Children's Interstitial Lung Disease (ChILD)
- Author: James S Hagood, MD; Chief Editor: Michael R Bye, MD more...
Interstitial lung diseases (ILDs) in childhood are a diverse group of conditions that primarily involve the alveoli and perialveolar tissues, leading to derangement of gas exchange, restrictive lung physiology, and diffuse infiltrates on radiographs. Because ILDs can involve the distal airspaces as well as the interstitium, the term diffuse infiltrative lung disease has been suggested. This nomenclature may be more accurate than ILD, but children's interstitial lung disease (chILD) has become the preferred term. In 2004, the Rare Lung Diseases Consortium, a network of clinical and research centers and patient support organizations, was formed to accelerate clinical research in rare lung diseases, including chILD.
As a result of the rarity of ILDs in children and the important differences between childhood ILD and ILDs that affect adults, a great deal of confusion surrounds their nomenclature, classification, and management. Idiopathic pulmonary fibrosis (IPF, also known as cryptogenic fibrosing alveolitis [CFA]), the most prominent adult ILD, mostly occurs after the fifth decade of life; this entity is not found in children. Unlike in adults, most ILDs in children are found to have an underlying cause. In addition, the clinical significance of the histologic classification differs significantly between children and adults.
For example, usual interstitial pneumonitis (UIP), the pattern associated with IPF in adults, is rarely described in children. Desquamative interstitial pneumonitis (DIP), which is associated with steroid responsiveness and a better prognosis in adults, has a very poor prognosis in children, particularly in infants. Neuroendocrine cell hyperplasia in infancy (NEHI) and pulmonary interstitial glycogenesis (PIG) are histologic patterns unique to children.
Management of ILD in children also differs from that in adults. Correct diagnosis is critical, requiring a comprehensive search for possible underlying causes. Case reports describing unique presentations and anecdotal responses to various therapeutic interventions abound. Definitive management of ILDs, particularly those of unknown etiology, is unclear at present. The recently formed consortium of centers, perhaps in collaboration with centers worldwide, may facilitate use of standardized diagnostic criteria and develop a network for clinical trials.
Childhood ILD is not a disease but a group of disorders (see Causes). However, most ILDs share a common pathophysiologic feature, namely, structural remodeling of the distal airspaces, leading to impaired gas exchange. In general, this remodeling has been believed to be the sequela of persistent inflammation; however, more recently, the paradigm has shifted away from inflammation to one of tissue injury with aberrant wound healing resulting in collagenous fibrosis. Until recently, most research in this field has been based on adult histopathology and data from animal models.
Wound healing and fibrosis are complex pathophysiologic processes that involve numerous cell types and cellular processes, such as adhesion; migration; proliferation; apoptosis; and a vast array of soluble mediators, extracellular matrix (ECM) molecules, and signaling intermediates. Detailed discussion of the pathophysiology of lung fibrosis can be found in several excellent reviews.[2, 3, 4] In chILD, these processes occur in an organ that is still developing, further complicating the pathophysiology.
Many types of ILD follow some type of injury to the distal airspaces, such as adenoviral infection or exposure to organic dust, resulting in damage to the epithelial or endothelial layers and the associated basement membrane. In an animal model of lung fibrosis using bleomycin, as well as in models of surfactant-dysfunction mutations (SDMs), apoptosis of the alveolar epithelium was demonstrated to be a key inciting event.
Fibroblasts, which are normally present in the attenuated interstitial spaces between alveoli and surrounding distal airways, play a key role in lung remodeling, which is characterized by proliferation and excessive elaboration of matrix molecules such as collagen. Fibroblasts also affect remodeling through production of proteases, protease inhibitors, cytokines, and chemokines. Recent data indicate alternate origins of fibroblasts, such as circulating precursors known as fibrocytes, which hone in on injured tissues, and transdifferentiation of other cells, such as epithelial-mesenchymal transition (EMT).
Inflammation is present in many types of ILD, and many forms of ILD are triggered by inflammatory events, such as infection or hypersensitivity. Neutrophils and lymphocytes are prominent in bronchoalveolar lavage (BAL) samples in many types of ILD. In DIP, the airspaces are filled with cells that were once believed to be desquamated epithelium but which are, in fact, activated macrophages. The mediators released by inflammatory cells, particularly IL-1 and transforming growth factor (TGF)-beta, are potent activators of fibroblast-mediated remodeling. Almost every type of inflammatory cell, including eosinophils and mast cells, have been described in various types of ILD and can interact with fibroblasts and other parenchymal cells. However, lung inflammation does not necessarily result in fibrotic remodeling, and fibrosis can occur in the absence of inflammation; therefore, inflammation has a prominent, but not a central, role in lung remodeling and fibrosis.
