Acute Exacerbations in ILD: Causes and Mechanisms
Acute exacerbations in interstitial lung disease (ILD) are NOT all due to infection—they represent a heterogeneous group of triggers including idiopathic causes, infection, mechanical stress, microaspiration, drug toxicity, and cardiovascular events, with infection being only one of several potential precipitants. 1, 2
Definition and Core Concept
Acute exacerbation of ILD is defined as acute, clinically significant deterioration developing within less than 1 month without obvious clinical causes like fluid overload, left heart failure, or pulmonary embolism. 2 The pathophysiology centers on diffuse alveolar damage, manifesting radiologically as bilateral ground-glass opacities superimposed on pre-existing fibrotic changes. 1, 2
Causes of Acute Exacerbations in ILD
Idiopathic/Unknown Triggers
- Many acute exacerbations occur without identifiable cause, representing true "idiopathic" events where diffuse alveolar damage develops spontaneously on the background of chronic ILD. 1, 2
- The American Thoracic Society emphasizes that infection, left heart failure, and other identifiable causes of acute lung injury must be systematically excluded before diagnosing an idiopathic acute exacerbation. 1
Infectious Triggers
- Viral and bacterial infections can precipitate acute exacerbations in ILD patients, though this represents only one subset of causes. 2, 3
- The distinction between pneumonia as a superimposed infection versus pneumonia as a trigger for organizing pneumonia or diffuse alveolar damage is clinically crucial. 4
- Organizing pneumonia represents an aberrant healing response that can be triggered by infectious agents and persist as chronic ILD if inadequately treated. 4
Mechanical Stress and Iatrogenic Causes
- Mechanical ventilation, surgical procedures (particularly lung biopsy), and other forms of mechanical stress to the lung parenchyma can trigger acute exacerbations. 2, 3
- Drug-induced contributions must be considered, as medications like nitrofurantoin and immunosuppressants can cause ILD patterns that mimic acute exacerbations. 4
Microaspiration
- Chronic microaspiration is recognized as a potential trigger for acute deterioration in ILD patients. 2, 3
Cardiovascular Events
- Pulmonary embolism, acute coronary syndrome, and worsening congestive heart failure can trigger or mimic acute exacerbations and must be excluded. 1, 2
Distribution Across ILD Subtypes
Acute exacerbations occur most frequently in idiopathic pulmonary fibrosis (IPF) but are increasingly recognized across all ILD subtypes. 2, 5
- Acute exacerbations affect patients with usual interstitial pneumonia (UIP) pattern most frequently. 2
- Hypersensitivity pneumonitis and connective tissue disease-associated ILD (particularly rheumatoid arthritis-related pulmonary fibrosis) experience acute exacerbations at apparently equal frequency to IPF. 5, 3
- Non-specific interstitial pneumonia (NSIP) and other fibrotic ILDs can also experience acute exacerbations, though potentially less frequently. 1, 5
Critical Diagnostic Pitfalls
The most dangerous error is assuming all acute deteriorations in ILD are infectious without systematically excluding other causes. 1, 2
- High-resolution CT showing new bilateral ground-glass opacities and/or consolidation superimposed on reticular pattern or honeycombing is the radiologic hallmark. 1, 2
- Histopathology typically shows mixed patterns of underlying ILD (e.g., UIP) with superimposed diffuse alveolar damage, organizing pneumonia, or prominent fibroblastic foci. 1
- Chest radiography is essential to exclude pneumonia, pneumothorax, pulmonary edema, and lung cancer as alternative diagnoses. 1
Prognostic Implications
Acute exacerbations carry extremely poor prognosis with mortality of 50% or more and high mortality within 6-12 months. 2, 5 This high mortality applies across ILD subtypes, though outcomes may vary between IPF and non-IPF ILD with different treatment responses. 6