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Acquired Pulmonary Alveolar Proteinosis

a) Historical Aspects
– First described in 1958 (Rosen et al)
– 27 occurences, 2 in children
– Definitive diagnosis by open lung biopsy
– Accumulation of large amounts of proteinaceous surfactant phospholipid-laden material in the alveoli
– Results in impaired gas exchange and hypoxemia
– No response to antibiotics, postural drainage, inhaled and systemic corticosteroids.

b) Epidemiology
– Described across the age spectrum (infancy to 73 yrs), mostly young or middle-aged adults.
– Youngest reported infant is 5 mos of age (Sakai, 1999, Eur J Peds)
– Male:female 2-4:1 in adults, smokers:non-smokers 3:1
– 2 forms have been described: idiopathic or primary and secondary
– Reported secondary causes include: lysuruic protein intolerance, lipoid pneumonia, malignancy, infection (HIV, MAI), and inhalant exposure (silica, aluminum)
– Rare (~1 in 2,000,000)

c) Pathogenesis
– Initially noted in mouse model - knock out mice of pulmonary alveolar proteinosis (PAP) – Genetically altered mice with GM-CSF deficiency (either GM-CSF or GM-CSF Bc receptor) have surfactant protein accumulation, treating with GM-CSF or correcting expression will correct PAP
– Reported bone marrow transplant and aerosolized GM-CSF corrects the defect in mice
– GM-CSF essential for surfactant clearence/catabolism
– However, the human model is speculated to be different as humans have: No Intrinsic cellular defect (GM-CSF receptor abnormality, intracellular signaling defect)
Synthesize and respond to GM-CSF Abnormal GM-CSF or deficiency
– GM-CSF neutralizing factor (IL-10) has been identified
– Anti GM-CSF antibody has been identified in patients with PAP (Kitamura, 1999, J Exp Med)
– It is not known whether antibody titres correlate with disease activity or removal will improve the disease. (Thomassen et al, 2000, Clinical Immunology)
– All the cases suggest that GM-CSF deficiency is not the etiology in humans. Carraway et al (2000) AJRCCM
– found elevated GM-CSF in bronchoalveolar lavage fluid of patients with PAP.

d) Gross Pathology
– Gross - heavy lungs, insoluble/yellow substance with patchy distribution and unaffected pleural \ surface, with little or no fibrosis; the conducting airways unaltered
– Histology - alveoli filled with PAS + material, lipid and protein rich. There are cuboidal alveolar cells, hyperplastic cells (type II), large macrophages, no fibrosis
– EM shows: lamellar bodies, tubular myelin-like

e) Clinical Manifestations * Denotes important features
– Children and Adults - variable clinical picture, but common features include:
– * Exercise intolerance (80%) - insidious onset
– Mild cough ( +/- productive) (60%)
– Chest pain, fatigue rare
– Failure to thrive/ weight loss
– Infants; may present with decreased spontaneous activity, but 30% are asymptomatic
– Fever mostly with superinfection
– Physical Examination: tachypnea, normal breath sounds or diffuse inspiratory crackles, clubbing (~30%)
– Cyanosis (late), cor pulmonale uncommon

f) Radiological Findings
– CXR: *"batwing" or "butterfly" pattern (perihilar)
– Variable findings; focal/diffuse; consolidative or reticulonodular appearance, alveolar infiltrates, no cardiomegaly, no pleural disease, no nodes, no cavitation (Holbert et al, 2001, Am J Roentgenology)
– Reported lobar involvement (Shah et al, 2000, Thorax)

CT Scan (HRCT) : Alveolar filling; patchy and variable
– Retrospective review: 139 chest CT scans from 27 patients with PAP, before and after lavage pictures in 9 patients.

– Geographic or diffuse, uniform zonal pattern, lower zone predominance, no peripheral sparing
– Ground glass opacities (100%), "geographic pattern", Interlobular septal thickening (85%)
– Airspace opacities (78%), Substantial fibrosis (7%), Intralobular opacities (7%)
– Proportion of ground glass and interlobular opacities decreased significantly after lavage.
– Often mixed pattern
– *Polygonal shapes "CRAZY PAVING", branching pattern of white linear areas forming geometric shapes around 10 mm in diameter overlying consolidated areas.
– Mixed pattern (Holbert, 2001, AJR)

– (Albafouille, 1999, Pediatric Radiology): HRCT in Children - retrospective review (n=5), age 3 mos - 4 yrs:

– Diagnosis of PAP established by BAL or lung biopsy
– Initial: diffuse reticulomicronodular pattern with posterior bilateral infiltrates
– Post-lavage: variable decrease in infiltrates
– Two patterns reported: Type I; alveolar infiltrate +/- reticulo-nodular pattern; Type II; diffuse pseudo-interstitial pattern

g) Investigations
- Lab markers: CBCD and chemistry normal

*Elevated LDH
*Hypoxemia, normal pH, +/- low PaCO2 (mild respiratory alkalosis), midly elevated A-a gradient
*Increased shunt (R to L with exercise) (Wang, 1997, Chest)

Other experimental markers:
– Elevated SP-A in serum and sputum
– Elevated SP-D can correlate with disease severity but also raised in interstitial lung disease and idiopathic pulmonary fibrosis
– KL-6 from BAL, mucin-like protein secreted from type II pneumocytes, correlates with disease activity (Takahaski, 1998, AJRCCM)

– PFT: mild restrictive pattern, DLCO impaired disproportionately to decrease in FVC and TLC Sputum studies not helpful as cough is often dry.

h) Diagnostic Considerations
– For diagnosis *Characteristic features as mentioned above.
– Rule out superinfection, and rule out mycobacterium, Nocardia, PCP
– Evaluate immune status
– BAL; milky fluid, large amount of surfactant proteins in BAL is confirmatory
– EM; lamellar bodies and FEW tubular myelin
– Tumor markers (CEA), KL-6 have been indentified, but diagnostic role is limited
– Definitive lung biopsy (either with transbronchial lung biopsy or open lung biopsy) not necessary if BAL findings and HRCT are suggestive.
– Transbronchial biopsy (TBLB diagnostic yield 29% in 68 patients with PAP (Golstein et al, 1998, Chest)

Other helpful features:
– Increased total phospholipids, decrease in phosphotidylcholine, phosphatidylglycerol, phosphotidylserine; increased phosphotidylinositol, and increased A, B, D surfactant. Ratio of surfactant protein (SP)-A to disaturated phophslipid (DSP) - high ratio in PAP (Honda et al, Chest, 1993); Doyle, 1998, JRCCM). The ratio may help in predicting response to therapy in adults (n=2) (Crocker, 2000, Eur Respir J), but unknown significance in children
– Microscopy: acellular globules, few and foamy macrophages, cell debris, increase in lymphocytes if infection
– Cell count sparse and differential cell count is not helpful. Need special stains (PAS, and alcian blue)
– Papanicolaou-stain for PAP - globules stain green, orange, or orange in the centre with green rim) - seen with light microscope are multilamellated structures. (Chou et al, 2001, Arch Dis Med). Thought to be highly sensitive and specific as patients with PAP have high numbers of globules, but can be seen in other diseases in small numbers.



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