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Pulmonology > Idiopathic Lung Disorders
Pulmonary Alveolar Proteinosis
Article Last Updated: Nov 19, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Roger B Olade, MD, MPH, Medical Director, Providence Health Group
Roger B Olade is a member of the following medical societies: American College of Occupational and Environmental Medicine and American College of Physicians
Coauthor(s):
Klaus-Dieter Lessnau, MD, FCCP, 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;
Ali Hmidi, MD, Staff Physician, Department of Internal Medicine, Brooklyn Hospital Center, Cornell University;
Oluwatoyin E Ijitola, MD, PhD, Adjunct Professor, International University for Graduate Studies (IUGS)
Editors: 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; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Gregg T Anders, DO, Medical Director, Great Plains Regional Medical Command , Brook Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Author and Editor Disclosure
Synonyms and related keywords:
pulmonary alveolar proteinosis, PAP, alveolar filling with floccular material, periodic acid-Schiff, PAS, surfactant-associated protein B deficiency, SP-B deficiency, GM-CSF antibodies, GM-CSF deficiency, inhalation of silica dust, acute silicoproteinosis, insecticide exposure, aluminum dust exposure, titanium dioxide exposure, inorganic dust exposure, hematologic malignancy, myeloid disorder, lysinuric protein intolerance, HIV infection, AIDS
Background
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder of unknown etiology characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff (PAS) method and is derived from surfactant phospholipids and protein components (see Media File 1). PAP was first described in 1958.1 Two forms are recognized, (1) primary (idiopathic) and (2) secondary (due to lung infections; hematologic malignancies; and inhalation of mineral dusts such as silica, titanium oxide, aluminum, and insecticides). Incidence of PAP is increased in patients with hematologic malignancies and AIDS, suggesting a relationship with immune dysfunction. A similar disorder affects neonates deficient in surfactant-associated protein B (SP-B). The discovery that PAP may be related to granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies or GM-CSF deficiency has been noted.
A related Medscape CME course is Nontuberculous Mycobacteria: Update on Diagnosis and Treatment.
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-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 elevator. A clear relationship has been demonstrated between PAP and impaired macrophage maturation or function, which might account for the high 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 yielded animals with PAP-like disease. GM-CSF has been demonstrated to increase the effectiveness of alveolar macrophages in the catabolism of surfactant. Recent studies have demonstrated the presence of neutralizing autoantibodies against GM-CSF in patients with PAP. Also documented is that 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.2
Frequency
United States
PAP has an estimated prevalence of 1 case per 100,000 population.
International
Frequency is believed to be similar to that in the United States, but notification systems do not exist.
Mortality/Morbidity
- Mortality rates of as high as 30% within several years of disease onset have been reported previously, but the actual mortality rate may be less than 10%. Solitary pulmonary PAP is increasingly being seen and may resolve spontaneously over several months.
- The natural history of secondary PAP depends on the underlying etiologic entity.
Race
- Isolated studies have reported predominance in patients of Arabian origin, but no other definitive studies are available.
Sex
- Incidence for males is 4 times higher than for females.
Age
- Patients are typically aged 20-50 years at presentation.
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 (CXR) abnormalities. Symptoms include the following:
- Persistent dry cough (or scant sputum production)
- Progressive dyspnea
- Fatigue and malaise
- Weight loss
- Intermittent low-grade fever and/or night sweats
- Pleuritic chest pain
- Cyanosis (rare)
- Hemoptysis (rare)
Physical
Physical findings are usually nonspecific. Symptoms include the following:
- Fine end-inspiratory crackles
- Clubbing (25%)
- Cyanosis (20%)
- Pulmonary hypertension and cor pulmonale (rare)
Causes
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:
- Inhalation of silica dust (acute silicoproteinosis)
- Exposure to insecticides, aluminum dust, titanium dioxide, and other inorganic dusts
- Hematologic malignancies, mostly myeloid disorders
- Lysinuric protein intolerance (rare)
- HIV infection (AIDS)
- Leflunomide - Case report (disease-modifying antirheumatic arthritis therapy)3
Hypersensitivity Pneumonitis
Lung Cancer, Non-Small Cell
Lung Cancer, Oat Cell (Small Cell)
Pneumocystis Carinii Pneumonia
Pulmonary Edema, Cardiogenic
Sarcoidosis
Other Problems to be Considered
Bronchoalveolar cell carcinoma
Desquamative interstitial pneumonitis
Alveolar microlithiasis
Alveolar hemorrhage
Lipoid pneumonia
Lab 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 titer of neutralizing autoantibody against GM-CSF (immunoglobulin G [IgG] isotype) in serum and BAL fluid may be useful. Recent studies have proposed that deficiency of GM-CSF causes pulmonary alveolar proteinosis (PAP); all patients studied had the antibody to GM-CSF.4, 5
- Serum lactate dehydrogenase (LDH) level is usually elevated, but this finding is nonspecific.
