Distinct Molecular Phenotypes of Direct vs Indirect ARDS in Single-Center and Multicenter Studies

Calfee, Carolyn S.; Janz, David R.; Bernard, Gordon R.; May, Addison K.; Kangelaris, Kirsten N.; Matthay, Michael A.; Ware, Lorraine B.

doi:10.1378/chest.14-2454

Cited by 314 publications

(308 citation statements)

References 40 publications

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“…We therefore included these biomarkers in the current analysis. Four biomarkers were measured previously for other studies (IL-6, IL-8, surfactant protein D, and von Willebrand factor) (12,13); the other four were measured for this analysis (intercellular adhesion molecule-1, protein C, soluble tumor necrosis factor receptor-1 [sTNFr1], and plasminogen activator inhibitor 1). We also included two previously measured ARDS biomarkers, angiopoietin-2 (Ang-2) and the receptor for advanced glycation end-products (RAGE), which were not available for our prior study (12,13).…”

Section: Latent Class Analysismentioning

confidence: 99%

Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy

Famous

Delucchi²,

Ware

et al. 2017

Am J Respir Crit Care Med

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605

575

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Rationale: We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure.Objectives: To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification.Methods: We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes. Measurements and Main Results:We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90-day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-conservative strategy versus 18% with fluid-liberal, whereas mortality in subphenotype 2 was 40% with fluid-conservative strategy versus 50% in fluid-liberal. A threevariable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes.Conclusions: This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches.

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Section: Latent Class Analysismentioning

confidence: 99%

Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy

Famous

Delucchi²,

Ware

et al. 2017

Am J Respir Crit Care Med

Self Cite

605

575

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“…Larger studies are warranted and should consider subgroups matched according to severity of illness and shock to further evaluate the possibility that mechanisms of ARDS may differ among patients with variable manifestations of nonpulmonary organ failure. Further study in gene expression programs is likely to increase understanding to subtypes of complex illnesses like ARDS (13,15). Recent discoveries in sepsis demonstrate how gene expression subphenotypes can be identified and applied in clinical settings (72).…”

Section: Discussionmentioning

confidence: 99%

“…For example a patient with a WBC of 18,000 cells/l may have increased expression of some genes simply due to an increase in the number of neutrophils rather than a functional upregulation of the neutrophil itself. Since pulmonary and nonpulmonary sepsis may lead to ARDS through independent mechanisms, we accounted for indirect (nonpulmonary) vs. direct (pneumonia or aspiration) risk factors for lung injury in the analysis (15).…”

Section: Methodsmentioning

confidence: 99%

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS

Kangelaris

Prakash

Liu

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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137

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The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.

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“…In panels of biomarkers, Ang-2 has been reported as a relevant marker for diagnosis and/or mortality (32). In addition, Ang-2 levels have been found to be an indicator of non-pulmonary ARDS (41).…”

Section: Angiopoietin-2 (Ang-2)mentioning

confidence: 99%

Biomarkers for the acute respiratory distress syndrome: how to make the diagnosis more precise

García‐Laorden¹,

Lorente²,

Flores³

et al. 2017

Ann. Transl. Med.

102

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Abstract:The acute respiratory distress syndrome (ARDS) is an acute inflammatory process of the lung caused by a direct or indirect insult to the alveolar-capillary membrane. Currently, ARDS is diagnosed based on a combination of clinical and physiological variables. The lack of a specific biomarker for ARDS is arguably one of the most important obstacles to progress in developing novel treatments for ARDS. In this article, we will review the current understanding of some appealing biomarkers that have been measured in human blood, bronchoalveolar lavage fluid (BALF) or exhaled gas that could be used for identifying patients with ARDS, for enrolling ARDS patients into clinical trials, or for better monitoring of patient's management. After a literature search, we identified several biomarkers that are associated with the highest sensitivity and specificity for the diagnosis or outcome prediction of ARDS: receptor for advanced glycation end-products (RAGE), angiopoietin-2 (Ang-2), surfactant protein D (SP-D), inteleukin-8, Fas and Fas ligand, procollagen peptide (PCP) I and III, octane, acetaldehyde, and 3-methylheptane. In general, these are cell-specific for epithelial or endothelial injury or involved in the inflammatory or infectious response. No biomarker or biomarkers have yet been confirmed for the diagnosis of ARDS or prediction of its prognosis.However, it is anticipated that in the near future, using biomarkers for defining ARDS, or for determining those patients who are more likely to benefit from a given therapy will have a major effect on clinical practice.

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Distinct Molecular Phenotypes of Direct vs Indirect ARDS in Single-Center and Multicenter Studies

Cited by 314 publications

References 40 publications

Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy

Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS

Biomarkers for the acute respiratory distress syndrome: how to make the diagnosis more precise

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