Pulmonary alveolar proteinosis (PAP) is a disease characterized by accumulation of surfactant in alveoli due to defects in surfactant clearance. The accumulation impairs gas exchange and can cause respiratory failure. Whole lung lavage is the primary treatment and improves symptoms in most patients by removing surfactant from the lungs. Exogenous GM-CSF may also be used but does not provide a cure. The document provides details on the pathophysiology, clinical presentation, diagnosis, and management of PAP.

1. Pulmonary Alveolar
Proteinosis

2. Overview
• (PAP) is a syndrome
Characterized by progressive
accumulation of surfactant
Phospholipids and proteins
within alveoli and terminal
airways.
• The disease is not associated with inflammation,
and lung architecture is typically preserved

3. Patho-physiology
• The alveoli in PAP are filled with proteinaceous
material, that is found to be normal surfactant
composed of 90% lipids and 10% surfactant-associated
proteins A, B, C, and D (SP-A , SP-B .. )
Defect in surfactant
Homeostatic mechanisms
Increase production
Of surfactant
Decreased clearance
of surfactant

4. surfactant production, recycling and catabolism

8. Function of GM-CSF
Maturation of Alveolar Macrophages
Surfactant
Catabolism
Cellular
Immunity
Physiological effect of
GM-CSF knockout
Surfactant accumulation Impaired Innate immunity
Infection
Impaired Gas
exchange

9. Physiological effect of PAP
• This surfactant-derived alveolar fluid may
cause increased work of breathing, a
diminished surface area for gas diffusion, and,
ultimately, respiratory failure.
• The development of superinfection, which is
thought to be a relatively common
consequence of pulmonary macrophage
dysfunction, may further complicate the
condition “Nocardia spp.”

10. PAP
Causes types
Auto GM-CSF
Antibodies
leukemia
myelodysplastic
syndromes
HIV
Occupational (silica)
(SP) B deficiency and
GM-CSF receptor β chain
abnormality
1ry/autoimmune/
Idiopathic
Secondary
Neonatal /
Congenital

11. ADULT IDIOPATHIC PAP most common
NEONATAL/CONGENITAL PAP (AR)  Respiratory distress in a
newborn not responsive to surfactant replacement  Death within
first few months
SECONDARY PAP
1. leukemic cells lacking expression of the βc chain of the GM-CSF
receptor),
2. the effects of chemotherapy and radiation on macrophage
number and function
3. the possible use of CST affects cell- mediated immunity
EXOGENOUS/OCCUPATIONAL EXPOSURE Silica "acute silico-proteinosis"
, wood dust , aluminum dust , cellulose fibers , cement
dust

12. Epidemiology
• PAP is extremely rare
• Mortality rate :
 In neonates (congenital )  100%.
 acquired PAP , the 5-year survival rate was 75%.
• M : F ratio of 2.65:1), 72% have a history
of smoking
• 90% of all cases of PAP are the acquired type. The
median age at the time of diagnosis is 39 years.

13. Clinical Presentation
• Progressive dyspnea
• cough ≈ 75 %
• occasional hemoptysis and fever ≈ 20%
• constitutional symptoms.
• Crackles ≈ 50%
• clubbing, and cyanosis have been reported.

14. Radiology
• a"butterfly"
distributionTypically a
bilateral, symmetrical
alveolar filling pattern is
seen. With
• interstitial, mixed,
diffusely nodular, and
focally dense patterns
have been reported
DD
• pulmonary edema (ARDS)
• Pneumocystis jirovecii (carinii)
pneumonia.
• Hypersensitivity pneumonitis

15. Figure PAP in a cinorhc htiw nam dlo-raey-61
dna eugitaf fo tesno tnecer dna aimekuel suonegoleym
hpargoidar tsehc roiretnaoretsoP .hguocshows symmetric, perihilar
ground-glass and reticulonodular opacities evitaler eht etoN .
.selgna cinerhpotsoc eht fo gniraps

