alveolar proteinosis

Digital cases

 Case 87 (HPC:87)

Definition: Pulmonary alveolar proteinosis (PAP) is a rare cause of chronic interstitial lung disease in children characterised by accumulation of a lipoproteinaceous material in the alveoli.

Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP).

Synopsis

 Bronchoalveolar lavage

• milky appearance of the return fluid
• periodic acid-Schiff staining material in the alveolar macrophages
• homogeneous, granular material typical of PAP.

Ultrastructure

The material is composed of extracellular, multilamellated bodies when viewed by electron microscopy.

Etiology

 genetic primary PAP

• SFTPB mutations with SP-B deficiency (early-onset PAP) (#8163685#)
• SFTPC mutations with SP-C deficiency (MIM.178620) at 8p21
• ABCA3 mutations with neonatal surfactant deficiency
• CSF2RB mutations (GM-CSF receptor ß subunit) (MIM.138981)
• TTF1 (TITF-1) gene mutation (MIM.600635) (#15517377#)
• CSF2RB mutations (GM-CSF/IL-3/IL-5 receptor common beta chain) (#9694696#)

 acquired pulmonary alveolar proteinosis (PAP)

• adult idiopathic PAP
• autoimmune alveolar proteinosis (autoimmune PAP) (#18202348#)
  • autoantibody anti-GM-SCF (#16423275#, #15618581#)

 secondary PAP (associated PAP)

• immunodeficiency
  • constitutional immunodeficiency
  • acquired immunodeficiency
    • AIDS and HIV infection
    • bone marrow allograft (#16162733#)
    • umbilical cord blood transplantation (#12111790#, #12562244#)
    • lung allograft recipients (#9416695#)

• immunosuppression
  • corticosteroids
  • antirheumatoid arthritis drug leflunomide (#16916345#)

• leukemias and blood diseases (#7429503#)
  • chronic myeloid leukemia (chronic myelogenous leukemia or CML) (#9568140 #)
  • acute myeloid leukemia (#16173954#, #16432866#)
  • acute lymphoblastic leukemia
  • sideroblastic anemia
  • myelodysplastic syndrome (#10407875#, #12547151#)
  • Fanconi anemia (Fanconi disease) (#515542#)
  • myelofibrosis after essential thrombocythemia (#12854908#)

• pulmonary infections
  • Pneumocystis carinii
  • Nocardia asteroides
  • Histoplasma sp.

• systemic infections
  • nocardiosis (#9517865#)

• lysinuric protein intolerance (#8163273#)
• dermatomyositis
• Imatinib treatment (#14656624#)

• dusts
  • silicosis (silicoproteinosis of the lung)
  • cotton and linen dust (#15757263#)
  • fibrous insulation material (#10858425#)
  • Orasol Navy Blue dust (#7530021#)
  • cement dust (#2918407#)
  • aluminum dust exposure (#6465685#)
  • glass fiber (#372672#)

• NO2 exposure (?) (#1870017#)

Associations

 busulfan lung (#2316373#)
 end-stage pulmonary fibrosis
 malignant mesothelioma (#15838000#)
 disseminated atypical mycobacteriosis (#2316373#)

• disseminated Mycobacterium kansasii infection (#14587059#)

 cytomegalovirus infection (#218518#)
 human parainfluenza virus giant cell pneumonia (#12562244#)
 sporadic associations

• renal tubular acidosis (#7742818#)
• Fanconi disease (#7742818#)
• glioblastoma multiforme (#7742818#)
• atrioventricular septal defect (#7742818#)

Animal model

 development of PAP in

• GM-CSF knock-out mice / (GM-CSF)(-/-) mice
• GM-CSF receptor knock-out mice

References

 de Blic J. Pulmonary alveolar proteinosis in children. Paediatr Respir Rev. 2004 Dec;5(4):316-22. PMID: #15531257#

 Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003 Dec 25;349(26):2527-39. PMID: #14695413#

 Yousem SA. Alveolar lipoproteinosis in lung allograft recipients. Hum Pathol. 1997 Dec;28(12):1383-6. PMID: #9416695#

 Bedrossian CW, Luna MA, Conklin RH, Miller WC. Alveolar proteinosis as a consequence of immunosuppression. A hypothesis based on clinical and pathologic observations. Hum Pathol. 1980 Sep;11(5 Suppl):527-35. PMID: #7429503#