Nonspecific symptoms are among the obstacles to diagnosis Pulmonary alveolar proteinosis: An easy-to-miss diagnosis key words: Alveolar proteinosis, Surfactant, Whole lung lavage

Pulmonary alveolar proteinosis (PAP) was first described in 1958 by Rosen and colleagues.¹ It is characterized by the accumulation of lipid-rich periodic acid-Schiff (PAS)-positive proteinaceous material in the alveoli.

The incidence of PAP is 0.37 cases per million. It occurs in all age groups, commonly between 20 and 50 years of age, with a male-to- female ratio of 3:1.^2-5 PAP is 3 times more common in smokers than nonsmokers. There are 2 clinically distinct forms of PAP: congenital (2%) and acquired (primary, 90%; secondary, less than 10%).⁴

Because PAP is uncommon and causes nonspecific symptoms, such as shortness of breath and cough, the diagnosis is often overlooked. Although some patients have spontaneous remission, others are at risk for pulmonary infection and respiratory failure. In this article, we review the clinical presentation and diagnosis of PAP and review the approach to management.

ETIOLOGY

The etiology of primary PAP has not been fully elucidated. Secondary PAP has been associated with several infectious processes, malignancy, and exposure to certain inorganic dust (Figure 1).^6-10

An uncommon cause of secondary PAP is lysinuric protein intolerance, an autosomal recessive disease characterized by defective transport of cationic amino acids.¹¹ Patients with lysinuric protein intolerance are strongly predisposed to alveolar proteinosis. Secondary PAP can also accompany amyloid- osis, lung transplantation, renal tubular acidosis, Fanconi disease, glioblastoma multiforme, and atrio- ventricular septal defect.

PATHOGENESIS

There are 4 main surfactant proteins: SP-A, SP-B, SP-C, and SP-D. SP-A is necessary for the production of tubular myelin, a lipid transport structure unique to the lungs. SP-D regulates surfactant balance. SP-B can fluidize a monolayer by preventing lipid packing; this leads to smaller domains in a liquid-condensed state and makes widespread collapse more difficult. It has been suggested that SP-C can act as a lever to move lipids.

Congenital PAP is transmitted in an autosomal recessive pattern and is caused by mutation in SP-B gene, which leads to reduced protein levels and secondary disturbances of SP-C processing.^12-14

Important advances in the past decade contribute to the understanding of the pathogenesis of primary or idiopathic PAP. Granulocyte-macrophage colony-stimulating factor (GM-CSF) binds to the receptors on the surface of type II alveolar epithelial cells, leading to activation of alveolar macrophages. It has been proposed that GM-CSF deficiency or destruction/inactivation by anti-GM-CSF antibodies leads to a defect in alveolar macro- phage function and accumulation of proteinaceous material in alveoli (Figure 2).^15,16 Lung lesions with histological resemblance to PAP have been found in mice deficient in GM-CSF.^17,18

GM-CSF-neutralizing autoantibodies have been identified in bronchoalveolar lavage (BAL) fluid and serum specimens from patients with primary PAP; these autoantibodies were not present in specimens from patients with congenital or secondary PAP.^19,20

DIAGNOSIS

Presentation

Because the symptoms are nonspecific, PAP is often misdiagnosed and therefore untreated, leading to increased morbidity and mortality.⁵ The most common symptoms are dyspnea on exertion and cough; the cough is usually nonproductive and rarely is productive of chunky, gummy sputum. Weight loss, fatigue, chest pain, and hemoptysis have also been reported.

Fever is present primarily in patients with superinfection or other disease processes. Up to 13% of patients have superinfection with fungi, bacteria, or viruses, notably with Mycobacterium avium-intracellulare or Nocardia. Up to one third of patients are only mildly symptomatic, with chronic symptoms for more than 2 years. Physical examination findings include fine crackles in involved areas, cyanosis, and clubbing.^1,4,21,22

Laboratory tests

The results of routine blood tests, including complete blood cell count, chemistry, and liver function tests, are usually normal in patients with PAP. It has been shown that lactate dehydrogenase (LDH) increases less than 2-fold. Serum levels of SP-A and SP-D are elevated in patients with PAP. However, SP-A is also elevated in patients with idiopathic pulmonary fibrosis (IPF), and SP-D is elevated in those with IPF and interstitial pneumonia associated with rheumatological disorders and collagen-vascular disease.^23-27

Radiographic/imaging features

In patients with PAP, chest radiographs typically show bilateral, symmetrical airspace disease with an ill-defined nodular or confluent pattern. This gives a typical "bat wing" or "butterfly" appearance, as is seen in heart failure. Other radiological patterns include:

•Asymmetrical, unilateral, or nodular infiltrates.

•Air bronchograms (rare).

•A thin lucent band that sharply outlines the diaphragm and heart, consistent with sparing of the lung that is immediately adjacent to these structures.

•Segmental atelectasis that devel- ops as a result of bronchiolar obstruction from the thick lipoprotein- aceous material.

