Pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by an abnormal intra-alveolar accumulation of surfactant-derived lipoproteinaceous material.

On imaging, pulmonary alveolar proteinosis is classically associated with the lung crazy paving pattern on CT, although it is a rare cause of this non-specific finding.

Epidemiology

Pulmonary alveolar proteinosis is rare and usually presents in young and middle-aged adults (20-50 years of age) ^6,7. Smoking is strongly associated with the condition, and in smokers, there is a recognized male predilection (M:F of ~2:1) ⁶, which is absent in non-smoking patients ⁴.

When the disease presents before the age of 1 year, there is an association with thymic alymphoplasia ⁶.

Clinical presentation

Clinical presentation is usually with non-specific respiratory symptoms such as dyspnea or a minimally-productive cough. Approximately one-third of patients may be asymptomatic. In children, the presentation is often less clearly respiratory in nature, with diarrhea, vomiting, failure to thrive and even cyanosis being more common ⁶. Symptoms may also be due to superadded opportunistic infections (see below). Signs include crackles on auscultation, clubbing or cyanosis.

Pathology

The understanding of pulmonary alveolar proteinosis has evolved considerably over time.

Pulmonary alveolar proteinosis was originally defined by histopathologic findings of amorphous periodic acid-Schiff (PAS) stain positive, lipoproteinaceous material filling the alveoli, with relatively normal background lung architecture ¹¹. Upon discovery that the PAS(+) material represents debris derived from the pulmonary surfactant, it became clear that pulmonary alveolar proteinosis represents a disorder of surfactant turnover ¹².

Multiple causative factors for pulmonary alveolar proteinosis have been elucidated. Alveolar macrophages, the key to surfactant homeostasis, are regulated by the granulocyte-macrophage-colony-stimulating factor (GM-CSF). Acquired autoimmunity to GM-CSF is now believed to be the most common cause of pulmonary alveolar proteinosis in adults ^4,12. Concurrent lung diseases which cause impaired alveolar macrophage function may also lead to a secondary form of pulmonary alveolar proteinosis. Much more rarely, genetic mutations which phenotypically yield abnormal surfactant or GM-CSF cause a severe congenital form of pulmonary alveolar proteinosis ¹².

Thus, pulmonary alveolar proteinosis may be divided into three broad categories:

• autoimmune: formerly referred to as idiopathic or primary, 90% of cases

  • also termed adult or acquired

  • IgG antibodies to GM-CSF

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

  • hematological malignancies

    • most commonly in those of myeloid origin ¹³

      • more frequent in patients with CML than in those AML

  • inhalational lung disease

    • silica (known as silicoproteinosis)

    • titanium oxide

  • immunodeficiency/immunosuppression (e.g. HIV/AIDS and after hematopoietic stem cell transplantation ¹³) with coexistent infection, e.g. nocardiosis, aspergillosis, PCP

• congenital: 2%

  • presents in the neonatal period in term babies

  • poor prognosis if left untreated (lung transplantation)

  • may be a distinct entity also known as chronic pneumonitis of infancy

  • due to a mutation in genes encoding SP-B, SP-C, or GM-CSF receptor ^8,9

Although imaging, bronchial lavage and sputum examination can strongly suggest the diagnosis, lung biopsy is sometimes required ^4,6.

Markers

• elevated acute inflammatory markers, e.g. lactate dehydrogenase (LDH) ⁴

• (+) BAL or serum anti-GM-CSF antibodies ¹²

Radiographic features

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

Plain radiograph

Chest radiograph findings are inconclusive ². Findings can be variable, including ^4,6:

• batwing pulmonary opacities

  • bilateral central symmetrical lung opacities with relative apical and costophrenic angle sparing

  • reminiscent of pulmonary edema

  • most common appearance in adults

• diffuse small pulmonary opacities

  • reminiscent of a miliary pattern

  • more common in children

• extensive diffuse consolidation

• reticulonodular opacities

Pleural effusions, cardiomegaly and lymphadenopathy are usually not features of uncomplicated pulmonary alveolar proteinosis.

CT

Two main features characterize the appearance of pulmonary alveolar proteinosis on HRCT: 

1. smooth thickening of interlobular and intralobular septal lines, and

2. ground glass opacities

The combination of these two features is termed a crazy paving pattern, which although highly characteristic, is not pathognomonic.

Additionally, pulmonary consolidation may be evident. However, if the known lung changes are generally stable, new consolidations should primarily raise the suspicion of pneumonia.

Lung changes are of either patchy or geographic distribution and may have a slightly lower lobe predilection ².

Ground glass opacity typically resolves after therapeutic bronchoalveolar lavage, although septal thickening may persist ¹⁰.

Findings of pulmonary fibrosis are not typical of adult pulmonary alveolar proteinosis ², although are more common in neonatal disease ¹².

Treatment and prognosis

Standard treatment includes therapeutic whole-lung bronchoalveolar lavage to remove alveolar material, although its role in children is less certain ⁶. GM-CSF supplementation has been used with varying effectiveness ¹².

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 ⁶. The 5-year mortality has now been reduced to approximately 5% ⁴. In children, that figure is much higher due to the reduced efficacy of bronchoalveolar lavage ⁶.

Double lung transplant has been used in the treatment of pulmonary alveolar proteinosis, although the disease may recur ⁴.

Complications

• superimposed infection: especially with Nocardia asteroides sp. ¹, although there are many others

  • Aspergillus spp.

  • Candida spp.

  • Cryptococcus neoformans

  • cytomegalovirus (CMV)

  • Histoplasma capsulatum

  • Mycobacterium (tuberculous and non-tuberculous)

  • Pneumocystis spp.

  • Streptococcus pneumoniae

• pulmonary fibrosis (occurs in ≈30%)

Differential diagnosis

Imaging differential considerations for specific patterns include:

• crazy paving pattern

• ground glass opacities

• miliary opacities

• batwing pulmonary opacities

  • pulmonary edema: pleural effusions and cardiomegaly usually absent in pulmonary alveolar proteinosis