Pulmonary alveolar proteinosis in children on La Réunion Island: a new inherited disorder?
- Laurent Enaud†1,
- Alice Hadchouel†2, 3Email author,
- Aurore Coulomb4,
- Laureline Berteloot5,
- Florence Lacaille6,
- Liliane Boccon-Gibod4,
- Vincent Boulay7,
- Françoise Darcel8,
- Matthias Griese9,
- Mélinée Linard10,
- Malek Louha11,
- Michel Renouil1,
- Jean-Pierre Rivière12,
- Bruno Toupance13,
- Virginie Verkarre14,
- Christophe Delacourt2, 3 and
- Jacques de Blic2, 3
© Enaud et al.; licensee BioMed Central Ltd. 2014
Received: 11 March 2014
Accepted: 5 June 2014
Published: 14 June 2014
Pulmonary alveolar proteinosis (PAP) is very rare in children. Only a few small series have been published, with little information about long-term progression. The objective of our study was to describe the clinical, radiological and pathological features, and the long-term course of PAP in a cohort of 34 children from La Réunion Island.
Data were retrospectively collected from medical files. Radiological and pathological elements were reviewed by two pediatric radiologists and three pathologists, respectively.
Thirteen cases were familial and 32/34 (94%) cases were family connected. Disease onset occurred in the first six months of life in 82% of the patients. Thoracic computed tomography scans showed the typical “crazy-paving” pattern in 94% of cases. Respiratory disease was associated with a liver disorder, with the detection of liver enlargement at diagnosis in 56% of cases. The course of the disease was characterized by frequent progression to chronic respiratory insufficiency, accompanied by the appearance of cholesterol granulomas and pulmonary fibrosis. Overall prognosis was poor, with a mortality of 59% and an overall five-year survival rate from birth of 64%. Whole-lung lavages were performed in 21 patients, with no significant effect on survival. Liver disease progressed to cirrhosis in 18% of children, with no severe complication.
PAP in children from la Réunion Island is characterized by an early onset, associated liver involvement, poor prognosis and frequent progression to lung fibrosis, despite whole-lung lavages treatment. The geographic clustering of patients and the detection of many familial links between most of the cases strongly suggest a genetic etiology, with an autosomal recessive mode of inheritance.
KeywordsPulmonary alveolar proteinosis Pulmonary fibrosis Child Liver disease
Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the alveolar accumulation of lipoproteinaceous material . Diagnosis is suggested on computed tomography (CT) scans, showing a typical “crazy paving” appearance and alveolar consolidations . It is confirmed by periodic acid-Schiff (PAS) staining of bronchoalveolar lavage fluid (BALF) or histological examinations of lung biopsy specimens . Most of the reported cases occur in adults and are related to the presence of anti-granulocyte macrophage colony stimulating factor (GM-CSF) autoantibodies [4–6]. PAP is very rare in children, with only a few small series and case reports published to date. It may be primary or secondary to various diseases, including immune deficiencies, metabolic disorders and infections . The mechanisms underlying primary PAP in children remain unknown, except for 15 published cases, for which mutations were found in the genes encoding the alpha and beta chains of the GM-CSF receptor [8–13]. The long-term prognosis of primary PAP in children remains also largely unknown. Whole-lung lavages (WLL) have been reported to provide short-term benefits in both adults  and children [10, 14]. However, the long-term benefits of such treatment are unknown for children. The aim of this study was to describe the clinical, radiological and pathological features and the long-term course of PAP in a cohort of 34 patients from La Réunion Island.
We retrospectively reviewed the files of 34 children born between 1970 and 2012, seen at La Réunion Island University Hospital, with a diagnosis of PAP of unknown cause, confirmed by pathological analysis. Eighteen of these cases have been published before in other series but with only a brief description [7, 14–21]. In order to search for known causes of PAP, immunological explorations allowed to exclude immune deficiencies in all patients. Chromatography of amino and organic acids in plasma and urine were also performed in all patients and their results excluded the diagnosis of lysinuric protein intolerance in all of them. GM-CSF autoantibody assays on serum and BALF were performed in 13 patients. Sequencing of SFPTB, SFTPC, ABCA3, CSF2RA and CSF2RB genes was performed for 17, 16, 10, 10 and 10 children, respectively. Two patients were heterozygous for the missense variant p.Arg167Gln of the SFTPC gene. This variant is reported as a single nucleotide polymorphism (SNP) in computer databases (dbSNP reference: rs34957318), its minor allele frequency was estimated at 9% among Réunion Island population  and this SNP was also found in healthy individuals without any respiratory disorder . The results of genes sequencing were normal in the other patients. Radiological and pathological data were reviewed by two pediatric radiologists and three pathologists, respectively. This study was approved by the Institutional Review Board of the French Respiratory Society (CEPRO 2013–019).
