Pulmonary Alveolar Proteinosis

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Practice Essentials

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder of unknown etiology characterized by disorders of surfactant homeostasis (clearance and production), which are caused in part by mutations in genes necessary for normal surfactant production.[1, 2, 3]  The alveoli and terminal airways[1]  fill with floccular material that stains positive using the periodic acid-Schiff (PAS) method and is derived from surfactant phospholipids and protein components (see the images below). This process results in impaired gas exchange and may lead to respiratory failure.[1, 2, 3, 4]  PAP was first described in 1958.[5]  



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Pulmonary alveolar proteinosis. A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of g....



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Pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase-PAS, x200).

Two forms of PAP are recognized: hereditary and acquired. The hereditary form is autosomal-recessive and usually is diagnosed in infancy or early childhood, although adult onset has been reported.[6, 7]  The acquired form is subdivided into autoimmune and secondary forms. Approximately 90% of PAP cases comprise the autoimmune form, which is related to granulocyte-macrophage colony-stimulating factor (GM-CSF) deficiency, GM-CSF-receptor defects, abnormal macrophage function from endogenous or exogenous triggers, and genetic anomalies of surfactant production.[3]  Secondary forms include those associated with malignancies, immunodeficiency disorders, infectious diseases, drug reactions, and occupational exposure to silica, indium, and various toxic inhalation injuries.[8]  Associations with Niemann-Pick disease,[9]  myelodysplastic syndrome,[10, 11]  and hemophagocytic lymphohistiocytosis[12]  have been reported.

A similar disorder affects neonates deficient in surfactant-associated protein B (SP-B).

The clinic course of PAP is variable, ranging from spontaneous resolution (< 10%) to respiratory failure and death. As many as 30% of patients are asymptomatic, even with diffuse chest radiograph (CXR) abnormalities. The most common clinical symptoms are gradual onset with progressive dyspnea, cough, fever, and chest pain. Physical examination findings may include inspiratory crackles, digital clubbing, and cyanosis. The diagnosis is reached on the basis of clinical history, radiologic, and bronchoalveolar lavage and/or histopathologic findings.[1]

Management of pulmonary alveolar proteinosis (PAP) depends on the progression of the illness, coexisting infections, and degree of physiologic impairment. The standard of care for PAP is mechanical removal of the lipoproteinaceous material by whole-lung lavage (WLL). Inhaled GM-CSF was initially shown to be safe and effective in providing a sustained therapeutic effect in autoimmune PAP[13] ; more recently, it appears to have only a modest salutary laboratory effects on arterial oxygen tension without clinical benefits in mild-to-moderate autoimmune PAP.[14]  For refractory PAP, rituximab, plasmapheresis, and lung transplantation may be therapeutic considerations.[3]  In secondary PAP, appropriate treatment of the underlying cause is warranted. Lung transplantation is the treatment of choice in patients with congenital PAP and in adult patients with end-stage interstitial fibrosis and cor pulmonale.

Pathophysiology

The alveoli in pulmonary alveolar proteinosis (PAP) are filled with proteinaceous material, which has been analyzed extensively and determined to be normal surfactant composed of lipids and surfactant-associated proteins A, B, C, and D (SP-A, SP-B, SP-C, SP-D). Evidence exists of a defect in the homeostatic mechanism of either the production of surfactant or the clearance by alveolar macrophages and the mucociliary escalator.[1, 2, 3]  A relationship has been demonstrated between PAP and impaired macrophage maturation or function, which accounts for the association with malignancies and unusual infections (eg, infection with Nocardia asteroides).

Studies of genetically altered mice ("knock-out mice") with targeted gene deletions for GM-CSF have yielded animals with PAP-like disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the effectiveness of alveolar macrophages in the catabolism of surfactant. Other studies have demonstrated the presence of neutralizing autoantibodies against GM-CSF in patients with PAP. In addition, alveolar macrophages from some PAP patients have decreased levels of the transcription factor peroxisome proliferator-activated receptor–gamma (PPAR-gamma), which normalize after treatment with GM-CSF.[15]

Etiology

The etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it has been associated with a number of other processes, implying a causal relationship. Causes may include the following:

