Granulocyte-macrophage Colony-stimulating Factor Inhalation Therapy Research Articles

Valuable Serum Markers in Pulmonary Alveolar Proteinosis.

Objective Several serum markers were reported to reflect the severity of pulmonary alveolar proteinosis (PAP). The aim of this study is to investigate a reliable and facile marker to access and monitor the clinical course of PAP in a large cohort. Methods PAP patients from January 2010 to June 2018 were enrolled. Hospital records were used as data sources. The levels of various serum indicators were detected. We evaluated the correlation between pulmonary function test results and clinical variables. Results Diffusion capacity for carbon monoxide (DLCO) level was positively correlated with the level of high-density lipoprotein cholesterol (HDL-C) (P < 0.05) in 122 patients of PAP at baseline. The levels of HDL-C and DLCO significantly increased while carcinoembryonic antigen (CEA), CYFRA21-1, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH) levels decreased six months after granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy between 14 patients with PAP. Nevertheless, the increased DLCO was significantly correlated with decreased CEA (r = ‐0.579, P = 0.031) and CYFRA 21-1 (r = ‐0.632, P = 0.015). In 10 PAP patients without GM-CSF inhalation therapy, HDL-C and DLCO significantly decreased while NSE and LDH levels increased after six months of follow-up. The decreased DLCO was significantly correlated with increased LDH (r = ‐0.694, P = 0.026). Conclusions Serum CEA, CYFRA21-1, and LDH are valuable serum markers for the evaluation of disease activity of PAP and may predict the response to treatment of PAP.

Granulocyte-Macrophage Colony-Stimulating Factor Inhalation Therapy for Severe Pulmonary Alveolar Proteinosis.

Some patients with pulmonary alveolar proteinosis (PAP) still present with high recurrence rate after large-volume whole lung lavage (WLL). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been proved to be effective for PAP, but clinical research on GM-CSF inhalation therapy combined with WLL for severe PAP is rare in Asia. This study aimed to investigate the clinical efficacy of GM-CSF inhalation combined with WLL in Chinese patients with PAP. We performed regression analysis on 33 patients with severe PAP who underwent WLL alone or WLL combined with GM-CSF inhalation. The patients were put into 2 groups, WLL group and GM-CSF/WLL group. Physiologic, serologic, and radiologic features of the 2 groups at different time points after treatment and the recurrence rates at 1-year follow-up were compared. There were no significant differences in lung function, blood gas analysis indices, and lung CT between the 2 groups after 1-week treatment (P > 0.05). After 3-month treatment, the GM-CSF/WLL group showed significantly faster improvement in FEV1%Pred (P = 0.028), FVC%Pred (P = 0.014), PaO2 (P = 0.022), PA-aO2 (P = 0.009), PaO2/FiO2 (P = 0.025), 6-minute walking test (P = 0.002), and lung CT parameters (P < 0.05) compared with the WLL group. The recurrence rate at the 1-year follow-up in the GM-CSF/WLL group (5.5%) was significantly higher than that in the WLL group (46.67%; P < 0.05). GM-CSF inhalation therapy combined with WLL is an effective treatment for patients with severe PAP, with further improvement in lung function at the base of WILL as well as reduction on re-WLL incidence.

Bilateral Peripheral Infiltrates Refractory to Immunosuppressants were Diagnosed as Autoimmune Pulmonary Alveolar Proteinosis and Improved by Inhalation of Granulocyte/Macrophage-Colony Stimulating Factor

A 55-year-old non-smoking woman was admitted to our hospital for re-evaluation of unimproved peripheral ground-glass opacities despite prednisolone and cyclosporine treatment. She was diagnosed with autoimmune pulmonary alveolar proteinosis (PAP) based on transbronchial lung biopsy and granulocyte/macrophage colony-stimulating factor (GM-CSF) antibody testing. GM-CSF inhalation therapy markedly improved the opacities. Bilateral, centrally located lung opacities are typical in PAP, however 10 PAP cases with peripheral infiltration were reported in Japan recently, of which GM-CSF antibody was positive in six. To avoid inappropriate immunosuppressant treatment, PAP should be considered in the differential diagnosis of such peripheral opacities. GM-CSF antibody might be useful for diagnosis.

Direct evidence that GM-CSF inhalation improves lung clearance in pulmonary alveolar proteinosis

Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear. To figure out changes in surfactant clearance during GM-CSF inhalation therapy. We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5-21 mg, duration 12-24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference ≥13 mmHg (n = 10) and low responders with that < 13 mmHg (n = 9). Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment. 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.

A combination therapy of whole lung lavage and GM‐CSF inhalation in pulmonary alveolar proteinosis

Systemic and inhalation therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) is usually effective in controlling autoimmune pulmonary alveolar proteinosis (PAP), but some cases are refractory to GM-CSF therapy and subjected to whole lung lavage (WLL). A 9-year-old girl developed severe respiratory failure due to autoimmune PAP was treated with inhalational 250 microg of GM-CSF daily, however, it was ineffective. Unilateral WLL was performed three times and subsequent GM-CSF inhalation therapy yielded marked physiological and radiological improvement and was continued for 1 year.

Granulocyte‐macrophage colony‐stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long‐term treatment with aerosolized granulocyte‐macrophage colony‐stimulating factor: a case report

Idiopathic pulmonary alveolar proteinosis (IPAP) is considered to be caused by an autoantibody to the granulocyte-macrophage colony-stimulating factor (GM-CSF), which neutralizes GM-CSF and therefore impairs the differentiation of alveolar macrophages. The authors have previously characterized the BAL fluid and alveolar macrophages obtained from three IPAP patients who were successfully treated with aerosolized GM-CSF and demonstrated restoration of the cell number, expression of surface marker, and phagocytic ability of the alveolar macrophages as well as a decrease in the autoantibody levels in the BAL fluid. The condition recurred in one of the patients after 20 months. This patient underwent a second and third course of GM-CSF inhalation therapy with the same dose and schedule as the first one. Since the second therapeutic intervention did not succeed in producing any improvement in the symptoms and disease markers, the authors used a new nebulizer and a liquid preparation of the drug instead of the lyophilized preparation for the third therapeutic session and this restored the respiratory function considerably. A 6-month maintenance therapeutic regimen with a lower GM-CSF inhalation frequency brought about a further improvement in the disease markers. The results suggest that the efficacy of GM-CSF inhalation therapy might be related to the drug preparation mode, choice of nebulizer, and duration of treatment.