{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T17:58:03Z","timestamp":1789408683177,"version":"build-2803163510"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Childhood interstitial lung diseases (ILD) (chILD) refer to a rare heterogeneous group of disorders. Global collaborations have been working on the etiologies and classification scheme of chILD. With the development of medical technologies, some new diseases were identified to be associated with chILD and its etiologic spectrum is expanding. The aim of this study is to describe the etiologic spectrum of chILD in children older than 2\u2009years of age and summarize the approaches to diagnosis of chILD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We made a retrospective analysis of children older than 2\u2009years of age with chILD who referred to Beijing Children\u2019s Hospital from 21 provinces all over China from 2013 to 2018. After excluding pulmonary infection, congenital heart disease, bronchopulmonary dysplasia, bronchiolitis obliterans and bronchiectasis, 133 patients were included and categorized by etiology. Clinical manifestations, high-resolution computed tomography, laboratory data, genetic data and pathologic findings were all collected and reviewed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Systemic disease associated ILD were the most common causes, accounting for 49.6% of the patients, followed by alveolar structure disorder-associated ILD (27%), exposure related ILD (13.5%), and disorders masquerading as ILD (3.8%). In systemic disease associated ILD, in addition to common etiologies such as vasculitis (10.5%) and connective tissue diseases (9.0%), primary immunodeficiency diseases (PID) associated ILD (9.8%), interstitial pneumonia with autoimmune features (6.8%), and metabolic diseases (6.8%) were not rarely found. Some newly\u00a0reported etiologies such as STING\u2013associated vasculopathy with onset in infancy, COPA syndrome and <jats:italic>STAT3<\/jats:italic> mutation were included in PID associated ILD. Genetic tests contributed to 15% of the diagnoses which mainly distributed in PID associated ILD, metabolic diseases and surfactant dysfunction disorders, and contributed to the final diagnoses more than lung biopsies (13.5%) and biopsies of rashes or other tissues (12%).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study first demonstrated an etiologic spectrum of chILD in Chinese children older than 2\u2009years of age and summarized the approaches to diagnosis. The etiologic spectrum of chILD is expanding with more genetic etiologies being recognized.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-019-1270-7","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T02:02:42Z","timestamp":1579744962000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Etiologic spectrum of interstitial lung diseases in Chinese children older than 2\u2009years of age"],"prefix":"10.1186","volume":"15","author":[{"given":"Xiaolei","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinrong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,22]]},"reference":[{"issue":"3","key":"1270_CR1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1055\/s-2007-981654","volume":"28","author":"R Deterding","year":"2007","unstructured":"Deterding R. Evaluating infants and children with interstitial lung disease. Semin Respir Crit Care Med. 2007;28(3):333\u201341.","journal-title":"Semin Respir Crit Care Med"},{"key":"1270_CR2","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/S0031-3955(16)38769-7","volume":"41","author":"RE Bokulic","year":"1994","unstructured":"Bokulic RE, Hilman BC. Interstitial lung disease in children. Pediatr Clin N Am. 1994;41:543\u201367.","journal-title":"Pediatr Clin N Am"},{"key":"1270_CR3","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1002\/ppul.1950160309","volume":"16","author":"LL Fan","year":"1993","unstructured":"Fan LL, Langston C. Chronic interstitial lung disease in children. Pediatr Pulmonol. 1993;16:184\u201396.","journal-title":"Pediatr Pulmonol"},{"key":"1270_CR4","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/1750-1172-5-22","volume":"5","author":"A Clement","year":"2010","unstructured":"Clement A, Nathan N, Epaud R, et al. Interstitial lung diseases in children. Orphanet J Rare Dis. 2010;5:22.","journal-title":"Orphanet J Rare Dis"},{"key":"1270_CR5","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1164\/rccm.200703-393OC","volume":"176","author":"GH Deutsch","year":"2007","unstructured":"Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176:1120\u20138.","journal-title":"Am J Respir Crit Care Med"},{"issue":"6","key":"1270_CR6","doi-asserted-by":"publisher","first-page":"421","DOI":"10.2350\/08-11-0559.1","volume":"12","author":"C Langston","year":"2009","unstructured":"Langston C, Dishop MK. Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Pediatr Dev Pathol. 2009;12(6):421\u201337.","journal-title":"Pediatr Dev Pathol"},{"key":"1270_CR7","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1111\/his.12185","volume":"63","author":"A Rice","year":"2013","unstructured":"Rice A, Tran-Dang M, Bush A, et al. Diffuse lung disease in infancy and childhood: expanding the chILD classification. Histopathology. 2013;63:743\u201355.","journal-title":"Histopathology."