Description

• Pulmonary alveolar proteinosis (PAP) or pulmonary alveolar phospholipoproteinosis, first described on 1958 by Rosen et al., is characterized by overproduction of abnormal, nonfunctional lipoproteinaceous surfactant-like material inside the alveolar space.
• Failure to clear this substance leads to its accumulation and therefore impaired gas exchange (1,2).
• PAP can be classified in the following categories based on its pathophysiology (1):
  • Primary or idiopathic PAP (90% of cases) commonly presents in adults (2,3).
  • Secondary PAP (sPAP) (4% cases) (4)
  • Congenital PAP (cPAP) (1% of cases) (4)
  • Unclassified PAP: Patient with evidence of granulocyte-macrophage colony-stimulating factor (GM-CSF) impair signal without evidence of antibody presence.

Epidemiology

• Median age of onset at 39 to 51 years
• Male > female (2:1) incidence in autoimmune (4)
• Male > female (1.2:1) incidence in secondary PAP, however, may be confounded by increased smoking rates in males, a known association

Incidence
Estimated 0.2 per million of habitants per year (5)

Prevalence
Remains to be rare disease with prevalence of 0.1/100,000 individuals (1)

Etiology and Pathophysiology

• As mentioned above, PAP is a result of dysregulation of surfactant metabolism either by ineffective formation or by its impaired clearance rather than overproduction. Accumulation of this proteinaceous material in alveolar space overwhelmed macrophage antimicrobial function (phagocytosis, chemotaxis, superoxide production, pathogen recognition, cytokine release, cellular adhesion), leading to impaired gas exchange and increase infection recurrence. Of notice, there are four main subtype surfactant proteins (SFTP): A, B, C, D.
  • Primary or Idiopathic or Autoimmune Pap (aPAPP) is associated with antibodies (IgG) against GM-CSF disrupting adequate macrophage maturation (differentiation, proliferation, survival) pathways (1,2,4), which is indispensable to defend against opportunistic infections. Impaired cells are known to be monocytes, neutrophils, dendritic cells, pneumocyte type II. Healthy individuals may have IgG anti–GM-CSF, but they have been suggested to help in autoregulation, and it is theorized that only becomes pathogenic when surpasses certain concentrations level (4,5).
  • sPAP: occurs in patients with baseline macrophage malfunction and/or relative deficiency of GM-CSF. Patients are usually heavily exposed to environmental factors (i.e., dust) which act as direct toxin against macrophages. It is also associated with immune deficiency disorders, hematologic disorders (i.e., myelodysplastic syndrome [MDS] 84%, plasma cell dyscrasias, acute myelogenous leukemia [AML] 14%, chronic myelogenous leukemia [CML] 8%; 15.2% overall, lymphomas), primary immune deficiency diseases (DiGeorge syndrome, common variable immunodeficiency, HIV), nonhematologic malignancy has also been reported (mesothelioma, lung cancer, glioblastoma), autoimmune diseases (rheumatoid arthritis, Behçet disease, dermatomyositis), drug induced (i.e., sirolimus, leflunomide) (1,4,5).
  • cPAP: as a result from genetic variation including mutations in SFTP, proteins involving surfactant metabolism, and defect in cationic amino acid transport (4,5)
• Pathology
  • Autopsy findings commonly describe up to 2-cm yellow-grey nodules throughout the lung; thick, firm, and with milky secretion
  • Histologic review with general light microscopy with hematoxylin reveals unaltered alveolar with epithelial cell lining damaged, sloughed from wall (alveoli and terminal bronchi), and peribronchial lymphocytic infiltration.
  • All structures are filled with milky lipoproteinaceous material, periodic acid–Schiff (PAS) positive.
  • Under electron microscopy, bronchoalveolar lavage fluid (BALF) shows free and/or intracellular (eosinophils, macrophages) concentrically laminated phospholipid bodies, within lysosomes (lamellar bodies) (2).
  • Advance chronic cases of congenital cases might demonstrate varying degrees of interstitial remodeling with reactive septal thickening from pneumocyte type II hyperplasia.

Genetics

• Gene deficiency includes GATA2 (20%), DiGeorge, whereas gene mutation includes CSF2RA and CSF2RB (encodes α and β chains of GM-CSF receptor), NK2 homeobox-1 gene, thyroid transcription factor-1 gene, SFTPB, SFTPC, ATP-binding cassette 3 (ABCA3), TTF1, NPC2, NPB, variants in SLC7A7 (leading to dysfunctional arginine transport and dysfunctional macrophage), and variant in methionyl-tRNA synthetase (MARS-missense mutation) (2,3).
• Congenital SLC7A7, CSF2RA, and CSF2RB variant are transmitted in autosomal-recessive pattern with incomplete penetrance.

Risk Factors

• Tobacco smoke exposure (found in 53–85% of patients) (4)
• Exposure to inhalational toxins such as organic dust (found in 48% of patients): flowers, fertilizers, silica, aluminum, cement, indium, titanium dioxide, nitrogen dioxide, insulation fibers
• Infectious processes such as Pneumocystis jirovecii, Nocardia, and some mycobacterial infection have been related to trigger autoimmune response. Pediatric infections may be related to mycoplasma, influenza, and respiratory syncytial virus infections (3).
• Lung-transplant patients undergoing macrolide calcineurin inhibitors and/or mTOR inhibitors

Pediatric Considerations

• cPAP leads to neonatal idiopathic pulmonary hypertension and neonatal respiratory distress syndrome not responsive to surfactant or corticosteroids. It is caused by a mutation in surfactant-protein B or C genes or GM-CSF receptor β- or α-chain abnormalities. Lung transplant is primary therapy for cPAP, but prognosis is poor (3)[C].
• Hereditary PAP may present in children and is treated with whole lung lavage (WLL).

General Prevention

There are nonspecific measures for prevention other than to avoid tobacco smoke exposure and to minimize other risk factors as mentioned above.