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Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults

Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults
Literature review current through: Jan 2024.
This topic last updated: Oct 27, 2022.

INTRODUCTION — Pulmonary alveolar proteinosis (PAP), also known as pulmonary alveolar phospholipoproteinosis, is a diffuse lung disease characterized by the accumulation of amorphous, periodic acid-Schiff (PAS)-positive lipoproteinaceous material in the distal air spaces [1-3]. There is little or no lung inflammation, and the underlying lung architecture is preserved. The lipoproteinaceous material is composed principally of surfactant phospholipid and apoproteins.

The etiology, pathogenesis, clinical manifestations, and diagnosis of PAP in adults will be reviewed here. The presentation and management of PAP in children and the treatment and prognosis of PAP in adults are discussed separately.

(See "Pulmonary alveolar proteinosis in children".)

(See "Treatment and prognosis of pulmonary alveolar proteinosis in adults".)

DEFINITIONS AND CLASSIFICATION — PAP is caused by a spectrum of disorders that negatively affect production and clearance of surfactant. Three main categories of PAP are recognized (table 1) [2,4]:

Disruption of granulocyte-macrophage colony-stimulating factor signaling (autoimmune and hereditary PAP) – Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates clearance of surfactant by alveolar macrophages. Disorders that disrupt GM-CSF signalling include autoimmune PAP (the most common type of PAP in adults) and hereditary PAP due to recessive variants of the GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB). Antibodies to GM-CSF neutralize the effect of GM-CSF on alveolar macrophages, while genetic variants in the GM-CSF receptor impair signaling by intact GM-CSF.

Disorders of surfactant production (congenital PAP) – Disorders of surfactant production are traditionally considered congenital PAP. These disorders often present in the neonatal period and encompass a number of genetic variants:

Variants in surfactant proteins (SFTPB and SFTPC) [5-7]

Variants in proteins involved in the metabolism of surfactant (ATP-binding cassette, subfamily A [ABCA3]) [8]

Variants in NK2 homeobox-1 (NKX2.1) thyroid transcription factor-1 (TTF1), which regulates transcription of SFTPB, SFTPC, and ABCA3 [9]

Variants in the gene SLC7A7, which causes a defect in the plasma membrane transport of cationic amino acids (known as lysinuric protein intolerance). (See "Pulmonary alveolar proteinosis in children", section on 'Congenital form'.)

Methionyl-tRNA synthetase (MARS) catalyzes the incorporation of methionine into tRNA and is critical for protein biosynthesis. Genetic variants of the MARS gene are associated with a rare childhood form of PAP prevalent on Réunion Island. (See "Genetic disorders of surfactant dysfunction", section on 'Related disorders'.)

Congenital alveolar proteinosis is discussed in greater detail separately. (See "Pulmonary alveolar proteinosis in children".)

Secondary PAP – The secondary form of PAP develops in adulthood and is found in association with high level dust exposures (eg, silica, aluminum, titanium, indium-tin oxide) [10-19], hematologic dyscrasias (eg, myelodysplastic syndrome, GATA2 deficiency, hematologic malignancy) [20-25], and after allogeneic hematopoietic cell transplantation for myeloid malignancies [26-28]. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

While certain infections may give rise to a PAP-like pathology (eg, pneumocystosis), PAP may also increase vulnerability to such infections.

In most cases, secondary PAP appears related to a relative deficiency of GM-CSF and related macrophage dysfunction [10-14,19-21]. High level dust inhalation appears to impair macrophage function through direct toxicity. Although indium-tin oxide inhalation has been associated with secondary PAP, in one report, one of two patients with indium-tin oxide-related PAP had elevated levels of antibodies to GM-CSF [15], raising the hypothesis that inhalation of an agent that causes PAP on lung pathology may be the consequence of an autoimmune process [29-31]. However, a subsequent study of 87 indium-tin oxide facility workers did not identify any workers with evidence of PAP or antibodies to GM-CSF [32]. Thus, it appears unlikely that PAP in this setting is an autoimmune process.

