PULMONARY ALVEOLAR PROTEINOSIS

Pulmonary Alveolar Proteinosis

 

Clinical Characteristics and Presentation

Epidemiology

The average age of patients with idiopathic PAP in four recent case series comprising 140 patients was 42.6 years (range 6-73) with the majority being between 20 and 50 years old.^[2,7-9] There was a male predominance with a male to female ratio of 2.7:1. These figures are similar to earlier reports.^[2,10] Smokers outnumber nonsmokers by 3:1 in series that reported smoking status.^[2,8] Although cases from Canada, Japan, and Israel were reported soon after the original description,^[11-13] the two most recent case series from the United States (58 total patients)^[2,7] contained only Caucasian patients. Whether this represents a true racial pattern of disease is unclear. Familial patterns have been reported primarily in congenital PAP ^[14] with one report in adult siblings with an immunoglobulin deficiency.^[15] Although the incidence and prevalence remain unknown, PAP is likely a rare disorder. A report from Israel suggests a prevalence of 3.7 per 10⁶,^[16] whereas one from Pittsburgh estimates an ther incidence of 2 per 10⁷ per year.^[17]

PAP has been associated with many conditions. Hematologic malignancies, predominantly myelogenous leukemias, are well established secondary causes.^[18-21] Similarly, several exposures, including silica, aluminum, titanium, and nitrogen dioxide have been reported to precede the development of PAP.^[22-26] Infections such as pneumocystis carinii pneumonia (PCP) (with or without acquired immunodeficiency syndrome),^[27,28] mycobacteria,^[29-32] nocardia,^[33] cytomegalovirus,^[28] and anaerobes^[34] have also been associated with PAP. These infections are occasionally felt to precede the development of PAP, but often are seen complicating the disease. This is supported by reports of decreased incidence of most infections with earlier recognition and treatment of PAP.^[35] Other reported associations include amyloidosis,^[36] and lung transplantation.^[37]

Clinical Presentation

The clinical presentation is variable and nonspecific. Up to 30% of patients may be asymptomatic.^[8] Others present with acute symptoms suggestive of pneumonia. Still others present with subacute or chronic symptoms and nonresolving infiltrates. The nonspecific presentation may lead to months or years of misdiagnosis.

Symptoms are frequently milder than expected from radiographic findings. Dyspnea and cough are the most common presenting symptoms. Chest pain, hemoptysis, fever, and weight loss are variably reported (Table 1).^[1,2,7-9]

The physical exam is likewise nonspecific. Crackles, clubbing, and cyanosis all may be detected (Table 1).^[1,2,7-9] Uncommon but reported features include pneumothorax^[38] and cor pulmonale.^[39,40]

Radiology

Many patterns of chest x-ray (CXR) abnormalities have been described. Typically a bilateral, symmetric alveolar filling pattern is seen. Infiltrates classically are perihilar, extending to the periphery (lower > upper) sparing the costophrenic angles, yielding a "butterfly" distribution (Fig. 1).^[1] The pattern is similar to that of pulmonary edema and PCP. This typical picture seems somewhat less common in the latest case series.^[2,7,41] Interstitial, mixed alveolar and interstitial, nodular, asymmetric, and focal patterns have all been described.^[2,7-9] Although the absence of pleural effusions, adenopathy, and cardiomegaly help to narrow the differential diagnosis of the CXR pattern, the appearance is generally nonspecific.

 

Computed tomography (CT) is felt to more clearly define the extent, distribution, and nature of the infiltrates. This is particularly true when thin sections are used.^[42] The infiltrates have been described as patchy or diffuse, and central or peripheral. Reticular, reticulonodular, ground glass, and patchy or confluent air space patterns can be seen, oftentimes in the same patient. The infiltrates are often clearly delineated with sharp margins surrounded by normal lung. These areas have been referred to as "geographical" in appearance. A branching pattern of white linear areas forming geo-metric shapes of around 10 mm in diameter is seen overlying consolidated areas. This pattern, described as "crazy paving" (Fig. 2) has been seen in other diseases.^[43] Air bronchograms are variably reported and the visibility of the pulmonary vessels is often preserved. Again absent are pleural effusions and adenopathy. The CT appearance has been said to be characteristic of PAP^[42] though not all agree

 

 

CXR and high-resolution CT (HRCT) appearances have been shown to correlate with the presence of a restrictive ventilatory defect, reduced diffusing capacity, and hypoxemia.^[44] Although HRCT correlated somewhat better, the difference was not significant enough to justify the use of CT for follow-up.