A large number of other pathophysiologic events are increasingly recognized as having clinically significant effects on lung remodeling. Markers of angiogenesis have been prominent in several animal models of ILD and substantially affect outcomes. The ECM is a complex, biologically active structure that signals cells either by direct means or by means of its soluble breakdown products and that binds, sequesters, and presents growth factors and other mediators to cells. The ECM is altered in ILDs, and alterations in the ECM may also have a causative role.
Resolution of fibrotic remodeling involves a complex series of orderly steps, including matrix breakdown and restructuring, reepithelialization, and apoptosis of fibroblasts and inflammatory cells.
Fibrotic remodeling is responsible for most of the morbidity and mortality associated with ILD. Remodeling of distal airspaces results in hypoxemia. Persistent hypoxemia results in pulmonary hypertension and vascular remodeling, leading to cor pulmonale. The increased work of breathing associated with reduced compliance results in increased energy expenditure, which, combined with the effects of inflammatory mediators, can result in cachexia. Portions of the lung may be replaced by fibrotic septae between dilated airspaces, the so-called honeycomb changes of endstage interstitial disease. Although the events described above are necessary for repair of the injured lung, excessive activation or failure of resolution of any of these pathways can result in disabling fibrosis.
ILD is rare in children. Because of a lack (until recently) of consensus on case definition, the broad differential diagnosis, and the lack of organized reporting systems (eg, a national database), determining the precise incidence or prevalence of ILDs is impossible. Cases tend to cluster in infancy, and 10-16% appear to be familial.
Most of the literature is composed of case reports and small series. One of the largest reported series is a combined retrospective and prospective study by Fan et al performed over a 15-year period at a leading referral center for ILD. The investigators reported 99 patients, in whom the case definition included respiratory symptoms lasting longer than one month, diffuse infiltrates depicted on chest radiography, and absence of known bronchopulmonary dysplasia (BPD), heart disease, malignancy, immunodeficiency, autoimmunity, cystic fibrosis (CF), aspiration, or acquired immunodeficiency syndrome (AIDS). A more recent retrospective study that attempted a relatively complete case ascertainment of children undergoing biopsy for ILD in 11 referral centers in the United States and Canada over a 5-year period (1999-2004) reported 187 cases in children younger than 2 years old.
A national survey of cases of chronic ILD in immunocompetent children aged 0-16 years in the United Kingdom and Ireland over a three year period (1995-1998) yielded an estimated prevalence of 3.6 per million.
The same factors that make estimating the incidence of ILD difficult make estimating its mortality rates difficult.
In the series of 99 patients discussed above, the probability of surviving 24, 48, or 60 months was 83%, 72%, and 64%, respectively.6 Mean survival interval from onset in this group of patients was 47 months.
Factors associated with poor outcome included pulmonary hypertension at the time of diagnosis and a final diagnosis of DIP or pulmonary vascular disease.
In general, accurate definitive diagnosis should be pursued before attempting to predict associated morbidity or mortality. Certain specific histologic diagnoses in newborns adversely influence prognosis; these include diffuse developmental disorders and patterns associated with certain surfactant protein mutations. Without lung transplantation, the prognosis for most of these conditions is poor.  However, for other types of ILD, such as NEHI, significant morbidity but no mortality has been reported.
No data are available in the pediatric literature concerning differences in racial incidence or prevalence.
There appears to be a slight male predominance (roughly 60:40) in reported cases of chILD.
Approximately 50% of chILD cases occur in infants, but presentation can occur throughout childhood and adolescence.
In one of the largest series, the mean age at onset was 43 months (range, 0-212 mo). The median age at onset was 8 months, but the median age at evaluation was 30 months. These data indicate that some clustering of ILD occurs in infancy, and that, as is seen in adults, the delay between the onset of symptoms and appropriate diagnostic evaluation is often lengthy.
