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Pulmonary alveolar proteinosis (PAP) is a syndrome characterized
by the accumulation of surfactant lipids and proteins within the
pulmonary alveoli, resulting in impaired gas exchange and respiratory
insufficiency.1 Our understanding of PAP has advanced
significantly over the past several decades due to a series of contributions
from basic, clinical, and translational research.2,3 These
studies have revealed a critical role for pulmonary granulocyte/macrophage-colony
stimulating factor (GM-CSF) in the terminal differentiation of alveolar
macrophages and in alveolar macrophage-mediated surfactant catabolism,
pulmonary surfactant homeostasis, and lung host defense.4-6 PAP
comprises part of a larger group of disorders associated with disruption
of surfactant homeostasis and includes disorders of surfactant production
(hereafter referred to as pulmonary surfactant metabolic
dysfunction disorders) and disorders of surfactant clearance
(hereafter referred to as PAP; Table
518-1). The distinct epidemiological, pathogenic, clinical,
and prognostic features of these two disease categories indicate
they are usually considered separately rather than as a continuum
of a single disease process. PAP can be further divided into primary
and secondary PAP, which, respectively, are associated with either
loss of GM-CSF signaling or the presence of an underlying disorder
that reduces alveolar macrophage numbers or functions.
++
Epidemiological studies of disorders of surfactant homeostasis
are hampered by their rarity and values for incidence, and prevalences
provided here are considered estimates. Autoimmune pulmonary alveolar proteinosis (PAP)
is the most common clinical form, accounting for 90% of
all cases, and has an incidence and prevalence of 0.49 and 6.2 per
million, respectively, in the general population.2,15 It is
twice as common in males as females, possibly due to an association
with smoking, typically presents in the third or fourth decade,
and it is rarely observed in children under 10 years old.15,23 Secondary
PAP is the next most common, accounting for 9% to 10% of
cases, with an incidence and prevalence of 0.05 and 0.5 per million,
respectively. Secondary PAP is linked to the occurrence of the underlying
clinical conditions that cause it (Table 518-1). Only
isolated cases of PAP associated with GM-CSF receptor α-14 or β-15 chain
abnormalities and none associated with GM-CSF deficiency have been
reported24; thus, PAP caused by genetic mutations
appears to comprise less than 1% of cases.
++
Pulmonary surfactant metabolic dysfunction disorders, which have
varying degrees of surfactant accumulation, occur in individuals
with mutations in the genes encoding surfactant protein B (SP-B),
ATP-binding cassette A3 (ABCA3), and SP-C (SFTPB, ABCA3 and SFTPC
genes, respectively). SP-B deficiency due to autosomal recessive
SFTPB mutations is estimated to occur in 1 in 1.5 million births.11,25,26 ABCA3
dysfunction and pulmonary disease due to autosomal recessive ABCA3
mutations is predicted to occur more commonly than mutations causing
SP-B deficiency.11,27 Population studies of SFTPC
mutations have not been reported. However, case and small familial
cohort studies demonstrate that autosomal dominant and sporadic
SFTPC mutations are associated with interstitial lung disease in
adults9,10,28 and very rarely in young children.10,29,30 Other
genetic causes of PAP and pulmonary metabolic dysfunction disorders
likely exist.
++
Surfactant is vital to lung structure and function and acts at
the alveolar wall’s air-liquid-tissue interface to reduce
surface tension, thereby preventing alveolar collapse and transudation
of capillary fluid into the alveolar lumen. It is composed primarily
of lipids (~90%) and proteins (~10).31 Surfactant
proteins (SP-A, B, C, D) contribute to the surface-active properties
and structural forms of intra-alveolar surfactant,32 participate
in regulation of surfactant metabolism,33 opsonize
microbial pathogens,34 and stimulate host defense
functions of alveolar macrophages.35 Surfactant
lipids and proteins are synthesized, stored, and secreted into alveoli
by alveolar type II epithelial cells. They are cleared by uptake
and recycling in alveolar type II cells and by uptake and catabolism in
alveolar macrophages.5 Surfactant pool size is
tightly regulated by coordinate mechanisms controlling its synthesis,
recycling, and catabolism.
++
The pathogenesis of disorders of surfactant homeostasis is usefully
considered in terms of defects in the production or clearance of
pulmonary surfactant. PAP, an example of the latter, appears to
result from reduced alveolar macrophage-mediated pulmonary clearance
of surfactant. This can occur due to a reduction in the alveolar
macrophage’s ability to catabolize surfactant lipids and
proteins (ie, reduced intrinsic clearance) or to a reduction in
their numbers (ie, reduced clearance capacity).
