pulmonary alveolar proteinosis ( pap ) was first described by rosen et al . in 1958
the clinical course of the disease is variable , ranging from spontaneous resolution to death due to pneumonia or respiratory failure .
pulmonary alveolar proteinosis occurs in three clinically distinct forms : congenital , secondary , and idiopathic ( acquired ) .
congenital pap is a heterogeneous group of disorders ( 2 ) caused by mutations in the genes encoding surfactant protein b , c or c chain of the receptor for granulocyte - macrophage colony stimulating factor ( gm - csf ) ( 3 , 4 ) .
secondary pap occurs as a consequence of any one of a heterogeneous group of underlying clinical conditions ( hematologic cancers , pharmacologic immunosuppression , inhalation of inorganic dust or toxic fumes , and certain infections ) that impair alveolar macrophage function , resulting in surfactant accumulation ( 5 ) .
idiopathic ( acquired ) pap is a disorder of unknown etiology that is thought to represent approximately 90% of pap cases .
the prevalence of idiopathic pulmonary alveolar proteinosis has been estimated to be 0.37 per 100,000 persons ( 6 - 9 ) .
the median age at the time of diagnosis is 39 yr ; most patients are men , and 72% have a history of smoking ( 10 ) .
recent observations in transgenic mice and humans , however , have provided important clues about its pathogenesis .
the first real clue was provided by the discovery that mice deficient in gm - csf develop a lung phenotype that is biochemically , histologically , physiologically , and ultrastructurally indistinguishable from idiopathic pap ( 11 , 12 ) .
the observation of pap in gm - csf - deficient mice was quickly followed by the evaluation of gm - csf therapy , first in a single patient and then in several small series of patients ( 13 - 16 ) .
gm - csf deficiency has not been reported in humans ( 17 , 18 ) . however , a second vital pathogenic clue was the observation that primary pap is specifically and strongly associated with very high levels of gm - csf autoantibodies ( 19 ) .
so far , most reports have focused on pap patients from western countries , but reports on asian populations are extremely rare , with only one report based on a japanese population ( 20 ) . the first case in korea was reported in 1987 ( 21 ) and kim and colleagues reviewed twelve cases in 1999 ( 22 ) .
we reviewed the clinical features , treatment outcomes , and prognosis of patients with idiopathic pap in korea .
the data were collected from 10 clinical research centers in korea ( college of medicine in university of ulsan , seoul national university , yonsei university , sungkyunkwan university , korea university , kyungpook national university , soonchunhyang university , gachon university , hallym university , and inha university ) .
patients with pap were identified by review of the korean interstitial lung disease study group .
the medical records of eligible patients were reviewed by one investigator of each institution , and data were extracted using a standard data collection instrument .
the diagnosis of pap was confirmed by a physician diagnosis and pathologic specimens were obtained by video - assisted thoracoscopic surgery or transbronchial lung biopsy with bronchoalveolar lavage ( bal ) .
the symptoms and signs present at the initial assessment at each institution were used as data .
arterial blood gas analysis , spirometry , and lung volume measurements were estimated at diagnosis and if possible , estimated again after whole lung lavage .
eighty six percent of patients were symptomatic at diagnosis and the most common symptom at presentation was dyspnea , and followed by cough ( table 2 ) .
the most prominent finding on physical examination was crackles in 50% of patients , with cyanosis present in one patient .
the chest radiographs for all but one patient showed bilateral air - space disease with an ill - defined nodular or confluent pattern .
high resolution computed tomography showed patchy ground - glass opacifications with superimposed interlobular septal thickening in all patients . on pulmonary function testing , a mild restrictive ventilatory defect was common , the mean percent predicted forced vital capacity ( fvc ) was slightly decreased at 77% , the mean percent predicted forced expiratory volume in one second ( fev1 ) was normal at 84.6% , but the mean percent predicted total lung capacity ( tlc ) of 81% was not decreased .
however , the percent predicted diffusing capacity of the lung for carbon monoxide ( dlco ) was disproportionately reduced ( meansd ; 67.731.6 ) among 29 patients .