Recessive CSF2RA mutations have been implicated in the hereditary form of PAP. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling may be absent or severely reduced, and the GM-CSF-receptor alpha chain may be absent or abnormal, paralleling the GM-CSF signaling defects. This is unlike secondary PAP, in which a deficiency of GM-CSF and increased autoantibodies are noted. Genetic analysis may reveal multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing.[20, 21]  In 2011, a homozygous missense mutation in CSF2RB was reported to cause PAP in a 9-year-old girl.[22]  Onset of the hereditary form of PAP is generally in infancy or early childhood, but adult onset has been reported.[6, 7]

Biallelic missense mutations in MARS were identified in a specific severe form of pediatric PAP, prevalent on the island of Réunion in the Indian Ocean.[23]  

Epidemiology

Autoimmune pulmonary alveolar proteinosis (PAP) acounts for 90% of cases, with an estimated prevalence of 1 case per 100,000 population. A specific, severe hereditary form of PAP is prevalent on Réunion Island, in the Indian Ocean, where the incidence is at least 1 in 10,000 newborns.[24, 23]  The male incidence four times higher than for females, and the presentation is typically in adults aged 20-50 years.

Prognosis

The overall prognosis for primary pulmonary alveolar proteinosis (PAP) is very good, with complete remission achieved in many patients. Whole-lung lavage most often results in a dramatic response. Some patients require repeated lavages; these patients usually progress to pulmonary fibrosis and have a poor outcome. Congenital PAP responds favorably to lung transplantation.

The major complications are lung infections with Nocardia asteroides, Pneumocystis carinii, and/or Mycobacterium avium-intracellulare.[25]  Pulmonary fibrosis and/or cor pulmonale also can complicate PAP.

There has been some association between anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) autoantibodies and some cases of cryptococcal meningitis in otherwise immunocompetent patients.[26]

Mortality as high as 30% within several years of disease onset has been reported, but the actual mortality rate may be less than 10%. A severe form of congenital PAP in children from la Réunion Island has an overall mortality rate of 59% and is characterized by an early onset, associated liver involvement, and frequent progression to lung fibrosis, despite treatment with whole-lung lavage treatment.[24]  

The natural history of secondary PAP depends on the underlying etiologic entity.

History and Physical Examination

History

Patients with pulmonary alveolar proteinosis (PAP) typically present with a gradual onset of symptoms. As many as 30% of patients are asymptomatic, even with diffuse chest radiograph abnormalities. Symptoms include the following:

Physical examination

Physical findings are usually nonspecific. Symptoms include the following:

Laboratory Studies

Serologic studies are generally not useful for pulmonary alveolar proteinosis (PAP). Flexible bronchoscopy with bronchoalveolar lavage (BAL) remains the criterion standard. Elevated levels of the proteins SP-A and SP-D in serum and BAL fluid may be useful. Elevated titers of neutralizing autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) (immunoglobulin G [IgG] isotype) in serum and BAL fluid may be useful.

It has been proposed that deficiency of GM-CSF causes PAP; all patients studied had the antibody to GM-CSF.[27, 28]  Serum lactate dehydrogenase (LDH) is usually elevated, but this finding is nonspecific.

There appears to be a correlation between the levels of some tumor markers (eg, carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], and squamous cell carcinoma [SCC]) and the severity of PAP.[29]

The diagnosis can be made by BAL only if periodic acid-Shiff PAS staining is requested. Therefore, PAP is probably underdiagnosed.

Lung biopsy findings are classic for PAP. Alveoli are filled with nonfoamy material. Transbronchial biopsies are adequate, and open lung biopsy is not required.

Imaging Studies

Chest radiography in pulmonary alveolar proteinosis (PAP) shows bilateral perihilar infiltrates[3, 4] with consolidation in a "bat-wing" configuration, which may mimic pulmonary edema, although with a typical absence of cardiomegaly or pleural effusion. Unilateral involvement occurs occasionally, and lymphadenopathy is rarely present. Typically, changes progress over weeks to months into a diffuse reticulogranular pattern.

