Familial Pulmonary Fibrosis

Familial pulmonary fibrosis is pulmonary fibrosis occurring in two or more biological relatives within the family. It accounts for about 5 to 20% of idiopathic pulmonary fibrosis and other fibrosing interstitial lung diseases, and the true share is higher when the family history is asked about carefully.

The inheritance is usually autosomal dominant with variable penetrance, and onset is in the fifth to seventh decades, earlier with genetic anticipation in telomere related disease. Family members may have different fibrotic phenotypes (idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, hypersensitivity pneumonitis pattern, unclassifiable).

Pathophysiology. Two main mechanisms are recognised: telomere shortening (variants in TERT, TERC, RTEL1, PARN and others) causing replicative failure of alveolar type II stem cells, and surfactant protein variants (SFTPC, SFTPA1, SFTPA2, ABCA3) causing protein misfolding and endoplasmic reticulum stress. Smoking and other exposures modify the risk.

Progressive exertional dyspnoea and dry cough, bibasal crackles and clubbing, much like sporadic fibrosis. Features of short telomere syndrome are important clues: premature greying of hair before age 30, unexplained macrocytosis, thrombocytopenia or aplastic anaemia, liver disease (cirrhosis or nodular regenerative hyperplasia), and early emphysema, with a history of cancer in relatives.

Rapid worsening of breathlessness, hypoxaemia or pneumothorax needs urgent assessment since acute exacerbation is common.

• Family history: at least two relatives with pulmonary fibrosis in three generations. Ask about liver disease, bone marrow failure and early greying.
• High resolution CT: usual interstitial pneumonia pattern in most (basal subpleural reticulation, traction bronchiectasis, honeycombing), with other patterns possible.
• Lung function: restriction with low DLCO, and six minute walk test with oximetry.
• Genetic testing through a multi-gene panel (telomere and surfactant genes) after counselling, and blood telomere length by flow-FISH (lower than the first percentile for age suggests telomere disease).
• Full blood count, liver function and bone marrow assessment when cytopenias are present.
• Exclude secondary causes: connective tissue disease serology, hypersensitivity pneumonitis exposure, drugs and asbestos.
• Multidisciplinary discussion to confirm the diagnosis; biopsy is seldom needed.

Differential diagnosis.

• Sporadic idiopathic pulmonary fibrosis
• Hypersensitivity pneumonitis
• Connective tissue disease associated interstitial lung disease
• Pulmonary alveolar proteinosis (with some surfactant gene variants)
• Combined pulmonary fibrosis and emphysema

• Antifibrotic treatment: nintedanib 150 mg twice daily with food (100 mg twice daily in mild hepatic impairment) or pirfenidone titrated to 801 mg three times daily, which slow decline in FVC, as they do in sporadic fibrosis. Monitor liver function monthly for 3 months, then every 3 months.
• Avoid immunosuppression: the combination of prednisolone, azathioprine and N-acetylcysteine increases death and hospitalisation, and azathioprine and mycophenolate are poorly tolerated with short telomeres because of marrow toxicity. Steroids are used only for acute exacerbation.
• Supportive care: oxygen when PaO2 is 7.3 kPa or less, pulmonary rehabilitation, vaccination against influenza, pneumococcus and COVID-19, smoking cessation, treatment of gastro oesophageal reflux and sleep apnoea, and palliative care for symptoms.
• Early referral for lung transplantation assessment (age below 65 to 70 years, progressive disease), warning the team about short telomeres since marrow failure, infection and renal problems after transplant are more frequent, and liver disease may exclude single organ transplant.
• Genetic counselling and cascade testing of first degree relatives, with baseline lung function, CT and blood tests for carriers. Advise avoidance of smoking and fibrogenic dusts and fumes.
• Associated problems: transfusions for marrow failure, and hepatic surveillance.

Complications and prognosis. Median survival is about 2 to 4 years from diagnosis in telomere related fibrosis, and is worse than sporadic fibrosis. Acute exacerbation, lung cancer and pulmonary hypertension are common.

Monitoring. Spirometry and DLCO every 3 to 6 months, oximetry at rest and on exertion, CT annually or if worsening, and full blood count with liver tests every 6 months in telomere disease.

Referral and escalation. Refer to an interstitial lung disease centre, clinical genetics and a lung transplant service early.