A few patients with cytologic or histopathologic evidence of PAP have reduced GM-CSF signalling, but no evidence of anti-GM-CSF antibodies or mutations in the GM-CSF receptor alpha or beta chains. These patients are considered to have unclassified PAP [2].

PATHOGENESIS — The various forms of PAP develop because of reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) levels or function and/or impaired processing of surfactant by alveolar macrophages. (See 'Definitions and classification' above.)

Role of GM-CSF — Several lines of evidence suggest that diminished GM-CSF protein or function plays a key role in PAP and is responsible for the observed impairments in surfactant processing [4]. As examples:

Genetically engineered mice that lack the GM-CSF gene have an accumulation of surfactant and surfactant apoprotein in the alveolar spaces similar to that seen in patients with PAP [33]. Reconstitution with the GM-CSF gene completely corrects the alveolar proteinosis in these GM-CSF knockout mice, as does treatment with aerosolized GM-CSF [34,35]. However, lack of GM-CSF production does not appear to play a major role in adult PAP [36,37].

Defects in the heterodimeric GM-CSF receptor, which is composed of the ligand-binding alpha-chain (encoded by the CSF2RA gene) and the signal-transducing beta-chain (encoded by the CSF2RB gene), can lead to PAP or PAP-like disease. Mice that lack the GM-CSF receptor beta-chain develop a PAP-like syndrome [38]. Likewise, some congenital and rare acquired forms of PAP are associated with decreased or absent function of the GM-CSF receptor beta-chain [36,39,40]. Two separate reports of patients with familial PAP have found a genetic defect in the CSF2RA gene that results in decreased functional GM-CSF receptor alpha-chain [41,42]. As a result, there is greatly diminished GM-CSF binding to its receptor and reduced GM-CSF receptor signaling.

Humoral autoimmunity leading to functional deficiency of GM-CSF is present in the vast majority of adult patients with acquired PAP [43-51]. In a series of 248 patients with a pathologic diagnosis of PAP, serum autoantibodies to GM-CSF were found in 223 patients (90 percent) classified as autoimmune PAP; of the remaining 25 with negative anti-GM-CSF antibody tests, 24 (10 percent) had diseases known to cause PAP (classified as secondary PAP) and 1 (<1 percent) had unclassified PAP [49].

The role of antibodies to GM-CSF in the pathogenesis of PAP is further supported by studies of infusions of human immunoglobulin G1 (IgG1) containing anti-GM-CSF antibodies into nonhuman primates [52,53]. The primates developed milky bronchoalveolar lavage (BAL) fluid containing increased amounts of surfactant lipids and proteins. Surgical lung biopsies revealed alveoli filled with foamy, surfactant-filled alveolar macrophages. Evidence of decreased GM-CSF signaling was also noted.

Downstream effects of GM-CSF signaling impact proteins involved in surfactant clearance. Compared with normal controls, alveolar macrophages from patients with PAP demonstrate decreased levels of transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the macrophage scavenger receptor CD36, which PPAR-gamma regulates [54]. PPAR-gamma and CD36 levels can be restored to normal following treatment with GM-CSF administered subcutaneously. The interrelationship between GM-CSF and PPAR-gamma may explain how GM-CSF deficiency could cause alveolar and macrophage accumulation of surfactant lipoprotein.

The association of PAP with leukemia (eg, chronic myeloid leukemia) and allogeneic bone marrow transplantation may be reflective of relative GM-CSF deficiency [21,55]. Another possibility is the presence of concomitant anti-GM-CSF antibodies, described in one patient [56].

Macrophage dysfunction — Findings in patients and transgenic mice suggest that impaired processing of surfactant by alveolar macrophages contributes to the pathogenesis of PAP. Evidence that macrophage dysfunction (either primary or acquired) plays an important role in the initiation and propagation of disease includes the following:

Alveolar macrophage and type II cell clearance mechanisms are progressively overwhelmed by the accumulation of the surfactant-rich material, resulting in impaired phagocytosis and phagolysosome fusion [5,57,58]. Alveolar macrophages themselves, upon dying, may further contribute to the amorphous material [13].