Recently identified pediatric ILD syndromes unique to infancy, including NEHI, PIG, and chronic pneumonitis of infancy, may present at or shortly after birth. SDMs often cause severe symptoms during the newborn period (see Causes).
Dishop MK. Paediatric interstitial lung disease: classification and definitions. Paediatr Respir Rev. 2011 Dec. 12(4):230-7. [Medline].
Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998 Apr. 157(4 Pt 1):1301-15. [Medline].
Selman M, King TE, Pardo A, American Thoracic Society, European Respiratory Society and American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001 Jan 16. 134(2):136-51. [Medline].
Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004. 55:395-417. [Medline].
Fan LL, Kozinetz CA, Wojtczak HA, Chatfield BA, Cohen AH, Rothenberg SS. Diagnostic value of transbronchial, thoracoscopic, and open lung biopsy in immunocompetent children with chronic interstitial lung disease. J Pediatr. 1997 Oct. 131(4):565-9. [Medline].
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 Dec 1. 176(11):1120-8. [Medline].
Dinwiddie R, Sharief N, Crawford O. Idiopathic interstitial pneumonitis in children: a national survey in the United Kingdom and Ireland. Pediatr Pulmonol. 2002 Jul. 34(1):23-9. [Medline].
Doan ML, Guillerman RP, Dishop MK, et al. Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax. 2008 Apr. 63(4):366-73. [Medline].
Das S, Langston C, Fan LL. Interstitial lung disease in children. Curr Opin Pediatr. 2011 Jun. 23(3):325-31. [Medline].
Fan LL, Mullen AL, Brugman SM, Inscore SC, Parks DP, White CW. Clinical spectrum of chronic interstitial lung disease in children. J Pediatr. 1992 Dec. 121(6):867-72. [Medline].
Young LR, Nogee LM, Barnett B, Panos RJ, Colby TV, Deutsch GH. Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest. 2008 Jul. 134(1):192-5. [Medline].
Vece TJ, Fan LL. Diagnosis and management of diffuse lung disease in children. Paediatr Respir Rev. 2011 Dec. 12(4):238-42. [Medline].
de Blic J. Pulmonary alveolar proteinosis in children. Paediatr Respir Rev. 2004 Dec. 5(4):316-22. [Medline].
Sano H, Kuroki Y. The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity. Mol Immunol. 2005 Feb. 42(3):279-87. [Medline].
Yusen RD, Cohen AH, Hamvas A. Normal lung function in subjects heterozygous for surfactant protein-B deficiency. Am J Respir Crit Care Med. 1999 Feb. 159(2):411-4. [Medline].
Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001 Feb 22. 344(8):573-9. [Medline].
Chibbar R, Shih F, Baga M, et al. Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis. Mod Pathol. 2004 Aug. 17(8):973-80. [Medline].
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004. 350(13) Mar 25:1296-303. [Medline].
Prestridge A, Wooldridge J, Deutsch G, et al. Persistent tachypnea and hypoxia in a 3-month-old term infant. J Pediatr. 2006 Nov. 149(5):702-6. [Medline].
Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 2005 Oct 15. 172(8):1026-31. [Medline].
Bullard JE, Wert SE, Nogee LM. ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease. Semin Perinatol. 2006 Dec. 30(6):327-34. [Medline].
Kobayashi I, Ono S, Kawamura N, et al. KL-6 is a potential marker for interstitial lung disease associated with juvenile dermatomyositis. J Pediatr. 2001 Feb. 138(2):274-6. [Medline].
Al-Salmi QA, Walter JN, Colasurdo GN, et al. Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease. Chest. 2005 Jan. 127(1):403-7. [Medline].
Satoh H, Kurishima K, Ishikawa H, Ohtsuka M. Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases. J Intern Med. 2006 Nov. 260(5):429-34. [Medline].
Owens C. Radiology of diffuse interstitial pulmonary disease in children. Eur Radiol. 2004 Mar. 14 Suppl 4:L2-12. [Medline].
Copley SJ, Coren M, Nicholson AG, Rubens MB, Bush A, Hansell DM. Diagnostic accuracy of thin-section CT and chest radiography of pediatric interstitial lung disease. AJR Am J Roentgenol. 2000 Feb. 174(2):549-54. [Medline].
Brody AS. Imaging considerations: interstitial lung disease in children. Radiol Clin North Am. 2005 Mar. 43(2):391-403. [Medline].