Family trees of patients were constructed by questioning parents on their family history at diagnosis assessment and retrieved form medical files. Furthermore, for the purpose of this retrospective study, and when parental consent was obtained, we reconstructed the thorough ascending genealogy of patients, retracing their ancestry, generation by generation, back in time. We identified the ancestors of the patients from published genealogies for Reunion Island for the years before 1935 [22, 23], or directly from the civil registration records for subsequent years. These genealogies were stored in a computer database comprising 6,105 individuals. We developed a computer program to extract all genealogical paths linking at least two patients and to identify couples of common ancestors. We used Graphviz software  to visualize the resulting genealogical network as a marriage node graph  in which each couple is represented by a single symbol (octagon) rather than by two distinct individuals.
The clinical data included sex, age and type of first symptoms; age, clinical and biological features at diagnosis; mode of diagnosis; disease course and patient outcome. A history of failure to thrive and/or progressive dyspnea, sometimes associated with cough, vomiting or digital clubbing, were considered as first symptoms . The radiologic lesions were classified according to the Fleischner Society’s Glossary of Terms for Thoracic Imaging . The pathological review assessed the following lesions: PAP, cholesterol clefts, pulmonary interstitial and intra-alveolar cholesterol granulomas (PICG), other inflammatory lesions and fibrosis. A semi-quantitative grading scale was used to score each lesion, with 0 indicating absence; + indicating rare or mild lesions; ++ indicating moderate or localized lesions and +++ indicating diffuse lesions.
Quantitative variables are presented as medians and interquartile ranges (IQR). Qualitative variables are expressed as percentages. Data were analyzed with Statview software (Abacus Concepts Inc, Piscataway, New Jersey), by analysis of variance, Fisher’s exact test, simple regression and logistic regression. Survival analyses were performed by the Kaplan-Meier method and group comparisons by logrank tests. P < 0.05 was considered statistically significant.
Lung pathology findings at diagnosis
The diagnosis was confirmed by BALF analysis in 15 patients, by the examination of lung specimens in 18 patients, and by both methods in one patient.
Bronchoalveolar lavage cell counts and differentials at diagnosis
Total cell count (ml-1)*
330,000 – 900,000
48 – 75
21.5 – 55
4.5 – 13
Histological diagnosis specimen (n = 19/34)
Last available histological specimen (n = 14/34)
(5.3 months -10.3 years)
(6 years – 13.9 years)
Mode: n (%)
Results: n (%)
General characteristics and medical history
Twenty-two patients were boys (sex ratio = 1.8). Nine patients (26%) were born preterm and 25 (74%) presented intrauterine growth retardation, which was unexplained in 19 cases.
Presentation at diagnosis: respiratory
Clinical and biological features at diagnosis
Dyspnea and/or tachypnea
Low SaO2 (<92%) or low PaO2 (<70 mmHg)
Crackles at pulmonary auscultation†
Failure to thrive (weight < - 2 SD)
Anemia (Hb < 11 g/dL)
Hyperleukocytosis (≥15 000/mm3)
Thrombocytosis (≥450 000/mm3)
High IgG level
Hypoalbuminemia (<30 g/L)
Last available CT
n = 17
n = 13
Age (median (IQR))
10 m (4.5 m – 22 y)
10 y (4.1 y – 14.1 y)
Elementary lesions n (%)
Ground glass opacity
Interlobular septal thickening
Presentation at diagnosis: extra-respiratory
Extra-respiratory characteristics are detailed in Table 3. Failure to thrive was frequent and weight was equal to or below -4 standard deviations in 15 children. Liver involvement was also frequent, with a clinically enlarged liver noted in 19 of the 34 patients (56%). Abnormal liver test results were observed in 24 patients (71%). A liver ultrasound scan was carried out at diagnosis or within one year of diagnosis in 19 children and was abnormal in 17 cases (89%), with the liver found to be enlarged and containing a uniformly hyperechoic parenchyma suggestive of steatosis.
