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Classification of diffuse lung disease (interstitial lung disease) in infants and children

Author
Lisa R Young, MD
Section Editor
George B Mallory, MD
Deputy Editor
Alison G Hoppin, MD

INTRODUCTION

Diffuse lung disease (DLD), traditionally known as interstitial lung disease (ILD), consists of a diverse group of disorders that involve the pulmonary parenchyma and interfere with gas exchange. These disorders are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations.

Although some of the conditions that cause DLD in children and adults are similar, they occur in different proportions in each age group, and certain diseases are unique to infants [1-6]. Historically, the approach to DLD in children has been patterned after nomenclature and prognosis in adults (see "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'Classification'), and such practice has unfortunately created a great deal of confusion. There are important differences in disease etiology and natural history in the pediatric age group as compared with adults, and the classification of the idiopathic interstitial pneumonias (IIP) used in adults is overall a poor fit for childhood DLD. Prominent examples of these differences are idiopathic pulmonary fibrosis (IPF) and desquamative interstitial pneumonia (DIP). Specifically, IPF, a common IIP in adults that has a very poor prognosis, does not occur in children. Furthermore, pediatric cases of DIP tend to have high mortality and have been associated with ABCA3 and SFTPC mutations, which contrasts with the association between DIP and tobacco smoking and relatively good prognosis in adults [7-9].

In addition, there are forms of DLD that are either unique to young children or have differing manifestations as compared with adults. In the past 10 to 15 years, several new entities have been described in infants and young children, including neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis (P.I.G). A great advance has been the recognition and identification of genetic defects of surfactant function, metabolism, and clearance as causes of DLD, including mutations in the genes producing surfactant protein B (SFTPB), surfactant protein C (SFTPC), member A3 of the ATP binding cassette family of transporters (ABCA3), components of the GM-CSF receptor (CSF2RA), and NKX2.1 (thyroid transcription factor-1). (See "Genetic disorders of surfactant dysfunction".)

For all of these reasons, a classification system has been developed specifically for pediatrics [7,10]. The classification of DLD in infants and children will be discussed here. The approach to the infant and child with DLD is presented separately. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)".)

TERMINOLOGY

The term "diffuse lung disease" (DLD) describes a diverse group of disorders that involve the pulmonary parenchyma and interfere with gas exchange. This term reflects the spectrum of underlying pathology, which often includes extensive alteration of alveolar and airway architecture, in addition to changes in the interstitial compartment. These disorders have traditionally been described as "interstitial lung disease" (ILD), but that term is less accurate because the interstitium is not involved in some types, such as neuroendocrine cell hyperplasia of infancy. Another term used in the literature is "diffuse parenchymal lung disease" [11].

                               

