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

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
Literature review current through: Jul 2022. | This topic last updated: May 10, 2022.

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 overlapping 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]. A great advance in the field of pediatric DLD has been the recognition and identification of genetic defects of surfactant function, metabolism, and clearance as causes of DLD. Other entities recognized uniquely in infants and young children include neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis (P.I.G.).

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 some types, such as neuroendocrine cell hyperplasia of infancy (NEHI) and bronchiolitis obliterans (BO), have airway centric manifestations. Another term used in the literature is "diffuse parenchymal lung disease" [7].

The terms "childhood ILD syndrome" or "DLD syndrome" are sometimes used to describe a case in which DLD is suspected based on clinical and radiologic features but a specific cause has not yet been established.

CLASSIFICATION SYSTEM

Pediatric classification system – The terminology and classification system used to describe DLD in children is based on both clinical characteristics and histopathology and emphasizes unique disorders in young children. It is important to recognize that classification does not necessarily provide a specific diagnosis, but instead is a framework for approaching the diverse groups of disorders that comprise childhood DLD. Therefore, the classification categories are used to group disorders with similar clinical characteristics and/or pathophysiology.

Age at presentation is a key organizing principle of this classification structure. The classification is broadly divided into "disorders more prevalent in infancy" and "disorders not specific to infancy" (table 1) [8-10].

Within this classification, it is also useful to distinguish between DLD that is primarily a pulmonary-specific process and forms that occur in association with a systemic disorder (table 2). For types of DLD that have no recognized causes and are not associated with a systemic disease, histopathologic patterns remain important components of classification (table 3). These histologic classifications are discussed in a separate section below. (See 'Implications of histopathologic patterns in childhood DLD' below.)

Thus, the more current classification is recognized to have some conceptual and practical limitations but provides a very useful framework for this field. It is anticipated that the classification system will continue to undergo revision, including a need to better incorporate advances in the understanding of disease mechanisms including genetic mechanisms, improved recognition of radiographic patterns enabling noninvasive diagnosis, and other ongoing studies in this field [10-12].

Comparison with adult classification and historical context – Historically, the approach to DLD in children was patterned after nomenclature and prognosis in adults (see "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'Classification'), and such practice 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 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 idiopathic interstitial pneumonia in adults that has a very poor prognosis, does not occur in children. Furthermore, pediatric cases of DIP tend to have relatively high mortality and have been associated with ABCA3 and SFTPC gene mutations, which contrasts with the association between DIP and tobacco smoking and relatively good prognosis in adults [8,13,14].

In the early 2000s, critical discoveries and recognition of new entities in infants prompted paradigm shifts in the approach and classification of DLD in children. For example, it was recognized that there are forms of DLD that are either unique to young children or have differing manifestations as compared with adults, including genetic disorders of surfactant dysfunction, neuroendocrine cell hyperplasia of infancy (NEHI), and pulmonary interstitial glycogenosis (P.I.G.). For all of these reasons, a classification system was developed specifically for pediatrics [8,9].

DISORDERS MORE PREVALENT IN INFANCY — A number of unique forms of DLD have been described in infants and neonates (table 1) [2]. These entities represent more precise and mechanistic descriptions of disorders that were previously misidentified or categorized based on histologic patterns [15].

Developmental lung disorders — Forms of aberrant lung development occur on a continuum; these are also termed diffuse developmental disorders [8] and lethal lung developmental disorders [16].

Alveolar capillary dysplasia with or without misalignment of the pulmonary veins — Alveolar capillary dysplasia (ACD), with or without misalignment of the pulmonary veins (ACD-MPV), is historically the primary entity in the category of developmental lung disorders. It is a rare developmental disorder of the lung that typically causes very early postnatal respiratory distress and persistent pulmonary hypertension. The presentation may overlap that of persistent pulmonary hypertension of the newborn, except infants with ACD are typically unresponsive to supportive measures, including mechanical ventilation and inhaled nitric oxide. Extracorporeal membrane oxygenation may be required while pursuing the diagnostic evaluation. This condition is almost always lethal, though milder cases have been rarely identified, including some presenting outside of the neonatal period [17-22].

The majority of affected infants with ACD (or ACD-MPV) have additional malformations, most commonly cardiac (often hypoplastic left heart), gastrointestinal (intestinal malrotation and atresias), and renal/urogenital abnormalities, though there is recognition of a broadening phenotypic spectrum [23]. Although ACD-MPV may be suspected clinically, the definitive diagnosis has been defined largely based on distinctive abnormalities of the pulmonary vasculature seen histologically at lung biopsy or autopsy, which include characteristic prominent veins within the bronchoarterial bundles [8]. Although these vessels are termed "misaligned" pulmonary veins, a report of two cases suggested an alternative hypothesis that they are merely prominent because of blood shunting from the pulmonary to systemic vasculature [24].

