Phenotypes and personalized medicine in the acute respiratory distress syndrome

Abstract

Although the acute respiratory distress syndrome (ARDS) is well defined by the development of acute hypoxemia, bilateral infiltrates and non-cardiogenic pulmonary edema, ARDS is heterogeneous in terms of clinical risk factors, physiology of lung injury, microbiology, and biology, potentially explaining why pharmacologic therapies have been mostly unsuccessful in treating ARDS. Identifying phenotypes of ARDS and integrating this information into patient selection for clinical trials may increase the chance for efficacy with new treatments. In this review, we focus on classifying ARDS by the associated clinical disorders, physiological data, and radiographic imaging. We consider biologic phenotypes, including plasma protein biomarkers, gene expression, and common causative microbiologic pathogens. We will also discuss the issue of focusing clinical trials on the patient's phase of lung injury, including prevention, administration of therapy during early acute lung injury, and treatment of established ARDS. A more in depth understanding of the interplay of these variables in ARDS should provide more success in designing and conducting clinical trials and achieving the goal of personalized medicine.

Keywords: Acute lung injury; Acute respiratory distress syndrome; COVID-19; Phenotype; Precision medicine; Pulmonary edema; Sepsis.

Fig. 1

Some recognized etiologies of ARDS. Circle size represents approximate relative frequency, although we do not have enough information regarding frequency for this figure to be an accurate estimate for COVID-19 viral pneumonia. Clinical disorders associated with ARDS include drug-induced ARDS and ARDS following major surgical procedures such as cardiopulmonary bypass

Fig. 2

Kaplan–Meier survival curve censored at day 28 in HARP-2 stratified by phenotypes assigned using a 3-variable ancillary parsimonious model (interleukin-6, soluble tumour necrosis factor receptor-1, and vasopressor-use) and treatment (simvastatin or placebo). The variables selected in the parsimonious model were dictated by the availability of data. This figure was previously published in Lancet Respir Med [85]. Published with permission

Fig. 3

Differences in peripheral leukocyte gene expression have been used to identify ARDS subphenotypes. The plasma and alveoli represent distinct compartments, as direct comparison of peripheral monocytes and alveolar macrophages has also shown profound differences in gene expression

Fig. 4

Timeline of recent therapies investigated in clinical trials for lung injury prevention, early acute lung injury, and ARDS. The role of Acetaminophen and Vitamin C will be studied in the future. A phase 2b trial reported that the use of aspirin did not reduce the risk of ARDS. A phase 3 trial showed no mortality benefit of early vitamin D3 supplementation among critically ill, vitamin D-deficient patients. An ongoing phase 3 clinical trial is testing the impact of a restrictive fluids strategy (early vasopressors followed by rescue fluids) as compared to a liberal fluid strategy (early fluids followed by rescue vasopressors) in patients with sepsis-induced hypotension on 28-day mortality. High-flow nasal oxygen reduced the rate of intubation and reduced mortality in acutely hypoxemic patients. A phase 2a randomized trial demonstrated the safety and feasibility of early administration of a combination of an inhaled corticosteroid and beta agonist in patients at high risk of ARDS, and there is a larger phase 2b trial ongoing. In a clinical trial of 1006 patients with PaO₂/FiO₂ < 150 mm Hg and PEEP ≥ 8 cm of H₂O, neuromuscular blockade did not result in a significant difference in 90-day mortality. A phase 2b trial of 167 patients showed that high dose Vitamin C in sepsis-induced ARDS was associated with a significant reduction in SOFA score and 28-day mortality, as well as an increase in ICU-free days and hospital-free days.