• LIP is a rare interstitial lung disease characterized by the diffuse proliferation of lymphoid tissue within the lung interstitium.
• In lymphocytic interstitial pneumonia (LIP), there is an inflammatory component as well as infiltrative features.
• What is it:
  • Lymphocytic Interstitial Pneumonia (LIP) is a rare form of interstitial lung disease (ILD) characterized by:
    • Diffuse or patchy lymphocytic infiltration of the
      • airways
      • interstitium and
      • alveolar walls
    • Associated with
      • hyperplasia of lymphoid tissue in the lungs.
  • LIP can occur as an
    • idiopathic condition or
    • secondary to other systemic diseases.
• Etymology:
  • Derived from the Greek word lympho- (referring to lymphocytes) and -itis (inflammation), describing the inflammatory lymphocytic infiltration of the lung tissue.
• AKA:
  • Lymphocytic lung disease.
• What causes it:
  • Primary (idiopathic):
    • The underlying cause is unknown, but it is considered idiopathic in some cases.
  • Secondary (associated conditions):
    • Autoimmune diseases:
      • Sjögren’s syndrome (most common association).
      • Systemic lupus erythematosus (SLE).
      • Rheumatoid arthritis.
    • Immunodeficiency states:
      • HIV/AIDS.
      • Common variable immunodeficiency (CVID).
      • Post-transplant lymphoproliferative disorder.
    • Infections:
      • Epstein-Barr virus (EBV), Cytomegalovirus (CMV).
• What is the result:
  • Lymphocytic infiltration causes:
    • Thickening of the alveolar walls, impairing gas exchange.
    • Cystic changes in advanced cases due to small airway involvement.
  • If untreated or progressive, it may lead to:
    • Pulmonary fibrosis or
    • Lymphoid malignancies (e.g., lymphoma).
• How is it diagnosed:
  • Clinical findings:
    • Gradual onset of respiratory symptoms over months to years.
    • Symptoms include:
      • Progressive dyspnea,
      • Chronic dry cough,
      • Constitutional symptoms such as fever, weight loss, and fatigue.
  • Imaging studies:
    • Chest X-ray:
      • Diffuse reticular or ground-glass opacities.
      • Poorly defined nodules in advanced cases.
    • Chest CT:
      • Parts:
        • peribronchovascular thickening
        • small nodules.
        • patchy or diffuse ground-glass opacities
        • Cysts
          •  typically located along bronchovascular bundles, forming a characteristic
            • peribronchovascular distribution.
          •  often intermixed with areas of
            • ground-glass opacity and
            • small nodules.
          • Size:
            • Cysts range from a few millimeters to over 2 cm, often variable within the same patient.
          • Shape:
            • Thin-walled, round to ovoid, occasionally irregular.
          • Position
            • More prominent mid to lower lung fields
          • Pattern:
            • Cysts may cluster in specific regions but are typically diffuse and bilateral.
      • Position:
        • Peribronchovascular
        • Diffuse involvement, often bilateral
        • Mostly lower lung fields and mid lung fields.
      • Character:
        • Ground-glass opacity, interstitial thickening, and cystic changes.
      • Time:
        • Gradual progression over months to years.
  • Histopathology (gold standard):
    • Dense lymphocytic infiltration in the alveolar walls, interstitium, and airways.
    • Reactive lymphoid hyperplasia with the formation of germinal centers.
    • Absence of features of malignancy (key for differentiation from lymphoma).
  • Laboratory findings:
    • Elevated autoimmune markers (e.g., ANA, anti-Ro/SSA, anti-La/SSB in Sjögren’s syndrome).
    • Evidence of immunodeficiency (e.g., low immunoglobulin levels in CVID).
• How is it treated:
  • First-line therapy:
    • Corticosteroids (e.g., prednisone): Used to control inflammation.
  • Second-line options:
    • Immunosuppressive agents (e.g., cyclophosphamide, azathioprine) in refractory cases or when corticosteroids fail.
  • Treatment of underlying conditions:
    • Manage associated autoimmune disease or immunodeficiency.
  • Supportive care:
    • Oxygen therapy for hypoxemia.
    • Pulmonary rehabilitation in advanced disease.
  • Monitoring:
    • Serial imaging to assess progression or response to treatment.
    • Surveillance for the development of lymphoma.
• Radiological implications:
  • Key findings include diffuse ground-glass opacities, peribronchovascular thickening, and thin-walled cysts associated with the bronchovascular bundles.
  • Serial imaging helps monitor for progression to fibrosis or transformation to lymphoma.
• Key points and pearls:
  • Cystic changes: Thin-walled cysts in LIP are unique and may overlap with findings in lymphangioleiomyomatosis (LAM) or pulmonary Langerhans cell histiocytosis (PLCH).
  • Autoimmune associations: Sjögren’s syndrome is the most common systemic disease linked with LIP; testing for autoimmune markers is essential.
  • Progression risk: Untreated or chronic LIP can lead to pulmonary fibrosis or transform into lymphoma, requiring close monitoring.
  • Differentiation from lymphoma: Histopathology and imaging are critical to rule out lymphoid malignancies in advanced cases.
• 