++
The first real clue about the pathogenesis of PAP was the observation
that mice deficient in GM-CSF developed PAP due to a decrease in
the alveolar macrophages’ ability to catabolize surfactant.6,3
6Defective catabolism was caused by reduced levels of macrophage
differentiation-stimulating transcription factor PU.1.4 Surfactant
catabolism was restored by replacing GM-CSF in the lungs of these
mice37 or by expressing PU.1 in GM-CSF-deficient
alveolar macrophages.4 Mice deficient in the GM-CSF
receptor β chain also develop PAP.38 Although
GM-CSF deficiency has not been observed in humans,24 90% of
PAP patients have high levels of neutralizing GM-CSF autoantibodies,
which eliminate GM-CSF bioactivity in vivo and presumably mediate
pathogenesis by blocking GM-CSF signaling to alveolar macrophages. In
support of this mechanism, PU.1 levels are reduced in these patients
and are increased by GM-CSF therapy in parallel with clinical improvement.39 Importantly,
the phenotype of humans with autoimmune PAP is histologically, physiologically,
biochemically, immunologically, and ultrastructurally similar to
PAP in GM-CSF-deficient mice; this suggests that the mechanisms
by which GM-CSF regulate myeloid cells, including surfactant catabolism
and antimicrobial functions, are similar in mice and humans.3,4,39,40 The
recent identification of familial PAP in association with recessive
mutations of the GM-CSF receptor a chain supports the critical role
of GM-CSF signaling in surfactant homeostasis and the pathogenesis of
PAP in humans. By convention, primary PAP is defined as occurring
due to the interruption of GM-CSF signaling in the absence of other
diseases known to be associated with PAP.
++
Several clinical disorders have been associated with the development
of secondary PAP (Table 518-1). Although
not well studied, the mechanism appears to be caused by either a
reduction in the intrinsic ability of alveolar macrophages to catabolize
surfactant or a reduction in the number of alveolar macrophages (resulting
in a reduction in the capacity of the pulmonary alveolar macrophage
population to catabolize surfactant). For example, myelofibrosis
that impairs macrophage functions and chemotherapy sufficient to
cause prolonged neutropenia can also reduce the numbers of otherwise
intrinsically functional alveolar macrophages, resulting in decreased
clearance capacity and surfactant accumulation.
++
Surfactant metabolic dysfunction disorders due to a deficiency
or dysfunction of surfactant proteins SP-B,41 SP-C,9 or
ABCA311 result in production of abnormal surfactant,
which alters lung mechanics and causes respiratory distress syndrome
in infants and interstitial lung disease in older patients. The
pathological features of these disorders include fibrosis, alveolar
wall thickening, and significant parenchymal lung distortion (Fig. 518-1). This differs markedly from the
pathological features of primary PAP, which in most cases is comprised
primarily of the alveoli filling with surfactant without significant
alveolar wall pathology (Fig. 518-1). The
association of mutations in genes critical in surfactant production,
metabolism, and function implicates the alveolar type II cell and
surfactant homeostasis in the pathogenesis of interstitial lung
disease (ILD) and pulmonary fibrosis.42,43
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Clinical Features
and Differential Diagnosis
++
The clinical presentation in disorders of surfactant homeostasis
differs widely, providing important initial clues to the underlying
etiology. In primary pulmonary alveolar proteinosis (PAP), symptoms
typically occur when surfactant has accumulated to sufficient levels
to impair pulmonary gas exchange, at which time dyspnea develops
insidiously. Autoimmune PAP typically presents as dyspnea in a previously
healthy adult who may or may not have a history of smoking or other
pulmonary exposures. Cough and production of whitish sputum are less
common, and fever, hemoptysis, and chest pain are unusual unless
infection is also present. Clubbing is uncommon. In the few individuals with
primary PAP due to GM-CSF receptor abnormalities, insidious onset
of dyspnea occurs in infancy or childhood. Secondary PAP occurs in
individuals with a prior illness usually known to be associated
with development of PAP. Thus, a high degree of suspicion is helpful.
++
Pulmonary surfactant metabolic dysfunction disorders have a wide
range of presentations. SP-B deficiency presents in term infants
as severe unexplained respiratory distress requiring emergent intubation
and mechanical ventilation. ABCA-3 deficiency may present similarly
to SP-B deficiency with neonatal respiratory failure in a term infant,
but it may also present subacutely as ILD with symptoms of tachypnea, dyspnea,
cough, hypoxemia, and diffuse infiltrates in older children.11,12,30 The
manifestations of SP-C mutations are highly variable and can present
at birth, throughout childhood, or in adulthood. Clinical or histological
evidence of proteinosis has not been reported in adult cases.9–11,28,30
++
The differential diagnosis of respiratory failure in a term neonate
also includes developmental lung anomalies, including alveolar capillary
dysplasia with misalignment of the pulmonary veins (ACD-MPV), pulmonary
hypoplasia, pulmonary interstitial glycogenosis, and lymphatic or
vascular disorders.30 The differential diagnosis
of PAP in older children includes mutations in SP-C, ABCA-3, CSF2RA,
CSF2RB; autoimmune PAP; secondary PAP; and other interstitial lung
diseases without alveolar proteinosis. The differential diagnosis
of PAP in adolescents and adults includes autoimmune PAP, secondary
PAP, and mutations in SP-C and possibly ABCA3.
