Is Acute Respiratory Distress Syndrome (ARDS) a diagnosis of exclusion?

Is ARDS a Diagnosis of Exclusion?

ARDS is fundamentally a clinical syndrome diagnosis based on defined criteria (bilateral infiltrates, hypoxemia, acute onset, non-cardiogenic edema), but critically requires systematic exclusion of specific treatable "ARDS-mimics" that present identically yet demand distinct therapies. 1

ARDS as a Syndromic Diagnosis

• ARDS is diagnosed using consensus criteria (Berlin definition) that include acute onset within one week of a known insult, bilateral pulmonary opacities on imaging, profound hypoxemia (PaO2/FiO2 ≤300 mmHg), and inability to explain respiratory failure by cardiac failure or fluid overload. 2, 3

• The diagnosis combines clinical, hemodynamic, and oxygenation criteria rather than relying on a specific clinical sign or diagnostic test. 4

• The pathological hallmark is diffuse alveolar damage, but only a minority of patients meeting Berlin criteria actually demonstrate this finding at autopsy, revealing significant heterogeneity within the syndrome. 1, 5

The Critical Role of Excluding ARDS-Mimics

• The European Respiratory Society emphasizes that ARDS-mimics are conditions presenting with identical clinical features but requiring distinct treatments such as immunosuppressants, antimicrobials, or drug withdrawal—making their recognition essential to prevent inappropriate management. 1

• These mimics fall into three key categories that must be systematically evaluated: 1

  • Diffuse interstitial acute lung diseases (acute interstitial pneumonia, organizing pneumonia, acute eosinophilic pneumonia, hypersensitivity pneumonitis)
  • Diffuse pulmonary infections (Pneumocystis jirovecii, viral pneumonitis including COVID-19/influenza, disseminated fungal infections, miliary tuberculosis)
  • Drug/chemical-induced diffuse lung disease (vaping-induced injury, chemotherapy-induced pneumonitis, amiodarone toxicity)

Algorithmic Diagnostic Protocol

The European Respiratory Society recommends establishing and applying a systematic diagnostic protocol to identify treatable diseases within the syndrome diagnosis of ARDS: 1

1. Obtain detailed exposure history: 1

   • Substance use (vaping, injection drugs, recreational drugs)
   • Occupational and environmental exposures
   • Complete medication review
   • Travel history and animal exposures

2. Assess immune status: 1

   • HIV status
   • Immunosuppressive medications
   • Underlying immunodeficiency

3. Consider bronchoscopy with bronchoalveolar lavage: 1

   • Diagnostic yield of 41% in treatment failures
   • Identifies Legionella, anaerobes, resistant pathogens, tuberculosis, fungi, and Pneumocystis

4. Evaluate for systemic disease: 1

   • Connective tissue disease markers
   • Vasculitis markers
   • Tuberculin skin test or interferon-gamma release assay

5. Review temporal relationship: 1

   • Timing of symptom onset relative to potential exposures
   • Response to initial interventions

Common Diagnostic Pitfalls

• Assuming all bilateral infiltrates with hypoxemia represent ARDS leads to misdiagnosis, as the Berlin criteria are highly sensitive but relatively non-specific. 1, 6

• Overlooking noninfectious mimics such as pulmonary embolus, obstructing bronchogenic carcinoma, lymphoma, intrapulmonary hemorrhage, Wegener's granulomatosis, and sarcoidosis delays appropriate treatment. 1

• Failing to recognize iatrogenic "second hits" (excess fluid administration, transfusions, injurious mechanical ventilation) can aggravate pulmonary edema in patients with ARDS risk factors. 1

• Standard chest X-rays are poor predictors of oxygenation defect severity and cannot reliably distinguish ARDS from its mimics. 7

Management Implications Based on Diagnosis

• For confirmed ARDS-mimics, withdraw offending agents immediately in drug/chemical-induced disease, initiate pathogen-specific antimicrobial therapy for infectious causes, and consider immunosuppression (particularly corticosteroids) for inflammatory/autoimmune mimics. 1

• For true ARDS, continue lung-protective ventilation as supportive care while treating the underlying condition, as no pharmacologic therapies targeting ARDS pathophysiology have proven beneficial. 1, 3

• COVID-19 ARDS represents a specific exception where dexamethasone provides benefit, unlike typical ARDS where routine corticosteroids are not recommended. 1

Why This Matters Clinically

• Recognition of the underlying cause is fundamental to ARDS care, as adequate treatment of the underlying disease represents one of the cornerstones of management. 1

• ARDS-mimics may be inappropriately included in clinical trials if additional diagnostic tests are not performed, contributing to decades of failed therapeutic trials due to heterogeneous patient populations. 1, 5

• In-hospital mortality for severe ARDS ranges from 40-60%, making accurate diagnosis and appropriate treatment critical for outcomes. 7, 2