Pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP)  was first described by Rosenet al in 1958.It  is a lung disease characterised by abnormal  accumulation of large amounts intra-alveolar surfactant-like lipoproteinaceous material . It has a variable clinical presentation and course.

Epidemiology

·        Pulmonary alveolar proteinosis is rare, and accurate estimates of its occurrence is not available.

·         It usually presents in young and middle aged adults (20-50 years of age) .Peak incidence is seen in 3^rd-4^th decade of life.80% of the reported cases occurs in this age group.

·         Smoking is strongly associated with the condition.

CLASSIFICATION

The disease can be divided into three broad categories:

·         idiopathic: 90% of cases

o    Also termed adult or acquired

o    Cause is autoimmune with IgG antibodies to GM-CSF

·         secondary: 5-10% presents in individuals with other precipitating illness

o    Haematological malignancy

o    Inhalational lung disease

§  Silicon (known as silicoproteinosis)

§  Titanium oxide

§  Insecticides

o    Immunodeficiency/immunosuppression with coexistent infection, e.g. nocardiosis, aspergillosis, PCP

·         congenital: 2%

o    Presents in neonatal period in term babies; has a very poor prognosis if left untreated

o    May be distinct entity also know as chronic pneumonitis of infancy

o    It is due to mutation in genes encoding SP-B, SP-C, or GM-CSF receptor.

Pathology

GROSS

The gross pathological findings in pulmonary alveolar proteinosis are patchy areas of yellow consolidation with an oily substance exuding from abraded surfaces.

LIGHT MICROSCOPY

The classical finding on light microscopy is filling of the alveoli and terminal bronchioles with a granular lipoproteinaceous substance which stains a deep pink with periodic acid Schiff (PAS) stain.The alveolar architecture is usually well preserved although septal thickening from oedema  or lymphocytic infiltration has been observed.

ELECTRON MICROSCOPY

alveolar lumen shows abundant cellular debris and lamellar bodies

alveolar macrophages that are present in the alveoli are enlarged and contain numerous complex phospholipoprotein inclusions

Clinical presentation

·        Patients with pulmonary alveolar proteinosis (PAP) typically present with a gradual onset of symptoms.

·         One-third of patients are asymptomatic, even with diffuse chest radiograph (CXR) abnormalities.

·        Symptoms include the following:

Persistent dry cough (or scant sputum production)

Progressive dyspnea.

Fatigue and malaise.

Weight loss.

Intermittent low-grade fever and/or night sweats.

Pleuritic chest pain.

Cyanosis (rare).

Hemoptysis (rare).

INVESTIGATIONS

PULMONARY FUNCTION TESTS

The predominant abnormality is a restrictive pattern with a reduction in lung volumes and diffusion capacity.

Obstructive ventilatory changes are unusual but may be observed in smokers.

Hypoxaemia is a prominent finding.

Pulmonary function tests can be used to assess disease severity, progression, and response to treatment.

Radiographic features

As a general rule, radiographic features are often much more severe than the clinical presentation would suggest ⁶.

Plain film

Finding can be variable including :

·         Bat wing pulmonary opacities:

o    Bilateral central symmetrical lung opacities with relative apical and costophrenic angle sparing

o    Resembles of pulmonary oedema

o    Most common appearance in adults

·         Diffuse small pulmonary opacities

o    Resembles of miliary pattern

o    More common in children

·         Extensive diffuse consolidation

·         Reticulonodular opacities

Pleural effusions, cardiomegaly and lymphadenopathy usually not features of uncomplicated PAP.

HRCT

The appearance of pulmonary alveolar proteinosis on HRCT is characterised by two main features: 

1.    Smooth thickening of interlobular and intra-lobular septal lines, and

2.    Ground glass opacities

The combination of these two features results in what is termed crazy paving pattern, which although a highly characteristic feature is unfortunately not pathognomonic. Additionally pulmonary consolidation or later in the disease pulmonary fibrosis may be evident.

Lung changes are of either patchy or geographic distribution and may have a slight lower lobe predilection .

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BRONCHOALVEOLAR LAVAGE

Milky fluid is usually obtained on BAL  of an affected segment.

Centrifuged  demonstrates a basophilic granular extracellular deposit with a few enlarged foamy macrophages and cellular debris on Giemsa stain.

 The extracellular substance is stained pink with PAS but negative with alcian blue, differentes phospholipoprotein aggregates from mucins.

The ultrastructural appearance on electron microscopy is characteristic with abundant lamellar bodies and cellular debris but only a few tubular myelin aggregates.

The alveolar macrophages are usually enlarged with abundant lipid inclusions with the same ultrastructural characteristics as those found in the extracellular material.

The major constituent of the lavage fluid is phospholipid, mainly lecithin, the main component of surfactant.

Definitive diagnosis is by bronchoalveolar lavage, transbronchial or open lung biopsy.

Treatment

Whole lung lavage

·        whole lung lavage is used therapeutically to remove alveolar material and is considered the treatment of choice.

Multiple segmental lung lavage

·        performed through a FOB

·        used as alternate to whole lavage and done in patients who cannot tolerate whole lung lavage

PROGNOSIS

·        Prognosis is variable ranging from improvement (with treatment) to a chronic and terminal course.

·        A 30% 2 year mortality has been reported in adults prior to routine use of bronchoalveolar lavage. The 5 year mortality has now been reduced to approximately 5% .

Complications

·         superimposed infection: especially with Nocardia asteriodes sp. 

·         pulmonary fibrosis (occurs in ≈30%)
PS:

A number of opportunistic pathogens may cause a superimposed pneumonia in patients with PAP. Offending agents include : 

·         Aspergillus spp

·         Candida spp

·         Cryptococcus neoformans

·         Cytomegalovirus (CMV)

·         Histoplasma capsulatum

·         Mycobacterium (tuberculous and nontuberculous)

·         Nocardia spp

·         Pneumocystis spp

·         Streptococcus pneumonia