156Crossref PubMed Scopus (23) Google ScholarStatins associated with lower mortality in sepsis-related ARDS with a Pao2/Fio2 ratio < 100 mm Hg30Mansur A. Steinau M. Popov A.F. et al.Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study.BMC Med. 2015; 13: 128Crossref PubMed Scopus (58) Google ScholarSimvastatin associated with higher mortality in higher APACHE II score29Santhakumaran S. Gordon A. Prevost A.T. O'Kane C. McAuley D.F. Shankar-Hari M. Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials.Crit Care. 2019; 23: 156Crossref PubMed Scopus (23) Google ScholarNone identified for rosuvastatin31Sinha P. Delucchi K.L. Thompson B.T. 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. 2018; 44: 1859-1869Crossref PubMed Scopus (205) Google ScholarACURASYS = ARDS et Curarisation; ALVEOLI = Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury; APACHE II = Acute Physiology and Chronic Health Evaluation II; ARMA = Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and Acute Respiratory Distress Syndrome; ExPress = Expiratory Pressure Study; FACTT = Fluids and Catheters Treatment Trial; HARP-2 = Hydroxymethylglutaryl-CoA Reductase Inhibition in Acute Lung Injury to Reduce Pulmonary Inflammation 2; HFOV = high-frequency oscillatory ventilation; LOVS = Lung Open Ventilation Study; NMBA = neuromuscular blocking agent; OSCAR = Oscillation in ARDS; PEEP = positive end-expiratory pressure; PROSEVA = Effect of Prone Positioning on Mortality in Patients with Severe Acute Respiratory Distress Syndrome; ROSE = Reevaluation of Systemic Early Neuromuscular Blockade; SAILS = Statins for Acutely Injured Lungs from Sepsis; VFD = ventilator-free days. Open table in a new tab ACURASYS = ARDS et Curarisation; ALVEOLI = Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury; APACHE II = Acute Physiology and Chronic Health Evaluation II; ARMA = Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and Acute Respiratory Distress Syndrome; ExPress = Expiratory Pressure Study; FACTT = Fluids and Catheters Treatment Trial; HARP-2 = Hydroxymethylglutaryl-CoA Reductase Inhibition in Acute Lung Injury to Reduce Pulmonary Inflammation 2; HFOV = high-frequency oscillatory ventilation; LOVS = Lung Open Ventilation Study; NMBA = neuromuscular blocking agent; OSCAR = Oscillation in ARDS; PEEP = positive end-expiratory pressure; PROSEVA = Effect of Prone Positioning on Mortality in Patients with Severe Acute Respiratory Distress Syndrome; ROSE = Reevaluation of Systemic Early Neuromuscular Blockade; SAILS = Statins for Acutely Injured Lungs from Sepsis; VFD = ventilator-free days. 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Clinical trials in acute respiratory distress syndrome: challenges and opportunities.Lancet Respir Med. 2017; 5: 524-534Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar These so-called "negative" trials may have been the result of truly ineffective therapies. Alternatively, therapies may have helped some patients but harmed others, resulting in no net clinical effect in the trial. As such, there is an increasing interest in identifying different subphenotypes among patients with ARDS.42Bos L.D. Martin-Loeches I. Schultz M.J. ARDS: challenges in patient care and frontiers in research.Eur Respir Rev. 2018; 27Crossref PubMed Scopus (33) Google Scholar Potential subphenotypes that have been identified as possible effect-modifiers include variables that are physiological (eg, Pao2/Fio2 ratio, respiratory system compliance), clinical (eg, underlying cause, direct vs indirect), and biological (eg, biomarkers, hyperinflammatory vs hypoinflammatory).43Sinha P. Calfee C.S. 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It is more correct to state that they did not show benefit, and in most cases they are indeterminate, as few were conducted as noninferiority trials. We present evidence for HTE according to disease severity