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.
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)
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.
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
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
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)
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 *Polygonal shapes "CRAZY PAVING", branching pattern of white linear areas forming geometric shapes around 10 mm in diameter overlying consolidated areas.
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
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
- Lab markers: CBCD and chemistry normal
*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.
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)
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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