Pulmonary alveolar proteinosis

What is pulmonary alveolar proteinosis?

Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by impaired surfactant metabolism that leads to accumulation of an amorphous, largely cell-free, lipoproteinaceous material in the alveoli.¹ The lungs become stiff with restricted ventilatory function. Secondary infection may occur. Two forms are recognised:²

• Primary: idiopathic.

• Secondary: due to lung infections, haematological malignancies, inhalation of mineral dusts (eg, silica, titanium oxide, aluminium) and insecticides.

It is thought that impairment of surfactant clearance by alveolar macrophages, by autoantibody inhibition of the action of granulocyte-macrophage colony-stimulating factor (GM-CSF), may underlie many acquired cases, whereas congenital disease is most commonly attributable to mutations in surfactant protein genes, but may also be caused by GM-CSF receptor defects. Therapy with GM-CSF has shown promise in acquired cases of pulmonary alveolar proteinosis.³

How common is pulmonary alveolar proteinosis? (Epidemiology)

• The estimated prevalence is 1 case per 100,000 population.² Pulmonary alveolar proteinosis is probably underdiagnosed.

• It is more common in males than females and typically presents in those aged 20-50 years.²

• Incidence is increased in patients with haematological malignancies and AIDS, suggesting a relationship with immune dysfunction.

Causes of pulmonary alveolar proteinosis

Causes include:²

• Inhalation of silica dust.

• Exposure to insecticides, aluminium dust, titanium dioxide and other inorganic dusts.

• Haematological malignancies.

• HIV infection.

Symptoms of pulmonary alveolar proteinosis (presentation)

See also separate article Respiratory System History and Examination.

Usually presents at age 20-50 years, with a gradual onset of nonspecific dyspnoea or dyspnoea on exertion and persistent dry cough.⁴ As many as 30% of patients are asymptomatic, even with diffuse CXR abnormalities. Symptoms Include:²

• Persistent dry cough (or scant sputum production); haemoptysis is rare.

• Progressive dyspnoea.

• Fatigue and malaise.

• Weight loss.

• Intermittent low-grade fever and/or night sweats.

• Pleuritic chest pain.

Signs are usually nonspecific and include:²

• Fine end-inspiratory crackles.

• Clubbing.

• Cyanosis.

Differential diagnosis

Any cause of increasing dyspnoea but particularly:²

• Hypersensitivity pneumonitis.

• Pneumocystis jirovecii pneumonia.

• Pulmonary oedema.

• Sarcoidosis.

• Acute (adult) respiratory distress syndrome.

Diagnosing pulmonary alveolar proteinosis (investigations)²

• Serum lactate dehydrogenase (LDH) is usually elevated.

• CXR: bilateral perihilar infiltrates with consolidation. Changes progress into a diffuse reticulogranular pattern.

• Flexible bronchoscopy with bronchoalveolar lavage: alveolar secretions are PAS-positive but contain no organisms or any excessive cellular response.

• High-resolution CT scan of the chest: patchy ground-glass opacification with interlobular thickening (crazy-paving appearance).¹ Appearance is similar to that seen in lipoid pneumonia, sarcoidosis and acute respiratory distress syndrome.

• Lung biopsies: definitive diagnosis requires lung biopsy that typically shows partial or complete filling of alveoli with PAS-positive granular and eosinophilic material with preserved alveolar architecture.¹

Adults affected by pulmonary alveolar proteinosis (PAP) have circulating neutralising anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) antibodies. More effective diagnostic tests (eg, anti-GM-CSF antibodies) are under investigation.⁵

Management of pulmonary alveolar proteinosis

Patients with minimal symptoms require only symptomatic treatment but patients with hypoxaemia require more aggressive management.¹

• Appropriate treatment of any underlying cause.

• Mechanical removal of the lipoproteinaceous material by whole-lung lavage (WLL), which is the most widely accepted form of therapy for symptomatic pulmonary alveolar proteinosis (PAP):^{1 6}
  

  • This is performed under general anaesthesia. The lung is ventilated briefly with 100% oxygen before lavage with isotonic sodium chloride solution.

  • Lung lavage may take several hours.

  • WLL is usually very effective but repeated lavages are usually necessary.

• Correction of functional granulocyte-macrophage colony-stimulating factor (GM-CSF) deficiency with exogenous GM-CSF has emerged as an alternative therapy.¹

• Lung transplantation for patients with congenital PAP and adult patients with end-stage interstitial fibrosis and cor pulmonale.²

• In the past, patients have also been treated with systemic steroids and aerosol mucolytics, but without much success.

Complications of pulmonary alveolar proteinosis

• Lung infections: often Nocardia asteroides, Pneumocystis jirovecii, or Mycobacterium avium.

• Pulmonary fibrosis.

• Pulmonary hypertension.

• Cor pulmonale.

Prognosis

• In a third of patients, no appreciable disability develops and the disease remits spontaneously or fails to progress. The natural history depends on the underlying aetiology.

• Estimates of 5-year mortality rates vary between 10% and 30%.²

• Whole-lung lavage (WLL) often produces a dramatic response but recurrences are common and require repeated lavages.

• Lung transplantation for congenital pulmonary alveolar proteinosis (PAP) often has a good outcome.

Prevention of pulmonary alveolar proteinosis

Patients with alveolar proteinosis related to inhalation of inorganic dusts or insecticides should avoid further exposure.²