The importance of chronic inflammation was highlighted by high levels of immunoglobulin G and lactate dehydrogenase (LDH), thrombocytosis, hyperleukocytosis and anemia. Malnutrition with hypoalbuminemia was observed in 17 out of 25 patients (Table 3). No other organ involvement suggestive of a multisystem disease was detected.
Respiratory course, treatment and outcome
Overall mortality and survival analyses
Progression to chronic respiratory insufficiency (CRI) and lung fibrosis
Nine patients died in a context of terminal CRI (Figure 5). Among these patients, two died from postoperative complications shortly after lung transplantation. Ten patients are still alive but have respiratory problems (median age: 12.5 years, 11 – 19.6): one of these patients requires continuous oxygen supplementation, four require nocturnal oxygen supplementation, four display exercise desaturation only and one underwent lung transplantation one year ago for terminal CRI. Since the lung transplantation, PAP did not recur in this patient. Indeed, she had several BAL and transbronchial lung biopsies after the transplantation and there was no sign of pulmonary alveolar proteinosis nor on BAL fluid neither on lung specimens’ examination.
Regarding lung function tests, lung volumes were normal in two patients. All the other patients in whom lung function tests were carried out displayed a restrictive pattern, with a median total lung capacity and median vital capacity equal to 47% (37% – 59%) (n = 10) and 42% (31% – 53%) (n = 15) of the predicted values, respectively. DLCO values were below 80% of the predicted value in 15 of 18 patients.
Thoracic CT scans were available for review for 13 patients (Table 4). All images showed persistent thickening of the interlobular septa, intralobular lines and fissures (Figure 4B and D). In 12 of 13 patients, the course of the disease was characterized by the regression of consolidation and distention zones, associated with the appearance of lesions suggestive of fibrosis (Table 4, and Figure 4B and D) .
Histological progression was characterized by a progressive regression of PAP lesions accompanied by the appearance of cholesterol granulomas and fibrosis (Figure 3B, 3C and Table 2). At least one lung biopsy was carried out in 28 patients. Lung fibrosis lesions were identified on histological examination in 19 cases (69%). Kaplan-Meier analysis based on the occurrence of significant fibrosis (i.e. moderate or diffuse, n = 15 specimens) showed the probability of significant pulmonary fibrosis to be almost 50% by the age of 14 years (Figure 5C).
Disease course according to treatment group and the effects of WLL
Disease course according to treatment group is detailed in Figure 5. WLL were not performed in 13 patients for several reasons. Eight of these patients were the cases initially diagnosed with cholesterol pneumonia. All progressed to CRI and seven of them died. The other five cases were diagnosed before one year of age. Three died from respiratory insufficiency within the first year of life. PAP diagnosis in these cases was retrospective and based on post-mortem lung sample analysis. The other two patients were diagnosed before the introduction of WLL for children. Both are still alive and have reached adulthood. One has exercise dyspnea and the other is asymptomatic.
Overall, 67% (14/21) of the patients undergoing WLL and 77% (10/13) of those not undergoing this treatment survived infancy but this difference is not statistically significant (p = 0.7). Similarly, WLL seemed to have no influence on long-term prognosis. Progression to CRI and/or death occurred whether or not patients underwent WLL and this treatment had no significant effect on survival rates (Figure 6D, p = 0.46). However, it is difficult to determine the true effect of WLL due to the retrospective nature of this study and the heterogeneity of the treated and non-treated groups, particularly in terms of age at diagnosis. Even when we restricted the analysis to patients diagnosed before the age of one year with a larger number of WLL carried out earlier (WLL+, n = 14/WLL-, n = 5), WLL had no significant effect on overall survival rates (Figure 6E, p = 0.39).
Patients n (%)
A liver biopsy was performed in 12 children and two specimens were obtained from autopsy. The results were normal for 2 patients. However, one of these 2 patients presented high levels of GGT and a hyperechoic liver on ultrasound scan. Marked steatosis was observed in 9 cases. Fibrosis was observed in 10 patients and was classified as mild in 2 patients, extensive in 2 patients, and as cirrhosis in 6 patients (Figure 3D). In all children with extensive fibrosis or cirrhosis, regular screening was carried out for liver failure and portal hypertension. Grade I esophagal varices were found in five patients. Screening for hepatopulmonary syndrome was negative for all these patients. There were never signs of severe liver failure.