Long FR, Castile RG. Technique and clinical applications of full-inflation and end-exhalation controlled-ventilation chest CT in infants and young children. Pediatr Radiol. 2001. 31(6):413-22. [Medline].
Lynch DA, Hay T, Newell JD Jr, Divgi VD, Fan LL. Pediatric diffuse lung disease: diagnosis and classification using high-resolution CT. AJR Am J Roentgenol. 1999 Sep. 173(3):713-8. [Medline].
Brody AS, Crotty EJ. Neuroendocrine cell hyperplasia of infancy (NEHI) [clinical image]. Pediatr Radiol. 2006 Dec. 36(12):1328. [Medline].
Jensen SP, Lynch DA, Brown KK, Wenzel SE, Newell JD. High-resolution CT features of severe asthma and bronchiolitis obliterans. Clin Radiol. 2002 Dec. 57(12):1078-85. [Medline].
He ML, Lai H, Cao Y, Shuai YZ, Yu SC. High resolution computed tomography and classification of children with interstitial lung diseases. Genet Mol Res. 2014 Jun 9. 13(2):4241-51. [Medline].
Meyer KC. The role of bronchoalveolar lavage in interstitial lung disease. Clin Chest Med. 2004 Dec. 25(4):637-49, v. [Medline].
Langston C, Patterson K, Dishop MK, Askin F, Baker P. A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the chILD pathology co-operative group. Pediatr Dev Pathol. 2006 May-Jun. 9(3):173-80. [Medline].
American Thoracic Society, European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med. 2000 Feb. 161(2 Pt 1):646-64. [Medline]. [Full Text].
Deterding RR, Pye C, Fan LL, Langston C. Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia. Pediatr Pulmonol. 2005 Aug. 40(2):157-65. [Medline].
Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol. 2004 Nov. 38(5):369-78. [Medline].
Kinane BT, Mansell AL, Zwerdling RG, Lapey A, Shannon DC. Follicular bronchitis in the pediatric population. Chest. 1993 Oct. 104(4):1183-6. [Medline].
Hull J, Chow CW, Robertson CF. Chronic idiopathic bronchiolitis of infancy. Arch Dis Child. 1997 Dec. 77(6):512-5. [Medline].
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 Jun 1. 165(11):1557-65. [Medline].
Mallory GB Jr. Surfactant proteins: role in lung physiology and disease in early life. Paediatr Respir Rev. 2001 Jun. 2(2):151-8. [Medline].
Garcia CK, Raghu G. Inherited interstitial lung disease. Clin Chest Med. 2004 Sep. 25(3):421-33, v. [Medline].
Fan LL, Kozinetz CA, Deterding RR, Brugman SM. Evaluation of a diagnostic approach to pediatric interstitial lung disease. Pediatrics. 1998 Jan. 101(1 Pt 1):82-5. [Medline].
Hamman L, Rich AR. Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp. 1944. 74:177-212.
Vassallo R, Thomas CF. Advances in the treatment of rheumatic interstitial lung disease. Curr Opin Rheumatol. 2004 May. 16(3):186-91. [Medline].
Wylam ME, Ten R, Prakash UB, Nadrous HF, Clawson ML, Anderson PM. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006 Mar. 27(3):585-93. [Medline].
Venkateshiah SB, Yan TD, Bonfield TL, et al. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest. 2006 Jul. 130(1):227-37. [Medline].
Rosen DM, Waltz DA. Hydroxychloroquine and surfactant protein C deficiency. N Engl J Med. 2005 Jan 13. 352(2):207-8. [Medline].
Awasthi S, Coalson JJ, Yoder BA, Crouch E, King RJ. Deficiencies in lung surfactant proteins A and D are associated with lung infection in very premature neonatal baboons. Am J Respir Crit Care Med. 2001 Feb. 163(2):389-97. [Medline].
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 Jan. 23(1):55-61. [Medline].
Bokulic RE, Hilman BC. Interstitial lung disease in children. Pediatr Clin North Am. 1994 Jun. 41(3):543-67. [Medline].
Coren ME, Nicholson AG, Goldstraw P, Rosenthal M, Bush A. Open lung biopsy for diffuse interstitial lung disease in children. Eur Respir J. 1999 Oct. 14(4):817-21. [Medline].