16. HRCT : crazy-paving

17. • ‘‘crazy-paving’’ pattern that consists of scattered or diffuse
ground-glass attenuation with superimposed interlobular
septal thickening and intralobular lines
• Changes correlate with the presence of a restrictive
ventilatory defect, reduced diffusing capacity, and
hypoxemia

19. Figure 6b. Crazy-paving in PAP.
Frazier A A et al. Radiographics 2008;28:883-899
©2008 by Radiological Society of North America

21. 32-year-old man with
HIV  BAL shows
cystic forms of P carinii
(arrows).
Diffuse mucinous BAC
in a 78-year-old man 
open lung biopsy shows
neoplastic cells with
abundant intr-acytoplasmic
mucin
(arrows).
53-year-old woman
with SLE and
massive hemoptysis.
acute intraalveolar
hemorrhage.

22. Lipoid pneumonia in a
64-year-old
Woman open lung
biopsy shows
numerous lipid-laden
macrophages that fill
and distend the
alveoli (arrow) and
interstitium
Methotrexate-induced
NSIP in a 41-year-old
woman with rheumatoid
arthritis

23. PFTs
• Mild restrictive.
• reduction in diffusing capacity.
• mildly hypoxemic
• elevated alveolar-arterial PO2 difference along with a
compensated respiratory alkalosis.
• The shunt fraction has been shown to be elevated as
compared to patients with other diffuse lung
diseases

24. LAB
• Serum LDH is frequently elevated ( 82% ) .
• Surfactant proteins SP-A, SP-B, and SP-D have been
reported to be elevated in the sera of patients with
PAP. ( nonspecific  ALI , IPF )

25. BAL
• Grossly milky and opaque , forming sediment when
left to settle.
Milky proteinaceous whole lung lavagate from
a patient with PAP. Note the foamy surfactant
layer.

26. Microscopic features of BALF -cytospin preparation
BALF is composed of granular, acellular, and amorphous material
and a small number of cells. Cell components consist of large,
(1) foamy alveolar macrophages
(2) small monocyte-like macrophages

27. • The most striking observation of the BAL sediment is
the gross appearance of the alveolar macrophage.
These cells are enlarged and engorged with lipid
material with a foamy, vacuolated appearance under
light microscopy .

28. Biopsy
3) Pathological Findings
Microscopically, alveoli and terminal bronchioli are filled with a
fine eosinophilic material stained strongly for surfactant proteins
with periodic acid-Schiff reagent. The alveolar wall and interstitial
architecture are relatively well-preserved.

29. Treatment
According to the cause
Congenital
Secondary
Lung transplantation
Rx of the cause
Idiopathic Asymptomatic
Limiting S/S
No Rx
•Whole Lung Lavage
•Exogenous GMCSF
•Plasmapheresis

30. WLL : Whole Lung Lavage
•repeated segmental flooding with saline ( 20-40 L) under GA
via a double lumen endotracheal tube  significant clinical,
physiologic, and radiologic improvements in up to 84% of cases
after the first lavage ( repeat treatments commonly required )
•Recently, alternative techniques using fiberoptic bronchoscopy
Whole lung lavage fluid. The
retrieved fluid of the left
lung in the first bottle is
more milky and turbid. The
turbidity and amount of
sediment decreased
gradually.

31. recommendations for WLL
 Sever Dyspnea
 PaO2 < 60 mmHg
 P ( A – a ) O2 > 40 mmHg
 Shunt fraction > 10% to 12%
Parameter of improvement
Arterial PO2 (mm Hg)
(A - a)PO2 (mm Hg)
FEV1 (L)
Vital capacity (L)
DLCO (mL/mm Hg per min)
Complications of WLL include
hypoxemia
Pneumonia
Sepsis
hydropneumothorax,
adult respiratory distress
syndrome

32. GM-CSF ( experimental approaches)
The initial therapy included 5 – 20 μg/kg/day of GM-CSF
subcutaneously with a rapid dose
GMCSF via aerosol
GM-CSF therapy is not curative, and some patients relapse
after discontinuing therapy