++
The diagnostic evaluation of disorders of surfactant homeostasis
depends on the clinical context (ie, whether the disease is congenital
or acquired, stable or rapidly progressive, or has occurred in other
family members). Assessment may include a history and a physical,
a chest radiograph, computed tomography of the chest, arterial blood
gas measurements, bronchoscopy with bronchoalveolar lavage and transbronchial biopsy,
surgical lung biopsy, serum GM-CSF autoantibody testing, and genetic
testing.
++
In acquired pulmonary alveolar proteinosis (PAP) (autoimmune
PAP, secondary PAP), the chest radiograph shows diffuse ground-glass
opacification typically involving both lungs. This same pattern
is seen in primary PAP due to GM-CSF receptor a-chain mutations
(eFig. 518.1A). In both of these clinical
forms, abnormalities seen on chest radiograph may appear disproportionately
worse than suggested by the clinical appearance of the patient,
which can be of diagnostic significance. In SP-B deficiency, the
chest radiograph reveals diffuse ground-glass opacities consistent
with neonatal respiratory distress syndrome (RDS). The findings
on chest radiography are similar to those in patients with ABCA3
mutations (eFig. 518.1B).
++
++
Computerized tomography (CT) of the chest can aid diagnosis and
help guide selection of surgical biopsy sites; however, CT is insufficient
to establish a diagnosis and, in young children, requires sedation and
controlled-volume ventilation for imaging. In PAP associated with
neutralizing GM-CSF autoantibodies or GM-CSF receptor α-chain
dysfunction, the chest CT shows diffuse ground-glass opacification
superimposed on a reticular pattern (a characteristic but nondiagnostic
pattern referred to as “crazy paving”) throughout
both lung fields (eFig. 518.2A). In pulmonary
surfactant metabolic disorders, ground-glass opacification can also
be seen throughout both lung fields (eFig. 518.2B).
Although not well studied, the CT abnormalities in primary PAP (eFig. 518.2A) appear in a geographic distribution
(normal-appearing secondary pulmonary lobules adjacent to highly
abnormal secondary lobules) in contrast to the CT appearance in
ABCA3-related disease in which the pattern is homogeneous. A similar
homogeneous appearance is seen in secondary PAP.
++
++
Lung biopsy plays an important role in diagnosing PAP because
of the characteristic histologic appearance (Fig.
518-1A). Surgical lung biopsy can be useful in pulmonary surfactant
dysfunction disorders when genetic testing is nondiagnostic or when
the disease severity or progression mandates diagnosis before the
results of genetic testing can be obtained. Characteristic histopathologic
findings have been reported for autoimmune PAP and in lung diseases
associated with mutations in ABCA3 (Fig. 518-1C)
and SP-C.30,43 Proper tissue handling, including
processing for electron microscopy to assess lamellar body ultrastructure,
is critical to maximize the diagnostic yield of lung biopsy in these
cases.44
++
In uncomplicated cases of PAP in a previously healthy adult with
no underlying disease, the cytological findings from bronchoalveolar
lavage fluid and cells can be helpful in establishing a diagnosis
of PAP and in excluding other processes (ie, infection) as a cause
for symptoms. Notwithstanding, analysis of the surfactant components
in bronchoalveolar lavage fluid is performed on research basis only
and is not routinely recommended for clinical decision-making.
++
In neonates and children suspected of having PAP or pulmonary
surfactant metabolic diseases, genetic testing to establish a diagnosis
of disease-related SFTPB, SFTPC, or ABCA3 gene mutations is recommended.
If these studies are negative, testing for lysinuric protein intolerance
should also be considered. (Labs offering clinical genetic testing
for these disorders are listed at www.genetests.org.) An
advantage of genetic testing is its noninvasive nature. Disadvantages
include the relatively long time before results are obtained and
the lower sensitivity with current methods. Genetic counseling should be
offered to families undergoing genetic testing.
