Orphan lung diseases are defined as lung diseases with a prevalence of 1 or less in 2,000 individuals. Despite an increase in the numbers of patients with such diseases, few studies on Korean children have appeared. To obtain epidemiologic and demographic data on these diseases, we systematically reviewed reports on pediatric orphan lung diseases in Korea over the last 50 years.
We reviewed 223 articles that have appeared since 1958 on orphan lung diseases in Korean children. These articles described a total of 519 patients aged between 0 and 18 years. We classified patients by year of publication, diagnosis, geographic region, and journal.
Of 519 patients, 401 had congenital cystic lung diseases and 66 had bronchiolitis obliterans. About 80% of patients were described in reports published in three journals, Pediatric Allergy and Respiratory Disease (Korea), the Korean Journal of Pediatrics, and the Korean Journal of Thoracic and Cardiovascular Surgery, in which papers on 157 (30.2%), 138 (26.6%), and 111 (21.4%) patients appeared, respectively. The frequency of publication of case reports has increased since 1990. Of the 519 patients, 401 (77.3%) were from Seoul/Gyeonggi-do and 72 (13.9%) from Busan/Gyeongsangnam-do.
The prevalence of pediatric orphan lung disease has increased since 1990, and some provinces of Korea have a higher incidence of these diseases than do others. Studies exploring the incidence of pediatric orphan lung diseases in Korea are needed for effective disease management.
An orphan disease is a rare disease, with a frequency of 1 or less per 2,000 individuals. Around 7,000 orphan diseases have been reported throughout the world. Although the number of patients with any particular disease is small, the numbers of patients with orphan diseases are quite large. For example, about 6-8% of the entire population of Europe, or 27 million people, have an orphan disease
Over the last several decades, with advances in imaging and diagnostic methods, the number of patients with orphan diseases has increased, emphasizing the need for systematic and comprehensive research. Because of the scarcity of individual diseases, research has been sporadic and management variable. In 1983, the United States enacted a law promoting research on orphan diseases. Also, since 1999, the European Community has introduced nation-based programs promoting health issues related to orphan diseases, and national governments and related institutions have begun to register and manage patients with such conditions
In Korea, the Orphan Intractable Disease Department at the Center for Disease Control and Prevention of the National Institutes of Health has (a) established an Orphan Intractable Disease Helpline (
The symptoms of many pediatric orphan respiratory diseases are frequently expressed earlier than those of other orphan diseases, allowing prompt diagnosis and treatment of children and extending the life expectancy of such patients
We searched the internet and academic journals for publications on orphan respiratory diseases reported in Korean children. Our initial work indicated that the Korean Journal of Pediatrics and the Korean Journal of Pediatric Allergy and Respiratory Disease were major potential sources of academic articles.
All issues of the Korean Journal of Pediatrics from 1992 to 2008 were searched using the homepage of the Pediatric Society (
From the 24 journals, we extracted a total of 237 reports. Among these, 14 were redundant or were review articles, and were therefore excluded. Thus, 223 reports, describing 519 patients, were included in our analysis. These 519 patients were sorted according to journal, geographic area where medical center located in each studies, and date of publication. To gather geographic data, Korea was divided into nine provinces. With regard to date of publication, 10-year intervals were employed.
Congenital cystic lung diseases were divided into four categories based on pathological findings; the diseases were congenital lobar emphysema, congenital cystic adenomatoid malformation, pulmonary sequestration, and bronchogenic cysts. Patients with any of these four diseases were analyzed separately and included 30 prenatally diagnosed patients.
As no worldwide standardized classification system for pulmonary parenchymal diseases exists, we classified patients using the current recommendations of the American Thoracic Society and European Respiratory Society
For each disease, we sorted patients by gender and age to obtain male-female ratios and means and standard deviations for each age group. Distributions with respect to journal of publication, date of publication, and geographic area are represented as percentiles.
The 223 published reports on pediatric orphan respiratory diseases dealt with 519 pediatric patients, varying in age from prenatal to 18 years. After excluding some patients who were autopsied or for whom we had no age information, we found that the average age of patients was 58.3 months (±62.7 months). As gender was not reported for 57 patients, the overall male-female ratio is not known, but, of the 462 pediatric patients for whom gender was available, 270 (58.4%) were male. Of the 519 patients, 301 (58%) had congenital cystic lung disease, and the other conditions (in order of frequency) were bronchiolitis obliterans (66 patients, 12.7%), interstitial lung disease (56 patients, 10.8%), and bronchiectasis (49 patients, 9.4%). Among patients with congenital cystic lung disease, one also had pulmonary sequestration and bronchogenic cysts, and six additionally suffered from pulmonary sequestration and congenital cystic adenomatoid malformation (
In our review of journals publishing relevant reports, we found that about 80% of patients were described in papers published in three journals, the Korean Journal of Pediatric Allergy and Respiratory Disease, the Korean Journal of Pediatrics, and the Korean Journal of Thoracic and Cardiovascular Surgery, in which reports on 157 (30.2%), 138 (26.6%), and 111 (21.4%) patients, respectively, appeared. The remaining 21 journals published reports on the residual 113 patients (21.8%) (
By date of publication, we found that 29 patients (5.6%) were described before or in 1980, 132 (25.4%) in 1981-1990, 155 (29.9%) in 1991-2000, and 203 (39.1%) in 2000 or later, showing that the numbers of patients with pediatric orphan respiratory diseases has increased since the 1980s (
