Many different conditions can lead to ARDS, although sepsis is the most common cause, usually with a pulmonary origin (e.g., pneumonia). Other conditions associated with ARDS include aspiration, inhalation injury (including e-cigarette or vaping product-associated lung injury), acute pancreatitis, trauma, burns, pulmonary contusion, transfusion-related lung injury, cardiopulmonary bypass, fat embolism, disseminated intravascular coagulation, and drug overdose.
ARDS is a common feature of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for pandemic coronavirus disease 2019 (COVID-19). Early reports indicate that older age, neutrophilia, and organ and coagulation dysfunction are risk factors associated with the development of ARDS, and progression from ARDS to death, in patients with COVID-19 pneumonia.
The pathophysiology of ARDS is complex and incompletely understood. Early in the development of ARDS, the primary pathological finding is diffuse alveolar damage, although this is not seen uniformly in all patients. The diffuse alveolar damage leads to injury to the alveolar-capillary membrane, made up of type I and type II alveolar pneumocytes and capillary endothelial cells. The alveolar air spaces are subsequently flooded with proteinaceous oedema fluid, inflammatory cells (neutrophils and activated alveolar macrophages), and inflammatory mediators, including pro-inflammatory cytokines, lipid mediators, and oxidants. Epithelial injury may be severe, with necrosis and sloughing of the type I cells exposing the basement membrane. Fibrin deposition occurs along the denuded basement membrane, resulting in the hyaline membranes that are characteristic of diffuse alveolar damage. Injury to type II cells and alveolar flooding contribute to surfactant dysfunction.
Mechanical ventilation with high pressures and high volumes may further injure the lung, contributing to the pro-inflammatory cytokine cascade.
The early phase of ARDS manifests clinically as acute hypoxaemic respiratory failure with an increased alveolar-arterial oxygen gradient and poorly compliant lungs. Concomitant multiple organ failure may occur, particularly if the underlying cause of ARDS is sepsis. Right ventricular dysfunction is also common and is associated with worse outcomes.
After the acute onset of alveolar flooding and inflammation, some patients have rapid resolution and return to normal lung histology and function. Pulmonary oedema fluid is cleared by active transport of sodium and chloride across the alveolar epithelium. In other patients, this early exudative inflammatory phase progresses to a fibroproliferative phase. During this later phase, the lung develops organised fibrous tissue and collagen deposition, which leads to irreversible and sometimes catastrophic lung fibrosis. This phase is characterised by continued respiratory failure, high minute ventilation, and poorly compliant lungs.
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