Pulmonary Amyloidosis

Pulmonary amyloidosis is deposition of amyloid in the lung parenchyma and interstitium, either localised or as part of systemic disease. The forms are nodular (usually a single or several nodules from local light chain production), diffuse alveolar septal (usually systemic AL amyloidosis), and pleural.

The amyloid is of light chain type (AL) in most, and transthyretin amyloid can affect the lung less often. Diffuse disease is a marker of systemic disease with cardiac and renal involvement, and has a poor outlook, while the nodular form is benign.

Pathophysiology. Misfolded proteins (immunoglobulin light chains, or transthyretin) aggregate into beta sheet fibrils that deposit in the alveolar septa and vessel walls, impairing gas exchange and compliance. In the nodular form, a local clone of plasma cells makes the light chains, and it can be linked to marginal zone lymphoma and Sjogren syndrome.

Nodular disease: usually no symptoms and found on imaging, sometimes cough or haemoptysis. Diffuse disease: progressive dyspnoea and cough, haemoptysis, with signs of systemic amyloidosis (heart failure, proteinuria, neuropathy, macroglossia, periorbital purpura, hepatomegaly).

Respiratory failure, haemoptysis or heart failure needs urgent assessment.

• High resolution CT: nodular disease shows single or multiple well defined nodules, sometimes calcified or cavitated, mostly subpleural. Diffuse disease shows septal thickening, ground glass, small nodules, cysts and calcified lymph nodes.
• Tissue diagnosis: biopsy (transbronchial, CT-directed, surgical) with Congo red apple green birefringence, and typing of the amyloid by mass spectrometry or immunohistochemistry.
• Search for systemic disease: serum free light chains, serum and urine electrophoresis with immunofixation, 24-hour urine protein, creatinine, liver tests, troponin, NT-proBNP, echocardiography, cardiac MRI, bone marrow biopsy and fat pad or other organ biopsy.
• Technetium pyrophosphate scintigraphy and genetic testing for transthyretin when ATTR is suspected.
• Lung function: restriction with reduced DLCO in diffuse disease.

Differential diagnosis.

• Lung cancer or metastasis (nodular disease)
• Lymphoma (marginal zone, with amyloid)
• Granulomatous infection (tuberculosis, fungal)
• Sarcoidosis
• Pulmonary oedema and interstitial lung disease from other causes
• Light chain deposition disease

• Nodular amyloidosis: no treatment if asymptomatic, or resection of a single nodule for diagnosis, with follow up imaging. Screen for lymphoma and Sjogren syndrome, and search for systemic AL amyloid with free light chains.
• Systemic AL amyloidosis with diffuse lung disease: referral to a haematology amyloidosis centre. Typical first line therapy is daratumumab 1800 mg subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks, with cyclophosphamide 300 mg/m2 weekly, bortezomib 1.3 mg/m2 weekly and dexamethasone 20 to 40 mg weekly, and doses adjusted for cardiac and renal function. Autologous stem cell transplantation for selected fit patients.
• Transthyretin amyloidosis: tafamidis 61 mg orally daily, or vutrisiran 25 mg subcutaneously every 3 months, with cardiology care.
• Supportive: oxygen when PaO2 is 7.3 kPa or less, diuretics for fluid overload with caution (hypotension is common), and pulmonary rehabilitation.
• Haemoptysis: tranexamic acid 500 mg to 1 g orally three times daily for up to 5 days, and bronchial artery embolisation if needed.
• Vaccination against influenza, pneumococcus and COVID-19.

Complications and prognosis. The nodular form has an excellent outlook. Diffuse alveolar septal disease has a median survival of about 1 to 2 years when systemic, and better with modern therapy and early response.

Monitoring. Haematological response (free light chain difference) every 1 to 3 months during treatment, cardiac markers and echocardiography every 3 to 6 months, and imaging for lung disease every 6 to 12 months.

Referral and escalation. Refer to a haematology amyloidosis service and to cardiology and nephrology when involved. Refer urgently for heart failure or respiratory failure.