In the present study, we prospectively evaluated the effects of inhaled GM-CSF on mild-to-moderate autoimmune pulmonary alveolar proteinosis (aPAP) patients. In contrast to previous report, no obvious effects were found in our study. During the 6 months treatment and 18 month subsequent observation, the primary endpoint, A-aDO2 did not changed. Health-related quality of life as measured as SGRQ improved from 3 months of treatment and maintained to 24 months. Marginal improvement was also noted that TLC and DLCO were improved at the end of the study. This research provides valuable clinical data and experience for inhaled GM-CSF treatment in aPAP patients who do not meet the criteria for WLL.
Current therapy for PAP patients involves the physical removal of surfactant using a procedure in which the lungs are repeatedly filled with saline and emptied–WLL–which is invasive, inefficient, and is not widely available. Some authors reported that fever, hypoxemia, fluid leakage and other complications occurred in patients treated with WLL [6]. Meanwhile, the media time to next WLL is around 15 months[7], and about 30%-57.6% of patients requiring further therapy after the first WLL [8, 9]. Though no consensus of the indication for WLL in treating PAP, most physicians believe that patients with PaO2 of less than 70 mmHg on room air or an alveolar-arterial [A-a] oxygen gradient of more than 40 mmHg, or patients with disease progression should receive WLL as treatment [6]. In a cohort study from our center, 33% patients are stable or experience spontaneous remission [9], and the spontaneous remission rate varies from 8–18% in different reports [7, 9–11]. Considering the rate of spontaneous remission, rate of recurrence and the cumbersome procedure of WLL, it becomes a critical question whether GM-CSF inhalation could become a primary treatment for mild to moderate aPAP patients.
After GM-CSF was confirmed to play an important role in the disease mechanism of aPAP, the efficacy of exogenous GM-CSF replacement was assessed in previous report. The response rate to this treatment varied and the efficacy rate was 62–100% when using inhaled GM-CSF [5, 11, 12] while the efficacy rate was 43–75% when using subcutaneously administered GM-CSF [13, 14]. Because of better responsiveness and tolerance, the use of inhaled GM-CSF is generally recommended [4] .
In previous studies, inhaled GM-CSF treatment was prescribed in patients with moderate to severe disease [15–19], and the mean PaO2 level in a large prospective study of inhaled GM-CSF treatment on aPAP patients is 61.7 ± 1.4 mmHg [11]. During preparation of our manuscript, a randomized placebo-controlled study of inhaled GM-CSF was published, A-aDO2 and CT density quantitative measurement were significantly improved though they concluded that clinical benefits were not significant [20]. The major differences in design between our study and Tazawa et al’s study are two points: (1) Tazawa et al recruited patients with PaO2 less than 70 mmHg (or less than 75 mmHg with symptoms), the average PaO2 was 66.4±8.66 mmHg and 68.8±8.96 mmHg in GM-CSF group and control group. We recruited patient with DSS 1–3, 11/19 from GM-CSF group and 13/17 from control group had PaO2 over 70 mmHg, with average PaO2 77.51±8.53 mmHg in GM-CSF group and 76.88 ± 11.23 mmHg in control group. (2) Both trials use 6-month treatment. Tazawa et al used 125 µg bid continuously and we used 150 µg bid for 3 months and then 150 µg qd for 3 months. The reasons for the no or marginal response rate in our group may be related to the relatively good baseline oxygen content making changes of this indicator less obvious. Based on our study and previous report, the beneficial effects of GM-CSF treatment for aPAP with PaO2 over 70 mmHg (DSS 1 and 2) may be very limited. There were no enough DSS3 cases (PaO2 60–70 mmHg) in our study for subgroup analysis. However, Tazawa, et al has answered this question with a randomized placebo-controlled study. We believe GM-CSF could be beneficial for those with PaO2 less than 70 mmHg.
We found that inhaled GM-CSF therapy is a well-tolerated choice for aPAP patients as previous studies showed [11, 15–17]. Though more than half of our patients in the GM-CSF group were found have slight increases in amino-transferase levels, and a number of abnormal liver function results were observed in the GM-CSF treatment group, the elevation of transaminase levels were all slight and no medical intervention was needed for all patients. All patients remained stable or gradually improved after the cessation of alcohol and stopping intake of possible related combination medicines. Therefore, inhaled GM-CSF therapy is a safe and convenient choice for patients.
Our research has some limitations. Firstly, the sample size of the study was small, and there was no enough DSS3 patients for analysis. Our estimated target sample size was based on the prior results of patients population with more disease severity [11], which may underestimate the sample size actually needed. Secondly, more patients from the control group dropped out of the study during the observation period, which might affect the evaluation of effectiveness for comparing these two groups. Thirdly, the patients in our study did not receive a tailored dosage of GM-CSF treatment, nor did they receive prolonged therapy after the 6 months of treatment, which may make some latent responders, requiring higher dosages or longer treatment time for a positive response, remain hidden.