Inflammatory Component in the
Interalveolar Septa

Infiltrative Component of
Lymphocytes Plasma Cell And Histiocytes

Key Pathological Features

1. Inflammatory Component:
   • LIP is primarily driven by a polyclonal lymphocytic infiltration of the interstitium.
   • This inflammation predominantly consists of T-cells, with smaller numbers of B-cells and plasma cells.
   • The inflammation may also extend to involve alveolar walls, airways, and blood vessels.
2. Infiltrative Features:
   • Reactive lymphoid hyperplasia is a hallmark, with scattered lymphoid aggregates sometimes forming germinal centers.
   • These lymphoid infiltrates can involve peribronchovascular areas, interlobular septa, and subpleural regions.
3. Associated Findings:
   • Occasionally, there is infiltration of plasma cells that may produce immunoglobulin, potentially leading to the presence of monoclonal protein production in rare cases (e.g., in the context of Sjögren’s syndrome).
   • The alveolar spaces may show collections of macrophages and lymphocytes.

Imaging Correlation

On HRCT, LIP typically shows:

• Diffuse or patchy ground-glass opacities (inflammatory component).
• Thin-walled cysts scattered in a random distribution.
• Reticular or nodular opacities, particularly in the peribronchovascular or lower lung zones.
• In severe or chronic cases, fibrosis may develop.

Clinical Significance

The inflammatory nature of LIP is critical because it means the disease can respond to immunosuppressive therapy (e.g., corticosteroids or other immunomodulatory agents). However, progression to fibrosis or transformation into lymphoid malignancy (e.g., lymphoma) is a potential concern.

In summary, LIP includes both an inflammatory and an infiltrative component, with the inflammatory aspect being central to its pathogenesis and clinical management.

• Lower and midlung predominance
• infiltration of lymphocytes and plasma cells into the
  • perilymphatic
    • bronchovascular bundles
    • venules
  • interstitium.

Lymphocytic Infiltration  Along the
Bronchovascular Bundles in the Mid and
Lower Lung Fields

Lymphocytic Infiltration  Along the
Lymphatics of the
Interalveolar and
Interlobular Septa

Infiltration of Lymphocytes, Plasma Cells, and Histiocytes into the
Walls of the Bronchioles and Small Airways, Obstruction,
Necrosis and
Cyst Formation

 Mid and Lower Lung Field
Thin Walled Cysts

Thin Walled Cysts in
Close Association with Bronchovascular Bundles

Nodules
Ill Defined Centrilobular and Subpleural Nodules

 

CT Finding	Description
Cysts and Nodules:	Development of cysts and nodules varying in size and distribution. hypotheses perhaps bronchiolar obstruction similar to the pathogenesis of Langerhans cysts but many other hypotheses
Peribronchovascular and Perilymphatic Distribution:	Clustering of lymphocytic infiltrates around bronchovascular bundles and lymphatic vessels.
Interstitial Thickening:	Thickening of interlobular septa and bronchovascular bundles contributing to a reticular pattern.
Ground-Glass Centrilobular Nodules:	Centrilobular ground-glass nodules may be present.

