Acute respiratory distress syndrome

Abstract

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30-40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

Conflict of interest statement

M.A.M. declares grant support from Bayer (current), GlaxoSmithKline (prior) and Amgen (prior); has served as Data Safety and Monitoring Board chair for Roche-Genentech and has served as a consultant for GlaxoSmithKline, Bayer, Boehringer, CSL Berhring, Navigen, Quark and Cerus. G.A.Z. has served as a consultant for Navigen. Y.M.A. has served as a consultant for Gilead Sciences (past), Regeneron (past) and SAB Therapeutics (current). A.M. received fees for serving on a steering committee for Faron Pharmaceuticals, consulting fees from Air Liquide Medical Systems, grant support for research and lecture fees from Fisher & Paykel and Covidien, and lecture fees from Drager, Pfizer and ResMed. A.G.R. declares grant support from Roche-Genentech (current) and has served as a consultant for La Jolla Pharma and Bristol Meyer Squibb. C.S.C. declares grant support from Bayer (current) and GlaxoSmithKline (prior) and has served as a consultant for GlaxoSmithKline, Bayer, Boehringer, Prometic, Roche-Genentech, CSL Behring and Quark. The remaining authors declare no competing interests.

Figures

Fig. 1. The normal alveolus.

The alveolar epithelium is a continuous monolayer of alveolar type I (ATI) cells (very thin cells that permit gas exchange) and alveolar type II (ATII) cells (which produce surfactant to enable lung expansion with a low surface tension); both cells transport ions and fluid from the alveolus to maintain dry airspaces. The intact alveolar epithelium is linked by intercellular tight junctions. Tight junctions are responsible for barrier function and regulating the movement of fluid and ions across the epithelium and are composed of transmembrane claudins and occludins and cytoplasmic zonula occludens (ZO) proteins that anchor tight junctions to the actin cytoskeleton. Alveolar epithelial cells express plasma membrane E-cadherin and β-catenin. β-Catenin also functions as a transcriptional cofactor and has a role in cell turnover in the subset of ATII cells that function as stem cells during homeostasis. Endothelial cells serve to regulate the influx of fluid and inflammatory cells into the interstitial space and are connected by intercellular junctions comprising tight junctions and adherens junctions. Adherens junctions contain vascular endothelial cadherin (VE-cadherin), which mediates cell–cell contact through its extracellular domain and has a key role in barrier function. p120–catentin binds to and stabilizes VE-cadherin, which is linked to the actin cytoskeleton via α-catenin (α in the figure) and has multiple additional functional interactions. TIE2 acts in concert with vascular endothelial-protein tyrosine phosphatase (VE-PTP), which dephosphorylates VE-cadherin, stabilizing it. Normally, transvascular flux of fluid out of the capillary moves water and low-molecular-weight solutes into the interstitial space and then into the lymphatics; in health, this fluid does not cross the epithelial barrier. Resident alveolar macrophages populate the airspaces, providing host defence. Large numbers of polymorphonuclear leukocytes (PMNs) reside in the alveolar capillaries and can be rapidly mobilized to the airspaces in the setting of infection. β, β-catenin; BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel; JAM, junctional adhesion molecule; RBC, red blood cell.

Fig. 2. Microscopic findings in lung tissue in patients with ARDS.

In acute respiratory distress syndrome (ARDS), features of diffuse alveolar damage (DAD), such as in the acute ‘exudative’ phase (~7 days) (panel a), are typically followed by alveolar type II (ATII) cell hyperplasia and interstitial fibrosis in a ‘proliferative’ phase. Eosinophilic depositions termed hyaline membranes are defining features of DAD (pink structure lining the central alveolus, indicated by the arrowhead in panel b) are defining features of DAD. Leukocytes are embedded in the hyaline membranes (arrows in panel b). Electron microscopic analyses (panel c) demonstrate that alterations in endothelial and epithelial cells are critical features of acute alveolar injury in ARDS,. Focal epithelial destruction of alveolar type I (ATI) cells and denudation of the alveolar basement membrane occur early in ARDS, whereas endothelial continuity is preserved with modest alterations in most cases. The pattern shown in panel c was identified in the lungs of a patient with indirect acute lung injury resulting from sepsis,. A, alveolar space; BM, basement membrane; C, capillary; EC, erythrocyte; EN, endothelial cell; HM, hyaline membrane; LC, leukocyte. Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Matthay, M. A. & Zimmerman, G. A. (2005) Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am. J. Respir. Cell Mol. Biol. 33, 319–327. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Fig. 3. The injured alveolus.

