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Editorial |

In ARDS, Heterogeneity = Opportunity FREE TO VIEW

Benjamin T. Suratt, MD, FCCP; Polly E. Parsons, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

The Robert Larner, MD College of Medicine at the University of Vermont, Burlington, VT

CORRESPONDENCE TO: Benjamin T. Suratt, MD, FCCP, Department of Medicine, The Robert Larner, MD College of Medicine at the University of Vermont, 89 Beaumont Ave, Given E407A, Burlington, VT 05405-0075


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


Chest. 2017;151(4):731-732. doi:10.1016/j.chest.2016.11.016
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Published online

The first report of ARDS was by Ashbaugh et al in 1967. The 12 patients in that initial report all had acute respiratory distress in common, but the underlying conditions were variable and included trauma, pneumonia, and pancreatitis. Since that time, clinicians and scientists have debated as to whether all patients with ARDS were “the same” and therefore should be “lumped together” or they were different and should be “split” into distinct subgroups. Significant advances have been made by using each of those philosophies.

FOR RELATED ARTICLE SEE PAGE 755

Those of us involved in the early translational and clinical studies became increasingly frustrated by the lack of consistency in results and the failure of therapeutic interventions that seemed so promising in animal models. In general, we were “lumpers,” but we all likely realized that ARDS was more complex. We both remember our own aha moments when transitioning from discussions of data from a lipopolysaccharide (LPS)-induced ARDS animal model to the collection of ICU samples from patients at risk for ARDS. Early animal models often followed the “lumper” strategy by examining young, generally healthy male animals and data from both direct (ie, hyperoxia, intratracheal LPS administration) and indirect (ie, cecal ligation/puncture, IV LPS administration) injury aggregated to discern the pathogenesis of the syndrome. However, patients in the ICUs were vastly different from the animals being studied. They had a variety of risk factors (including sepsis and trauma), and they were not all young, previously healthy, male, or white. In addition, they had various organ failures, were mechanically ventilated, and taking multiple medications. The ability to be a “lumper” became increasingly untenable.

Initially, the challenge of heterogeneity was daunting, but over time it became clear that it provided an opportunity to better elucidate the pathogenesis of ARDS and for the potential to develop targeted therapeutic interventions. Definitions for both ARDS and underlying risk factors (ie, sepsis) evolved,, and encompassed not only etiologies such as sepsis and trauma but the division of patients into those sustaining direct vs indirect lung injury. The impact of preexisting and comorbid conditions (including age, sex, ethnicity, diabetes, alcohol, obesity, kidney injury, smoking, and genetics), as well as features of clinical care such as mechanical ventilation, fluid management, and sedation, was identified. Furthermore, the site of measurements (ie, BAL vs blood) and the assay methods used to measure myriad biomarkers were also recognized as important contributors to the variations seen in the results. The initial translational and clinical studies were small and often included patients from only a single center, making it difficult to both identify and characterize the many heterogeneous patient populations that were included within the syndrome. However, large, well-characterized cohorts (including ones from the National Heart, Lung, and Blood Institute’s ARDS Network, the Mayo Clinic, and Vanderbilt) have been created over the last two decades, significantly increasing the power to both detect and analyze differences, identifying new and unique clinical phenotypes and biomarkers.

The article by Luo et al in this issue of CHEST is an important addition to the ARDS story. Although previous studies have clearly shown that the pathogenesis of direct and indirect ARDS is different, it was not known if the clinical characteristics and predictors of mortality differed between these groups. Taking advantage of the opportunities provided by the large number of carefully phenotyped patients enrolled in the Validation of Biomarkers for Acute Lung Injury Diagnosis (VALID) study, the authors evaluated the clinical characteristics and predictors of mortality in patients with ARDS from direct insults vs those with ARDS from indirect insults. They determined that the overall mortality rate was not different between the two groups, but the clinical characteristics associated with mortality did vary. In patients with direct injury, age, lung injury score, and nonpulmonary organ failure were all associated with an increased mortality, whereas diabetes was associated with a decrease in hospital mortality. In contrast, in indirect ARDS, only an increase in organ failure was associated with an increase in mortality. Moreover, factors previously associated with mortality from ARDS in general were found only to associate with mortality from direct ARDS, suggesting that many of our established assumptions about ARDS may, in fact, be as heterogeneous as those afflicted.

As Luo et al clearly point out, there are limitations to this study, including the lack of inclusion of patients with common risk factors such as trauma, the difference in size of the direct (250 patients) vs indirect (167 patients) injury cohorts, and the retrospective nature of the study, which prevented assessment of causality (ie, the impact of diabetes on mortality). Furthermore, the American European Consensus Definition of ARDS was used in this study and not the Berlin definition, which is more commonly used currently. Despite those limitations, the results are important. They provide further evidence that there are distinct patient populations who all share the same diagnosis (ARDS) but vary in clinical characteristics. Whenever a new, potentially distinctive, cohort has been identified, it has led to studies providing unique insights into the pathogenesis of the syndrome, identification of novel biomarkers, and new analytic approaches such as latent class analysis. Each of these approaches moves us closer to the goals of improved diagnostics, targeted therapeutic interventions, and a more personalized approach to care.

