ARDS: Diagnosis and Pathophysiology

Introduction

• ARDS is a rapidly progressive and life-threatening form of respiratory failure caused mainly by an intense inflammatory response in the lungs. Acute onset, bilateral pulmonary infiltrates, and severe hypoxemia that cannot be fully explained by cardiac failure or fluid overload are its defining features. Histologically, ARDS is characterized by diffuse alveolar damage and injury to the pulmonary capillary endothelium, which impairs gas exchange, surfactant function, and lowers lung compliance.¹
• ARDS accounts for approximately 10% of all ICU admissions and poses significant diagnostic and therapeutic challenges due to its heterogeneous presentation, range of severity, and variety of underlying causes.²
• The COVID-19 pandemic has heightened awareness of ARDS, underscoring its global impact and the need for enhanced treatment methods.
• Although treatment remains largely supportive, recent advancements in understanding the pathophysiology of ARDS have improved patient outcomes and reduced mortality rates.³

Diagnosis of ARDS

• The definition and diagnostic paradigm for ARDS have evolved. The most widely accepted criteria are outlined in the Berlin Definition (2012), which modified the earlier American-European Consensus Conference guidelines. The Berlin Definition is based on four main components.⁴
  • Timing: The onset must occur within one week of a confirmed clinical insult or appearance of new or worsening respiratory symptoms.
  • Imaging: Bilateral opacities must be present on chest radiograph or computed tomography, and cannot be explained by effusions, lobar collapse, or nodules.
  • Origin of edema: Respiratory failure should not be attributable solely to heart failure or fluid overload. If no risk factors are present, objective testing (e.g., echocardiography) is recommended to rule out hydrostatic edema.
  • Oxygenation impairment:
    • Mild: PaO₂/FiO₂ between 200–300 mm Hg with PEEP or CPAP ≥ 5 cm H₂O
    • Moderate: PaO₂/FiO₂ between 100–200 mm Hg with PEEP ≥ 5 cm H₂O
    • Severe: PaO₂/FiO₂ ≤ 100 mm Hg with PEEP ≥ 5 cm H₂O
• Once ARDS develops, patients usually have varying degrees of pulmonary artery vasoconstriction and may subsequently develop pulmonary hypertension.
• Despite a significant improvement in the diagnostic criteria, radiographic interpretation remains dependent on clinician assessment.
• The newly developed Radiographic Assessment of Lung Edema score (RALE) is proposed to eliminate interrater variability.
• RALE score utilizes the extent and density of alveolar opacities on chest radiographs in each lung quadrant, with high agreement between independent reviewers. Higher RALE scores were independently associated with lower PaO2/FiO2 ratios and poorer survival outcomes.⁵

Differential Diagnosis of ARDS

The differential diagnoses for ARDS include the following:

• Cardiogenic edema
• Exacerbation of interstitial lung disease
• Acute interstitial pneumonia
• Diffuse alveolar hemorrhage
• Acute eosinophilic lung disease
• Organizing pneumonia
• Bilateral pneumonia
• Pulmonary vasculitis
• Cryptogenic organizing pneumonia
• Disseminated malignancy

Etiology of ARDS

• ARDS is a clinical illness caused by a variety of direct and indirect stressors that damage alveolar capillary integrity and activate an abnormal inflammatory response. These precipitating factors can be classified into direct (pulmonary) injury or indirect (extrapulmonary) causes (Table 1).
• Sepsis remains the leading cause, with pulmonary infections, particularly pneumonia, accounting for most cases. Non-pulmonary causes of sepsis, such as abdominal or urinary tract infections, can also trigger ARDS via systemic inflammation. Among non-infectious causes, aspiration of gastric contents, acute pancreatitis, major trauma with hemorrhagic shock, and multiple transfusions are prominent contributors.⁶
• Several host factors increase susceptibility to ARDS, including chronic alcohol use, smoking, pollutant exposure, and genetic predispositions such as the haptoglobin Hp-2 allele, particularly in sepsis. Most genetic variants show modest effects and have been studied in limited populations, highlighting the need for more diverse, globally representative research.⁷
• Transfusion-related acute lung injury causes and increases the risk in predisposed individuals. Drug-induced lung injury, particularly from chemotherapeutic agents and immune checkpoint inhibitors, is an increasingly acknowledged cause.⁸
• Since 2000, the epidemiology of ARDS has evolved. Trauma-related ARDS has declined, likely due to improved ventilation, fluid, and transfusion strategies. In contrast, e-cigarette or vaping-associated lung injury has emerged as a distinct etiology, particularly in young patients.⁹
• Viral pneumonias have long been recognized contributors but gained renewed attention during pandemics, notably with SARS-CoV (2003), H1N1 influenza (2009), MERS-CoV (2012), and SARS-CoV-2 (2019), which caused severe ARDS-related morbidity and mortality globally during the COVID-19 pandemic.

Pathophysiology of ARDS

• ARDS is a multifactorial and dynamic condition characterized by intense systemic inflammation, injury to the alveolar-capillary membrane, and resultant pulmonary dysfunction.
• The syndrome typically evolves through three overlapping phases: exudative, proliferative, and fibrotic, although not all patients progress through every stage.
  • In the exudative phase, which occurs within the first 7–10 days after a precipitating insult, inflammatory mediators such as cytokines, neutrophils, and macrophages disrupt the integrity of the endothelial and epithelial cells in the lung parenchyma. This leads to increased capillary permeability, leakage of protein-rich fluid into the alveolar spaces, surfactant dysfunction, and alveolar flooding. The accumulation of cellular debris and the formation of hyaline membranes further impair gas exchange and lung compliance.¹⁰
  • The proliferative phase, spanning days to weeks, represents the lung’s initial reparative response. Anti-inflammatory signaling pathways promote neutrophil apoptosis and clearance by macrophages, while type II pneumocytes proliferate and differentiate to reconstitute the alveolar epithelium. Alveolar fluid is actively cleared, and partial restoration of the alveolar-capillary barrier begins.¹¹
  • In some individuals, this reparative process becomes dysregulated, resulting in a fibrotic phase. Persistent fibroblast activation and excessive deposition of extracellular matrix components, such as collagen, result in architectural remodeling and the development of irreversible pulmonary fibrosis. This impairs compliance and perpetuates hypoxemia.
• Additional mechanisms contributing to ARDS pathophysiology include ventilation-perfusion mismatch, intrapulmonary shunting, and reduced lung compliance, all of which severely impair oxygenation. In mechanically ventilated patients, ventilator-induced lung injury—including barotrauma, volutrauma, and atelectrauma—may exacerbate lung damage if not mitigated by lung-protective strategies.