Crouch E. Pathobiology of pulmonary fibrosis. Am J Physiol. 1990 Oct. 259(4 Pt 1):L159-84. [Medline].
Desmarquest P, Tamalet A, Fauroux B, et al. Chronic interstitial lung disease in children: response to high-dose intravenous methylprednisolone pulses. Pediatr Pulmonol. 1998 Nov. 26(5):332-8. [Medline].
Dinwiddie R. Treatment of interstitial lung disease in children. Paediatr Respir Rev. 2004 Jun. 5(2):108-15. [Medline].
Du Bois RM. Interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis. N Engl J Med. 1999 Oct 21. 341(17):1302-4. [Medline].
Fan LL, Kozinetz CA. Factors influencing survival in children with chronic interstitial lung disease. Am J Respir Crit Care Med. 1997 Sep. 156(3 Pt 1):939-42. [Medline].
Fan LL, Langston C. Chronic interstitial lung disease in children. Pediatr Pulmonol. 1993 Sep. 16(3):184-96. [Medline].
Fan LL, Lung MC, Wagener JS. The diagnostic value of bronchoalveolar lavage in immunocompetent children with chronic diffuse pulmonary infiltrates. Pediatr Pulmonol. 1997 Jan. 23(1):8-13. [Medline].
Hacking D, Smyth R, Shaw N, Kokia G, Carty H, Heaf D. Idiopathic pulmonary fibrosis in infants: good prognosis with conservative management. Arch Dis Child. 2000 Aug. 83(2):152-7. [Medline].
Hilman BC. Diagnosis and treatment of ILD. Pediatr Pulmonol. 1997 Jan. 23(1):1-7. [Medline].
Hilman BC, Amaro-Galvez R. Diagnosis of interstitial lung disease in children. Paediatr Respir Rev. 2004 Jun. 5(2):101-7. [Medline].
Huddleston CB, Bloch JB, Sweet SC, de la Morena M, Patterson GA, Mendeloff EN. Lung transplantation in children. Ann Surg. 2002 Sep. 236(3):270-6. [Medline].
Huddleston CB, Sweet SC, Mallory GB, Hamvas A, Mendeloff EN. Lung transplantation in very young infants. J Thorac Cardiovasc Surg. 1999 Nov. 118(5):796-804. [Medline].
Kerem E, Bentur L, England S, et al. Sequential pulmonary function measurements during treatment of infantile chronic interstitial pneumonitis. J Pediatr. 1990 Jan. 116(1):61-7. [Medline].
Kurland G, Michelson P. Bronchiolitis obliterans in children. Pediatr Pulmonol. 2005 Mar. 39(3):193-208. [Medline].
Leslie KO. Pathology of interstitial lung disease. Clin Chest Med. 2004 Dec. 25(4):657-703, vi. [Medline].
Liebow AA. Definition and classification of interstitial pneumonias in human pathology. Prog Respir Res. 1975. 8:1-33.
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 Feb 11. 328(6):406-10. [Medline].
Osika E, Muller MH, Boccon-Gibod L, et al. Idiopathic pulmonary fibrosis in infants. Pediatr Pulmonol. 1997 Jan. 23(1):49-54. [Medline].
Puthothu B, Krueger M, Heinze J, Forster J, Heinzmann A. Haplotypes of surfactant protein C are associated with common paediatric lung diseases. Pediatr Allergy Immunol. 2006 Dec. 17(8):572-7. [Medline].
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004 Jan 8. 350(2):125-33. [Medline].
Selman M, Lin HM, Montano M, et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum Genet. 2003 Nov. 113(6):542-50. [Medline].
Sharief N, Crawford OF, Dinwiddie R. Fibrosing alveolitis and desquamative interstitial pneumonitis. Pediatr Pulmonol. 1994 Jun. 17(6):359-65. [Medline].
Sondheimer HM, Lung MC, Brugman SM, Ikle DN, Fan LL, White CW. Pulmonary vascular disorders masquerading as interstitial lung disease. Pediatr Pulmonol. 1995 Nov. 20(5):284-8. [Medline].
Stillwell PC, Norris DG, O'Connell EJ, Rosenow EC 3rd, Weiland LH, Harrison EG Jr. Desquamative interstitial pneumonitis in children. Chest. 1980 Feb. 77(2):165-71. [Medline].
Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 1999 Oct 21. 341(17):1264-9. [Medline].