When we examined patient geographic distribution, we found that 401 (77.3%) were from the Seoul/Gyeonggi-do area, 72 (13.9%) from Busan/Gyeongsangnam-do, 13 (2.5%) from Gwangju/Jollanam-do, and 12 (2.3%) from Daegu/Gyeongsangbuk-do, with fewer than 2% of patients from the other five provinces of Korea (
Among the pediatric orphan respiratory diseases included in this study, the most frequent disease within the BPOLD registration program was congenital cystic lung disease. Six patients with congenital central hypoventilation syndrome have been reported to date, with the first report published in 1993 in the Korean Journal of Pediatric Allergy and Respiratory Disease
Interstitial lung disease has been reported in 56 patients since 1985, and idiopathic pulmonary hemosiderosis in 7, with the first report appearing in 1985
Of the 519 pediatric patients with orphan respiratory diseases, 31 had conditions not registered in BPOLD, including 12 with paragonimiasis, 11 with primary ciliary dyskinesia, 6 with cystic fibrosis, 1 with a bronchial cast, and 2 with allergic bronchopulmonary aspergillosis. In terms of paragonimiasis, the first patient was reported in 1974. Four additional patients have been described since 2000. The first pediatric patient with cystic fibrosis was reported in 1988
The first Korean report on congenital cystic lung disease appeared in the Korean Journal of Pathology in 1961, describing the disease in seven fetuses, accompanied by an article on bronchogenic cysts and pulmonary sequestration, and describing sequestration and congenital cystic adenomatoid malformation in six patients
Congenital lobar emphysema was reported in 8 patients between 1973 and 1990, in 15 from 1991 to 2000, and in 11 since 2000. Pulmonary sequestration was first reported in 1961
Idiopathic pulmonary fibrosis has been reported in nine patients to date, including the first report of four patients in 1985
We analyzed 519 pediatric patients diagnosed with orphan respiratory diseases in Korea over the last 50 years by year of publication, geographic area, and journal. We found that pediatric orphan respiratory diseases in Korea have increased in frequency and diversity since 1980. We also found that the largest number of patients was from Seoul/Gyeonggi-do, compared with other geographic regions of the country.
The increase in frequency and diversity of pediatric orphan respiratory diseases is likely attributable to elevated rates of detection, arising primarily from advances in diagnostic technologies and methods, including improvements in medical equipment
When we assessed patients by geographic area, we found that 401 of the 519 pediatric patients with orphan respiratory diseases (77.3%) were from Seoul/Gyeonggi-do province, including the capital area. This is probably because 24 of the 44 (54.5%) general medical institutions in the country are in the capital area (2008, Ministry of Health and Welfare -
However, we found that six patients in Gwangju/Jollanam-do and six in Seoul/Gyeonggi-do were diagnosed with paragonimiasis. This is consistent with a previous report
Interstitial lung diseases were reported in 56 patients, and the frequency increased over time, from 5 in the 1980s, to 12 in the 1990s, and 39 in 2000 and later. However, this apparent increase is likely not attributable to a real rise in incidence but rather to elevated concern about such diseases and a higher frequency of early diagnosis. Indeed, early diagnosis has been associated with a decreased dependence on open-lung biopsy and more frequent use of high-resolution CT in pediatric patients
Although pulmonary hemosiderosis is sometimes classified as an interstitial lung disease, depending on etiology
Cystic fibrosis was reported in six patients in seven reports, with one report describing 15 years of follow-up of a boy with this disease who was first described in 1988. In all six patients, a cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation was confirmed through genetic testing. Cystic fibrosis is a relatively common genetic disease in Caucasians, with a frequency of 1 per 2,000 persons, but is extremely rare among Asians, with a frequency, for example, of 1 per 350,000 persons in Japan
In the present study we collected, classified, and analyzed pediatric patients with orphan respiratory diseases reported over the last 50 years. Although we observed changes in the incidence of these diseases, most papers were case reports, focusing on specific patients. Thus, we could not accurately determine the prevalence of the various diseases or adequately follow the clinical course of the patients. In addition, we cannot exclude the possibility that some reports may have described the same patients. Therefore, the number of patients reported may not be the real total.
Despite these limitations, however, our results indicate that the number of reported patients with pediatric orphan respiratory diseases is increasing in Korea. These results form a baseline for systematic and continuous orphan disease control, as occurs in the United States and Europe. Our findings also point to the need for more consistent and accurate epidemiological investigation and disease control in the future.
Numbers and percentages of patients described in papers published in each journal. The highest number of patients was described in reports in Pediatric Allergy and Respiratory Disease (Korea).
Numbers of patients with pediatric orphan lung diseases reported in the last 5 decades. The incidence of these diseases has increased since the 1980s.
Regional distribution of pediatric orphan lung diseases in Korea. Most patients were from Seoul/Gyeonggi-do and Busan/Gyeosangnam-do. Abbreviations: GW, Gangwon-do; GK, Gyeonggi-do; CB, Chungcheongbuk-do; CN, Chungcheongnam-do; GB, Gyeongsangbuk-do; JB, Jeollabuk-do; JN, Jeollanam-do; GN, Gyeongsangnam-do.
Numbers of patients with diffuse parenchymal lung diseases of childhood reported in Korea. The first such patient was described in 1995; after 2000, the number of patients has increased markedly.
Pediatric Patients with Orphan Lung Diseases Reported in Korea
Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; BC, bronchogenic cyst; BO, bronchiolitis obliterans; Br, Bronchiectasis; CCAM, congenital cystic adenomatoid malformation; CCHS, congenital central hypoventilation syndrome; CCLD, congenital cystic lung disease; CLE, congenital lobar emphysema; CF, cystic fibrosis; IIP, idiopathic interstitial pneumonia; IPH, idiopathic pulmonary hemosiderosis; LP, Lipoid granuloma; Lymp, Lymphangiectasis; Para, Paragonimiasis; PS, pulmonary sequestration; Karta, kartagener syndrome