What are the differential diagnoses of Acute Respiratory Distress Syndrome (ARDS)?

Differential Diagnosis of ARDS

The differential diagnosis of ARDS encompasses three critical categories: diffuse interstitial acute lung diseases, diffuse pulmonary infections, and drug/chemical-induced diffuse lung disease—all of which present with bilateral infiltrates and hypoxemia but require distinct treatments rather than standard ARDS supportive care. 1

Primary Categories of ARDS Mimics

Diffuse Interstitial Acute Lung Diseases

These conditions respond to immunosuppression rather than standard ARDS management:

• Acute interstitial pneumonia presents with bilateral infiltrates and hypoxemia but may respond to corticosteroids, unlike typical ARDS 1
• Organizing pneumonia mimics ARDS radiographically but typically requires immunosuppressive therapy 1
• Acute eosinophilic pneumonia responds dramatically to corticosteroids, making its recognition essential 1
• Hypersensitivity pneumonitis requires identification and removal of the inciting antigen rather than ventilatory support alone 1

Diffuse Pulmonary Infections

These require pathogen-specific antimicrobial therapy:

• Pneumocystis jirovecii pneumonia requires trimethoprim-sulfamethoxazole and adjunctive corticosteroids 1
• Viral pneumonitis (including COVID-19 and influenza) may benefit from antiviral therapy and targeted corticosteroid use 1
• Disseminated fungal infections require antifungal therapy 1
• Miliary tuberculosis demands anti-tuberculous therapy 1

Drug/Chemical-Induced Diffuse Lung Disease

These resolve with drug cessation and possible corticosteroids:

• Vaping-induced lung injury exemplifies rapidly emerging ARDS-mimics requiring specific recognition 1
• Chemotherapy-induced pneumonitis may require corticosteroids and drug discontinuation 1
• Amiodarone toxicity requires drug withdrawal and possible corticosteroid therapy 1
• Drug-induced acute interstitial pneumonitis resolves with drug cessation 1

Additional Conditions to Exclude

Noninfectious Mimics

• Pulmonary embolus can present with acute hypoxemia and bilateral infiltrates 1
• Obstructing bronchogenic carcinoma or lymphoma may cause diffuse radiographic changes 1
• Intrapulmonary hemorrhage presents with bilateral infiltrates but requires distinct management 1
• Wegener's granulomatosis and sarcoidosis can mimic ARDS radiographically 1

Cardiogenic Pulmonary Edema

• Congestive heart failure typically presents with signs of fluid overload and must be differentiated from ARDS 2
• Computerized tomographic scanning can separate pleural fluid from parenchymal disease and demonstrate parenchymal abscesses, helping distinguish focal pneumonia from diffuse ARDS 1

Systematic Diagnostic Protocol

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

Detailed Exposure History

• Substance use including vaping, injection drug use, and recreational drugs should be specifically asked about 1
• Occupational and environmental exposures must be documented 1
• Medication review for potential drug-induced pneumonitis 1
• Travel history and animal exposures to identify infectious causes 1

Immune Status Assessment

• Evaluate for immunosuppression that increases risk of opportunistic infections 1
• Consider connective tissue disease markers and vasculitis markers 1
• Perform tuberculin skin test or interferon-gamma release assay 1

Bronchoscopy with Bronchoalveolar Lavage

• Has a diagnostic yield of 41% in treatment failures 1
• Identifies Legionella, anaerobes, resistant pathogens, tuberculosis, fungi, and Pneumocystis 1

Temporal Relationship Evaluation

• Review the timeline of symptom onset relative to potential exposures or medication changes 1

Critical Management Implications

Immediate Actions Based on Diagnosis

• Withdraw offending agents immediately in drug/chemical-induced disease 1
• Initiate pathogen-specific antimicrobial therapy for infectious mimics 1
• Consider immunosuppression, particularly corticosteroids, for inflammatory/autoimmune mimics 1
• Continue lung-protective ventilation as supportive care while treating the underlying condition 1

Special Considerations for Specific Conditions

• COVID-19 ARDS benefits from dexamethasone, unlike typical ARDS where routine corticosteroids are not recommended 1
• Influenza-associated ARDS with hemorrhage requires immediate oseltamivir regardless of symptom duration in severe disease 1

Common Pitfalls to Avoid

• Assuming all bilateral infiltrates with hypoxemia are ARDS can lead to misdiagnosis, as only a minority of patients meeting Berlin criteria actually have diffuse alveolar damage at autopsy 1
• Failing to recognize iatrogenic "second hits" such as excess fluid administration, transfusions, or injurious mechanical ventilation can aggravate pulmonary edema in patients with ARDS risk factors 1
• Overlooking noninfectious mimics can lead to delayed diagnosis and treatment 1
• Not performing additional diagnostic tests may result in inappropriately including ARDS-mimics in standard ARDS management protocols when they require specific treatments 1

Why Recognition Matters

Recognition of the underlying cause is essential because adequate treatment of the underlying disease is one of the fundamentals of ARDS care 1. ARDS-mimics show known and distinct pathophysiology requiring specific treatment, and these patients may be inappropriately managed if additional diagnostic tests are not performed 1. The enormous heterogeneity within ARDS has contributed to disappointing results in targeted treatment trials 3, making precise diagnosis of mimics critical for both individual patient outcomes and future research validity.