What is the appropriate management for a patient experiencing an Interstitial Lung Disease (ILD) exacerbation, potentially with a history of pulmonary hypertension and/or connective tissue disease?

Management of Interstitial Lung Disease Exacerbation

For patients experiencing an ILD exacerbation with acute or subacute respiratory deterioration, initiate high-dose intravenous corticosteroids (such as IV methylprednisolone up to 1 gram per day) as first-line therapy, while simultaneously ruling out alternative causes including infection, pulmonary embolism, pneumothorax, and aspiration. 1

Initial Assessment and Differential Diagnosis

When a patient presents with acute respiratory worsening in the context of ILD, immediately evaluate for:

• Infectious etiologies (bacterial, viral, fungal pneumonia) 1
• Pulmonary embolism 1
• Pneumothorax 1
• Aspiration events 1
• Lymphoproliferative disorders (particularly in Sjögren's-associated ILD) 1
• Drug-induced lung disease from immunosuppressive agents (methotrexate, leflunomide, rituximab, cyclophosphamide, TNF-alpha inhibitors) 1

Acute Pharmacologic Management

High-Dose Corticosteroids (First-Line)

• Administer IV methylprednisolone for rapidly progressive or exacerbating ILD with acute respiratory failure 1
• Dosing: Intravenous corticosteroids up to 1 gram per day have been reported in case series, though specific dose and duration recommendations cannot be definitively made due to lack of controlled trials 1
• Evidence quality: This recommendation is based on anecdotal reports and the high mortality of acute ILD exacerbation (weak recommendation, very low-quality evidence) 1

Escalation to Immunosuppression (Second-Line)

If the patient fails to respond to initial high-dose corticosteroids and experiences acute or subacute hypoxic respiratory failure requiring hospitalization:

• Add rituximab OR cyclophosphamide to high-dose corticosteroids 1
• For cyclophosphamide use: Provide mandatory Pneumocystis jirovecii prophylaxis and use IV route (rather than oral) to reduce bladder cancer risk 1
• Monitor for serious adverse effects: pneumonitis worsening, infections (including hepatitis B reactivation, progressive multifocal leukoencephalopathy), cytopenias, hypogammaglobulinemia 1

Supportive Care Measures

Oxygen Therapy

• Initiate long-term oxygen therapy (LTOT) if resting PaO₂ ≤7.3 kPa (55 mmHg) 1
• Lower threshold for oxygen: PaO₂ ≤8 kPa (60 mmHg) in the presence of peripheral edema or pulmonary hypertension 1
• Rationale: LTOT may improve survival, tissue oxygenation, and prevent complications such as worsening pulmonary hypertension, though evidence is extrapolated from COPD studies 1
• Monitor oxygen saturation at rest and with exertion; prescribe supplemental oxygen if desaturation below 88% occurs during 6-minute walk test 1, 2

General Supportive Measures

• Supportive care is the mainstay of therapy for acute exacerbation alongside pharmacologic intervention 1
• Consider pulmonary rehabilitation to improve functional status and patient-centered outcomes, though long-term benefit remains unclear 1

Special Considerations by ILD Subtype

Connective Tissue Disease-Associated ILD

For CTD-ILD with acute exacerbation:

• First-line: High-dose IV corticosteroids 1
• Second-line escalation: Rituximab or cyclophosphamide if refractory 1
• Maintenance therapy consideration: Mycophenolate mofetil for chronic management after acute phase stabilization 3, 2

Idiopathic Pulmonary Fibrosis

For IPF exacerbation:

• Corticosteroids remain first-line despite very low-quality evidence 1
• Avoid chronic glucocorticoids in stable IPF as they are associated with increased mortality 3
• Consider antifibrotic therapy (nintedanib or pirfenidone) for maintenance after acute phase, not during acute exacerbation 3, 2

Management of Concurrent Pulmonary Hypertension

Diagnostic Approach

• Right heart catheterization is required to confirm presence and severity of pulmonary hypertension; echocardiography is inaccurate in fibrotic lung disease 1
• Brain natriuretic peptide may correlate with moderate-to-severe PH but is not validated as a screening tool 1

Treatment Considerations

• Generally avoid pulmonary vasodilators in most ILD patients with PH (weak recommendation, very low-quality evidence) 1
• Exception: Consider vasomodulatory therapy trial only in moderate-to-severe PH (mean PAP >35 mmHg) documented by right heart catheterization 1
• Critical warning: Epoprostenol can worsen shunt flow and oxygenation in ILD-associated PH 1, 4
• Inhaled treprostinil may improve walking distance and symptoms in end-stage fibrotic ILD with PH 2

Critical Pitfalls to Avoid

• Do not use pulmonary vasodilators empirically without right heart catheterization confirmation of severe PH, as they may worsen gas exchange 1, 4
• Do not delay evaluation for infection or other reversible causes while initiating corticosteroids 1
• Do not continue medications that may cause drug-induced ILD (methotrexate, leflunomide, TNF inhibitors) during acute exacerbation 1
• Do not rely on echocardiography alone to diagnose or exclude pulmonary hypertension in ILD patients 1

Prognosis and Transplant Consideration

• Early lung transplant referral should be considered for rapidly progressive ILD, as median survival post-transplant is 5.2-6.7 years compared to <2 years without transplant in advanced disease 3, 2
• Acute exacerbation carries high mortality despite treatment, emphasizing the importance of aggressive supportive care 1