Cases using gallium^[45] and Xenon-133^[46] scintigraphy have been described but do not have practical applications in the routine diagnosis or management of PAP.

Physiological Testing

In general, the most common pulmonary function dis-order is restriction. The forced vital capacity (FVC) and total lung capacity (TLC) are mildly reduced in most series with a disproportionate reduction in diffusing capacity. Patients tend to be mildly hypoxemic with an elevated alveolar-arterial oxygen gradient and a compensated respiratory alkalosis (Table 2).^[2,7-9] The shunt fraction has been shown to be elevated as compared to patients with other diffuse lung diseases.^[47]

The severity of pulmonary function abnormalities has varied in different case series. This may in part be explained by differences in the proportion of patients requiring whole lung lavage and mortality in these case series, suggesting the populations differed.

Diagnostic Evaluation

Although history, physical examination, radiographic studies, and physiological testing may suggest PAP, further evaluation is usually needed to confirm the diagnosis. Blood tests, sputum, and BAL results similarly support the diagnosis, however transbronchial or open lung biopsy remain the standard. Table 3 summarizes the clinical and diagnostic features of PAP.

Serum lactate dehydrogenase (LDH) levels have been shown to be elevated relative to other diffuse lung diseases.^[48] These levels are also increased in BAL fluids and have some correlation with the A-a gradient. Krebs von den Lungen-6 (KL-6), a mucin-like protein secreted from type II pneumocytes, has been reported to be elevated in serum and BAL fluids of PAP patients.^[49] The levels were higher than for interstitial lung diseases and correlated with disease activity, radiographic appearance, and pO2.

49,50 Surfactant protein A (SP-A) is elevated in sera of PAP and idiopathic pulmonary fibrosis patients compared with control and other lung diseases.^[51] It is similarly elevated in the sputum, but not all patients can expectorate.^[52] Surfactant protein D (SP-D) is also elevated in the sera of PAP patients and has been shown to correlate with disease severity.^[53] It was similarly elevated in idiopathic pulmonary fibrosis and interstitial lung disease associated with collagen vascular diseases.

BAL findings of PAP have occasionally been used as diagnostic.^[7,8] Typically, however, tissue is obtained. Traditionally tissue was obtained by open lung biopsy. It has been suggested that transbronchial biopsy can be used to accurately make the diagnosis.^[9] Recent case series support this, with a trend toward a greater percentage of cases being diagnosed with transbronchial biopsy.^[2,8]

Histopathology

Analysis of BAL fluid has revealed increased concentrations of lipids and proteins, particularly those associated with surfactant. The classes and distribution of surfactant phospholipids do not substantially differ from normals,54,55 though there is much variability. Cholesterol concentrations are consistently elevated.^[54,55] Surfactant protein levels vary considerably from patient to patient though they are consistently elevated. SP-A has been reported to increase out of proportion to the total protein^[56] though this is variable.^[57] The SP-A: phospholipid ratio is also elevated.^[55,57] SP-B is similarly increased, with an increased SP-B:phospholipid ratio and a normal SP-B:SP-A ratio.^[55] A dimeric form of surfactant associated protein C is present in increased quantities.^[58] SP-D has also been identified to be elevated in PAP patients though to a smaller degree than other surfactant associated proteins.^[59] This accumulated PAP material has been shown to have normal surface activity after processing.^[54]

A small study of cells in the BAL fluid revealed an increase in both the CD4 and CD8 lymphocyte population.^[60] The CD4:CD8 ratio tended to be high but was variable.^[60]

Macroscopically, both biopsy and necropsy specimens reveal multiple, up to 2-3 cm, yellow-gray nodular areas of consolidation. These areas are firm and exude a fatty substance when cut.^[1,7,11] Microscopically, the alveoli are filled with a granular and floccular acidophilic material that is periodic acid Schiff (PAS) positive (Fig. 3). This substance is seen to extend to the small bronchioles at times. Staining these specimens for surfactant specific apoprotein reveals uniform uptake in primary PAP and patchy uptake in secondary PAP.^[61] Alveolar and interstitial architecture are typically preserved, though infiltration of bronchial walls with lymphocytes and thickening or fibrosis may be seen. The vasculature appears normal.^[1,7,11] Electron microscopy reveals characteristic multilamellated structures within the alveolar material as well as inclusions in the cytoplasm of macrophages.^[7,62] Papanicolaou-stained specimens from PAP contain scattered, amorphous, or granular globules that are PAS positive and contain these multilamellated structures when examined ultrastructurally