Nonspecific Interstitial Pneumonia

Nonspecific interstitial pneumonia is an interstitial lung disease with uniform interstitial inflammation, fibrosis or both, and a better outlook than usual interstitial pneumonia. It can be idiopathic, but most cases are linked to connective tissue disease, drugs, hypersensitivity pneumonitis or HIV infection.

It occurs mainly in women, at 40 to 50 years. Two forms are described: cellular (mainly inflammation) and fibrotic, and the fibrotic form is the commoner.

Pathophysiology. An immune mediated injury to the alveolar wall leads to lymphoplasmacytic infiltrate and temporally uniform collagen deposition, with preserved alveolar architecture, unlike the patchy, temporally varied scarring of usual interstitial pneumonia.

Subacute breathlessness and dry cough over months, with fatigue, low grade fever and weight loss. Examination shows fine basal crackles and, in some, clubbing (less common than in idiopathic pulmonary fibrosis). Look for features of connective tissue disease: Raynaud, joint swelling, rashes, dry eyes and mouth, and muscle weakness.

Rapid worsening, hypoxaemia at rest or fever need urgent evaluation for infection, acute exacerbation or drug toxicity.

• High resolution CT: bilateral symmetrical lower zone ground glass opacity with fine reticulation and traction bronchiectasis, with sparing of the subpleural region in a proportion, and minimal honeycombing.
• Lung function: restrictive pattern with reduced FVC and a low transfer factor (DLCO). Six minute walk test with oximetry.
• Autoimmune serology: antinuclear antibody, rheumatoid factor, anti-CCP, extractable nuclear antigens, anti-dsDNA, anti-synthetase and myositis specific antibodies, anti-Scl-70, creatine kinase.
• Hypersensitivity pneumonitis workup (exposure history, specific IgG), drug history, HIV test, and bronchoalveolar lavage (lymphocytosis supports the diagnosis).
• Multidisciplinary discussion of clinical, imaging and, where needed, surgical or cryobiopsy findings.

Differential diagnosis.

• Idiopathic pulmonary fibrosis (usual interstitial pneumonia)
• Hypersensitivity pneumonitis
• Organising pneumonia
• Desquamative interstitial pneumonia
• Connective tissue disease associated interstitial lung disease
• Drug induced lung disease

• Remove the cause: stop the offending drug or exposure, and treat the underlying connective tissue disease.
• Induction: prednisolone 0.5 mg/kg daily (usually 30 to 40 mg) for 4 to 8 weeks, then taper over 6 to 12 months to 5 to 10 mg daily or less.
• A steroid sparing agent from the start in fibrotic or moderate-to-severe disease: mycophenolate mofetil 500 mg twice daily, increased over 4 weeks to 1 to 1.5 g twice daily, or azathioprine 1 to 2 mg/kg daily (maximum 150 mg) after checking thiopurine methyltransferase, with full blood count and liver tests every 2 weeks for 3 months and then every 3 months.
• Refractory or progressive disease: rituximab 1 g intravenously on days 1 and 15 (repeated at 6 months), or cyclophosphamide 600 mg/m2 intravenously monthly for 6 months.
• Progressive fibrosis despite immunosuppression: nintedanib 150 mg twice daily with food (100 mg twice daily in mild hepatic impairment), with liver tests monthly for 3 months, and management of diarrhoea with loperamide.
• Prophylaxis against Pneumocystis when prednisolone is 20 mg or more daily for over 4 weeks: co-trimoxazole 960 mg three times weekly (or 480 mg daily).
• Bone protection (calcium and vitamin D, alendronate 70 mg weekly), a proton pump inhibitor, and monitoring of glucose and blood pressure.
• Pulmonary rehabilitation, oxygen when PaO2 is 7.3 kPa or less, vaccination against influenza, pneumococcus and COVID-19, and lung transplantation for advanced fibrotic disease.

Complications and prognosis. The cellular form has a good outlook with a 5-year survival over 90%, and the fibrotic form about 70 to 80%. Disease progression, pulmonary hypertension and infection are the main problems.

Monitoring. Spirometry with DLCO and walk test every 3 months at first, then every 3 to 6 months, with a CT at 6 to 12 months or when worsening, and treatment response judged by a stable or improved FVC (change of 10% or more is significant).

Referral and escalation. Refer to an interstitial lung disease service for diagnosis and treatment, and to rheumatology for a connective tissue disease.