Alveolar macrophages obtained from patients with PAP after therapeutic whole lung lavage have greater migratory response to in vitro stimuli compared with macrophages from the same patients prior to the lavage [59].

Other causes of acquired macrophage dysfunction, such as immunosuppressive drug therapy or hematologic malignancies, may explain the occasional finding of PAP associated with these disorders [13,60]. As an example, lysinuric protein intolerance, a rare autosomal recessive disorder that results in defective transport of cationic amino acids, is associated with both macrophage dysfunction and PAP [60-64].

PAP has been described in rare patients with family myelodysplastic syndrome due to deficiency of GATA2, which is in the family of zinc finger transcription factors and contributes to regulation of macrophage phagocytosis [65,66]. (See 'Definitions and classification' above and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial MDS/AML with mutated GATA2'.)

Mice deficient in Bach2, a transcription repressor found in both innate and adaptive immune cells, have alveolar macrophage dysfunction and develop PAP despite having intact GM-CSF signaling [67]. Current lines of evidence suggest that the Bach2 deficiency must occur in both alveolar macrophages and CD4+ T cells for PAP to occur, ultimately resulting in hyperactivated CD4+ T cells that impair macrophage surfactant metabolism [68]. In other words, the normal function of Bach2 in alveolar macrophages is to prevent aberrant response to excessive T cell-induced inflammation and in T cells to prevent T cell hyperactivation. It has been hypothesized that Bach2 deficiency may account for some forms of secondary PAP but how hematopoietic malignancies or certain infections reduce Bach2 is not fully elucidated.

PATHOLOGY — Upon histologic examination, the normal alveolar architecture is generally preserved, although the alveolar septa may be slightly thickened due to type II epithelial cell hyperplasia. There is typically little or no inflammatory cell infiltration. The terminal bronchioles and alveoli are filled with a flocculent and granular lipoproteinaceous material that stains pink with periodic acid-Schiff (PAS) stain (picture 1). Within this lipoproteinaceous material, there are PAS-positive and oil red-O positive macrophages and scattered clefts of cholesterol crystals that may elicit a histiocytic giant-cell reaction [69].

While not commonly performed, electron microscopy of BAL fluid or lung tissue shows concentrically laminated structures called lamellar bodies. These bodies are comprised of phospholipids and are probably derived from the type II alveolar epithelial cells. Lamellar bodies may be found free in the alveolar airspaces, within alveolar macrophages, and in type II cells. A related ultrastructural finding of irregular concentric whorls (called tubular myelin) may represent the extracellular storage form or a breakdown product of surfactant.

CLINICAL MANIFESTATIONS — Among adults with PAP, the typical age at presentation is 40 to 50 years [49,70,71]. There is a male to female ratio of 2:1. Approximately 50 to 80 percent of patients with autoimmune PAP are current or former cigarette smokers [2].

A small number of patients also have other rheumatic diseases, including hemolytic anemia, polymyalgia rheumatica, ulcerative colitis, and granulomatosis with polyangiitis [49].

Symptoms — PAP typically has an insidious onset in adults, although approximately one-third of affected patients are asymptomatic [49]. The major symptoms are progressive dyspnea on exertion (52 to 94 percent), cough (23 to 66 percent), sputum production (1 to 4 percent), fatigue (0 to 50 percent), weight loss (0 to 43 percent), and low-grade fever (1 to 15 percent) developing over weeks to months [2,49,72-77]. A non-productive cough is common, and expectoration of "chunky" gelatinous material may occasionally occur.

Among patients with secondary PAP due to myelodysplastic syndrome, fever is reported by 45 percent and cough by 42 percent [2].

Fever may occur in other patients with PAP due to superinfection with organisms such as Nocardia, Mycobacteria, and endemic or opportunistic fungi [49,73,78]. In a series of 248 patients with PAP, four patients had Aspergillus infection, three had Mycobacterium tuberculosis, and two had atypical mycobacterial infection [49]. In a separate series of 70 patients, 10 patients had respiratory infection (Pneumocystis, E coli, Legionella, and Haemophilus influenza) [73].  

