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