Pulmonary AlveolarProteinosis

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

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 productionOf surfactant

Decreased clearance of surfactant

surfactant production, recycling and catabolism

Function of GM-CSF

SurfactantCatabolism

CellularImmunity

Maturation of Alveolar Macrophages

Surfactant accumulation Impaired Innate immunity

InfectionImpaired Gas

exchange

Physiological effect ofGM-CSF knockout

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.”

PAP

Auto GM-CSF Antibodies

leukemia myelodysplastic

syndromes HIV

Occupational (silica)

(SP) B deficiency and GM-CSF receptor β chain

abnormality

1ry/autoimmune/ Idiopathic

Neonatal / Congenital

Secondary

Causes types

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 PAP1. leukemic cells lacking expression of the βc chain of the GM-CSF

receptor),2. the effects of chemotherapy and radiation on macrophage

number and function3. the possible use of CST affects cell- mediated immunity

EXOGENOUS/OCCUPATIONAL EXPOSURE Silica "acute silico-proteinosis" , wood dust , aluminum dust , cellulose fibers , cement dust

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.

Clinical Presentation

• Progressive dyspnea

• cough ≈ 75 %

• occasional hemoptysis and fever ≈ 20%

• constitutional symptoms.

• Crackles ≈ 50%

• clubbing, and cyanosis have been reported.

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

Figure PAP in a 61-raey- cinorhc htiw nam dlo

suonegoleym dna eugitaf fo tesno tnecer dna aimekuel

hpargoidar tsehc roiretnaoretsoP .hguocshows symmetric, perihilar

ground-glass and reticulonodular opacities evitaler eht etoN .

selgna cinerhpotsoc eht fo gniraps .

HRCT : crazy-paving

• ‘‘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

Figure 6b. Crazy-paving in PAP.

Frazier A A et al. Radiographics 2008;28:883-899

©2008 by Radiological Society of North America

32-year-old man with HIV BAL showscystic 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 andmassive hemoptysis. acute intraalveolarhemorrhage.

Methotrexate-induced NSIP in a 41-year-old woman with rheumatoid arthritis

Lipoid pneumonia in a 64-year-oldWoman open lung biopsy shows numerous lipid-laden macrophages that fill and distend the alveoli (arrow) and interstitium

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

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 )

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.

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

• 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 .

3) Pathological FindingsMicroscopically, 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.

Biopsy

Treatment According to the cause

Congenital

Secondary

Idiopathic Asymptomatic

Rx of the cause

Lung transplantation

Limiting S/S

No Rx

•Whole Lung Lavage•Exogenous GMCSF•Plasmapheresis

•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

WLL : Whole Lung Lavage

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.

Parameter of improvement

Arterial PO2 (mm Hg)

(A - a)PO2 (mm Hg)

FEV1 (L)

Vital capacity (L)

DLCO (mL/mm Hg per min)

Sever Dyspnea

PaO2 < 60 mmHg

P ( A – a ) O2 > 40 mmHg

Shunt fraction > 10% to 12%

recommendations for WLL

Complications of WLL includehypoxemiaPneumoniaSepsishydropneumothorax, adult respiratory distress syndrome

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

GM-CSF ( experimental approaches)