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.

Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa O 2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO 2 ] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 mg Days 1-8, none Days 9-14; 3 six cycles; 12 wk); low-dose therapy (125 mg Days 1-4, none Days 5-14; 3 six cycles; 12 wk), and follow-up (52 wk). Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high-and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO 2 of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n 5 35, P , 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO 2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.

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GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis.

The granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody (GMAb) is the causative agent underlying autoimmune pulmonary alveolar proteinosis (aPAP). It consists primarily of the IgG isotype. At present, information on other isotypes of the autoantibody is limited. We detected serum the IgM isotype of GMAb (IgM-GMAb) in more than 80% of patients with aPAP and 22% of healthy subjects, suggesting that a continuous antigen pressure may be present in most patients. Levels of the IgM isotype were weakly correlated with IgG-GMAb levels but not IgA-GMAb, suggesting that its production may be associated with that of IgG-GMAb. The mean binding avidity to GM-CSF of the IgM isotype was 100-fold lower than the IgG-GMAb isotype, whereas the IC50value for neutralizing capacity was 20,000-fold higher than that of IgG-GMAb, indicating that IgM-GMAb is only a very weak neutralizer of GM-CSF. In bronchoalveolar lavage fluid from nine patients, IgG-GMAb was consistently detected, but IgM-GMAb was under the detection limit in most patients, confirming that IgM-GMAb is functionally a bystander in the pathogenesis of aPAP. It rather may be involved in the mechanism for development of IgG-GMAb in vivo.

Previous studies demonstrated that antigranulocyte colony-stimulating factor autoantibody (GMAb) was consistently present in patients with autoimmune pulmonary alveolar proteinosis (aPAP), and, thus, represented candidature as a reliable diagnostic marker. However, our large cohort study suggested that the concentration of this antibody was not correlated with disease severity in patients. We found that the κ/λ ratio of GMAb was significantly correlated with the degree of hypoxemia. The proportion of λ-type GMAb per total λ-type IgG was significantly higher in severely affected patients than those in mildly affected patients, but the proportion of κ-type was unchanged. The κ/λ ratio was significantly correlated with both KL-6 and SP-D, which have been previously reported as disease severity markers. Thus, the light chain isotype usage of GMAb may not only be associated with the severity of aPAP, but may also represent a useful disease severity marker.

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