Physical examination — The physical examination is often normal [2]. Crackles are present in approximately 50 percent of patients, but can be absent despite evidence of marked alveolar filling on radiographs, presumably because gas movement is absent in the completely fluid-filled distal airspaces [70]. Clubbing and cyanosis are present in about 25 percent [49].

Laboratory features — Each of the types of PAP has characteristic laboratory abnormalities.

Autoimmune PAP – Patients with autoimmune PAP will have positive testing for serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies, which are 100 percent sensitive and specific for autoimmune PAP [2]. While not used clinically, these patients have a reduced whole blood STAT5 phosphorylation, a measure of GM-CSF signaling.  

Secondary PAP – A complete blood count and differential is obtained to evaluate for hematologic malignancy or myelodysplastic syndrome. Testing for a GATA2 genetic variant may be appropriate in patients with the combination of familial myelodysplastic syndrome and PAP. (See 'Macrophage dysfunction' above.)

Hereditary PAP due to GM-CSF receptor defects – Patients with hereditary PAP due to rare genetic variants in the GM-CSF receptor alpha or beta subunits (CSF2RA and CSF2RB) have an elevated serum level of GM-CSF, reduced serum STAT5-PI, and abnormal receptor function [2]. Sequencing confirms the presence of recessive genetic variants CSF2RA and CSF2RB.

PAP due to surfactant production disorders – Patients with PAP due to a surfactant-related gene variants (eg, surfactant proteins B and C, ATP-binging cassette A [ABCA3], NK homeobox-1 [NKX2,1]) typically have a normal STAT5-phosphorylation. However, these disorders typically appear in childhood, so adults with PAP generally do not require testing for surfactant gene variants. (See "Pulmonary alveolar proteinosis in children", section on 'Laboratory tests'.)

Other laboratory abnormalities include polycythemia, hypergammaglobulinemia, and increased lactate dehydrogenase (LDH) levels, although these findings are nonspecific [79].

A number of biomarkers have been associated with PAP, but none are sufficiently sensitive or specific to be useful diagnostically. Elevated levels of lung surfactant proteins A and D (SP-A and SP-D), several tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigens sialyl Lewis-a [CA 19-9], and sialyl SSEA-1 [SLX]), and Kerbs von Lungren 6 antigen (KL-6) have been found in serum from patients with PAP, but have unclear diagnostic utility [2,49,80-87]. Bronchoalveolar lavage (BAL) biomarkers are described below. (See 'Flexible bronchoscopy' below.)

Imaging

Chest radiograph – Bilateral symmetric alveolar opacities located centrally in mid and lower lung zones are typical, often in a "bat wing" distribution (image 1). Additional findings include the following:

Asymmetric, unilateral, or nodular patterns may be present [88]

Despite the process being alveolar in distribution, air bronchograms are rare

A thin lucent band may sharply outline the diaphragm and the heart, consistent with sparing of the lung immediately adjacent to these structures

Segmental atelectasis can occur due to bronchiolar obstruction by thick lipoproteinaceous material [13]

Incomplete alveolar filling may result in reticular markings despite the predominant filling of alveoli observed pathologically [89]

In chronic cases, focal areas of fibrosis and even extensive pulmonary fibrosis leading to respiratory insufficiency have been rarely reported [90]

High-resolution computed tomography (HRCT) – HRCT typically reveals ground-glass opacification, predominantly in a homogeneous distribution. There may also be thickened intralobular structures and interlobular septa in typical polygonal shapes superimposed on ground glass opacities, referred to as "crazy-paving" (table 2 and image 2) [69,76,77,91]. In a series of 42 patients, a patchy, geographic pattern with crazy-paving was common among patients with autoimmune PAP, whereas a pattern of diffuse ground glass opacity without crazy-paving was more common among patients with secondary PAP [91].

However, crazy-paving is not specific for PAP and can also be observed in patients with the acute respiratory distress syndrome, organizing pneumonia, lipoid pneumonia, acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD), drug-related hypersensitivity reactions, and AIP/DAD superimposed on usual interstitial pneumonitis [92,93]. (See "High resolution computed tomography of the lungs", section on 'Ground-glass opacification'.)

