Inhaled Granulocyte/Macrophage–Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis

Abstract

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.

Elevated Serum Anti-GM-CSF Antibodies before the Onset of Autoimmune Pulmonary Alveolar Proteinosis in a Patient with Sarcoidosis and Systemic Sclerosis

“…WLL is the traditional therapy for PAP (Campo et al 2016). According to the pathogenesis of autoimmune PAP, we have other therapeutic options: inhalation or subcutaneous administration of GM-CSF (Tazawa et al 2010;Khan et al 2012), Rituximab (Borie et al 2009), and plasmapheresis ). Furthermore, the therapeutic strategy against autoimmune PAP associated with collagen disease or sarcoidosis is not totally established.…”

Immunotherapeutic effects of recombinant adenovirus encoding granulocyte–macrophage colony-stimulating factor in experimental pulmonary tuberculosis

“…In fact, administration of GM-CSF, or inducing its expression, has been useful in the treatment against other pulmonary infections such as aspergillosis [43], Chlamydia trachomatis [44] and pneumococcal pneumonia [45]. Moreover, the delivery of recombinant human GM-CSF by inhalation was shown to be beneficial in the treatment of alveolar proteinosis and it was well tolerated in healthy subjects [46]. However, there are no available data about their prophylactic use to augment anti-micobacterial host defence for mainly immunodeficient patients.…”

Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer

“…aerosolized GM-CSF for varying time periods, showed a positive response in 91% of the subjects [19] . In a more recent, well designed Japanese study, including a run-in period, followed by an induction dose, and finally a maintenance dose, the response rate in 35 PAP patients was 68% [20] . Taken together, the above reported data seem to suggest the superiority of the inhalation route vs the subcutaneous one.…”

“…No comparative studies have been performed, to the best of our knowledge, on the performance of both the AKITA² APIXNEB® device and the Pari LC-plus nebulizer, the latter having been used to aerosolize rGM-CSF to PAP patients in the above discussed papers [18][19][20] . The only available paper compared the effects of inhaled tobramycin in cystic fibrosis patients using an older version of AKITA [25] .…”