A variety of insults (such as acid, viruses, ventilator-associated lung injury, hyperoxia or bacteria) can injure the epithelium, either directly or by inducing inflammation, which in turn injures the epithelium. Direct injury is inevitably exacerbated by a secondary wave of inflammatory injury. Activation of Toll-like receptors (not shown) on alveolar type II (ATII) cells and resident macrophages induces the secretion of chemokines, which recruit circulating immune cells into the airspaces. As neutrophils migrate across the epithelium, they release toxic mediators, including proteases, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which have an important role in host defence but cause endothelial and epithelial injury. Monocytes also migrate into the lung and can cause injury, including epithelial cell apoptosis via IFNβ-dependent release of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which activates death receptors. Activated platelets form aggregates with polymorphonuclear (PMN) leukocytes, which are involved in NET formation, and monocyte–platelet aggregates. Red blood cells (RBCs) release cell-free haemoglobin, which exacerbates injury via oxidant-dependent mechanisms. Angiopoietin 2 inhibits TIE2-stabilization of vascular endothelial cadherin (VE-cadherin); vascular endothelial growth factor and other permeability-promoting agonists also destabilize VE-cadherin via dissociation from p120-catenin, resulting in its internalization and enhanced paracellular permeability. Additionally, loss of cell–cell adhesion in the setting of actomyosin contraction results in the formation of occasional gaps between endothelial cells. Epithelial injury also includes wounding of the plasma membrane, which can be induced by bacterial pore-forming toxins or mechanical stretch, and mitochondrial dysfunction. Together, these effects result in endothelial and epithelial permeability, which further facilitate the transmigration of leukocytes and lead to the influx of oedematous fluid and RBCs. Airspace filling with oedematous fluid causes hypoxaemia, resulting in the need for mechanical ventilation. The vascular injury and alveolar oedema contribute to the decreased ability to excrete CO2 (hypercapnia), accounting for the elevated pulmonary dead space in acute respiratory distress syndrome. In turn, hypoxaemia and hypercapnia impair vectorial sodium transport, reducing alveolar oedema clearance. ATI, alveolar type I cell; BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel.

Fig. 4. Epithelial cell regeneration in ARDS.

Mice in which the alveolar type II (ATII) epithelial cells and all their progeny express green fluorescent protein (GFP) (SftpcCreERT2;mTmG mice) were treated with intratracheal lipopolysaccharide to induce lung injury. Mice were euthanized 27 days later and lung sections were stained for GFP (green), the alveolar type I (ATI) cell marker T1α (purple) and 4′,6-diamidino-2-phenylindole (DAPI; for nuclear staining (blue)). Some ATII cell-derived cells (GFP-staining cells in panels a (×40) and c (×40)) expressed ATI markers (T1α-staining cells in panels b (×40) and c), as shown by dual GFP-staining and T1α-staining cells (panel c) — indicating transdifferentiation during repair after lung injury. Arrowheads indicate nascent ATI cells that transdifferentiated from ATII cells during repair after injury (dual GFP-staining and T1α-staining cells). Arrows indicate ATI cells that withstood the initial injury (GFP-negative but T1a-staining cells). These experimental data support the notion that ATI cells are damaged during acute lung injury and are then replaced by ATII cells that transdifferentiate into ATI cells. Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Jansing, N. L. et al. (2017) Unbiased quantitation of alveolar type II to alveolar type I cell transdifferentiation during repair after lung injury in mice. Am. J. Respir. Cell Mol. Biol. 57, 519–526. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Fig. 5. The repaired alveolus.

