Whole lung lavage combined with Granulocyte-macrophage colony stimulating factor inhalation for an adult case of refractory pulmonary alveolar proteinosis
© Yu et al.; licensee BioMed Central Ltd. 2014
Received: 23 February 2014
Accepted: 6 May 2014
Published: 19 May 2014
Whole-lung lavage (WLL) is classically the first-line treatment for symptomatic pulmonary alveolar proteinosis (PAP). However, some patients require multiple WLLs because of refractory nature of their PAP. In this instance, these patients may benefit from new treatment regimens, and new therapies should be tried for these patients.
We describe a 47-year-old Chinese woman who was confidently diagnosed with pulmonary alveolar proteinosis (PAP) after bronchoalveolar lavage and transbronchial lung biopsy. The patient received four sessions of bilateral whole lung lavage (WLL) and one session of WLL in combination with plasmapheresis, each only producing short-term symptomatic relief. The patient was given a trial of combination therapy, which consisted of WLL and Granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation. The patient showed a gradual improvement in oxygenation and her daily activity, as well as a dramatic improvement in her pulmonary CT examination.
Bilateral WLL, in combination with GM-CSF inhalation, may be an effective treatment option for severe refractory PAP.
KeywordsRefractory pulmonary alveolar proteinosis (PAP) GM-CSF inhalation Plasmapheresis Whole lung lavage (WLL) Combination therapy
Pulmonary alveolar proteinosis (PAP) is a rare but treatable disease that is characterized by the accumulation of a periodic acid Schiff (PAS) positive lipoproteinaceous substance in the alveoli. Idiopathic PAP (iPAP), also known as “autoimmune pulmonary alveolar proteinosis”, makes up 90% of all described cases . Whole lung lavage (WLL) is the most common first-line treatment for symptomatic iPAP. However, significant proportions of patients require multiple WLLs, or do not respond to WLL. Many alternatives to WLL, such as GM-CSF supplementation and plasmapheresis, have been introduced. However, the treatment of severe refractory cases still remains a major challenge for clinicians in which combination therapy instead of monotherapy maybe a better choice. Here we describe an adult case of severe refractory PAP successfully treated with WLL in combination with sequential GM-CSF inhalation therapy.
Treatment of the refractory adult PAP case (listed according to timeline)
SEP 16TH, 2010
Whole lung lavage
Left lung: 8 L saline flushed in, 7.5 L recycled. Right lung: 9 L saline flushed in, 8.88 L recycled.
Good response, improvement in symptoms and PA-a maintained throughout 1 year
OCT 13TH, 2011
Whole lung lavage
Left lung: 5.9 L saline flushed in, 5.68 L recycled. Right lung: 7 L saline flushed in, 6.8 L recycled.
Improved symptoms and PA-a;
NOV 16TH, 2011
Whole lung lavage
Left lung: 8.0 L saline flushed in, 7.7 L recycled. Right lung: 7 L saline flushed in, 6.75 L recycled.
Improved symptoms, PA-a, and pulmonary function; good control of symptoms through 3 months.
FEB 2ND, 2012
Whole lung lavage
Left lung: 8.0 L saline flushed in, 7.82 L recycled. Right lung: 8 L saline flushed in, 7.71 L recycled.
Symptoms and hypoxia not improved, still required high volume oxygen support;
FEB 8th-20th, 2012
5 sessions of plasmapheresis therapy
Exchange volume: 2.5 L, every 2–3 days during two weeks.
JUNE 1ST, 2012
Whole lung lavage
Left lung: 9.0 L saline flushed in, 9.33 L recycled. Right lung: 7.0 L saline flushed in, 6.98 L recycled.
Good symptomatic control, with no hypoxia and no further flare of PAP
JUNE 2nd, 2012
At a dosage of 150 μg, twice daily from day 1 to day 8, with inhalation stopped from day 9 to day 14, every 2 weeks for 3 months;
At a dosage of 150 μg, once daily from day 1 to day 8, every 2 weeks for 6 month;
Multiple treatment options have been introduced into clinical managment of PAP, including WLL, plasmapheresis, GM-CSF supplementation, Rituximab, and lung transplantation. Whole lung lavage, first introduced by Ramirez in 1965 , has long been the traditional choice of treatment in PAP, and was the only therapy for many years. Over years of practice and experience with PAP, the techniques regarding WLL have improved, however no consensus has yet been reached. The outcomes and efficacy of WLL has been studied extensively by various centers. A recent study by Campo et al. reported the follow up data of 44 Italian PAP patients treated with WLL from a single center . Over a two-decade period, 31/44 patients required only one WLL to maintain long term symptomatic control, with 13/44 requiring multiple WLLs. Beccaria et al. studied 21 idiopathic PAP patients treated with WLL, with 18/21 requiring only one session of WLL whereas 3/21 underwent multiple WLL for recurrent PAP. In this study, more than 70% of patients remained relapse-free over a 7-year follow up period . Also, Shah et al. shared their experience in treating PAP patients with WLL , concluding that in their experience more than 60% of patients had a good response within two sessions of WLL. Less than 15% of these patients required WLL every six months to maintain their functional status, and fewer than 10% were non-responsive. In our case, the patient had a good response for the first WLL. However, multiple sessions of WLLs were subsequently required, each with a shortened duration of effectiveness.