arterial blood gas analysis showed hypoxemia with a mean room air partial pressure of oxygen ( pao2 ) of 69.014.2 mmhg and a mean alveolar arterial o2 gradient ; d(a - a)o2 of 36.04.4 mmhg .
the serum lactate dehydrogenase ( ldh ) level was elevated with a mean value of 455.4183.1 iu / l ( range 153 to 834 iu / l ) .
transbronchial lung biopsy was performed in 35 patients ( 92% ) and video - assisted thoracoscopic surgery was performed in 16 patients ( 42% ) . diagnosis was established by transbronchial lung biopsy with bal or surgical lung biopsy . on light microscopic examination , we observed the characteristic finding of alveoli filled with a granular , eosinophilic material that stained with periodic acid - schiff , and a well - preserved alveolar architecture .
whole lung lavage was indicated for patients who presented with dyspnea or hypoxemia and deteriorated chest radiography .
whole lung lavage was performed in 26 patients ( 68% ) , of whom 11 patients underwent another lavage .
we defined the recurrence as significant progression of respiratory symptoms attributable to pap or the application of further therapeutic interventions such as repeated lavage .
we analyzed oxygenation / hypoxemia , spirometric measurements , lung volume parameters , and radiologic findings before and after whole lung lavage ( table 3 ) .
oxygenation improved dramatically after therapeutic lavage , and hypoxemia was corrected in 16 of 17 patients for whom data were available . d(a - a)o2 also improved after lung lavage .
there was no significant difference in the mean fvc before and after whole lung lavage ( p=0.388 ) , as analyzed using the wilcoxon signed rank test .
fev1 was increased in six patients and decreased in six patients . the difference in fev1 before and after whole lung lavage was not statistically significant ( p=0.609 ) .
tlc showed a slight improvement after lavage , but the difference before and after lavage was not significant ( p=0.089 ) .
using radiologic evaluation with chest radiography or chest computed tomography , we found that 22 of 26 patients ( 85% ) had improved after whole lung lavage therapy .
radiologic studies after lavage was unavailable in 2 patients , no changes in 2 patients .
the mean follow - up period was 3 yr ( range , 0.04 to 11.5 yr ) . at the end of the study , 20 patients were alive , 2 patients had died , and 16 patients were no longer available for follow - up .
one patient died soon after the whole lung lavage and the other patient died of advanced gastric cancer .
the definition of disease recurrence varied between reports , but significant progression of respiratory symptoms due to pap and the application of further therapeutic lavage were considered as recurrences .
pap recurred in 4 out of 24 patients ( 16.7% ) during the follow - up period .
of the four patients with a recurrence of pap , three underwent another whole lung lavage and the fourth patient was closely observed without lavage .
pap was first recognized in 1958 by rosen and colleagues ( 1 ) . since then
seymour and presneill ( 10 ) analyzed 410 identifiable separate cases of pap in 241 separate initial publications ; most of these cases involved patients from western countries .
asamoto and colleagues ( 20 ) reported on the clinical manifestations of pap in a japanese population .
the japanese report was unique because it focused on an asian population with idiopathic pap , but it was different from the retrospective meta - analysis by seymour and colleagues ( 10 ) in several respects .
first , two - thirds of the pathologic diagnoses were established by bronchoscopic biopsy instead of surgical lung biopsy .
further , it reported that the therapeutic outcomes of whole lung lavage were superior to those of other studies ( table 4 ) . before our study , however , this was the only data available on idiopathic pap in asian population . in this study , we retrospectively reviewed 38 patients with idiopathic pap in korea .
the median age at diagnosis was 52 yr for both genders , which is in contrast to the distribution of patients from the report by seymour and presneill ( 10 ) who reported a median age of 39 yr and a different median age in men and women ( table 4 ) .
the median age in our study was close to that of the recent report on autoimmune pap in japan by inoue and colleagues ( 23 ) .