Among the patients that did not have a liver biopsy, 18 cases presented with hepatomegaly or abnormal liver tests results at some point in the course of the disease. At last-follow-up or at death, 11 patients had a persistent liver enlargement or abnormal liver tests results, 5 have normal liver tests results and no hepatomegaly and for 2 there were no complete available data for liver follow-up.
As a whole, 31 patients (91%) had a liver involvement at some point in the course of the disease.
Failure to thrive and oral feeding difficulties required initial parenteral nutrition in 10 patients (29%) and prolonged gastro-enteral feeding in 23 patients (67%).
Correlation of clinical and biological data with pathological features
PICG lesions predominated in histological examinations at diagnosis for some patients. We therefore carried out additional analyses to determine whether the presence of such lesions was associated with a specific pattern of disease. The 28 patients that had had at least one lung biopsy were divided into two groups according to the presence of PICG lesions at some point in the course of the disease (n = 13) or the absence of such lesions (n = 15). We then assessed the association of these lesions with age at biopsy and with the main features of the disease: age at first symptoms, liver involvement, WLL treatment and outcome (dead or alive). Age at biopsy was the only feature significantly associated with cholesterol granulomas (mean age 10.8 years in the “PICG + ” group versus 4 years in the “PICG -” group, p = 0.001). This suggests that PICG lesions are part of the disease and that these lesions appear during its progression.
We report the largest series of cases of PAP in children from La Réunion Island. This cohort had particular characteristics: early onset, within the first months of life, a severe course with frequent progression to pulmonary fibrosis, associated liver involvement and more severe disease in boys than in girls.
The early onset of the disease seems to be highly specific to our series. PAP is a very rare cause of chronic lung disease in children, and is mostly diagnosed during adulthood. A pediatric onset has been reported for the forms due to CSF2RA and CSF2RB mutations, but at a wide range of ages. For CSF2RA mutations, reported ages at the onset of symptoms range from 1.5 to 9 years . For CSF2RB mutations, onset was neonatal in two cases, occurred at the ages of one month and at nine years in two other cases and during adulthood for the last case [11–13].
The second characteristic feature of our series was the severity of the disease, with a high rate of mortality and frequent progression to pulmonary fibrosis. Published mortality data relate to adult forms and report a better prognosis, with a five-year survival rate from diagnosis of 88% . Moreover, in adult PAP, and for autoimmune forms in particular, lung fibrosis is rarely described. Several case reports have mentioned focal interstitial fibrosis associated with adult PAP [28–32], but diffuse fibrosis is actually a very rare occurrence, with only a few cases reported [28, 33–38]. In a cohort of 223 patients with autoimmune PAP, lung fibrosis occurred in only two cases (0.9%) . In a retrospective radiologic study of 139 thoracic CT scans from 27 patients, substantial regions of fibrosis were observed in only two patients (7%) . In the adult with a CSF2RB mutation, thoracic CT scans showed the progressive appearance of traction bronchiectasis and cystic lesions suggestive of fibrosis , but no lung fibrosis was described in children bearing CSF2RA mutations [9, 10].
Given the small size of our population and the retrospective nature of the study, it is difficult to evaluate the efficacy of WLL in this cohort. Indeed, our clinical experience and management of patients diagnosed in the last 10 years suggest that WLL are effective in the short term, whereas statistical analyses on the entire cohort showed that there was no difference in survival between treated and untreated children. There are several possible reasons for this apparent discrepancy. First, the treated and untreated groups differed in terms of age at diagnosis, clinical presentation and severity. Second, this study covered a long time period (42 years), during which substantial changes occurred in both the WLL technique and the overall management of these patients. Prospective data collection would be required for the characterization of phenotypic groups and to identify the patients most likely to benefit from WLL.
Liver disease was also a distinctive feature in these patients, with no other organ involvement. As a whole, 31 patients (91%) had a liver involvement, and the absence of liver abnormalities in 3 patients could be attributable to a variable penetrance of this trait in this very likely genetic syndrome. Hepatic involvement can be observed in association with PAP in lysinuric protein intolerance  and adenosine deaminase deficiency [40, 41], but has never been reported in other forms, particularly those of the autoimmune type that is the most reported type of PAP. In our cohort, it is debatable whether the steatosis observed arose due to the severe malnutrition often present at diagnosis. However, the ultrasound findings were at all ages and in all states of nutrition suggestive of fat overload in the liver. Liver disease progressed to extensive fibrosis or cirrhosis in seven children in the absence of severe complications of portal hypertension or liver failure.
The pathophysiological mechanism underlying PAP in these children remains unknown. The clustering of this disease in a specific geographic area, the existence of cases among closely related individuals and the results of our thorough genealogical study (94% of patients are family connected) strongly suggest a genetic origin. Moreover, the frequency of inbreeding in this geographic area during the 18th and 19th centuries , the absence of vertical transmission (i.e. parent-to-child transmission) with all parents being healthy, and the recurrence among siblings are highly suggestive of an autosomal recessive mode of inheritance.
As the GM-CSF pathway has been implicated in the autoimmune form and in known genetic forms, genes encoding targets or partners of GM-CSF (reviewed in  and ) are potentially good candidates. However, the available animal models of disrupted GM-CSF signalling [44, 45] inducing a PAP phenotype have no liver phenotype and display no progression to pulmonary fibrosis. Furthermore, a dysfunction of GM-CSF signalling would led to alveolar macrophages’ dysfunction. In this hypothesis, one could expect that the disease would recur in transplanted patients. The absence of recurrence of the disease in the alive patient who underwent lung transplantation one year ago is one argument against the pivotal role of macrophages in the pathophysiology of this disorder. Nevertheless, it is impossible to draw definitive conclusions from the analysis of a single case with a relatively short follow-up since lung transplantation.
The associated liver involvement observed in our series raised questions about possible abnormal phospholipid metabolism or transport in both type II alveolar epithelial cells (type II AEC) and hepatocytes, potentially leading to abnormal surfactant turnover and fat overload in the liver. The fibrotic progression of the disease also suggests a potential role of type II AEC in this disease. Pathological review showed that inflammatory lesions were present at diagnosis in 16 children, seven of whom were investigated before the age of two years, suggesting that the inflammatory and subsequent fibrotic processes may occur at the same time as the accumulation of abnormal lipoproteinaceous material, rather than after this accumulation. PAP is classically characterized by preservation of the architecture of the alveoli, with normal and thin alveolar walls and rare descriptions of lymphocytic infiltrates [3, 5]. In interstitial lung diseases caused by SFTPC mutations, mutant surfactant protein C has been shown to accumulate in the endoplasmic reticulum (ER), leading to ER stress, type II AEC injury, inflammation and the activation of apoptosis [46, 47]. All these mechanisms seem to be involved in the fibrotic progression associated with SFTPC mutations . In the disease described here, similar mechanisms could be suggested, with a genetic mutation leading to an abnormal protein that is misfolded in the ER, leading to inflammation and fibrosis. The defective functioning of this abnormal protein would also lead to abnormal surfactant turnover and accumulation in the alveoli. The important systemic inflammation in those children could also play a role in the development of lung fibrosis.
The reasons for the greater severity of disease in boys remain to be determined, and will probably become clearer when genetic analyses have determined the etiology of the disease. X-linked inheritance is very unlikely because both boys and girls can be affected by the disease which exclude a recessive X-linked disorder. As mentioned above, there is no case of parent-to-child transmission and this element a priori excludes a dominant X-linked mode of inheritance. Instead, modifier genes or hormonal factors may be involved.
In conclusion, we describe a cluster of 34 cases of primary PAP in children from La Réunion Island with very particular features, including a high rate of mortality and frequent progression to cholesterol granulomas and pulmonary fibrosis, despite WLL treatment. In this setting, the cause is very likely to be genetic, with an autosomal recessive mode of inheritance. Genetic studies should make it possible to determine the cause and mechanism of PAP and fibrosis in this population.
Pulmonary alveolar proteinosis
Broncho-alveolar lavage fluid
Granulocyte macrophage colony stimulating factor
Whole lung lavages
Single nucleotide polymorphism
Pulmonary interstitial and intra-alveolar cholesterol granulomas
Chronic respiratory insufficiency
Alveolar epithelial cells
We thank Pr Gabriel Bellon, Dr Sophie Losi and Dr Emmanuelle Fleurence for their help in the acquisition of data. We also thank Dr Giséla Benoit-Eichel and Dr Alain Fourmaintraux who made the first diagnoses of PAP in la Réunion Island.
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