Long-term follow-up and treatment of congenital alveolar proteinosis
© Griese et al; licensee BioMed Central Ltd. 2011
Received: 28 March 2011
Accepted: 17 August 2011
Published: 17 August 2011
Clinical presentation, diagnosis, management and outcome of molecularly defined congenital pulmonary alveolar proteinosis (PAP) due to mutations in the GM-CSF receptor are not well known.
A 2 1/2 years old girl was diagnosed as having alveolar proteinosis. Whole lung lavages were performed with a new catheter balloon technique, feasible in small sized airways. Because of some interstitial inflammation in the lung biopsy and to further improve the condition, empirical therapy with systemic steroids and azathioprin, and inhaled and subcutaneous GMCSF, were used. Based on clinical measures, total protein and lipid recovered by whole lung lavages, all these treatments were without benefit. Conversely, severe respiratory viral infections and an invasive aspergillosis with aspergilloma formation occurred. Recently the novel homozygous stop mutation p.Ser25X of the GMCSF receptor alpha chain was identified in the patient. This mutation leads to a lack of functional GMCSF receptor and a reduced response to GMCSF stimulation of CD11b expression of mononuclear cells of the patient. Subsequently a very intense treatment with monthly lavages was initiated, resulting for the first time in complete resolution of partial respiratory insufficiency and a significant improvement of the overall somato-psychosocial condition of the child.
The long term management from early childhood into young adolescence of severe alveolar proteinosis due to GMCSF receptor deficiency requires a dedicated specialized team to perform technically demanding whole lung lavages and cope with complications.
Keywordspulmonary alveolar proteinosis therapeutic lung lavage GM-CSF-R alpha genetic defect stop codon
Pulmonary alveolar proteinosis (PAP) is characterized by a substantial and persistent increase in surfactant pool size [1, 2]. There are several causes of this rare condition; mouse models with deletion of granulocyte-macrophage-colony stimulating factor (GM-CSF) or the GM-CSF receptor (GM-CSFR) beta-chain showed the first evidence for involved molecularly mechanisms [3, 4]. Autoantibodies against GM-CSF, blocking GM-CSF signaling, are the cause for the most frequent form of PAP, mainly found in adults and also called autoimmune PAP . In 2008 the first two families with congenital PAP and mutations in the alpha-chain of the receptor for GM-CSF were described [6, 7] and very recently another six families were reported . The patients presented with progressive dyspnea of insidious onset between the ages of 1.5 and 9 years; some were asymptomatic. Short term responsiveness to whole lung lavage (WLL) treatment has been described, however not much information on the long term outcome of molecularly defined patients is yet available.
Other genetic conditions that lead to PAP include a recently identified mutation in the beta chain of the GMCSF receptor , surfactant protein B or C deficiency [10, 11], Niemann-Pick Type C2 disease  and lysinuric protein intolerance . Secondary PAP develops in association with conditions involving functional impairment or reduced numbers of alveolar macrophages like inhalation of inorganic dusts, myeloic leukemia, myelodysplastic syndrome, immunosuppression related to organ transplantation, and some infections including Pneumocystis .
Not much is known on the clinical spectrum, course and treatment options in patients with molecularly defined, congenital PAP due to mutations in the GM-CSF alpha chain. Also the role of long term WLL, which are be very demanding due to the small size of the airways, how to measure clinical response to lavage therapy and the relevance of glucocorticoid therapy have not been reported. Here we present the successful management of a child with a severe congenital PAP caused by the homozygous p.Ser25X mutation in exon 3 of the CSF2RA gene and its follow up for more than a decade. These data may be helpful for future treatment of infants and children with this rare condition.
Empirically, we found that WLL were the most efficient treatment. This was clearly shown for the short term; during 49 instances investigated until the age of 11, the amount of nasal oxygen flow was reduced in 40 after the lavages (Figure 3B). This effect could be sustained for many years demonstrating long term efficacy. However the extreme value of WLL was only very recently demonstrated unequivocally following implementation of our concept of very aggressive WLL. Up to the age of 10 years, WLL were done more or less to ameliorate partial respiratory insufficiency, i.e. to decrease the need for additional oxygen. From year 10 onward, we performed one lavage per month, in order to try to completely clear the lung from its proteinosis load. This approach was very successful and resulted in complete resolution of partial respiratory insufficiency for the first time. The patient started puberty, growth and weight were sustained by oral nutrition without need of using the percutaneous tube and the dependency on supplemental oxygen up to that point in time, could be finished. This also led to increased self-confidence and better integration at school. Also, the lung function improved very rapidly and chest radiograph cleared to almost normal (Figure 1D, E; Figure 3C). Together somato-psychosocial condition substantially improved. A consecutive brief trial to increase the time lag between the lavages failed and an interval of about 4 weeks was maintained.
Of interest, from age 3 to 4 1/2 years, well before the molecular nature of the PAP was determined, we used inhaled and subcutaneous recombinant GM-CSF (Figure 2B). A transient increase in peripheral blood eosinophils up to 17% of the neutrophils occurred  (data not shown), but clearly no improvement of the alveolar proteinosis (Figure 2A, B, Figure 4C, D). Due to the expectations of the treating physicians, the intervals between consecutive therapeutic WLL were increased during GM-CSF treatment: In parallel, this was associated with an increased load of protein, demonstrating a lack of an effect of GM-CSF treatment (Figure 4C, D).