recently , the use of surgical lung biopsy has decreased ( 24 , 25 ) because a diagnosis of pap can be established in approximately 75% of clinically suspected cases based on the typical findings of a milky fluid from the bal ( 25 ) that contains large and foamy alveolar macrophages or monocyte - like alveolar macrophage and an increased numbers of lymphocytes ( 26 , 27 ) .
there are relatively few inflammatory cells of other cell types , unless superinfection is present .
there is also a large amount of amorphous , lipoproteinaceous material that is characteristically eosinophilic , granular , and positive with a periodic acid - schiff stain ( 25 , 27 ) . in this study ,
pathologic diagnosis was established by surgical lung biopsy ( 42% ) or transbronchial biopsy with bal ( 58% ) .
milky fluid on bal and consistent transbronchial lung biopsy specimens provided diagnosis , such as surgical lung biopsy . pulmonary function test at diagnosis showed results that were similar to those of previous studies : a restrictive defect , with a disproportionate reduction in diffusing capacity , a slightly decreased mean fvc of 77.3% and a moderately decreased dlco of 67.7% .
arterial blood gas analysis at the initial presentation also showed the same results ; pao2 was decreased to 69.0 mmhg and d(a - a)o2 was increased to 35.3 mmhg at the initial presentation .
the efficacy of whole lung lavage was evaluated with radiologic findings and pulmonary function tests .
after the therapeutic lavage , oxygenation parameters such as pao2 and d(a - a)o2 improved significantly in comparison to the initial examinations ( fig .
fvc and tlc improved slightly , but this improvement was not statistically significant ( fig .
they described the patients as either having stable persistent symptoms , progressive deterioration in their process , or spontaneous improvement .
kariman and colleagues ( 28 ) reported that spontaneous resolution occurred in 24% of a series of 23 patients .
seymour and presneill ( 10 ) reported that 24 of 303 patients ( 7.9% ) showed a significant degree of spontaneous improvement .
the reason for the variation in the amount of spontaneous resolution reported by different studies and authors may be because authors used different individual criteria . in our study , we defined spontaneous resolution as radiographic and symptomatic improvement until follow - up .
based on these criteria , 5 of 38 patients ( 13% ) showed spontaneous resolution . in the survival analysis , there was no difference between the lavage and no lavage groups ( fig .
the mean follow - up period from the time of whole lung lavage of 3 yr was too short to compare the survival between the lavage and no lavage groups .
moreover , one patient died soon after therapeutic lavage in the lavage group and one patient died of stomach cancer in the no lavage group , but neither death was directly related to pap .
this study has several limitations ; it was a retrospective study , the follow - up period was too short to analyze survival outcomes , and the smoking history of the patients was unavailable .
the clinical features and pulmonary parameters of korean patients with idiopathic pap are consistent with reports in other published studies .
 idiopathic pulmonary alveolar proteinosis ( pap ) is a rare disorder in which lipoproteinaceous material accumulates within alveoli . 
 there were few reports on asian populations with idiopathic pap . 
 we retrospectively reviewed 38 patients with idiopathic pap in korea . 
 we assessed clinical features , therapeutic efficacy and outcomes of whole lung lavage in patients with idiopathic pap . 
 the mean age at diagnosis was 52 yr . eighty six percent of patients were symptomatic at diagnosis . 
 dyspnea and cough were the most common symptoms . 
 crackles were the most common physical examination finding . on pulmonary function test , a mild restrictive ventilatory defect was common , with a predicted mean forced vital capacity ( fvc ) of 77% and forced expiratory volume in one second ( fev1 ) of 84.6% . diffusing capacity was disproportionately reduced at 67.7% . 
 arterial blood gas analysis revealed hypoxemia with a decreased pao2 of 69.0 mmhg and an increased d(a - a)o2 of 34.2 mmhg . 
 after whole lung lavage , pao2 , d(a - a)o2 and dlco were significantly improved , but fvc and total lung capacity ( tlc ) were not different . 
 this is the first multicenter study to analyze 38 korean patients with idiopathic pap . 
 the clinical features and pulmonary parameters of korean patients with idiopathic pap are consistent with reports in other published studies . 
 whole lung lavage appears to be the most effective form of treatment . 
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION