Therapeutic effect of subcutaneous injection of low dose recombinant human granulocyte-macrophage colony-stimulating factor on pulmonary alveolar proteinosis

Fen Zhang, Dong Weng, Yiliang Su, Chengsheng Yin, Li Shen, Yuan Zhang, Ying Zhou, Qiuhong Li, Yang Hu, Huiping Li, Fen Zhang, Dong Weng, Yiliang Su, Chengsheng Yin, Li Shen, Yuan Zhang, Ying Zhou, Qiuhong Li, Yang Hu, Huiping Li

Abstract

Objective: To observe the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for pulmonary alveolar proteinosis (PAP).

Materials and methods: A total of 55 patients with PAP were screened at Shanghai Pulmonary Hospital between May 2014 and May 2018. Among these, 42 were diagnosed with idiopathic PAP, 24 were included in this study, 20 were treated for 6 months, and 17 were followed up for additional 6 months. All patients received a subcutaneous injection of 75μg/d GM-CSF qd for 1 month. The therapeutic dose was adjusted according to the changes in the lesions of chest CT. If the lesions were absorbed, subcutaneous injections of 75μg/d GM- CSF qd and 75μg/d GM-CSF qod were given for 2 and 3 months, otherwise, the dose was increased to 150μg/d GM-CSF qd and 150μg/d qod for 2 and 3 months, respectively. All cases were treated once a day in the first 3 months and once every other day in the last 3 months. The total course of treatment was 6 months. After withdrawal, the patients were followed up for another 6 months. The deadline of follow up was September 30, 2019.

Results: Twenty patients completed the treatment and efficacy evaluation. One patient was completely cured, 16 cases improved, three cases were noneffective. After 1-month evaluation, 12 patients received an increased dose (150μg) from the second month of treatment. Seventeen patients completed the 12-month follow-up, among which fourteen improved. CT showed the lesions were slightly increased in three cases. Economic burden was the following: RMB 7324-15,190 Yuan were required for the 6-month treatment course, which is significantly lower compared to other treatment methods.

Conclusion: Subcutaneous injection of rhGM-CSF at low dose (75μg-150μg /d) is effective treatment for patients with idiopathic PAP.

Trial registration: NCT01983657. Registered 16 April 2013.

Keywords: Injection; Pulmonary alveolar proteinosis; Recombinant human granulocyte-macrophage colony-stimulating factor.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Electron microscopic appearance of patient’s lavage fluid. Transmission electron microscopy (TEM) showing oval granules with bright and dark interlaced threadlike or fingerprint-like stripes. × 20,000 times
Fig. 2
Fig. 2
Patient screening process, * Methods to exclude secondary PAP: Medical history was inquired to exclude genetic factors; to inquire whether there is a history of industrial dust exposure and ask pneumonologists to help exclude occupational pneumoconiosis; Microbial examination was performed to exclude secondary PAP changes caused by viruses, bacteria, fungi, tuberculosis and other infections through sputum, bronchoalveolar lavage fluid, blood and other samples
Fig. 3
Fig. 3
a Study Scheme Design. b Administration and efficacy evaluation protocol
Fig. 4
Fig. 4
Changes of chest CT before and after treatment, a CT contrast of complete absorption of the lesion after 6 months of treatment. After 6 months of treatment, the lesion was completely absorbed. b CT contrast of apparent absorption of the lesion after treatment. The re-examination of chest CT showed that the lesion was obviously absorbed after 6 months of treatment. After 6 months of treatment, the patient stopped taking medicine and were followed up for additional 6 months (12 months); further slow absorption of the lesion was shown on chest CT. c CT contrast of partial absorption of the lesion after treatment. The re-examination of chest CT showed slight absorption after 6 months of treatment. The patient stopped taking medicine after 6 months of treatment. Follow-up of chest CT at 12 months showed that the lesion was stable. d Slight absorption of the lesion after 6 months of treatment and slight increase of the lesion after withdrawal for 6 months. The re-examination of chest CT showed similar lesions after 6 months of treatment. After the completion of 6 months of treatment, the patient stopped taking medicine, and the follow-up chest CT showed slightly increased lesions at 12 months. e The treatment of GM-CSF 75μg /d for 1 month showed poor efficacy, and the lesion was absorbed after the dose was increased to 150μg/d. The patient received GM-CSF 75μg /d treatment for 1 month, and the re-examination of chest CT showed no absorption, so the amount was increased to 150μg/d for 1 month, and the re-examination of chest CT showed absorption
Fig. 5
Fig. 5
Blood gas analysis before and after treatment: contrast of oxygen partial pressure, a, alveolar-arterial oxygen partial pressure difference (b). The oxygen partial pressure in arterial blood gas (a) was improved before and after 6 months of treatment, and the difference was statistically significant. Seventeen patients were followed up after 12 months and 16 patients completed blood gas analysis, the oxygen partial pressure at 12 months was also improved compared with that before treatment, and the difference was statistically significant. Alveolar-arterial oxygen partial pressure difference (b) was also improved before and after 6 months of treatment, and the difference was statistically significant. Seventeen patients were followed up after 12 months and 16 patients completed blood gas analysis, the difference of alveolar-arterial oxygen partial pressure at 12 months was also improved compared with that before treatment, with no significant difference
Fig. 6
Fig. 6
Contrast of pulmonary function indexes (FVC, DLCO%) before and after treatment, FVC (a) improved after 6 months of treatment, and the difference was statistically significant. Seventeen patients were followed up after 12 months and 14 patients completed lung function examination, FVC was improved at 12 months compared with that before treatment, and the difference was not statistically significant. DLCO% (b) was also improved after treatment for 6 months, and the difference was statistically significant. Seventeen patients were followed up after 12 months, and 14 patients completed lung function examination, DLCO% was also improved at 12 months compared with that before treatment, and the difference was statistically significant
Fig. 7
Fig. 7
Contrast of six-minute walking distance before and after treatment. After 6 months of treatment, the walking distance of patients was prolonged, and the results were statistically significant. Seventeen patients were followed up after 12 months and the walking distance was also prolonged at 12 months compared with that before treatment, and the difference was statistically significant

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