High-resolution computed tomography (HRCT) scanning of the chest demonstrates areas of patchy ground-glass opacification (GGO) with smooth interlobular septal thickening and intralobular interstitial thickening, which produces a polygonal pattern referred to as "crazy paving." The crazy-paving pattern also can be observed in exogenous lipoid pneumonia, sarcoidosis, mucinous bronchoalveolar cell carcinoma, and acute respiratory distress syndrome (ARDS).[30, 31] PAP presenting as ground-glass opacity (GGO) mimics carcinoma.[32] HRCT findings have been able to show several distinctive differences between exogenous lipoid pneumonia and PAP, which had previously only been distinguished pathologically.[33]

Procedures

Bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) may be helpful. Transbronchial biopsies of affected lung segments, coupled with findings on BAL, are sufficient to make the diagnosis. Use periodic acid-Shiff (PAS) reagent for BAL. Bronchoalveolar lavage fluid appears "milky." Papanicolaou staining may reveal green and orange globules that are diagnostic for PAP. Electron microscopy of BAL may reveal characteristic multilamellar structures.

Transbronchial biopsy may increase the yield. Surgical lung biopsy rarely is necessary for definitive diagnosis.



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Pulmonary alveolar proteinosis. Cytologic appearance of intra-alveolar granular material from a bronchoalveolar lavage sample (diastase-periodic acid-....



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Pulmonary alveolar proteinosis. Bronchoalveolar lavage sample depicting dense globules with sharp borders seen in patients with pulmonary alveolar pro....

Histologic Findings

Light microscopy of the lung parenchymal tissue shows alveoli filled with a granular periodic acid-Shiff (PAS) base-reactive and diastase-resistant eosinophilic material.



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Pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase-PAS, x200).

Electron microscopy of the material in the alveoli shows multilamellated structures and membranous vesicles. Eosinophilic granular material is present within the alveolar spaces (see the following images). 



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Pulmonary alveolar proteinosis. Alveoli are filled with an eosinophilic granular material. Note the preservation of the normal lung architecture (hema....



View Image

Pulmonary alveolar proteinosis. High magnification illustrating the granular material and alveolar macrophages surrounded by intact alveolar septal ti....

Approach Considerations

Management of pulmonary alveolar proteinosis (PAP) depends on the progression of the illness, the presence of coexisting infections, and the degree of physiologic impairment. The standard of care for PAP is mechanical removal of the lipoproteinaceous material by whole-lung lavage (WLL), as well as management of the underlying cause.[1, 2, 3]

Supplemental granulocyte-macrophage colony-stimulating factor (GM-CSF) is useful; however, there is continued debated regarding its indications, agent selection, and dosing.[3] Inhaled GM-CSF was initially shown to be safe and effective in providing a sustained therapeutic effect in autoimmune PAP[13] ; more recently, it appears to have only modest salutary laboratory effects on arterial oxygen tension without clinical benefits in mild-to-moderate autoimmune PAP.[14]  For refractory PAP, rituximab, plasmapheresis, and lung transplantation may be therapeutic considerations.[3]

Historically, patients have been treated with systemic steroids, mucolytics (aerosol), and proteinase (aerosol) without much success. In secondary PAP, appropriate treatment of the underlying cause is warranted.

Inpatient care is uncommon in primary PAP, except for concomitant superinfection or severe hypoxemia. Treatment of secondary PAP might require inpatient care and outpatient follow-up.

Medical Care

 

 

 

Surgical Care

Whole-lung lavage (WLL) remains the gold standard of therapy for PAP.[1, 2, 3]  Current indications for WLL vary from center to center, but the most common indications appear to be declining lung function, declining oxygenation, and radiographic worsening.[34, 35] The main indication is limitation in daily activities due to dyspnea.[35] An alveolar-arterial oxygen gradient of at least 40 mmHg and a PaO2 below 70 mmHg on room air are additional indications, as these patients are more likely to have disease progression.[35]

WLL is performed with a double-lumen endotracheal tube designed to allow simultaneous ventilation and lavage. Lung lavage is performed under general anesthesia, and the lung is ventilated briefly with 100% oxygen before lavage with isotonic sodium chloride solution. The standard is lavage with up to 50 L of fluid. Upon completion of the procedure, the lung is suctioned of most of the isotonic sodium chloride solution and allowed to recover before lavaging the other lung. Lung lavage has been performed in hyperbaric chambers, which has made lavage of both lungs possible on the same day. Lung lavage may require several hours.

Although WLL is an invasive procedure, it has been determined to be safe and associated with a low rate of procedure-related morbidity. The results of a global practice survey of 20 centers in 14 countries found the most complications to be fever (18%), worsened hypoxemia (14%), wheezing (6%), pneumonia (5%) and pleural effusion (3%).[34, 35]

Rarely, hyperbaric chamber or extracorporeal membrane oxygenation (ECMO) has been used to perform WLL in cases of severe hypoxemia.[36]

Lung transplantation is the treatment of choice in patients with congenital PAP and in adult patients with end-stage interstitial fibrosis and cor pulmonale.