- The diagnosis can be made by BAL only if PAS staining is requested. Therefore, PAP is probably underdiagnosed.
- Lung biopsies are classic for PAP: Alveoli are filled with nonfoamy material. Transbronchial biopsies are adequate, and open lung biopsy is not required.
Imaging Studies
- CXR in pulmonary alveolar proteinosis (PAP) shows bilateral perihilar infiltrates 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) scan of the chest demonstrates areas of patchy ground-glass opacification 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 lipoid pneumonia, sarcoidosis, mucinous bronchoalveolar cell carcinoma, and acute respiratory distress syndrome (ARDS).6, 7
Procedures
- Bronchoscopy with transbronchial biopsy and BAL: Transbronchial biopsies of affected lung segments, coupled with findings on BAL, are sufficient to make the diagnosis.
- Use 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 biopsies may increase the yield.
- Surgical lung biopsy rarely is necessary for definitive diagnosis.
Histologic Findings
Light microscopy of the lung parenchymal tissue shows alveoli filled with a granular PAS base-reactive and diastase-resistant eosinophilic material. Electron microscopy of the material in the alveoli shows multilamellated structures and membranous vesicles.
Medical Care
Management of pulmonary alveolar proteinosis (PAP) depends on the progression of the illness, coexisting infections, and degree of physiological impairment. The standard of care for PAP is mechanical removal of the lipoproteinaceous material by whole-lung lavage. Historically, patients have been treated with systemic steroids, mucolytics (aerosol), and proteinase (aerosol) without much success. Indications for this procedure are a histologic diagnosis in combination with any of the following: (1) an alveolar-arterial oxygen gradient greater than or equal to 40 mm Hg, (2) dyspnea and hypoxemia at rest or with exercise, or (3) a PaO2 of less than 65 mm Hg.
In secondary PAP, appropriate treatment of the underlying cause also is warranted. GM-CSF has been shown to improve PAP in several patients and is being investigated.8 - Whole-lung lavage 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.
Surgical Care
Lung transplantation is the treatment of choice in patients with congenital PAP and in adult patients with end-stage interstitial fibrosis and cor pulmonale.
Consultations
Pulmonologist
GM-CSF may be useful in approximately 50% of patients with acquired disease, although it is still regarded as experimental. (Adequate dosing schedules are being investigated.) GM-CSF is unsuccessful in congenital disease.
With solitary pulmonary opacities, not treating and observing the natural history of disease is appropriate. It often resolves over 3-9 months.
Further Inpatient Care
- Inpatient care is uncommon in primary pulmonary alveolar proteinosis (PAP), except for concomitant superinfection or severe hypoxemia.
- Treatment of secondary PAP might require inpatient care and outpatient follow-up.
Further Outpatient Care
- Patients 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.
Deterrence/Prevention
- Patients prone to alveolar proteinosis related to inhalation of inorganic dusts or insecticides should avoid further exposure.
Complications
Prognosis
- The overall prognosis for primary PAP is very good, with achievement of complete remissions in many patients.
- Whole-lung lavage most often results in a dramatic response.
- Some patients require repeated lavages, and these patients usually progress to pulmonary fibrosis and have a poor outcome.
- Congenital PAP responds favorably to lung transplantation.
Medical/Legal Pitfalls
- Because PAP presents with nonspecific signs and symptoms, misdiagnosis or delayed diagnosis may occur. Medicolegal issues could arise if patients develop chronic lung disease.
- Complications related to whole-lung lavage may occur.
| Media file 1:
A periodic acid-Schiff histochemical stain of transbronchial biopsy: Alveolar spaces contain considerable amounts of granular material. |
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Media type: Photo
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- Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med. Jun 5 1958;258(23):1123-42. [Medline].
- Bonfield TL, Farver CF, Barna BP, Malur A, Abraham S, Raychaudhuri B, et al. Peroxisome proliferator-activated receptor-gamma is deficient in alveolar macrophages from patients with alveolar proteinosis. Am J Respir Cell Mol Biol. Dec 2003;29(6):677-82. [Medline].
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Pulmonary Alveolar Proteinosis excerpt Article Last Updated: Nov 19, 2008
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