Lymphoid Interstitial Pneumonia

Lymphoid interstitial pneumonia is a rare interstitial lung disease with diffuse polyclonal lymphocytic and plasma cell infiltration of the alveolar septa and peribronchovascular tissue. It is now almost always secondary to another condition.

Main associations are Sjogren syndrome (the commonest in adults), HIV infection in children, common variable immunodeficiency, systemic lupus erythematosus, autoimmune hepatitis, Epstein-Barr virus infection and drugs. It is rare in idiopathic form. It can progress to lymphoma in a small proportion.

Pathophysiology. Chronic antigenic stimulation, often by viruses in an immunodysregulated host, produces lymphoid hyperplasia of the bronchus associated lymphoid tissue, with spread into the interstitium. Clonal transformation can lead to marginal zone B-cell lymphoma.

Progressive cough and dyspnoea over months to years, with fever, weight loss and arthralgia. In children with HIV, there is generalised lymphadenopathy, parotid enlargement and clubbing. Look for sicca symptoms, parotid swelling, rash and recurrent infection.

Rapid worsening, hypoxaemia, weight loss with fever and new lymphadenopathy need prompt assessment for infection and lymphoma.

• High resolution CT: thin walled cysts (in about two thirds, mostly peribronchovascular), ground glass opacity, centrilobular nodules and thickened septa, with lymphadenopathy.
• Lung function: restrictive pattern, with low DLCO.
• Bronchoalveolar lavage: lymphocytosis, with flow cytometry to exclude a clonal population.
• Lung biopsy (surgical or cryobiopsy): diffuse polyclonal lymphoid infiltrate, with immunohistochemistry and gene rearrangement studies to exclude lymphoma.
• Cause: HIV test, immunoglobulins and lymphocyte subsets, antinuclear antibody, anti-Ro and anti-La antibodies, rheumatoid factor, liver function, and Epstein-Barr virus load.

Differential diagnosis.

• Pulmonary lymphoma (marginal zone lymphoma)
• Follicular bronchiolitis
• Lymphangioleiomyomatosis
• Birt-Hogg-Dube syndrome
• Pulmonary Langerhans cell histiocytosis
• Amyloid or light chain deposition disease with cysts
• Hypersensitivity pneumonitis
• Pneumocystis pneumonia

• Treat the underlying disease: antiretroviral therapy for HIV, immunoglobulin replacement for common variable immunodeficiency (IVIG 400 to 600 mg/kg every 3 to 4 weeks, adjusted to trough IgG over 6 g/L), and disease modifying treatment for Sjogren syndrome or lupus.
• Corticosteroid for symptomatic disease: prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) for 4 to 8 weeks, then tapered over 6 months, with a response in most.
• Steroid sparing or refractory disease: azathioprine 1 to 2 mg/kg daily, mycophenolate mofetil 1 to 1.5 g twice daily, or rituximab 1 g intravenously on days 1 and 15. Cyclophosphamide is reserved for severe or progressive disease.
• Prophylaxis against Pneumocystis in patients on 20 mg or more of prednisolone for over 4 weeks: co-trimoxazole 960 mg three times weekly.
• Vaccination against influenza, pneumococcus and COVID-19, and treatment of infections early.
• Lymphoma, if found: chemotherapy or rituximab based treatment with haematology.

Complications and prognosis. Fibrosis and respiratory failure in a third of cases, and lymphoma in about 5%. Survival depends on the cause, and is better when the underlying disease is controlled.

Monitoring. Spirometry, DLCO and CT every 3 to 6 months initially then yearly, with review of immunoglobulins, lymphocyte subsets and lymphoma features (new nodes, rising LDH, monoclonal band).

Referral and escalation. Refer to an interstitial lung disease service, and to rheumatology, immunology or HIV services for the underlying disease.