References

Ashbaugh D.G. .Bigelow D.B. .Petty T.L. .Levine B.E. . Acute respiratory distress in adults. Lancet. 1967;2:319-323 [PubMed]journal. [PubMed]
 
Petty T.L. . Editorial: the adult respiratory distress syndrome (confessions of a lumper). Am Rev Respir Dis. 1975;111:713-715 [PubMed]journal. [PubMed]
 
Murray J.F. . The adult respiratory distress syndrome (may it rest in peace). Am Rev Respir Dis. 1975;111:716-718 [PubMed]journal. [PubMed]
 
Fowler A.A. .Hamman R.F. .Good J.T. .et al Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med. 1983;98:593-597 [PubMed]journal. [CrossRef] [PubMed]
 
Abraham E. .Dinarello C.A. .Matthay M.A. .et al Consensus conference definitions for sepsis, septic shock, acute lung injury and ARDS—time for re-evaluation. Crit Care Med. 2000;28:232-235 [PubMed]journal. [CrossRef] [PubMed]
 
Ranieri V.M. .Rubenfeld G.D. .Thompson B.T. .et al Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526-2533 [PubMed]journal. [PubMed]
 
Parsons P.E. .Moore F.A. .Moore E.E. .et al Studies on the role of tumor necrosis factor in ARDS: the lack of an independent standard. Am Rev Respir Dis. 1992;146:694-700 [PubMed]journal. [CrossRef] [PubMed]
 
Luo L. .Shaver C.M. .Zhao Z. .et al Clinical predictors of hospital mortality differ between direct and indirect acute respiratory distress syndrome. Chest. 2017;151:755-763 [PubMed]journal
 
Calfee C.S. .Janz D.R. .Bernard G.R. .et al Distinct molecular phenotypes of direct vs indirect ARDS in a single-center and multicenter studies. Chest. 2015;147:1539-1548 [PubMed]journal. [CrossRef] [PubMed]
 
Calfee C.S. .Delucchi K. .Parsons P.E. .et al Latent class analysis of ARDS subphenotypes: analysis of data from two randomized controlled trials. Lancet Respir Med. 2014;2:611-620 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Ashbaugh D.G. .Bigelow D.B. .Petty T.L. .Levine B.E. . Acute respiratory distress in adults. Lancet. 1967;2:319-323 [PubMed]journal. [PubMed]
 
Petty T.L. . Editorial: the adult respiratory distress syndrome (confessions of a lumper). Am Rev Respir Dis. 1975;111:713-715 [PubMed]journal. [PubMed]
 
Murray J.F. . The adult respiratory distress syndrome (may it rest in peace). Am Rev Respir Dis. 1975;111:716-718 [PubMed]journal. [PubMed]
 
Fowler A.A. .Hamman R.F. .Good J.T. .et al Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med. 1983;98:593-597 [PubMed]journal. [CrossRef] [PubMed]
 
Abraham E. .Dinarello C.A. .Matthay M.A. .et al Consensus conference definitions for sepsis, septic shock, acute lung injury and ARDS—time for re-evaluation. Crit Care Med. 2000;28:232-235 [PubMed]journal. [CrossRef] [PubMed]
 
Ranieri V.M. .Rubenfeld G.D. .Thompson B.T. .et al Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526-2533 [PubMed]journal. [PubMed]
 
Parsons P.E. .Moore F.A. .Moore E.E. .et al Studies on the role of tumor necrosis factor in ARDS: the lack of an independent standard. Am Rev Respir Dis. 1992;146:694-700 [PubMed]journal. [CrossRef] [PubMed]
 
Luo L. .Shaver C.M. .Zhao Z. .et al Clinical predictors of hospital mortality differ between direct and indirect acute respiratory distress syndrome. Chest. 2017;151:755-763 [PubMed]journal
 
Calfee C.S. .Janz D.R. .Bernard G.R. .et al Distinct molecular phenotypes of direct vs indirect ARDS in a single-center and multicenter studies. Chest. 2015;147:1539-1548 [PubMed]journal. [CrossRef] [PubMed]
 
Calfee C.S. .Delucchi K. .Parsons P.E. .et al Latent class analysis of ARDS subphenotypes: analysis of data from two randomized controlled trials. Lancet Respir Med. 2014;2:611-620 [PubMed]journal. [CrossRef] [PubMed]
 
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