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– *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
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.
Next page / 1 2
3 4
5 6