Long-Term Monitoring

Patients with pulmonary alveolar proteinosis (PAP) usually improve dramatically with whole-lung lavage, but relapses may occur. Repeated lavage usually is necessary. Patients should have regular follow-up with a pulmonologist.

Patients prone to alveolar proteinosis related to inhalation of inorganic dusts or insecticides should avoid further exposure.

Medication Summary

Granulocyte-macrophage colony-stimulating factor (GM-CSF) may be useful in approximately 50% of patients with acquired disease, although it is still regarded as experimental. (Adequate dosing schedules are under investigation.) GM-CSF is unsuccessful in congenital disease.

With solitary pulmonary opacities, not treating and observing the natural history of the disease is appropriate. It often resolves over 3-9 months.

Author

Roger B Olade, MD, MPH, Medical Director, Genesis Health Group

Disclosure: Nothing to disclose.

Coauthor(s)

Klaus-Dieter Lessnau, MD, FCCP, Former Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory, Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Disclosure: Nothing to disclose.

Oluwatoyin E Ijitola, MD, PhD, Dean and Professor, International University for Graduate Studies (IUGS)

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Gregory Tino, MD, Director of Pulmonary Outpatient Practices, Associate Professor, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center and Hospital

Disclosure: Nothing to disclose.

Philip T Cagle, MD, Professor, Department of Pathology, Weill Medical College of Cornell University; Director, Pulmonary Pathology, The Methodist Hospital; Senior Member, The Methodist Hospital Research Institute

Disclosure: Nothing to disclose.

Rodolfo Laucirica, MD, Professor, Department of Pathology and Immunology, Baylor College of Medicine; Medical Director of Cytopathology, Ben Taub General Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Gregg T Anders, DO Medical Director, Great Plains Regional Medical Command , Brooke Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio

Disclosure: Nothing to disclose.

Ali Hmidi, MD Staff Physician, Department of Internal Medicine, Brooklyn Hospital Center, Cornell University

Disclosure: Nothing to disclose.

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Pulmonary alveolar proteinosis. A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of granular material.

Pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase-PAS, x200).

Pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) and frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (A) (hematoxylin and eosin, x400) and broncheoalveolar lavage (BAL).

Pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) and frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (B) (Papanicolaou, x600). Note the negative images of the cysts impart the foamy characteristic of the exudate.

Pulmonary alveolar proteinosis. Cytologic appearance of intra-alveolar granular material from a bronchoalveolar lavage sample (diastase-periodic acid-Shiff [DPAS], x400).

Pulmonary alveolar proteinosis. Bronchoalveolar lavage sample depicting dense globules with sharp borders seen in patients with pulmonary alveolar proteinosis (PAP) (Papanicolaou, x400).

Pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase-PAS, x200).

Pulmonary alveolar proteinosis. Alveoli are filled with an eosinophilic granular material. Note the preservation of the normal lung architecture (hematoxylin and eosin, x200).

Pulmonary alveolar proteinosis. High magnification illustrating the granular material and alveolar macrophages surrounded by intact alveolar septal tissue with minimal reaction (hematoxylin and eosin, x400).

Pulmonary alveolar proteinosis. A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of granular material.

Pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) and frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (A) (hematoxylin and eosin, x400) and broncheoalveolar lavage (BAL).

Pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) and frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (B) (Papanicolaou, x600). Note the negative images of the cysts impart the foamy characteristic of the exudate.

Pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase-PAS, x200).

Pulmonary alveolar proteinosis. Cytologic appearance of intra-alveolar granular material from a bronchoalveolar lavage sample (diastase-periodic acid-Shiff [DPAS], x400).

Pulmonary alveolar proteinosis. Bronchoalveolar lavage sample depicting dense globules with sharp borders seen in patients with pulmonary alveolar proteinosis (PAP) (Papanicolaou, x400).

Pulmonary alveolar proteinosis. Alveoli are filled with an eosinophilic granular material. Note the preservation of the normal lung architecture (hematoxylin and eosin, x200).

Pulmonary alveolar proteinosis. High magnification illustrating the granular material and alveolar macrophages surrounded by intact alveolar septal tissue with minimal reaction (hematoxylin and eosin, x400).