Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan

Abstract

Rationale: Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data.

Objectives: To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP.

Methods: Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP.

Measurements and main results: Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease.

Conclusions: Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP.

Figure 1.

Disposition of the patients with pulmonary alveolar proteinosis (PAP) enrolled into the study. Participants were stratified according to the presence or absence of granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies and then by the presence or absence of an underlying disorder known to cause PAP.

Figure 2.

Histogram of the age at diagnosis of autoimmune pulmonary alveolar proteinosis in male (top) and female patients (bottom). Data are grouped into 10-year intervals. The age distribution in female subjects, but not male subjects, was normally distributed (P = 0.03 and 0.68, respectively; Kolmogorov-Smirnov test). The median age at diagnosis was similar in male and in female subjects (see Table 1).

Figure 3.

Concentration of granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies in the serum at enrollment of individuals with autoimmune pulmonary alveolar proteinosis (PAP) (n = 223), secondary PAP (n = 24), other lung diseases (n = 24), or healthy individuals (n = 14). In one individual with unclassified PAP, serum GM-CSF autoantibodies were undetectable (not shown).

Figure 4.

Histogram of serum granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody concentrations in male (top) and female (bottom) patients with autoimmune pulmonary alveolar proteinosis. The concentrations were not normally distributed and were significantly skewed toward high values (P < 0.001 for both, Kolmogorov-Smirnov test). The distribution of serum GM-CSF autoantibody concentrations was similar in males and female subjects (see Table 1).

Figure 5.

Distribution and regional prevalence of autoimmune pulmonary alveolar proteinosis (PAP) in Japan at the time of enrollment into the study. (A) Geographic locations of the patients. Shown are the nine separate regions (regional population size from the 2005 Japanese census report) representing all of Japan, including Hokkaido, (5,653,548), Tohoku (11,568,884), Kanto (41,760,805), Hokushinetsu (7,781,254), Tokai (14,894,128), Kinki (20,930,730), Chugoku (7,705,615), Shikoku (4,128,260), and Kyushu (14,757,324). Each solid dot represents one autoimmune PAP patient in the identified region. The Niigata prefecture, in which a second intensive screening for PAP cases was performed, is located within the Hokushinetsu region. The cities of Niigata (triangle), Osaka (circle) and Tokyo (diamond) and the global latitude (in degrees) for each region are indicated for orientation. (B) Correlation of the prevalence of autoimmune PAP cases and regional population size. Hokkaido (solid circle), Tohoku (solid square), Kanto (solid triangle), Hokushinetsu (inverted solid triangle), Tokai (solid diamond), Kinki (solid hexagon), Chugoku (open triangle), Shikoku (open square), Kyushu (open circle).

Figure 6.

Correlation of the disease severity score with carbon monoxide diffusing capacity (Dl_CO) in patients with autoimmune pulmonary alveolar proteinosis. Results are shown as mean (±SE) for individuals classified as disease severity score (DSS)-1 (n = 42), DSS-2 (n = 38), DSS-3 (n = 27), DSS-4 (n = 28), or DSS-5 (n = 12).