Non-Specific Interstitial Pneumonia (NSIP): Pathophysiology, Imaging, Clinical Features, and Treatment – A Comprehensive Review for Clinicians and Researchers

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Introduction

Non-specific interstitial pneumonia (NSIP) is a distinctive form of idiopathic interstitial pneumonia (IIP) that has drawn increasing global attention due to its overlapping features with other diffuse parenchymal lung diseases. Unlike usual interstitial pneumonia (UIP), NSIP is characterized by temporally uniform inflammation and fibrosis, presenting unique diagnostic and therapeutic challenges.

This comprehensive article explores the pathophysiology, epidemiology, clinical presentation, imaging features, differential diagnosis, diagnostic approaches, treatment strategies, and prognosis of NSIP. 

The review is grounded in recent literature, including pivotal studies from The New England Journal of Medicine, Lancet Respiratory Medicine, Radiology, and American Journal of Respiratory and Critical Care Medicine.

Pathophysiology

NSIP is primarily characterized by chronic interstitial inflammation and varying degrees of fibrosis. Unlike UIP, which displays spatial and temporal heterogeneity with fibroblastic foci, NSIP demonstrates homogeneous alveolar wall thickening.

  • Cellular NSIP: Predominantly lymphocytic infiltration with minimal fibrosis.

  • Fibrotic NSIP: Prominent interstitial fibrosis with reduced inflammation.

Pathogenesis involves:

  1. Immune-mediated injury: Autoimmune mechanisms play a central role, explaining its frequent association with connective tissue diseases (CTDs).

  2. Epithelial-mesenchymal crosstalk: Repeated alveolar epithelial injury stimulates fibroblast proliferation.

  3. Genetic predisposition: Familial pulmonary fibrosis gene variants have been identified in subsets of NSIP.

Epidemiology

  • NSIP is relatively uncommon compared to UIP but is the second most frequent form of IIP.

  • Incidence: Estimated 1–2 cases per 100,000 annually.

  • Demographics: Affects middle-aged adults, peak onset between 40–60 years.

  • Gender: Female predominance, particularly in CTD-associated NSIP.

  • Risk factors: Autoimmune disorders (systemic sclerosis, polymyositis, dermatomyositis), drug exposures (bleomycin, methotrexate), and environmental antigens.

Clinical Presentation

Patients typically present with insidious, non-specific respiratory symptoms, often delaying diagnosis.

  • Dyspnea on exertion – most common symptom.

  • Nonproductive cough.

  • Fatigue, weight loss, and low-grade fever in systemic cases.

  • Physical findings: Bibasilar inspiratory crackles, clubbing (less common than UIP).

Imaging Features

High-resolution computed tomography (HRCT) is pivotal in diagnosing NSIP.

Key radiologic features:

  • Ground-glass opacities (GGOs): Symmetric, basal predominant.

  • Reticular abnormalities: Fine interstitial lines, often less coarse than UIP.

  • Traction bronchiectasis: Common in fibrotic NSIP.

  • Absence of honeycombing: Crucial differentiating point from UIP.

Figures


[Figure 1] Axial lung window; Ground-glass opacity (GGO) centered at the lung fundus, with mild reticular opacity. Subpleural sparing confirmed.


[Figure 2] Axial lung window; diffuse ground-glass opacity centered on the left lower lobe, distributed evenly. No honeycombing observed.


[Figure 3] Axial lung window; Diffuse GGO spreads across the lung bases on both sides, symmetrically distributed.


[Figure 4] Axial lung window; interstitial thickening and reticular opacity, absence of honeycombing common in UIP → suggestive of NSIP.

Differential Diagnosis

  • Usual interstitial pneumonia (UIP): Patchy fibrosis, honeycombing, temporal heterogeneity.

  • Hypersensitivity pneumonitis: Centrilobular nodules, air-trapping.

  • Organizing pneumonia: Patchy consolidations with perilobular distribution.

  • Drug-induced pneumonitis: Exposure history critical.

  • Sarcoidosis: Upper lobe and perilymphatic distribution.