++
Therapy of disorders of surfactant homeostasis depends on the
specific disease present. Whole-lung lavage is standard therapy
for autoimmune pulmonary alveolar proteinosis (PAP) in adults and
in children.45–49 (See eFig. 518.3.) The
procedure is performed under general anesthesia and uses a double
lumen to ventilate one lung while the other is repeatedly filled
with warmed saline and then drained by gravity (followed by treatment
of the other lung). Chest percussion is used during the procedure
to optimize removal of the proteinosis material. Up to 15 to 50
liters is typically used to wash each lung. The procedure has not
been standardized among centers or evaluated in randomized, prospective
trials, nor have specific criteria indicating the need for, timing
of, or therapeutic response been developed. However, several small
studies have shown that whole-lung lavage improves the clinical,
physiological, and radiographic findings in most patients.48,50-56 Biochemical
evidence also supports the therapeutic efficacy of whole-lung lavage.57,58 Lobar
and segmental lavage by fiber-optic bronchoscopy has also been reported
for the treatment of PAP, although the practical clinical utility
of this approach is unclear.54,59,60 GM-CSF augmentation
is an experimental therapy for autoimmune PAP that is currently
being evaluated.Recombinant GM-CSF has been administered by subcutaneous
and aerosol routes in small trials and appears to be effective in
approximately 40% to 65% of patients.61-65 While
major side effects have not been observed, optimal dosing and timing
of administration have not been established, and further studies
are therefore needed. Based on the presumed concept that GM-CSF
autoantibodies are central to pathogenesis, other experimental approaches
for autoimmune PAP include plasmapheresis66 and
anti-B-lymphocyte antibody therapy to reduce the numbers of cells
producing GM-CSF autoantibodies.
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Therapy for secondary PAP is usually focused on treating the
underlying condition, the successful treatment of which can be associated
with correcting the associated pulmonary disorder.62 Efficacy
of lung lavage for secondary PAP has not been well established but
has been successful in some cases.67,68
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No definitive therapy other than lung transplantation currently
exists for pulmonary surfactant dysfunction disorders. Lung transplantation
is considered in cases of SP-B deficiency and in severe and progressive
disease from ABCA3 mutations.69,70 Neonates may
show transient improvement with exogenous surfactant administration.41 Whole-lung
lavage is extremely challenging and of uncertain efficacy in young
children, and an adapted technical approach to airway management
during lavage is required.71 While the use of chronic
systemic steroids, hydroxychloroquine, or other immunosuppressive
agents has been reported in children with surfactant metabolism
dysfunction disorders, there are no controlled studies supporting
their clinical utility in this setting.
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Common aspects of supportive care for children with surfactant
metabolic dysfunction disorders include assessing the need for supplemental
oxygen and nutritional support. Measures to prevent infections in children
with chronic respiratory disease include annual influenza vaccination
and prophylaxis with pneumococcal vaccines. Although there have
been no formal studies to address the use of palivizumab for respiratory
syncytial virus (RSV) immunoprophylaxis in surfactant metabolic
dysfunction disorders, it should be considered in significantly
compromised infants and young children.
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Clinical Course
and Prognosis
++
The clinical course and prognosis in patients with the PAP syndrome
vary widely, depending on the specific disease causing it. Most
patients with autoimmune PAP have ongoing persistent, albeit varying
degrees of, symptoms; in some individuals, the disease spontaneously
resolves and in others it progresses to respiratory failure.2,3,15 A
comprehensive meta-analysis of cases published over the last half
century reported a 5-year survival of 85 ± 5% without therapy,
which increased to 95 ± 2% with whole-lung lavage therapy.2 Seventy-two
percent of mortality was attributable to respiratory failure caused
by PAP. Recently, a large study of 223 contemporaneous patients
with autoimmune PAP reported a 5-year survival approaching 100%.15 Secondary
infections, frequently with opportunistic pathogens, are reported
to account for approximately 18% of mortality in autoimmune
PAP2; however, the recent large study of contemporaneous
autoimmune PAP patients failed to confirm this.15
++
SP-B deficiency almost always presents at birth and is associated
with a severe and progressive neonatal course that is fatal in the
early neonatal period.72,73In very rare cases,
SFTPB mutations have been recognized in older children.74,75 Mutations
in ABCA3 lead to more variable disease. The lung disease may be
severe and similar in nature to that seen with SFTPB mutations,
but milder lung disease may present later in childhood.11,12,30,43,76 A
particular ABCA3 mutation (E292V) has been identified in a cohort
of older ABCA3-deficient patients, suggesting genotype-phenotype
correlations for this disease.12 Dominantly expressed
SFTPC mutations are variably penetrant and may even be silent. Clinical
manifestations include fatal neonatal respiratory failure, neonatal
tachypnea and hypoxemia with apparent subsequent clinical stability,
ILD in older children, and pulmonary fibrosis in adults.9,28-30