Nutritional support was optimized with the help of a percutaneous gastrostomy (PEG, Figure 2B) placed at the age of 3 years, which was used regularly; the gastrostomy was changed to a jejunostoma at the age of 61/2 years, to completely exclude gastro-esophageal refluxes, although no such events had been demonstrated in pH- or impedance studies (Figure 2B).
GM-CSF, the GM-CSF receptors and their functional analysis
Here we report a patient with molecularly defined severe congenital PAP due to a previously undescribed autosomal recessive mutation in the alpha chain of the GM-CSF receptor. This mutation leads to a stop of transcription and to a lack of functional protein. The GM-CSF induced responses are mediated through activation of the transcription factor PU.1 and include increased surfactant catabolism and CD11b expression . Impairment of the latter was shown directly in mononuclear cells of the patient after stimulation with GM-CSF. Impaired GMCSF receptor activation of alveolar macrophages leads to decreased surfactant catabolism and accumulation of surfactant in the alveolar space, i.e. alveolar proteinosis.
Important messages from this study are related to the long-term management of this condition. First, persistent and aggressive removal of surfactant filling the alveolar space may eliminate gas exchange abnormalities and consecutive sequelae including developmental and growth failure, and restricted level of performance due to respiratory limitation. Second, immune insufficiency, a problem also primarily resulting from abnormalities of the GM-CSF signal transduction pathway , may be augmented by immunosuppressive therapy initiated to treat the condition empirically. Therefore, molecular genetic definition of the basic defect in all children with PAP is important. Lastly, we describe the successful use of outcome measures of the efficacy of therapeutic WLL, including oxygen demand, and amount of washed out protein and phospholipids.
A major strength of this study is to demonstrate the feasibility of technically demanding repetitive WLL in a very small child over extended periods of time. Although therapeutic WLL is generally accepted as the established treatment option for PAP in adults, its optimal method, frequency of application and many other details are currently not known in infants or children. Here we show that consecutive lavages via a small catheter located in a main stem bronchus (Figure 3A) can be used to efficiently remove accumulated surfactant from the alveolar space in a very small child. Furthermore we show that it is helpful to monitor efficacy of the washing procedure by determination of proteins and lipids removed from the lungs . These measurements allowed us to demonstrate only a marginal, but not clinically significant increase in the removal of surfactant material from the lungs, by the use of PFC for lavage. In a case report on an infant with alveolar proteinosis due Niemann Pick disease the usage of PFC was recently shown not to be of benefit as well .
Although feasibility of the long term management of congenital PAP with WLL was demonstrated in this case of severe PAP, molecular diagnosing PAP as caused by a genetic deficiency of GM-CSFRa may have other important prophylactic and therapeutic implications. First, based on experiments in mice with PAP bone marrow transplantation may cure the disease . Currently we believe however that the risks of a bone marrow transplant (chronic graft versus host disease, among others) outweigh its benefits (elimination of need for WLL). Second, if diagnosed early in a family with an index case, the opportunity of early intervention by lavages at times of good clinical condition will help to reduce complications.
Subcutaneous injections or inhalations of GM-CSF, which have been successfully utilized in adult patients with autoimmune PAP [22, 23], were not helpful in our case to reduce alveolar filling as assessed by CT scanning (not shown) or improvement in gas exchange (Figure 2). Treatment with 20 μg/kg of GM-CSF per day subcutaneously was also shown to be ineffective for the child with congenital PAP described by Martinez-Moczygemba et al. .
Immunosuppressive treatment was used empirically and because of the presence of neutrophils and some lymphocytes in the lavage specimens and in the interstitial space of the lung biopsy sample of the patient (Figure 2B). Unfortunately severe and prolonged infections occurred, including a cavity forming infection with Aspergillus fumigatus which was treated by i.v. and inhaled amphotericin B and surgical resection of the cavity. Sustained withdrawal of the systemic corticosteroids from age 8 years onward did not alter the activity of the underlying PAP, but reduced the rate of infectious respiratory complications considerably.
Our study exemplifies detailed long term management of severe molecularly defined alveolar proteinosis from childhood into young adolescence. It is of interest that a dedicated specialized team may be advantageous to maintain the appropriate expertise of complex procedures such as e.g. whole lung lavages in small children [8, 15, 24, 25]. Therefore a centralized approach, as it has been employed for rare lung diseases and PAP in particular on a national basis in France , may be warranted. A web-based system to collect these rare cases, follow them and also to receive support is available at the kids lung register (http://www.kids-lung-register.eu). The novel whole lung lavages technique using an inflatable balloon catheter was feasible in very small sized airways. Whereas empirical immunosuppressive therapy and inhaled and subcutaneous GMCSF were without significant benefit, a very intense treatment with WLL resulted in complete resolution of respiratory insufficiency, and a normalisation of lung physiology and overall somato-psychosocial condition of the child.
Pulmonary alveolar proteinosis
granulocyte-macrophage-colony stimulating factor
whole lung lavage; washing of a single right or left lung.
The Universities Institutional Review Board approved the study (EK 25032011 and 16.05.8) and written informed consents of the patient, the parents of the index case and of the control subjects were obtained. Written informed consent was obtained from the patient and the parents 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. Supported by grants from e-rare and BMBF Gold.net.
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