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Literature review current through: Nov 2016. | This topic last updated: Mon Oct 03 00:00:00 GMT+00:00 2016.
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References
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  1. Langston C, Fan LL. The spectrum of interstitial lung disease in childhood. Pediatr Pulmonol 2001; Suppl 23:70.
  2. Langston C, Fan LL. Diffuse interstitial lung disease in infants. Pediatr Pulmonol 2001; Suppl 23:74.
  3. Griese M, Haug M, Brasch F, et al. Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany. Orphanet J Rare Dis 2009; 4:26.
  4. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:1301.
  5. Nicholson AG, Kim H, Corrin B, et al. The value of classifying interstitial pneumonitis in childhood according to defined histological patterns. Histopathology 1998; 33:203.
  6. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol 1994; 18:136.
  7. 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.
  8. Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol 2004; 38:369.
  9. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188:733.
  10. 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; 188:376.
  11. Vece TJ, Young LR. Update on Diffuse Lung Disease in Children. Chest 2016; 149:836.
  12. 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; 12:1498.
  13. Soares JJ, Deutsch GH, Moore PE, et al. Childhood interstitial lung diseases: an 18-year retrospective analysis. Pediatrics 2013; 132:684.
  14. Rice A, Tran-Dang MA, Bush A, Nicholson AG. Diffuse lung disease in infancy and childhood: expanding the chILD classification. Histopathology 2013; 63:743.
  15. Fan LL, Langston C. Pediatric interstitial lung disease: children are not small adults. Am J Respir Crit Care Med 2002; 165:1466.
  16. Ito Y, Akimoto T, Cho K, et al. A late presenter and long-term survivor of alveolar capillary dysplasia with misalignment of the pulmonary veins. Eur J Pediatr 2015; 174:1123.
  17. Melly L, Sebire NJ, Malone M, Nicholson AG. Capillary apposition and density in the diagnosis of alveolar capillary dysplasia. Histopathology 2008; 53:450.
  18. Ahmed S, Ackerman V, Faught P, Langston C. Profound hypoxemia and pulmonary hypertension in a 7-month-old infant: late presentation of alveolar capillary dysplasia. Pediatr Crit Care Med 2008; 9:e43.
  19. Shankar V, Haque A, Johnson J, Pietsch J. Late presentation of alveolar capillary dysplasia in an infant. Pediatr Crit Care Med 2006; 7:177.
  20. Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary dysplasia. Am J Respir Crit Care Med 2011; 184:172.
  21. Zufferey F, Martinet D, Osterheld MC, et al. 16q24.1 microdeletion in a premature newborn: usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 2011; 12:e427.
  22. Sen P, Gerychova R, Janku P, et al. A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human. Eur J Hum Genet 2013; 21:474.
  23. Szafranski P, Yang Y, Nelson MU, et al. Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Mutat 2013; 34:1467.
  24. Sen P, Yang Y, Navarro C, et al. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum Mutat 2013; 34:801.
  25. Stankiewicz P, Sen P, Bhatt SS, et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet 2009; 84:780.
  26. Yu S, Shao L, Kilbride H, Zwick DL. Haploinsufficiencies of FOXF1 and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease. Am J Med Genet A 2010; 152A:1257.
  27. Prothro SL, Plosa E, Markham M, et al. Prenatal Diagnosis of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. J Pediatr 2016; 170:317.
  28. Szafranski P, Gambin T, Dharmadhikari AV, et al. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Genet 2016; 135:569.
  29. Reiter J, Szafranski P, Breuer O, et al. Variable phenotypic presentation of a novel FOXF1 missense mutation in a single family. Pediatr Pulmonol 2016; 51:921.
  30. Luk HM, Tang T, Choy KW, et al. Maternal somatic mosaicism of FOXF1 mutation causes recurrent alveolar capillary dysplasia with misalignment of pulmonary veins in siblings. Am J Med Genet A 2016; 170:1942.
  31. Cooney TP, Thurlbeck WM. Pulmonary hypoplasia in Down's syndrome. N Engl J Med 1982; 307:1170.