Rarely, PAP with concomitant lung fibrosis may occur and appear to be associated with underlying GATA2 mutation [22].

Pulmonary function tests — Pulmonary function tests typically demonstrate a reduction in the diffusing capacity for carbon monoxide (DLCO) that may be isolated or accompanied by a restrictive ventilatory defect (decrease in forced vital capacity) [49,94]. When present, the decrement in DLCO is often out of proportion to the degree of reduction in lung volume and correlates well with other measures of disease severity, such as symptoms and reduced arterial tension of oxygen (PaO2) [49]. Varying degrees of hypoxemia and compensated respiratory alkalosis are also common and frequently worsen with exercise. An elevated right-to-left shunt fraction is usually present.

DIAGNOSTIC EVALUATION

Overview — Our diagnostic algorithm for suspected PAP in an adult is shown in the figure (algorithm 1). When findings suggestive of PAP are noted on high-resolution computed tomography (HRCT) scan in patients with a compatible clinical presentation, one of the first steps is to assess the severity of respiratory impairment with pulmonary function tests, as more severe impairment dictates a more rapid pace of evaluation and may limit the invasiveness of testing. (See 'Pulmonary function tests' above.)

The next step is to evaluate for secondary PAP by reviewing the history of exposures and checking the complete blood count for evidence of hematologic malignancy or myelodysplastic syndrome.

We then proceed to flexible bronchoscopy to obtain bronchoalveolar lavage (BAL) fluid and, when possible, transbronchial lung biopsies (TBLB). BAL fluid characterized by a milky-opaque appearance is strongly suggestive of PAP and the subsequent evaluation focuses on determining the type of PAP.

In the absence of typical features on BAL or TBLB, the next step is usually surgical lung biopsy to determine whether the BAL was falsely negative or whether another process can be diagnosed. In the largest series of PAP, the diagnosis was made by HRCT and BAL in 59 percent; HRCT, BAL, and transbronchial biopsy in 34 percent; and video-assisted thoracoscopic biopsy in 7 percent [49].

Laboratory testing for antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) may be performed at the same time as bronchoscopy or subsequent to identification of typical BAL features (eg, opaque or milky appearance, copious periodic acid-Schiff [PAS]-positive material in and around alveolar macrophages), depending on the availability of the testing. As noted above, typical HRCT, BAL features in combination with positive serologic testing for anti-GM-CSF antibodies provide a confident diagnosis of autoimmune PAP. (See 'Laboratory features' above.)

For patients who have HRCT and BAL evidence of PAP, but do not have serum antibodies to GM-CSF, a serum GM-CSF level is obtained. If serum GM-CSF is elevated, the function of the GM-CSF receptor should be assessed. If this is abnormal, sequencing for genetic variants of the receptor subunits (hereditary PAP) is performed by a specialty laboratory.

If the HRCT and BAL suggest PAP, but the GM-CSF serum level is normal and antibodies to GM-CSF are absent, a surgical lung biopsy is needed for definitive diagnosis of PAP, which is then considered to be "unclassified" [2].

Exclusion of causes of secondary PAP — We normally obtain a complete blood count and differential early in the evaluation of interstitial lung disease. This is especially important in suspected PAP because of the occasional association of PAP with hematologic malignancies and myelodysplasia [20-25].

Other secondary causes of PAP, such as high level dust exposures (eg, silica, aluminum, titanium, indium-tin oxide) are excluded by a careful occupational history [95].

Flexible bronchoscopy — Flexible bronchoscopy with BAL and, when possible, TBLB is a key step in the diagnosis of PAP. TBLB is generally performed after the BAL and in a different subsegment. Among 36 patients with autoimmune or secondary PAP, the diagnosis of PAP was based on bronchoscopic findings in 30 (83 percent); BAL was used alone in 18 (50 percent) and combined with TBLB in 11 (30 percent) [73]. In a separate series of 248 patients with PAP, the diagnosis was established by BAL in 146 (59 percent) and BAL plus TBLB in 84 (34 percent) [49]. In both series, the diagnosis was made by surgical lung biopsy in the remainder. (See 'Surgical lung biopsy' below.)

