New Insights into Clinical and Mechanistic Heterogeneity of the Acute Respiratory Distress Syndrome: Summary of the Aspen Lung Conference 2021

Abstract

Clinical and molecular heterogeneity are common features of human disease. Understanding the basis for heterogeneity has led to major advances in therapy for many cancers and pulmonary diseases such as cystic fibrosis and asthma. Although heterogeneity of risk factors, disease severity, and outcomes in survivors are common features of the acute respiratory distress syndrome (ARDS), many challenges exist in understanding the clinical and molecular basis for disease heterogeneity and using heterogeneity to tailor therapy for individual patients. This report summarizes the proceedings of the 2021 Aspen Lung Conference, which was organized to review key issues related to understanding clinical and molecular heterogeneity in ARDS. The goals were to review new information about ARDS phenotypes, to explore multicellular and multisystem mechanisms responsible for heterogeneity, and to review how best to account for clinical and molecular heterogeneity in clinical trial design and assessment of outcomes. The report concludes with recommendations for future research to understand the clinical and basic mechanisms underlying heterogeneity in ARDS to advance the development of new treatments for this life-threatening critical illness.

Keywords: ARDS; biological mechanisms; clinical trials; critical care.

Figure 1.

Effect of the coronavirus disease (COVID-19) pandemic on numbers of ARDS cases. COVID-19 acute respiratory distress syndrome (ARDS) cases (940,000) are estimated from COVID-19 deaths in the United States from March 2020 through February 2022, assuming 80% of deaths had severe pneumonia/ARDS and mortality of 20% from COVID-19 ARDS. ARDS cases before COVID-19 (380,000) are estimated for a similar period from the annual incidence data of Rubenfeld and colleagues. (68). Modified with permission from reference (71).

Figure 2.

Mortality in subclasses is defined by latent class analysis in eight different clinical trials of ARDS. The numbers at the bottom of each column show the percentage of patients in each subclass in the clinical trial population. The proportion in subclass 2 (hyperinflammatory) ranged from 26–40% across trials. Data are from references (, –96, 100, 104).

Figure 3.

Biomarker strategies in clinical trial designs. (A) Biomarker enrichment designs use a biomarker to select a subpopulation for inclusion. (B) Biomarker stratified designs evaluate a treatment in biomarker-positive and biomarker-negative populations so that a treatment effect occurs in biomarker-positive but not in biomarker-negative participants. Reprinted by permission from reference .

Figure 4.

Lung macrophages: ontogeny and mechanisms of functional programming in injury and repair. Tissue-resident alveolar macrophages (TR-AMs) originate from the yolk sac and fetal liver monocytes during lung development. In homeostasis, TR-AMs are replenished by self-renewal, and the phenotype is determined by interaction with niche cells and niche-specific factors (e.g., surfactant, phagocytosed apoptotic cells, local microbes, and regulatory cytokines [e.g., epithelial GM-CSF and TGF-β]). In lung injury, TR-AMs are depleted, and BM-Mos enter the lung and differentiate into bone marrow-derived macrophages (BMDMs). BMDMs integrate diverse signals that create BMDM phenotypes in a spatially resolved and time-dependent manner. These phenotypes comprise a spectrum from the inflammatory BMDM that contributes to epithelial cell injury yet also has host defense functions and the resolution/repair BMDM that resolves alveolar inflammation and drives tissue repair. During resolution, BMDMs replenish depleted TR-AMs. These newly appearing TR-AMs often retain transcriptomic and epigenetic signatures different from the initial “homeostatic” TR-AMs, creating “innate immune memory”. Areas of uncertainty (A, B, and C) are shown with dashed lines and (?) and relate to questions about whether defined polarization phenotypes of BMDMs give rise to TR-AMs in a disease-specific context and whether and how innate memory functions of replenished TR-AMs relate to precursor BMDM polarization phenotypes. Modified with permission from reference ; permission conveyed through Copyright Clearance Center, Inc. BM-Mo = bone marrow-derived monocytes.

Figure 5.

Neutrophil extracellular trap (NET) formation pathways. NETosis is slow and begins with nuclear delobulation and disassembly of the nuclear envelope, followed by loss of cellular polarization, chromatin decondensation, plasma membrane rupture, and cell death. Nonlytic NETosis can occur independently of cell death and involves the secreted expulsion of nuclear chromatin and granule proteins, leaving anucleated cytoplasts that retain phagocytic capacity. Reprinted with permission from reference .

Figure 6.

TIE2 and vascular responses. (Left) Tie2 is activated by Angpt-1 (angiopoietin-1) and antagonized by Angpt-2. The orphan receptor Tie1 antagonizes Tie2 signaling, as does vascular endothelial protein tyrosine phosphatase VE-PTP. Active Tie2 maintains vascular barrier function. (Middle) In sepsis, coordinated changes in Tie proteins lead to signaling inhibition, promoting vascular leakage, inflammation, and thrombosis. (Right) Organs affected by vascular leakage during sepsis. The host vascular response contributes to systemic inflammation, disseminated intravascular coagulation, and multiorgan dysfunction. Modified with permission from reference . BM = basement membrane; EC = endothelial cell; PMN = polymorphonuclear leukocyte, VE-PTP = vascular endothelial protein tyrosine phosphatase.

Figure 7.

Proposed relationship between lung infection and neurovascular dysfunction. Infection causes the production of cytotoxic tau variants in lung capillary endothelium that disseminate through the circulation and access the brain, where they disrupt hippocampal neuronal information processing. Heparan sulfate from lung matrix degradation and β amyloid also increase in the circulation and interfere with neural information processing. It was modified with permission from reference .

Figure 8.

Paradigm for epithelial regeneration by AEC2 cells (alveolar epithelial type 2) showing crucial roles of Wnt signaling and TGFβ (transforming growth factor β) activity. (A) Lineage tracing showing alveolar stem cells (AEC2, red) and their progeny (AEC2 lineage, green). When Wnt/βcatenin activity is lost (top, middle panel), AEC2 cells differentiate into flattened AEC1 cells. When Wnt/βcatenin is constitutively active, AEC2 cells maintain the AEC2 phenotype, and AEC1 differentiation is inhibited (top, third panel). (B) After lung injury, AEC2 cells proliferate, then assume a transitional cell state characterized by partially flattened morphology and a unique gene expression signature regulated by TGFβ. With downregulation of TGFβ signaling, transitional cells mature into AEC1 cells to repopulate the alveolar walls, whereas, with persistent TGFβ signaling, transitional cells fail to mature into AEC1, and fibrosis may follow. The first panel is modified with permission from reference .