Causes of Lymphoid Interstitial Pneumonia
Most cases of LIP are secondary to underlying systemic conditions, with truly idiopathic LIP being extremely rare. 1
Primary Associated Conditions
The majority of LIP cases are associated with specific underlying disorders that must be systematically investigated:
Autoimmune Diseases
- Sjögren's syndrome is the most common association, present in approximately 50% of adult LIP cases 2, 3
- Other connective tissue diseases include rheumatoid arthritis, systemic lupus erythematosus, and polymyositis 3
- Primary biliary cirrhosis is another recognized autoimmune association 4
Immunologic Dysregulation
- Dysproteinemias (monoclonal or polyclonal gammopathy) occur in more than 60% of patients 2, 4
- Common variable immunodeficiency represents another immunologic cause 3
- Both hypergammaglobulinemia and hypogammaglobulinemia can be present 4
Infectious Associations
- HIV infection is a major cause, particularly in children where LIP is a recognized AIDS-defining condition 2, 5
- Epstein-Barr virus DNA has been detected in lung tissue of LIP patients, suggesting a potential viral etiology, though not all cases show this finding 5, 4
Idiopathic Cases
Truly idiopathic LIP is exceedingly rare, accounting for only a small minority of cases 1, 3:
- The 2013 ATS/ERS classification reclassified idiopathic LIP as a "rare IIP" because most cases are actually secondary 1
- Only 3 out of 15 patients (20%) in one surgical biopsy series were classified as idiopathic after extensive workup 3
- Many cases previously diagnosed as LIP are now recognized as cellular NSIP, further reducing the number of true idiopathic cases 1
Critical Diagnostic Pitfall
The diagnosis of idiopathic LIP should only be made after excluding all secondary causes through comprehensive evaluation 2:
- Mandatory screening includes serum protein electrophoresis, anti-SSA/SSB antibodies, HIV serology, and autoimmune disease markers 2
- Failure to identify an underlying cause may reflect incomplete investigation rather than true idiopathic disease 3
- The presence of pleural effusion or mediastinal adenopathy should raise suspicion for low-grade lymphoma rather than LIP 2
Pathophysiologic Considerations
The underlying mechanism appears to involve autoimmune-mediated diffuse hyperplasia of bronchus-associated lymphoid tissue 5:
- The polyclonal lymphoid infiltrate suggests a reactive rather than neoplastic process 5
- CD8-lymphocytosis in bronchoalveolar lavage, lung tissue, and peripheral blood has been documented, particularly in children with HLA-DR5 haplotype 4
- Approximately 5% of LIP cases transform to lymphoma, indicating LIP exists on a spectrum of pulmonary lymphoproliferative disorders 2, 5