Characteristic BAL findings of PAP include:

An opaque or milky appearance due to the abundant lipoproteinaceous material, which may settle upon standing

Cytopathology demonstrating engorgement of alveolar macrophages with PAS-positive material on a background of flocculent proteinaceous material that is similarly PAS positive (picture 2) with large acellular eosinophilic bodies in a background of eosinophilic granules (picture 3)

Papanicolaou-staining reveals large globules that are green, orange, or orange with a green rim [96]

To exclude infection that might cause a clinical picture similar to PAP or that is concurrent with PAP, BAL samples are sent for special stains and cultures for opportunistic infections (eg, Pneumocystis, Nocardia, mycobacteria, fungi). Differential cell counts are nonspecific in PAP, but may be useful for identifying other conditions. (See 'Clinical manifestations' above and 'Differential diagnosis' below.)

Certain biomarkers have been identified in BAL fluid and are similar to those identified in blood samples (see 'Laboratory features' above). In a series of 15 patients with PAP compared to control patients with other interstitial lung diseases, BAL levels of chemokine (C-C) motif ligand 2 (CCL2), Kerbs von Lungren 6 antigen (KL-6), and surfactant protein D were increased [87]. Higher levels of KL-6 in both the BAL fluid and blood correlated significantly with higher serum LDH levels, lower arterial tension of oxygen (PaO2), and a higher alveolar-arterial oxygen gradient [87]. Further studies are needed to determine the clinical utility of these tests.

Anti-GM-CSF titer — Measurement of serum anti-GM-CSF antibody is an important step in the diagnosis of autoimmune PAP. In the absence of any known secondary cause of PAP, an elevated serum anti-GM-CSF titer is 100 percent sensitive and 91 to 98 percent specific for the diagnosis of autoimmune PAP [45,46,97]. Low levels of GM-CSF antibodies can be observed in healthy individuals [97]. Serum samples generally need to be sent to a specialty laboratory for testing, such as the Pulmonary Alveolar Proteinosis laboratory at Cincinnati Children's Hospital.

BAL fluid levels of anti-GM-CSF antibodies correlate better with the severity of PAP compared to serum titers [98]. Serial measurements of BAL or serum anti-GM-CSF antibodies may prove useful in monitoring disease activity and response to treatment, although data to support this practice are limited [99,100].

Surgical lung biopsy — Surgical lung biopsy is needed to establish a diagnosis of PAP in approximately 10 to 20 percent of patients due to nondiagnostic findings on HRCT, BAL, and TBLB [2,49,73]. (See "Overview of minimally invasive thoracic surgery".)

Other specialty laboratory testing — Additional specialty laboratory testing may be needed for patients who have HRCT and BAL evidence of PAP, but do not have serum antibodies to GM-CSF. In these patients, abnormal GM-CSF receptor function or an as yet unclassified defect may be present. A serum GM-CSF level helps to guide the evaluation. An elevated level of GM-CSF suggests dysfunction of the GM-CSF receptor, which can be assessed by signalling analysis. If this is abnormal, sequencing for genetic variants of the receptor subunits (hereditary PAP) can be performed. As these patients are rare, testing is performed at a specialty laboratory such as the Pulmonary Alveolar Proteinosis laboratory at Cincinnati Children's Hospital.

DIAGNOSIS — A definitive diagnosis of PAP in an adult is based on the presence of typical histopathologic features of PAP (flocculent and granular periodic acid-Schiff [PAS] positive lipoproteinaceous material stain is demonstrated filling terminal bronchioles and alveoli) on a transbronchial or surgical lung biopsy (picture 1) (see 'Pathology' above). Alternatively, a confident diagnosis of autoimmune PAP can be made based on typical features on high-resolution computed tomography (HRCT) and bronchoalveolar lavage (eg, abundant PAS-positive proteinaceous material in and around alveolar macrophages) in combination with demonstration of granulocyte macrophage-colony stimulating factor (GM-CSF) antibodies in the serum [2,49,72,73,101-106]. (See 'Imaging' above and 'Flexible bronchoscopy' above.)

