Pulmonary alveolar proteinosis J84.0

Pulmonary alveolar proteinosis (PAP) is a very rare disease with accumulation of surfactant phospholipids and lipoproteins in the acini and adjacent peripheral air spaces.

Three forms of PAP are distinguished: primary, secondary and PAP-like syndromes (Carey and Trapnell 2010).

Autoimmune PAP: Autoimmune PAP is the most common form (90% of cases) with onset in adulthood. In autoimmune PAP, neutralizing GM-CSF- antibodies are detected, which are thought to cause macrophage dysfunction and impaired surfactant metabolism of surfactant proteins (Costabel and Guzman 2005).

Congenital PAP: Congenital PAP often presents in the neonatal period. It is associated with mutations in surfactant genes, with complete and partial surfactant protein B deficiency, mutations of the GM-CSF receptor, defects of the common β-chain, or defects in plasma membrane transport of cationic amino acids (known as related lysinuric protein intolerance) (Suzuki et al. 2010). The secondary form does not occur until adulthood and is found in association with high dust exposures (e.g., silica, aluminum, titanium, indium tin oxide), malignant hematologic disorders, and after allogeneic bone marrow transplantation. In most cases, secondary PAP results in a relative deficiency of GM-CSF and macrophage dysfunction. As in rheumatic diseases, it is debated whether dust exposure itself may be a trigger of autoimmunity, in this case of autoantibodies to GM-SCF (Costabel and Nakata 2010).

PAP-like syndromes: PAP-like syndromes occur rarely and are associated with abnormal surfactant metabolism (Carey and Trapnell 2010). Recessive gene mutations of SP-B, SP-C, and ABCA3 are reported as the cause (Carey and Trapnell 2010). The prognosis of such conditions is unfavorable and limited by the development of increasing diffusion capacity.

PAP is classified as a very rare lung disease (<1 per 100,000). Current epidemiologic data are based on 900 published cases. The incidence is reported to be 0.5-1.5 per 1,000,000. Prevalences are reported from 0.37 per 100,000 in the United States to 0.7 in Japan (Inoue et al. 2008).

The peak age at first diagnosis of idiopathic is 30 to 50 years of age (mean 39) (Seymour and Presneill 2002; Bonella et al. 2011), and 51 in Japan (Inoue et al. 2008). M:w= 2/3:1 (Inoue et al. 2008; Bonella et al. 2011). Smokers and ex-smokers are affected in 72% (Inoue et al. 2008; Seymour et al. 2002; Bonella et al. 2011). The primary autoimmune form affects >90% of cases.

Non-specific clinical symptoms. Gradual onset and progression over years. Sometimes crackles can be detected on auscultation during inspiration. Dyspnea on exertion, cough, and chest pain are most commonly reported. Fever, weight loss, and fatigue are rare (Bonella et al. 2011; Campo et al. 2013). Drumbeat fingers occur in 15-20% of patients with PAP.

Based on these nonspecific symptoms, chronic respiratory disease is usually diagnosed initially. In the primary form, detection of elevated autoantibodies to GM-CSF is diagnostic. In patients with secondary or congenital PAP, auto-AK are virtually absent.

1. Bonella F et al (2011) Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients. Respir Med 105:1908-1916.
2. Campo I et al (2013) Assessment and management of pulmonary alveolar proteinosis in a reference center. Orphanet J Rare Dis 8:40.
3. Carey B et al (2010) The molecular basis of pulmonary alveolar proteinosis. Clin Immunol 135(2):223-235.
4. Costabel U et al (2007) Bronchoalveolar lavage in other interstitial lung diseases. Semin Respir Crit Care Med 28:514-524.
5. Inoue Y et al (2008) Japanese Center of the Rare Lung Diseases C. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med 177:752-762.
6. Rosen SH et al (1958) Pulmonary alveolar proteinosis. N Engl J Med 258:1123-1142.
7. Seymour JF et al (2002) Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 166:215-235.
8. Suzuki T et al (2010) Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med 182:1292-1304PubMedCentralCrossRefPubMed.
9. Trapnell BC et al (2003) Pulmonary alveolar proteinosis. N Engl J Med 349:2527-2539.