What is the recommended initial treatment for nonspecific interstitial pneumonia (NSIP)?

Treatment of Nonspecific Interstitial Pneumonia (NSIP)

Corticosteroids are the first-line treatment for idiopathic NSIP, with the majority of patients showing improvement, and you should initiate prednisone at 0.5-1 mg/kg/day as soon as clinical or physiological impairment is documented. 1, 2

Critical Diagnostic Prerequisite

Before initiating treatment, you must confirm the diagnosis through surgical lung biopsy (video-assisted thoracoscopic surgery or open thoracotomy), as NSIP requires fundamentally different treatment than usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis, where corticosteroids are contraindicated and potentially harmful. 1, 2

• Histopathologic confirmation is mandatory: NSIP shows temporally uniform inflammation or fibrosis with preserved alveolar architecture, unlike the heterogeneous, patchy fibrosis with honeycombing seen in UIP. 1
• HRCT findings support but don't confirm diagnosis: Bilateral symmetric ground-glass opacities and lower zone reticular changes are typical, but biopsy provides definitive classification. 1, 2
• Exclude secondary causes: Rule out connective tissue disease (check ANA, RF, anti-CCP, anti-Scl-70, anti-Jo-1), drug toxicity, and hypersensitivity pneumonitis before diagnosing idiopathic NSIP. 3, 4

Initial Corticosteroid Therapy

Start oral prednisone at 0.5-1 mg/kg/day immediately upon diagnosis. 2 This immunosuppressive dose is critical—lower initial doses are significantly associated with relapse. 5

• The majority of NSIP patients (approximately 80-85%) respond favorably to corticosteroids alone. 1, 5
• Expect clinical improvement within weeks to months, with 15-20% five-year mortality when treated appropriately. 1
• Do not delay treatment: Initiate therapy at first identification of clinical or physiological impairment or documented decline in lung function. 1

Corticosteroid Tapering Protocol

After achieving clinical improvement:

• Taper slowly over more than 1 month for mild-to-moderate disease (analogous to Grade 2 pneumonitis protocols). 2
• Taper over more than 2 months for severe presentations (analogous to Grade 3-4 pneumonitis protocols). 2
• Monitor closely during taper, as 25% of patients experience relapse, though all typically improve with re-treatment. 5

Prophylaxis During Corticosteroid Therapy

Implement these protective measures for all patients:

• PCP prophylaxis if receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks. 2
• Calcium and vitamin D supplementation for long-term steroid use. 2
• Proton pump inhibitor for GI prophylaxis. 2
• Regular blood glucose monitoring with treatment per standard guidelines. 2
• Bone density testing and consider prophylactic bisphosphonates. 2

Adding Immunosuppressive Therapy

If the patient shows insufficient response to corticosteroids alone after 2-4 weeks, add cyclophosphamide or mycophenolate. 6, 2

When to Add Second-Line Agents

Add immunosuppressive therapy if:

• Inadequate improvement in symptoms, pulmonary function, or radiographic findings after 2-4 weeks of corticosteroids. 6
• Progressive disease despite adequate corticosteroid dosing. 6
• Inability to taper corticosteroids without disease recurrence. 7

Specific Agent Selection

Cyclophosphamide is the best-studied add-on therapy for steroid-refractory NSIP:

• Administer intravenous cyclophosphamide followed by oral maintenance. 6
• Case evidence demonstrates dramatic improvement in interstitial infiltrates when added to corticosteroids. 6
• In scleroderma-associated NSIP, cyclophosphamide stabilized lung function for 3 years after 1 year of therapy. 2

Mycophenolate is the preferred first-line immunosuppressive for SARD-associated NSIP:

• Conditionally recommended across all systemic autoimmune rheumatic disease-associated ILD subtypes. 1, 2
• Alternative options include rituximab, azathioprine, or calcineurin inhibitors depending on underlying disease context. 1

Phenotype-Based Treatment Considerations

Inflammatory NSIP Phenotype

This subgroup responds best to treatment:

• Prominent lymphocytic inflammation on biopsy and BAL (>20% lymphocytes). 7
• Mixed NSIP/organizing pneumonia pattern on HRCT. 7
• Expect excellent response to corticosteroids with or without immunosuppression. 7

Fibrotic NSIP Phenotype

This subgroup has less favorable prognosis:

• Prominent reticular changes and traction bronchiectasis on HRCT. 7
• High fibrotic background on biopsy without BAL lymphocytosis. 7
• Less responsive to immunosuppressive treatment with marginal risk of evolving toward IPF-like behavior. 7
• Consider earlier addition of second-line agents or antifibrotic therapy if progressive despite immunosuppression. 7

Monitoring Treatment Response

Use serial assessments every 3-6 months:

• Pulmonary function tests: FVC, FEV1, and DLCO are critical parameters. 2, 4
• HRCT imaging: Assess for improvement in ground-glass opacities and reticular changes. 2
• Clinical symptoms: Dyspnea, cough, and exercise tolerance. 4
• Mild ILD: PFTs every 6 months for first 1-2 years. 3
• Moderate-to-severe or progressive ILD: More frequent monitoring with short-interval PFTs and HRCT. 3

Treatment Failure and Progressive Disease

If NSIP progresses despite corticosteroids and immunosuppression, consider:

• Switching to alternative immunosuppressive agents (rituximab, mycophenolate if not already used). 1
• Do not use nintedanib or pirfenidone as first-line therapy for idiopathic NSIP, as evidence is limited and these are conditionally recommended against. 1, 2
• Lung transplantation referral for progressive deterioration meeting established criteria. 1, 2

Poor Prognostic Indicators

Be alert for these features predicting worse outcomes:

• Seropositivity for fluorescent antinuclear antibody is significantly associated with poor steroid response. 5
• Association with various systemic conditions predicts sustained disease progression. 5
• Sustained progression despite treatment occurs in approximately 14% of patients. 5

Critical Pitfalls to Avoid

Never treat NSIP like IPF: Corticosteroids are beneficial in NSIP but strongly contraindicated in UIP/IPF, where they may cause harm without improving survival or quality of life. 1, 2

Do not use inadequate initial corticosteroid doses: Low initial steroid doses are significantly associated with relapse requiring re-treatment. 5

Do not delay adding immunosuppression in steroid-refractory cases: Early intensive approach with simultaneous corticosteroids and immunosuppressive drugs is associated with better survival in inflammatory interstitial pneumonias compared to step-up approaches. 8

Distinguish idiopathic from secondary NSIP: Treatment approach may differ significantly if NSIP is associated with connective tissue disease, requiring rheumatologic co-management. 1, 4