Several mechanisms promote endothelial cell junctional reassembly. Slit binds to its receptor, ROBO4, stabilizing the adherens junctions by promoting the association between p120–catenin and vascular endothelial cadherin (VE-cadherin) (not shown). Activated platelets release the lipid mediator sphingosine 1-phosphate (S1P), which activates Rho/Rac signalling to induce cytoskeletal reorganization that promotes endothelial barrier integrity (not shown). The receptor tyrosine kinase TIE2 is bound by its activating ligand, angiopoietin 1, which results in actin cytoskeletal reorganization and stability of VE-cadherin at the adherens junctions (not shown). To repair the damaged epithelium, surviving alveolar type II (ATII) cells replace lost epithelial cells via proliferation and differentiation into alveolar type I (ATI) cells. Many growth factors promote ATII proliferation, including keratinocyte growth factor (KGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and granulocyte–macrophage colony-stimulating factor (GM-CSF); similarly, transcriptional pathways also promote ATII proliferation, including the WNT–β-catenin pathway,, and the forkhead box protein M1 (FOXM1) pathway. Toll-like receptor 4 and hyaluronan signalling also contribute. In severe injury, alternate progenitors (keratin 5-expressing epithelial progenitors (KRT5+) and club cells) are mobilized to proliferate and differentiate into ATII cells. Withdrawal of β-catenin signalling induces ATII cells to transdifferentiate into ATI cells. Fibroblasts and endothelial cells (and epithelial cells) secrete epithelial growth factors,; for example, platelet-derived stromal cell-derived factor 1 (SDF1) stimulates endothelial cells to secrete matrix metalloproteinase 14 (MMP14), which cleaves heparin-bound EGF (HB-EGF), enabling it to ligate the EGF receptor and stimulate ATII cell proliferation. Membrane pores can be patched and damaged mitochondria can be removed by mitophagy. Once the alveolar epithelium is regenerated, pro-resolving macrophages clear dead cells and debris and ATII and ATI epithelial cells reabsorb oedematous fluid. BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel; PMN, polymorphonuclear; RBC, red blood cell; Treg cell, regulatory T cell.

Fig. 6. Distinguishing ARDS on radiography.

Similarities in the chest radiographs from a patient with acute respiratory distress syndrome (ARDS) from influenza pneumonia (panel a) and a patient with pulmonary oedema due to cardiac failure (panel b) reflect the difficulty in identifying ARDS. In both cases, diffuse bilateral parenchymal opacities are consistent with alveolar filling. The cardiac silhouette (panel b) is slightly more globular, consistent with heart failure; however, this feature is not reliable for distinguishing ARDS from cardiogenic pulmonary oedema.

Fig. 7. Common respiratory pathogens in ARDS and associated demographic features and comorbidities.

Common community-acquired and hospital-acquired pathogens that cause pneumonia should always be considered in patients with suspected acute respiratory distress syndrome (ARDS). Some organisms such as Streptococcus pneumoniae are more common as community-acquired infections whereas Pseudomonas aeruginosa is more common as a hospital-acquired infection in ARDS. Enterobacteriaceae include Klebsiella pneumoniae, Escherichia coli and Enterobacter species. The group ‘other respiratory viruses’ includes parainfluenza virus, human metapneumovirus virus, respiratory syncytial virus, rhinovirus, coronaviruses and adenovirus. A detailed, expanded version of this figure can be found in Supplementary Fig. 1. COPD, chronic obstructive pulmonary disease.

Fig. 8. Identifying patients with early acute lung injury before progression to ARDS by the Berlin criteria.

Anterior–posterior chest radiographs in a critically ill 48-year-old man who presented to the emergency department with worsening dyspnoea, hypoxaemia (oxygen saturation of 70% on room air) and a 3-day history of fever, chills and a productive cough. He also had acute kidney failure with severe oliguria and a serum creatinine of 6.2 mg per dl. His systemic blood pressure was low, at 105/50 mmHg. He was diagnosed with acute pneumonia, acute renal failure and sepsis. a | Chest radiograph showing right lower lobe consolidation consistent with pneumonia. At this time, the patient was breathing spontaneously with 6 litres nasal oxygen that increased his oxygen saturation to 91%. b | Chest radiograph taken 24 hours later showing an endotracheal tube in place (arrows) for positive-pressure ventilation with bilateral opacities, consistent with the Berlin radiographic criteria. At this time, the patient had a partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio of 125 mmHg on positive-pressure ventilation with a tidal volume of 6 ml per kg predicted body weight and a positive end-expiratory airway pressure of 15 cmH2O. The patient also had a central line (arrowhead) inserted for administration of fluids and vasopressors as he progressed to developing septic shock. Time elapsed between the images demonstrates the potential window for early acute respiratory distress syndrome (ARDS) detection and early administration of therapies designed to prevent progression.