Diagnosis

Diagnosis requires a multidisciplinary approach (radiologist, pulmonologist, pathologist).

  1. Clinical history: Autoimmune symptoms, drug exposures.

  2. HRCT: Typical imaging patterns.

  3. Bronchoalveolar lavage (BAL): Lymphocytosis supports diagnosis.

  4. Lung biopsy: Gold standard.

    • Homogeneous interstitial inflammation.

    • Lack of fibroblastic foci and honeycombing.

Treatment

  • Corticosteroids: First-line, particularly in cellular NSIP.

  • Immunosuppressants: Mycophenolate mofetil, azathioprine, cyclophosphamide.

  • Biologic therapies: Rituximab has shown promise in CTD-associated NSIP.

  • Antifibrotic agents: Nintedanib and pirfenidone may benefit fibrotic NSIP, supported by INBUILD trial data.

  • Supportive care: Pulmonary rehabilitation, oxygen therapy, vaccination.

  • Lung transplantation: Option for refractory fibrotic NSIP.

Prognosis

  • Cellular NSIP: Good prognosis; 5-year survival > 80%.

  • Fibrotic NSIP: Intermediate prognosis, better than UIP but worse than cellular NSIP.

  • Predictors of poor outcome: Older age, male sex, severe fibrosis, CTD association with systemic involvement.

Quiz

Q1. Which of the following HRCT findings is most characteristic of NSIP?
A. Honeycombing
B. Centrilobular nodules
C. Ground-glass opacities with subpleural sparing
D. Upper lobe predominant fibrosis

Q2. What is the histopathologic hallmark of NSIP?
A. Temporal heterogeneity with fibroblastic foci
B. Noncaseating granulomas
C. Homogeneous interstitial inflammation and fibrosis
D. Necrotizing vasculitis

Q3. Which condition is most strongly associated with NSIP?
A. Rheumatoid arthritis
B. Systemic sclerosis
C. Sarcoidosis
D. Tuberculosis

Q4. Which therapy is most appropriate for initial management of cellular NSIP?
A. Pirfenidone
B. Corticosteroids
C. Anticoagulation
D. Antibiotics

Q5. Which feature distinguishes NSIP from UIP on HRCT?
A. Traction bronchiectasis
B. Honeycombing
C. Reticular opacities
D. Ground-glass opacity

Answer & Explanation

1. Answer: C. Explanation: NSIP typically shows bilateral ground-glass opacities with subpleural sparing, differentiating it from UIP.

2. Answer: C. Explanation: NSIP shows temporally uniform inflammation and fibrosis, unlike UIP.

3. Answer: B. Explanation: NSIP is particularly linked to systemic sclerosis and other CTDs.

4. Answer: B. Explanation: Corticosteroids remain the first-line therapy for cellular NSIP.

5. Answer: B. Explanation: The absence of honeycombing is critical for differentiating NSIP from UIP.

References

[1] T. E. King Jr, A. Pardo, and M. Selman, “Idiopathic pulmonary fibrosis,” Lancet, vol. 378, no. 9807, pp. 1949–1961, 2011.
[2] A. Travis et al., “An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias,” Am J Respir Crit Care Med, vol. 188, no. 6, pp. 733–748, 2013.
[3] K. Johkoh et al., “NSIP: Thin-section CT findings in 31 patients,” Radiology, vol. 211, pp. 555–560, 1999.
[4] J. S. Lee et al., “A cohort study of idiopathic NSIP: Outcomes and predictors,” Am J Respir Crit Care Med, vol. 178, pp. 376–382, 2008.
[5] V. Cottin, “Interstitial lung disease,” Clin Chest Med, vol. 33, no. 1, pp. 123–149, 2012.
[6] L. Flaherty et al., “Nintedanib in progressive fibrosing interstitial lung diseases,” NEJM, vol. 381, pp. 1718–1727, 2019.
[7] T. E. King, “NSIP: A distinct pattern of lung injury,” Chest, vol. 122, no. 6, pp. 1869–1873, 2002.

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