The diagnosis of secondary PAP is based on typical findings on HRCT and BAL combined with a history of high level dust exposure (eg, silica, aluminum, titanium, indium-tin oxide), demonstration of hematologic abnormalities (myelodysplasia or malignancy), or history of hematopoietic cell transplantation. (See 'Definitions and classification' above and 'Overview' above.)

Hereditary PAP due to genetic variants in the GM-CSF receptor alpha or beta subunits (CSF2RA and CSF2RB) are rare and the diagnosis is based on demonstration of abnormal GM-CSF receptor function and gene sequencing by a specialty laboratory. (See 'Other specialty laboratory testing' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of adult PAP includes those disorders with similar radiographic manifestations, such as a mosaic pattern of ground glass opacities, sometimes associated with "crazy-paving" due to thickened intralobular structures and interlobular septa (see 'Imaging' above). These disorders include infection (eg, due to Pneumocystis jirovecii or Mycoplasma), cardiogenic and noncardiogenic pulmonary edema, lipoid pneumonia, drug-related hypersensitivity reactions, organizing pneumonia, acute interstitial pneumonia (AIP), and diffuse alveolar damage superimposed on usual interstitial pneumonitis (UIP).

In addition to the absence of periodic acid-Schiff (PAS) positive proteinaceous material on BAL, the following features help to distinguish among the alternative diagnostic possibilities:

Cardiogenic or noncardiogenic pulmonary edema – The clinical presentation of fulminant respiratory failure with diffuse alveolar opacities would favor cardiogenic or noncardiogenic pulmonary edema (eg, due to acute respiratory distress syndrome), or AIP. Cardiogenic pulmonary edema can usually be excluded by the absence of clinical evidence of fluid overload, a normal brain natriuretic peptide, and normal echocardiogram. These processes are discussed separately. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults" and "Noncardiogenic pulmonary edema" and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

Infections and ARDS – Diffuse lung infections, such as Pneumocystis jirovecii pneumonia, coronavirus-19 pneumonia, influenza, and causes of diffuse alveolar damage (acute respiratory distress syndrome) typically have a more acute onset than PAP. While fever is more commonly associated with infection than with PAP, some patients with PAP have fever without identifiable infection and infection can complicate the course of PAP. The diagnosis is generally made on microbiologic studies of the blood and BAL. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Pneumonia'.)

Lipoid pneumonia – Lipoid pneumonia secondary to aspiration of lipoid material (eg, mineral oil) can present with ground-glass opacities and interlobular septal thickening in a "crazy paving" pattern, mimicking PAP, although basilar peribronchovascular areas of ground glass or consolidative opacities (sometimes with low attenuation) are more typical [107]. BAL demonstration of large numbers of lipid-laden macrophages would suggest lipoid pneumonia. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Idiopathic interstitial pneumonias – An HRCT appearance of a predominantly subpleural distribution of disease and sparse honeycombing would favor acute interstitial pneumonia or idiopathic pulmonary fibrosis over PAP. Organizing pneumonia is occasionally associated with crazy-paving, but the BAL would not show the copious PAS positive material typical of PAP. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)" and "Cryptogenic organizing pneumonia".)

Drug-induced pneumonitis – Drug-induced pneumonitis can present with similar time course and imaging characteristics as PAP. It should be suspected in patients with exposure to medications such as amiodarone, methotrexate, bleomycin, taxanes, and nitrofurantoin. BAL findings in drug-induced pneumonitis will not show abundant PAS positive material. (See "Amiodarone pulmonary toxicity" and "Bleomycin-induced lung injury" and "Nitrofurantoin-induced pulmonary injury" and "Methotrexate-induced lung injury" and "Taxane-induced pulmonary toxicity".)

Acute exacerbations of interstitial lung disease – Although diffuse pulmonary involvement and severely compromised DLCO are present in acute exacerbations of interstitial lung disease, the presence of additional interstitial fibrotic features, including subpleural septal thickening and honeycombing, distinguish the condition. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)

SUMMARY AND RECOMMENDATIONS

Definition – Pulmonary alveolar proteinosis (PAP), also known as pulmonary alveolar phospholipoproteinosis, is characterized by the intra-alveolar accumulation of surfactant phospholipid and apoproteins. (See 'Introduction' above.)