},{"issue":"10","key":"1270_CR8","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1513\/AnnalsATS.201501-064OC","volume":"12","author":"LL Fan","year":"2015","unstructured":"Fan LL, Dishop MK, Galambos C, et al. Diffuse lung disease in biopsied children 2 to 18 years of age application of the chILD classification scheme. Ann Am Thorac Soc. 2015;12(10):1498\u2013505.","journal-title":"Ann Am Thorac Soc"},{"issue":"3","key":"1270_CR9","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1164\/rccm.201305-0923ST","volume":"188","author":"G Kurland","year":"2013","unstructured":"Kurland G, Deterding RR, Hagood JS, et al. An official American thoracic society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Am J Respir Crit Care Med. 2013;188(3):376\u201394.","journal-title":"Am J Respir Crit Care Med"},{"issue":"4","key":"1270_CR10","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1183\/13993003.00150-2015","volume":"46","author":"A Fischer","year":"2015","unstructured":"Fischer A, Antoniou KM, Brown KK, et al. An official European Respiratory Society\/ American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976\u201387.","journal-title":"Eur Respir J"},{"key":"1270_CR11","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s10875-017-0465-8","volume":"38","author":"A Bousfiha","year":"2018","unstructured":"Bousfiha A, Jeddane L, Picard C, et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2018;38:129\u201343.","journal-title":"J Clin Immunol"},{"issue":"4","key":"1270_CR12","doi-asserted-by":"publisher","first-page":"231","DOI":"10.18176\/jiaci.0166","volume":"27","author":"R Yazdani","year":"2017","unstructured":"Yazdani R, Abolhassani H, Asgardoon M, et al. Infectious and noninfectious pulmonary complications in patients with primary immunodeficiency disorders. J Investig Allergol Clin Immunol. 2017;27(4):231\u201324.","journal-title":"J Investig Allergol Clin Immunol"},{"key":"1270_CR13","doi-asserted-by":"publisher","first-page":"180019","DOI":"10.1183\/16000617.0019-2018","volume":"27","author":"F Cinetto","year":"2018","unstructured":"Cinetto F, Scarpa R, Rattazzi M, et al. The broad spectrum of lung diseases in primary antibody deficiencies. Eur Respir Rev. 2018;27:180019.","journal-title":"Eur Respir Rev"},{"issue":"2","key":"1270_CR14","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.jaci.2004.05.057","volume":"114","author":"CA Bates","year":"2004","unstructured":"Bates CA, Ellison MC, Lynch DA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114(2):415\u201321.","journal-title":"J Allergy Clin Immunol"},{"issue":"8","key":"1270_CR15","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1513\/AnnalsATS.201601-079OC","volume":"13","author":"CY Lau","year":"2016","unstructured":"Lau CY, Mihalek AD, Wang J, et al. Pulmonary manifestations of the autoimmune lymphoproliferative syndrome. A retrospective study of a unique patient cohort. Ann Am Thorac Soc. 2016;13(8):1279\u201388.","journal-title":"Ann Am Thorac Soc"},{"issue":"6","key":"1270_CR16","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1056\/NEJMoa1312625","volume":"371","author":"Y Liu","year":"2014","unstructured":"Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507\u201318.","journal-title":"N Engl J Med"},{"issue":"4","key":"1270_CR17","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s10875-016-0271-8","volume":"36","author":"TJ Vece","year":"2016","unstructured":"Vece TJ, Watkin LB, Nicholas S, et al. Copa syndrome: a novel autosomal dominant immune dysregulatory disease. J Clin Immunol. 2016;36(4):377\u201387.","journal-title":"J Clin Immunol"},{"issue":"11","key":"1270_CR18","doi-asserted-by":"publisher","first-page":"e22","DOI":"10.1164\/rccm.201707-1500IM","volume":"197","author":"A Fabre","year":"2018","unstructured":"Fabre A, Marchal S, Forbes LR, et al. STAT3 GOF: a new kid on the block in interstitial lung diseases. Am J Respir Crit Care Med. 2018;197(11):e22\u20133.","journal-title":"Am J Respir Crit Care Med"},{"issue":"6204","key":"1270_CR19","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1126\/science.1255904","volume":"345","author":"HS Kuehn","year":"2014","unstructured":"Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623\u20137.","journal-title":"Science."},{"issue":"6","key":"1270_CR20","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/j.ajhg.2012.04.015","volume":"90","author":"G Lopez-Herrera","year":"2012","unstructured":"Lopez-Herrera G, Tampella G, Pan-Hammarstr\u00f6m Q, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986\u20131001.","journal-title":"Am J Hum Genet"},{"issue":"3","key":"1270_CR21","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/s10875-017-0376-8","volume":"37","author":"S Esenboga","year":"2017","unstructured":"Esenboga S, Emiralioglu N, Cagdas D, et al. Diagnosis of interstitial lung disease caused by possible hypersensitivity pneumonitis in a child: think CGD. J Clin Immunol. 2017;37(3):269\u201372.","journal-title":"J Clin Immunol"},{"issue":"8","key":"1270_CR22","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1007\/s10875-014-0089-1","volume":"34","author":"T Kawai","year":"2014","unstructured":"Kawai T, Watanabe N, Yokoyama M, et al. Interstitial lung disease with multiple microgranulomas in chronic granulomatous disease. J Clin Immunol. 2014;34(8):933\u201340.","journal-title":"J Clin Immunol"},{"issue":"2","key":"1270_CR23","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1007\/s10875-017-0473-8","volume":"38","author":"H Liu","year":"2018","unstructured":"Liu H, Yang H, Li H, et al. Hypersensitive pneumonitis: an initial presentation of chronic granulomatous disease in a child. J Clin Immunol. 