•An interstitial pattern resulting from incomplete alveolar filling.

•Pulmonary fibrosis (in chronic cases).

High-resolution CT reveals airspace opacification with a reticular, reticulonodular, or ground-glass appearance that is sharply demarcated from surrounding normal lung tissue. Intralobular and interlobular septal thickening produces the polygonal shapes--the "crazy pavement" appearance--that is characteristic but not specific to PAP. Lymphadenopathy is an unusual finding (Figure 3).^28-31

Additional diagnostic tests

Pulmonary function tests most commonly demonstrate mild restrictive disease, with a decreased carbon monoxide-diffusing capacity (DlCO).^2,5,21,22 Arterial blood gas analysis may show hypoxemia and hypocapnia, with an increase in shunt fraction or alveolar-arterial (A-a) oxygen gradient.^4,27,32

PAS-positive proteinaceous material in the sputum is a nonspecific finding that can also be seen in other pulmonary disorders, such as chronic bronchitis, bronchiectasis, pneumonia, and malignancy. The milky or muddy appearance of BAL is highly suggestive of PAP. Cell counts and differential counts are not helpful in the diagnosis; the BAL fluid can be either macrophage- or lymphocyte-predominant.^33,34 However, elevated levels of inflammatory cells may suggest infection, as either a primary or secondary process.

Electron microscopy reveals degenerating cell debris in alveoli, which forms osmiophilic, multi- lamellated "myelin" figures similar to condensed surfactant.^34,35 Biochemical analysis supports electron microscopy, showing phospholipids and proteins with large amount of surfactant in alveoli. Immunological studies of BAL fluid show large amounts of SP-A and SP-D.

Open lung biopsy is the gold standard for the diagnosis of PAP. The biopsy specimen reveals a collection of granular, PAS-positive, lipoproteinaceous material in alveoli, with minimal inflammatory cells unless superinfection is present.²¹ The alveolar and interstitial architecture are usually preserved, and vasculature appears normal (Figure 4).

TREATMENT

Not all patients with PAP require immediate treatment; some of them are asymptomatic with little or no physiological impairment despite extensive radiographic findings. Up to 25% of patients can have spontaneous remission. Hence, treatment is recommended only for symptom- atic patients.

Whole lung lavage (WLL) has been the standard of care for PAP since the disease was first recognized.^36,37 The recommended indications for WLL include a definitive histological diagnosis and 1 of the following:

•PaO₂ less than 65 mm Hg (at sea level).

•Measured shunt fraction greater than 10% to 12%.

•A-a oxygen gradient of 40 mm Hg.

•Severe dyspnea and hypoxemia (at rest or with exercise).

The procedure requires general anesthesia and intubation with a double-lumen endotracheal tube. One lung is lavaged with saline while the other is ventilated. It requires about 30 to 50 L of saline to produce clear effluent.^37-39 The second lung can be lavaged on the same day or after 3 to 7 days.

Significant clinical, radiological, and physiological improvement has been documented after therapeutic WLL. Physiological improvement includes an increase in forced vital capacity, total lung capacity, PaO₂, and DlCO and a decrease in shunt fraction and A-a gradient. A reduction in LDH level and radiographic clearance have been noted in some cases.^38,40 Complications of the procedure include hypoxemia, spill- ing of fluid from lavaged to ventilated lung, surgical emphysema, and hydropneumothorax.^38-40

Subcutaneous human recombinant GM-CSF at a dosage of 3 to 9 µg/kg/d has been shown to produce symptomatic, physiological, and radiographic improvement.³⁹ In a recent prospective, open-label clinical trial conducted at the Cleveland Clinic, daily subcutaneous GM-CSF therapy was given to 25 adults with idiopathic PAP. Significant physiological and clinical improvement was reported in 48% of patients. In addition, the serum anti-GM-CSF antibody titer correlated with lung disease activity and predicted responsiveness to therapy. These data indicate that subcutaneous GM-CSF therapy is a promising alternative to WLL for symptomatic patients with PAP.⁴¹

Multiple therapies, including corticosteroids, antibiotics, postural drainage, and intermittent positive pressure breathing with aerosolized saline, heparin, acetylcysteine, and trypsin, have been tried in patients with PAP with no success.

Treatment for congenital PAP is supportive, and lung transplantation has been successful in some patients. Intravenous immunoglobulin also has been successful in a few cases of congenital PAP.⁴² Treatment of secondary PAP should focus on the underlying diseases, such as infections and hematological malignancies, with additional supportive measures.

OUTCOME

The natural evolution of PAP is poorly understood. In patients with congenital PAP, death is almost inevitable without lung transplantation. The clinical course of acquired PAP follows 1 of the 3 paths: stable with persistent symptoms, progression to respiratory failure, or spontaneous recovery. The overall 5-year survival is about 95% with treatment and 85% without. The disease can be complicated by superinfection, pulmonary fibrosis, and secondary amyloidosis.

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