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.

Pulmonary alveolar proteinosis - a crazy presentation of dyspnea

“…PAP is a rare interstitial lung disease with an estimated annual incidence, and prevalence of 0.24–0.49 and 2.04–6.20 cases per million, respectively, for autoimmune PAP [3]. PAP is characterized by accumulation of surfactant protein in the alveoli typically due to macrophage dysfunction as a result of a defect in the GM-CSF pathway [5], reducing the macrophage maturation and their ability to clear surfactant, and, secondary, to clear lung infections.…”

“…The median age at presentation is 39 years with a male predomination (male:female ratio 2.7:1.0) [2]. Approximately 90% of the PAP cases are associated with an autoimmune production of antibodies against GM-CSF [3]. The remaining 10% are either congenital or related to previous inhalational exposures (e.g.…”

“…The symptoms are often vague and the onset is often slowly developing, and thereby delaying the diagnosis. The clinical presentation of dyspnea, cough, and weight loss is similar to other respiratory diseases, but symptoms and clinical presentation are variable [2,3]. One third of PAP patients are asymptomatic, while others unfortunately suffer from fatal respiratory failure.…”

“…myeloproliferative diseases and myeloid leukemia [1]. PAP often debuts with insidious dyspnea at exertion and dry cough [3], which resembles a wide range of respiratory differential diagnoses. Patients with PAP related symptoms are at high risk of years of delayed diagnostics.…”

Secondary Pulmonary Alveolar Proteinosis of Occupational Etiology: A Case Report

“…Recent observations have also suggested the possible role of autoimmunity in some, but not all dust-exposure related pulmonary alveolar proteinosis cases. Inhaled agents, such as mineral dusts, could thus be a trigger for autoimmune anti-GM-CSF antibody mediated PAP, blurring the boundaries between disease categories [14][15][16]. Our patient had a history of 15 years of occupational exposure to mineral and resin dust and fumes in the electronics industry, but as cases of secondary PAP are rare and idiopathic PAP is by far the most common, we could not exclude an autoimmune etiology at the time of diagnosis (anti-GM-CSF antibody tests were not available at the time at our institution).…”