Pathogenesis and classification – PAP is caused by a spectrum of disorders in surfactant homeostasis that affect production and clearance of surfactant. Three main categories of PAP are recognized, disruption of granulocyte-macrophage-colony stimulating factor (GM-CSF) signaling (eg, autoimmune PAP), disorders of surfactant production (eg, congenital PAP), and secondary PAP (eg, inhalant exposures, hematologic disorders) (table 1). Autoimmune PAP due to granulocyte macrophage-colony stimulating factor (GM-CSF) antibodies is the most common type in adults. (See 'Definitions and classification' above and 'Pathogenesis' above.)

Clinical manifestations

Symptoms and physical examination – Among adults with PAP, the typical age at presentation is 40 to 50 years and twice as many men are affected as women. The major symptoms are progressive dyspnea, cough, sputum production, fatigue, and weight loss, which develop over weeks to months. The physical examination may be normal or may show crackles and, less commonly, clubbing or cyanosis. (See 'Clinical manifestations' above.)

Imaging – Chest radiographs show bilateral symmetric alveolar opacities located centrally in mid and lower lung zones, sometimes resulting in a "bat wing" distribution. High-resolution computed tomography (HRCT) reveals ground-glass opacification that typically spares the periphery and may have a "crazy-paving" appearance due to thickening of the interlobular and intralobular septa. (See 'Imaging' above.)

Diagnostic Evaluation – When typical features of PAP are noted on chest radiograph and HRCT in a patient with a compatible clinical presentation, we follow a diagnostic algorithm to confirm the diagnosis and identify the exact etiology (algorithm 1). (See 'Overview' above.)

History and peripheral smear – First, we evaluate for secondary causes of PAP by history (eg, dust exposure, hematopoietic cell transplantation) and examination of the peripheral blood for evidence of myelodysplasia or hematologic malignancy, as the management of these patients depends on the underlying cause. (See 'Overview' above.)

Bronchoscopy – The next step is to perform flexible bronchoscopy with bronchoalveolar lavage (BAL) and, if possible, transbronchial biopsy. Typical BAL fluid in PAP has an opaque or milky appearance due to abundant lipoproteinaceous material. Cytologic examination of BAL reveals copious, flocculent periodic acid Schiff (PAS)-positive material surrounding alveolar macrophages engorged with the same material. These features are strongly suggestive of PAP and the subsequent evaluation focuses on determining the type of PAP. (See 'Flexible bronchoscopy' above.)

GM-CSF antibody testing – Adults with a strong suspicion for PAP based in HRCT and BAL should have serologic testing for antibodies to GM-CSF. This testing is available in specialized laboratories. (See 'Anti-GM-CSF titer' above.)

Additional steps in patients with negative GM-CSF antibodies – For patients who have HRCT and BAL evidence of PAP, but do not have serum antibodies to GM-CSF, we obtain a serum GM-CSF level is obtained. If serum GM-CSF is elevated, the function of the GM-CSF receptor should be assessed. If this is abnormal, sequencing for genetic variants of the receptor subunits (hereditary PAP) can be performed in specialized laboratories. (See 'Overview' above.)

If the HRCT and BAL suggest PAP, but antibodies to GM-CSF are absent and the GM-CSF serum level is normal, a surgical lung biopsy is needed for definitive diagnosis of PAP, which is then considered to be "unclassified." (See 'Diagnostic evaluation' above.)

Differential diagnosis – The differential diagnosis of adult PAP involves those disorders with similar radiographic manifestations, such as infection (eg, due to Pneumocystis jirovecii and Mycoplasma), cardiogenic and noncardiogenic pulmonary edema, lipoid pneumonia, drug-related hypersensitivity reactions, organizing pneumonia, acute interstitial pneumonia (AIP), and acute exacerbations of fibrotic interstitial lung diseases. (See 'Differential diagnosis' above.)

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Topic 4373 Version 21.0

References

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