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PULMONARY ALVEOLAR PROTEINOSIS
Pulmonary alveolar proteinosis is a rare disease and this case shows some clinical issues that pulmonologists face in dealing with this disease. It is important for pulmonologists to know about this disease and treatment options and considerations. I will now review the literature on pulmonary alveolar proteinosis.

The following sections will cover:
Definition
– Surfactant Review
– Types of alveolar proteinosis:
congenital alveolar proteinosis (SP-B deficiency) acquired alveolar proteinosis
– Historical
– Epidemiology
– Pathogenesis
– Clinical Manifestations
– Diagnosis
– Treatment
– Prognosis
– Application to this case

Pulmonary Alveolar Proteinosis
– Non-inflammatory lung disease
– Syndrome characterized by alveolar filling with surfactant-associated lipids and proteins
– No structural airway abnormalities and no fibrosis

Pulmonary Surfactant Review
– Composition of surfactant in humans: 90% phospholipid, 10% protein, minimal carbohydrate
– Premature infants are deficient in phosphotidylcholine, phosphotidylglycerol
– Exogenous surfactant restores function by reconstituting phospholipids
– Four surfactant proteins: (A, B, C, D) have been characterized at a moelcular level.

BELOW: Biosynthesis of surfactant protein B. Click to enlarge.


Phospholipid components of surfactant are synthesized from choline and fatty acid precursors in the endoplasmic reticulum and Golgi apparatus of type II alveolar cells. The SP-B gene on chromosome encodes mRNA, which in turn directs the translation of a preprotein. The protein is then processed from a multivesicular body to give rise to a lamellar body. The lamellar bodies and then extruded into the alveolar lumen where they form tubular myelin. This makes up the underlying latticeowrk upon which the phospholipid film lies. The film and the latticework are then degraded and cycled back by the type II pneumocytes or the taken up by alveolar macrophages.

Cellular and Molecular of Surfactant Protein-B (SP-B)
– SP-B exclusively found in human lungs, in type II pnuemocytes
– Function - increases organization of phospholipid film, which is required to decrease surface tension in alveoli: SP-B is necessary for formation of tubular myelin
– Regulation - there are glucocorticoid response elements in the promoter region which facilitate surfactant synthesis.
– Activity - an anti-SP-B antibody had been identified and plays a role in pulmonary inflammation

SP-B Deficiency In Humans
– First described in family of 3 infants (Nogee, 1993, NEJM, )
– Respiratory failure at birth despite being term infants - congenital alveolar proteinosis
– Mode of transmission is autosomal recessive, lethal disease without transplantation
– 30 subsequent families, 50 infants have been identified (1997)
– Rare, probably underrecognized

a) Molecular Aspects
– 2 mutations: which result in unstable transcription:

121ins2 mutation - Substitution of three bases for single nucleotide
Premature termination signal as a result of a frameshift mutation
Most common, accounts for 75% of alleles in SP-B deficient patients
R236C mutation - Nucleotide substitution which resulted in alteration of the amino acid

– Heterogenous disease - ? phenotypic variations

b) Clinical Features of SP-B Deficiency
– Born at or near term, clinically and radiographically similar to hyaline membrane disease with severe, progressive respiratory failure.
– There may be a family history:
– Homozygotes: Aggressive supportive interventions do not help including: surfactant replacement, corticosteroids, ECMO
– Heterozygotes: low, but detectable SP-B in tracheal fluid may benefit from steroids, spontaneous resolution has been reported
– 5 survivors total in literature despite onset in infancy which may represent a heterogenous disease.
– Adding SP-B did not help, death at age 54 days (Hamvas, 1994, J Peds)

c) Biochemical Features of SP-B Deficiency
– Complete lack of immunoreactive SP-B
– Abnormal surfactant composition and function: increased accumulation of proSP-C and an aberrant form of SP-C
– Role in pathophysiology of SP-B not yet known

d) Treatment and Prognosis of SP-B Deficiency
– Rapid fatal outcome without prompt recognition and treatment.
– Lung transplant; only available option, but longest reported survival was 34 months as of 1996 (Hamvas, 1997, Adv in Peds)
– Other temporizing measures: glucocorticoids, SP-B replacement have been tried, BAL - no long term benefit
– ? potential role for gene therapy in the future


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