Granulomatous-Lymphocytic Interstitial Lung Disease

Granulomatous lymphocytic interstitial lung disease is an immune dysregulation lung complication of common variable immunodeficiency and some other inborn errors of immunity. It combines granulomatous inflammation, lymphoid hyperplasia (follicular bronchiolitis and lymphoid interstitial pneumonia) and organising pneumonia in the same lung.

It affects about 10 to 20% of people with common variable immunodeficiency, usually in the third to fourth decades, and is more common in those with autoimmune cytopenias, splenomegaly and lymphadenopathy. It is the main non-infectious cause of death and morbidity in this group after malignancy.

Pathophysiology. Defective B and T cell regulation with chronic antigenic stimulation (and sometimes viral triggers such as human herpesvirus 8 and Epstein-Barr virus) leads to uncontrolled lymphoproliferation and non-caseating granuloma formation. Infection is not the cause but is often the trigger of presentation.

Progressive dyspnoea, dry cough, fatigue and weight loss over months, with recurrent sinopulmonary infections preceding it. Finger clubbing, basal crackles, splenomegaly and lymph node enlargement may be present. Many have mild symptoms and an abnormal CT.

Rapid hypoxaemia or fever with new consolidation needs urgent assessment since infection and lymphoma are the main concerns.

• A diagnosis of exclusion in a person with a known immunodeficiency, with typical imaging and (where possible) histology.
• High resolution CT: multiple pulmonary nodules (often peribronchovascular and subpleural), ground glass, consolidation, septal thickening, bronchiectasis, mediastinal and hilar lymph node enlargement and splenomegaly.
• Lung function: restriction with reduced DLCO, often out of proportion to symptoms.
• Immunoglobulin levels (IgG, IgA, IgM), lymphocyte subsets and B cell phenotyping (low class switched memory B cells and raised CD21-low B cells support the diagnosis).
• Bronchoalveolar lavage to exclude infection (bacteria, mycobacteria, Pneumocystis, fungi, viruses), and surgical or cryobiopsy when the picture is uncertain or lymphoma is possible.
• Exclude sarcoidosis (rare in immunodeficiency), lymphoma, tuberculosis and drug reaction.

Differential diagnosis.

• Infection (including nontuberculous mycobacteria and fungi)
• Lymphoma and lymphoproliferative disease
• Sarcoidosis
• Lymphoid interstitial pneumonia without granulomas
• Hypersensitivity pneumonitis
• Bronchiectasis from recurrent infection

• Optimise immunoglobulin replacement first: intravenous immunoglobulin 0.4 to 0.6 g/kg every 3 to 4 weeks (or equivalent subcutaneous dose) to achieve trough IgG above 8 g/L, which treats infection but does not clear granulomatous disease.
• Treat infection and bronchiectasis: airway clearance, and antibiotic regimens for exacerbations (for example amoxicillin-clavulanate 625 mg three times daily for 7 days).
• Mild or stable disease can be watched.
• Progressive or symptomatic disease: prednisolone 0.5 to 1 mg/kg daily (30 to 60 mg) for 4 to 8 weeks with a slow taper over 3 to 6 months, though relapse is common.
• Steroid sparing and second line therapy: rituximab 375 mg/m2 weekly for 4 doses (or 1 g on days 1 and 15) with azathioprine 1 to 2 mg/kg daily (after thiopurine methyltransferase testing), which has the best reported response. Mycophenolate mofetil 500 mg twice daily increased to 1 g twice daily and abatacept are alternatives.
• Prophylaxis against Pneumocystis while on combined immunosuppression: co-trimoxazole 960 mg three times weekly.
• Vaccination with inactivated vaccines, and avoidance of live vaccines.
• Haematopoietic stem cell transplantation or lung transplantation in selected severe cases.

Complications and prognosis. Median survival is shortened compared with other common variable immunodeficiency patients. Fibrosis, cor pulmonale and lymphoma are the main late complications.

Monitoring. Spirometry with DLCO every 3 to 6 months, CT every 6 to 12 months, IgG trough levels, and monitoring of neutrophil count, B cell count and infections during rituximab.

Referral and escalation. Refer to a clinical immunologist and a respiratory physician with interstitial lung disease experience; refer to haematology for lymphoma concern.