  32. Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 2013; 144:794.
  33. Ekşioğlu YZ, Scheffer IE, Cardenas P, et al. Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 1996; 16:77.
  34. Masurel-Paulet A, Haan E, Thompson EM, et al. Lung disease associated with periventricular nodular heterotopia and an FLNA mutation. Eur J Med Genet 2011; 54:25.
  35. de Wit MC, Tiddens HA, de Coo IF, Mancini GM. Lung disease in FLNA mutation: confirmatory report. Eur J Med Genet 2011; 54:299.
  36. Lord A, Shapiro AJ, Saint-Martin C, et al. Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns. Respir Care 2014; 59:e171.
  37. Langston C, Patterson K, Dishop MK, et al. A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the chILD pathology co-operative group. Pediatr Dev Pathol 2006; 9:173.
  38. Schroeder SA, Shannon DC, Mark EJ. Cellular interstitial pneumonitis in infants. A clinicopathologic study. Chest 1992; 101:1065.
  39. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 40-1999. A four-month-old girl with chronic cyanosis and diffuse pulmonary infiltrates. N Engl J Med 1999; 341:2075.
  40. Canakis AM, Cutz E, Manson D, O'Brodovich H. Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease. Am J Respir Crit Care Med 2002; 165:1557.
  41. Katzenstein AL, Gordon LP, Oliphant M, Swender PT. Chronic pneumonitis of infancy. A unique form of interstitial lung disease occurring in early childhood. Am J Surg Pathol 1995; 19:439.
  42. Fisher M, Roggli V, Merten D, et al. Coexisting endogenous lipoid pneumonia, cholesterol granulomas, and pulmonary alveolar proteinosis in a pediatric population: a clinical, radiographic, and pathologic correlation. Pediatr Pathol 1992; 12:365.
  43. Lanfranchi M, Allbery SM, Wheelock L, Perry D. Pulmonary interstitial glycogenosis. Pediatr Radiol 2010; 40:361.
  44. Castillo M, Vade A, Lim-Dunham JE, et al. Pulmonary interstitial glycogenosis in the setting of lung growth abnormality: radiographic and pathologic correlation. Pediatr Radiol 2010; 40:1562.
  45. Deutsch GH, Young LR. Lipofibroblast Phenotype in Pulmonary Interstitial Glycogenosis. Am J Respir Crit Care Med 2016; 193:694.
  46. Deutsch GH, Young LR. Histologic resolution of pulmonary interstitial glycogenosis. Pediatr Dev Pathol 2009; 12:475.
  47. Deutsch GH, Young LR. Pulmonary interstitial glycogenosis: words of caution. Pediatr Radiol 2010; 40:1471.
  48. Nogee LM, de Mello DE, Dehner LP, Colten HR. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med 1993; 328:406.
  49. Nogee LM, Dunbar AE 3rd, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001; 344:573.
  50. Brasch F, Griese M, Tredano M, et al. Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. Eur Respir J 2004; 24:30.
  51. Osika E, Muller MH, Boccon-Gibod L, et al. Idiopathic pulmonary fibrosis in infants. Pediatr Pulmonol 1997; 23:49.
  52. Tal A, Maor E, Bar-Ziv J, Gorodischer R. Fatal desquamative interstitial pneumonia in three infants siblings. J Pediatr 1984; 104:873.
  53. Buchino JJ, Keenan WJ, Algren JT, Bove KE. Familial desquamative interstitial pneumonitis occurring in infants. Am J Med Genet Suppl 1987; 3:285.
  54. Balasubramanyan N, Murphy A, O'Sullivan J, O'Connell EJ. Familial interstitial lung disease in children: response to chloroquine treatment in one sibling with desquamative interstitial pneumonitis. Pediatr Pulmonol 1997; 23:55.
  55. Kunig AM, Parker TA, Nogee LM, et al. ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn. J Pediatr 2007; 151:322.
  56. Henderson LB, Melton K, Wert S, et al. Large ABCA3 and SFTPC deletions resulting in lung disease. Ann Am Thorac Soc 2013; 10:602.
  57. Hadchouel A, Wieland T, Griese M, et al. Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island. Am J Hum Genet 2015; 96:826.
  58. Martinez-Moczygemba M, Doan ML, Elidemir O, et al. Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1. J Exp Med 2008; 205:2711.
  59. Suzuki T, Sakagami T, Rubin BK, et al. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med 2008; 205:2703.
  60. Colom AJ, Teper AM, Vollmer WM, Diette GB. Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis. Thorax 2006; 61:503.
  61. Moonnumakal SP, Fan LL. Bronchiolitis obliterans in children. Curr Opin Pediatr 2008; 20:272.