2018;38(2):155\u20138.","journal-title":"J Clin Immunol"},{"issue":"2","key":"1270_CR24","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jaci.2013.08.022","volume":"133","author":"PJ Maglione","year":"2014","unstructured":"Maglione PJ, Ko HM, Beasley MB, et al. Tertiary lymphoid neogenesis is a component of pulmonary lymphoid hyperplasia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;133(2):535\u201342.","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"1270_CR25","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.clim.2009.10.002","volume":"134","author":"JH Park","year":"2010","unstructured":"Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Immunol. 2010;134(2):97\u2013103.","journal-title":"Clin Immunol"},{"issue":"4","key":"1270_CR26","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1016\/j.jaip.2017.01.021","volume":"5","author":"JR Hurst","year":"2017","unstructured":"Hurst JR, Verma N, Lowe D, et al. British Lung Foundation\/United Kingdom primary immunodeficiency network consensus statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2017;5(4):938\u201345.","journal-title":"J Allergy Clin Immunol Pract"},{"issue":"1","key":"1270_CR27","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13023-017-0610-8","volume":"12","author":"J Liu","year":"2017","unstructured":"Liu J, Peng Y, Zhou N, et al. Combined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients. Orphanet J Rare Dis. 2017;12(1):58.","journal-title":"Orphanet J Rare Dis"},{"issue":"6","key":"1270_CR28","doi-asserted-by":"publisher","first-page":"e1510","DOI":"10.1542\/peds.2014-2779","volume":"135","author":"JR Liu","year":"2015","unstructured":"Liu JR, Xu XF, Zhou CJ, et al. Bronchiolitis obliterans organizing pneumonia due to gastroesophageal reflux. Pediatrics. 2015;135(6):e1510\u20133.","journal-title":"Pediatrics."},{"issue":"20","key":"1270_CR29","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1056\/NEJMcpc030010","volume":"348","author":"CM Fleming","year":"2003","unstructured":"Fleming CM, Shepard JAO, Mark EJ, et al. Case 15-2003: a 47-year-old man with waxing and waning pulmonary nodules five years after treatment for testicular seminoma: bronchiolitis obliterans with organizing pneumonia due to gastroesophageal reflux and occult aspiration. N Engl J Med. 2003;348(20):2019\u201327.","journal-title":"N Engl J Med"},{"issue":"45","key":"1270_CR30","first-page":"2383","volume":"17","author":"D Sadoun","year":"1988","unstructured":"Sadoun D, Valeyre D, Cargill J, et al. Bronchiolitis obliterans with cryptogenetic-like organizing pneumonia. Demonstration of gastro-esophageal reflux in 5 cases. Presse Med. 1988;17(45):2383\u20135.","journal-title":"Presse Med"},{"issue":"1","key":"1270_CR31","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1183\/09031936.00.15121700","volume":"15","author":"J de Blic","year":"2000","unstructured":"de Blic J, Midulla F, Barbato A, et al. Bronchoalveolar lavage in children. ERS task force on bronchoalveolar lavage in children. European Respiratory Society. Eur Respir J. 2000;15(1):217\u201331.","journal-title":"Eur Respir J"},{"issue":"9","key":"1270_CR32","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1164\/rccm.201202-0320ST","volume":"185","author":"KC Meyer","year":"2012","unstructured":"Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012;185(9):1004\u201314.","journal-title":"Am J Respir Crit Care Med"},{"key":"1270_CR33","doi-asserted-by":"publisher","first-page":"1779","DOI":"10.1016\/S0003-4975(01)02516-4","volume":"71","author":"MT Jaklitsch","year":"2001","unstructured":"Jaklitsch MT, Linden BC, Braunlin EA, et al. Open-lung biopsy guides therapy in children. Ann Thorac Surg. 2001;71:1779\u201385 (see comment).","journal-title":"Ann Thorac Surg"},{"key":"1270_CR34","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1034\/j.1399-3003.1999.14d16.x","volume":"14","author":"ME Coren","year":"1999","unstructured":"Coren ME, Nicholson AG, Goldstraw P, et al. Open lung biopsy for diffuse interstitial lung disease in children. Eur Respir J. 1999;14:817\u201321.","journal-title":"Eur Respir J"},{"key":"1270_CR35","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1080\/080352598750031590","volume":"87","author":"R Steinberg","year":"1998","unstructured":"Steinberg R, Freud E, Ben-Ari J, et al. Open lung biopsy\u2014successful diagnostic tool with therapeutic implication in the critically ill paediatric population. Acta Paediatr. 1998;87:945\u20138.","journal-title":"Acta Paediatr"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-019-1270-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13023-019-1270-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-019-1270-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:08:16Z","timestamp":1611187696000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-019-1270-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,22]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1270"],"URL":"https:\/\/doi.org\/10.1186\/s13023-019-1270-7","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,22]]},"assertion":[{"value":"13 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This retrospective study was approved by the ethical committee of the Beijing Children\u2019s Hospital, Capital Medical University (2018-k-138).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"25"}}