A GM-CSF autoantibody has been identified in PAP patients but not in healthy controls , indicating a potential pathologic role in PAP pathogenesis. More interestingly, Sakagami et al. successfully reproduced PAP in nonhuman primates after injecting patient derived GM-CSF autoantibodies into these experimental animals [7, 8]. This further suggests a direct role of GM-CSF autoantibodies in the pathogenesis of PAP. Thus it is a reasonable approach to use plasmapheresis to reduce circulating autoantibodies in the treatment of PAP. However, the experience of applying plamapheresis in PAP patients is still quite limited, with data only from case-reports to evaluate its efficacy. Also, there have been multiple conflicting conclusions amongst them. Bonfield et al.  reported a PAP patient which was unresponsive to GM-CSF treatment, and while waiting for lung transplantation received 10 sessions of plasmapheresis at an exchange volume of 1.5 L. Over a 2-month period the patient’s anti-GM-CSF titer was lowered, as well as a substantial improvement in their oxygen saturation and chest radiograph. The other case presented by Luisetti et al.  however showed a more passive result. After 10 sessions of plasmapheresis (at an exchange volume of 1.5 L) anti-GM-CSF levels were reduced by half. However, there were no improvement of the patient’s symptoms, chest radiographs, or pulmonary function. The interval between repeated WLLs seemed to have been elongated. Here in our case, 5 continuous sessions of plasmapheresis at an exchange volume of 2.5 L had a very small improvement in symptoms and pulmonary function. Plasmapheresis as an alternative treatment in PAP still requires more investigation.
Exogenous GM-CSF supplementation is a possible rescue treatment, and has thus been under extensive investigation. So far two routes of GM-CSF administration have been introduced: inhalation and subcutaneous. In a meta-analysis reviewing the efficacy of GM-CSF in PAP treatment, 5 observational studies (involving 94 cases) were examined, including 3 studies using subcutaneous GM-CSF administration and 2 studies on GM-CSF inhalation . According to this meta-analysis, the response rate of GM-CSF therapy ranged from 43% to 92% in different studies, and the calculated pooled response rate by the random effects model was 58.6% (95% CI, 42.7-72.9). Fever and local erythema at the injection site were the most commonly reported complications. As the alveolar space was deemed as the putative site of the GM-CSF signal disruption, inhalation therapy should have better deposition with lower dosage and less effects on the bone marrow than injection therapy. Although the difference was not statistically significant, the inhalation group had a better response rate than the subcutaneous group (76.5%; 95% CI, 34.5-95.3 vs 48.4%; 95% CI, 33.8-63.3). The relapse rate and incidence of adverse events were also lower in the inhalation group. Thus, GM-CSF inhalation was recommended for our patient. Evidence also shows a slightly better performance of GM-CSF inhalation therapy at a dosage of 250 μg/day, every second week . But, since the only available formulation of GM-CSF in our hospital is 150 ug per dose, we decided to give her GM-CSF at a dosage of 150 ug twice daily from day 1 to day 8, and repeated this every two weeks. It is important to note that in these trials there was usually a lag period of 4 to 12 weeks in the inhaled group prior to showing a clinical response [substantial P(A-a)O2 improvement (≥10 mm Hg)] . In conclusion, GM-CSF inhalation combined with WLL maybe used to achieve a better outcome in patients with PAP, as is the case in the patient we previously mentioned.
In conclusion, until now, there have been no studies conducted to evaluate the efficacy of combination therapy for PAP. Only several case reports are available, similar to ours. This case has demonstrated the effectiveness of combination therapy for a refractory PAP case. Combination therapy is primarily indicated, and holds promise, in refractory or unresponsive cases, and because of its scarcity, it is hard to summarize and compare the efficacy of different combinations. For severe refractory PAP cases, we suggest that bilateral WLL combined with sequential GM-CSF supplementation may be an excellent treatment option. However, WLL and plasmapheresis in combination were not as effective in this case. We regret that during our management of this case, due to lack of experience of our clinical laboratory’s ability to quantify the GM-CSF autoantibody, we were unable to test and monitor GM-CSF autoantibody levels during the diagnosis and treatment of this patient.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Pulmonary alveolar proteinosis
Granulocyte-macrophage colony-stimulating factor
Bronchoalveolar lavage fluid
Transbronchial lung biopsy.
This work was supported by grants from the National Natural Science Foundation of China [Grant 81170055]. We would also like to thank the patient and staff for their assistance with this case.
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