  62. Kurland G, Michelson P. Bronchiolitis obliterans in children. Pediatr Pulmonol 2005; 39:193.
  63. Lynch DA, Hay T, Newell JD Jr, et al. Pediatric diffuse lung disease: diagnosis and classification using high-resolution CT. AJR Am J Roentgenol 1999; 173:713.
  64. Kim KW, Ahn K, Yang HJ, et al. Humidifier disinfectant-associated children's interstitial lung disease. Am J Respir Crit Care Med 2014; 189:48.
  65. Hong SB, Kim HJ, Huh JW, et al. A cluster of lung injury associated with home humidifier use: clinical, radiological and pathological description of a new syndrome. Thorax 2014; 69:694.
  66. Zanetti G, Marchiori E, Gasparetto TD, et al. Lipoid pneumonia in children following aspiration of mineral oil used in the treatment of constipation: high-resolution CT findings in 17 patients. Pediatr Radiol 2007; 37:1135.
  67. Bandla HP, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics 1999; 103:E19.
  68. Becton DL, Lowe JE, Falletta JM. Lipoid pneumonia in an adolescent girl secondary to use of lip gloss. J Pediatr 1984; 105:421.
  69. Langston C, Dishop MK. Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Pediatr Dev Pathol 2009; 12:421.
  70. Dishop MK, Ashkin FB, Galambos C, et al. Classification of diffuse lung disease in older children and adolescents: a multi-institutional study of the Children's Interstitial Lung Disease (chILD) pathology working group. Mod Pathol 2007; 20:287.
  71. Thomas H, Risma KA, Graham TB, et al. A kindred of children with interstitial lung disease. Chest 2007; 132:221.
  72. O'Brodovich HM, Moser MM, Lu L. Familial lymphoid interstitial pneumonia: a long-term follow-up. Pediatrics 1980; 65:523.
  73. Kinane BT, Mansell AL, Zwerdling RG, et al. Follicular bronchitis in the pediatric population. Chest 1993; 104:1183.
  74. Milner JD, Vogel TP, Forbes L, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 2015; 125:591.
  75. Griese M, Zarbock R, Costabel U, et al. GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders. BMC Pulm Med 2015; 15:87.
  76. Svobodova T, Mejstrikova E, Salzer U, et al. Diffuse parenchymal lung disease as first clinical manifestation of GATA-2 deficiency in childhood. BMC Pulm Med 2015; 15:8.
  77. Lo B, Zhang K, Lu W, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 2015; 349:436.
  78. Giri N, Lee R, Faro A, et al. Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. BMC Blood Disord 2011; 11:3.
  79. Abe K, Kamata N, Okazaki E, et al. Chronic pneumonitis of infancy. Eur Radiol 2002; 12 Suppl 3:S155.
  80. Kavantzas N, Theocharis S, Agapitos E, Davaris P. Chronic pneumonitis of infancy. An autopsy study of 12 cases. Clin Exp Pathol 1999; 47:96.
  81. Thomas AQ, Lane K, Phillips J 3rd, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002; 165:1322.
  82. Battistini E, Dini G, Savioli C, et al. Bronchiolitis obliterans organizing pneumonia in three children with acute leukaemias treated with cytosine arabinoside and anthracyclines. Eur Respir J 1997; 10:1187.
  83. Inoue T, Toyoshima K, Kikui M. Idiopathic bronchiolitis obliterans organizing pneumonia (idiopathic BOOP) in childhood. Pediatr Pulmonol 1996; 22:67.
  84. Zahraa J, Herold B, Abrahams C, Johnson D. Bronchiolitis obliterans organizing pneumonia in a child with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1996; 15:448.
  85. Kleinau I, Perez-Canto A, Schmid HJ, et al. Bronchiolitis obliterans organizing pneumonia and chronic graft-versus-host disease in a child after allogeneic bone marrow transplantation. Bone Marrow Transplant 1997; 19:841.
  86. Young LR, Nogee LM, Barnett B, et al. Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest 2008; 134:192.
  87. Zapletal A, Houstĕk J, Samánek M, et al. Lung function in children and adolescents with idiopathic interstitial pulmonary fibrosis. Pediatr Pulmonol 1985; 1:154.
  88. Chetty A, Bhuyan UN, Mitra DK, et al. Cryptogenic fibrosing alveolitis in children. Ann Allergy 1987; 58:336.
  89. Steinkamp G, Müller KM, Schirg E, von der Hardt H. Fibrosing alveolitis in childhood. A long-term follow-up. Acta Paediatr Scand 1990; 79:823.
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