CT Finding	Description
Ground-Glass Opacities (GGOs):	Bilateral and diffuse opacities indicating partial airspace filling.
Interstitial Thickening:	Thickening of interlobular septa and bronchovascular bundles contributing to a reticular pattern.
Cysts and Nodules:	Development of cysts and nodules varying in size and distribution.
Ground-Glass Centrilobular Nodules:	Centrilobular ground-glass nodules may be present.
Pleural Effusion:	Pleural effusion is not common but mild effusion may be observed in some cases.

Rare

• Typical onset at ages 40 – 70 years old but can occur at any age (Chest 2002;122:2150)
• Typically in patients with Sjogren’s syndrome
• lower lobe predominance
• GGO’s
• Can have MALT lymphoma
• and Amyloidosis Light chain deposition disease
• More common in women
• No association with smoking history

• Bilateral lower lobes of the lung but also mid lung zones

Lower Lobes predominant Why?

• exact reason for this preference is
• not completely understood,
  • One possible explanation
  • lower lobes of the lungs are
  • more dependent on gravity, which
  • may affect the distribution of
  • lymphocytes and
  • other immune cells that are involved in the development of LIP.
    • Gravity may cause these cells to accumulate more easily in the lower lobes, where
    • blood flow and ventilation are also generally
      • lower
      • compared to the upper lobes.
• lymphatic drainage of the lower lobes
• less than the upper lobes, which could lead to the
  • accumulation of lymphocytes in the lower lobes.
• certain infections or environmental exposures that may
• contribute to the development of LIP
• may also have a greater impact on the lower lobes of the lungs.

Disease Process

• infiltration of lymphocytes and plasma cells into the lung interstitium

 

 

• Pathogenic mechanisms of LIP are still unclear
• Has aspects of lymphoproliferative disease and lymphoid hyperplasia of polyclonal T or B cells (Chest 2002;122:2150)
• Although it may transform to lymphoma, especially MALT, the risk is lower than initially reported (Eur Respir J 2006;28:364)

• Associated with several systemic diseases and conditions
  • Autoimmune (most common)
    • Sjögren syndrome (SjS); 25% of LIP cases have SjS and 1% of SjS cases present with LIP
    • Rheumatoid arthritis
    • Systemic lupus erythematosus
    • Polymyositis / dermatomyositis
    • Hashimoto disease
    • Hypothyroidism
    • Castleman disease
    • Myasthenia gravis
    • Autoimmune hemolytic anemia
    • Pernicious anemia
    • Primary biliary cirrhosis
  • Infection
    • Human immunodeficiency virus (HIV)
    • Epstein-Barr virus
    • Human T cell lymphotropic virus type 1
    • Legionella pneumonia
    • Mycoplasma
    • Chlamydia
    • Tuberculosis
  • Immunodeficiency
    • Acquired immunodeficiency syndrome (AIDS); especially in children
    • Monoclonal or polyclonal gammopathy
    • Common variable immunodeficiency
  • Idiopathic LIP accounts for 20% of cases (Eur Respir J 2006;28:364)

• Very slowly progressive respiratory symptoms
  • Dyspnea on exertion
  • Dry cough
  • Systemic symptoms such as malaise, fever and weight loss
  • Duration of the symptoms prior to diagnosis can exceed a year
• Bibasilar inspiratory crackles on chest auscultation

• Based on clinical, radiological and pathological findings (multidisciplinary diagnosis)
• No firm diagnostic criteria currently exist

• Dysproteinemia is often present
  • Hypergammaglobulinemia is more common than hypogammaglobulinemia
• Restrictive pattern on pulmonary function tests
  • Reduced forced vital capacity (FVC)
  • Reduced diffusing capacity of the lung for carbon monoxide (DLCO)

• Chest radiography
  • Bibasilar opacities with lower lobe predominance
• High resolution computed tomography (Eur J Radiol 2015;84:542, Respirology 2016;21:600)
  • Ground glass opacity with / without consolidation with lower lobe predominance
  • Cyst formation and thickening of bronchovascular bundle and interlobular septa are often present
  • Cysts often remain even after resolution of symptoms