Dataset Information

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.

SUBMITTER: Inoue Y

PROVIDER: S-EPMC2720118 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Inoue Yoshikazu Y Trapnell Bruce C BC Tazawa Ryushi R Arai Toru T Takada Toshinori T Hizawa Nobuyuki N Kasahara Yasunori Y Tatsumi Koichiro K Hojo Masaaki M Ichiwata Toshio T Tanaka Naohiko N Yamaguchi Etsuro E Eda Ryosuke R Oishi Kazunori K Tsuchihashi Yoshiko Y Kaneko Chinatsu C Nukiwa Toshihiro T Sakatani Mitsunori M Krischer Jeffrey P JP Nakata Koh K

American journal of respiratory and critical care medicine 20080117 7

<h4>Rationale</h4>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.<h4>Objectives</h4>To describe the epidemiologic, clinical, physiologic, and laboratory features ...[more]

PMID: 18202348

Similar Datasets

Project description:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) and the PPAR?-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation.This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages.BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes.Mean PPAR? and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p???0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPAR? KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy.Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.

Dataset Information

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

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

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

Similar Datasets

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