Disruption of the transcription factor FOXF1 plays a role in the majority of cases of ACD (or ACD-MPV). A subset of newborns with ACD have germline FOXF1 gene deletions or mutations [22,25-32]. Among cases in which parental origin can be determined, most arise de novo on the maternal chromosome 16, suggesting genomic imprinting of the FOXF1 locus. Somatic mosaicism may occur, emphasizing the role of genetic counseling for families with this disorder [33-35].

With sufficient clinical suspicion, early initiation of clinical genetic testing may obviate the need for lung biopsy and facilitate timely referral to a lung transplant center. These genetic insights are also facilitating mechanistic studies toward promise of targeted therapies. For example, in a murine model of ACD with the S52F FoxF1 mutation, it was demonstrated that the FOXF1 protein acts through STAT3 to stimulate neonatal lung angiogenesis, suggesting potential future therapeutic strategies through stimulating STAT3 signaling [36].

Acinar dysplasia and congenital alveolar dysplasia — Disruption of the TBX4-FGF and FGF10 pathways has also been associated with altered lung development, including a spectrum of acinar dysplasia and congenital alveolar dysplasia. It has been proposed that there is a spectrum of developmental arrest from acinar dysplasia to congenital alveolar dysplasia, with the former reflecting arrest at the late pseudoglandular stage with only bronchioles amid mesenchyme, whereas distal acinar airspaces reflective of the canalicular stage are seen in cases termed congenital alveolar dysplasia [37].

Additional features observed with TBX4 alteration include small patella syndrome and pulmonary arterial hypertension. FGF10 deletion has been described in patients with acinar dysplasia and aplasia of the lacrimal and salivary glands and lacrimo-auriculo-dento-digital syndrome [38,39]. It is likely that additional genetic mechanisms will be identified in the future [37,40].

Alveolar growth abnormalities — Alveolar growth abnormalities, sometimes referred to as deficient alveolarization, are a prominent finding in many infants with DLD who undergo lung biopsy [8]. Furthermore, the clinical features of tachypnea, retractions, hypoxemia, and diffuse radiographic abnormalities are often similar to those seen in other forms of childhood DLD.

Alveolar growth abnormalities are predominantly found in the context of prematurity (see "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features") and prenatal-onset pulmonary hypoplasia due to congenital diaphragmatic hernia, giant omphalocele, or thoracic dystrophies. This pathobiology also occurs in the setting of congenital heart disease, chromosomal abnormalities (particularly trisomy 21), and, sometimes, in otherwise normal term infants with early postnatal lung injury.

Radiologic findings are variable, depending on the etiology, age of the infant, and severity of the growth abnormality. Subpleural cysts may be present and are frequently seen in pulmonary hypoplasia associated with trisomy 21 [41]. In one study, most infants diagnosed with lung growth abnormalities by lung biopsy had more severe clinical symptoms and radiographic abnormalities than would be expected for their known comorbidities or other clinical characteristics [8]. In these cases, the disproportionate clinical severity led to the suspicion for an additional form of DLD and to the decision to pursue surgical lung biopsy in these patients. Pulmonary vascular disease or patchy pulmonary interstitial glycogenosis (P.I.G.) are common concurrent histologic findings in infants with these disorders [8].

Several single-gene disorders causing alveolar growth abnormalities have been associated with DLD. Mutations or deletions in NKX2-1 may present with alveolar simplification as the predominant finding or, alternatively, with a phenotype of surfactant dysfunction [42]. Mutations in filamin A (FLNA) cause X-linked periventricular nodular heterotopia and have also been associated with severe DLD with alveolar simplification (mimicking emphysema) and pulmonary hypertension, as well as a variety of extrapulmonary manifestations [43-47]. FLNA-associated DLD has been suggested to have common radiologic patterns of upper lobe overinflation, coarse pulmonary lobular septal thickening, and lower lobe patchy atelectasis [48,49].

Lung growth abnormalities are associated with considerable morbidity and mortality when compared with other causes of DLD. In one multicenter study, mortality was 34 percent for lung growth abnormality cases, a proportion similar to the entire study cohort. However, among the group with lung growth abnormalities, prematurity and pulmonary hypertension were independent clinical predictors of mortality. On lung biopsy, severe lung growth abnormality, as judged by degree of alveolar enlargement and simplification of the lobular architecture, was associated with a high mortality (80 percent) [8]. When lung biopsy is performed, proper tissue handling is essential, especially with respect to inflation of the biopsy sample, and expert pathologic review may be required [50].

Other forms of diffuse lung disease presenting in infancy

Pulmonary interstitial glycogenosis — P.I.G., previously known as cellular interstitial pneumonitis of infancy, was originally described in several infants who presented with tachypnea since birth and diffuse infiltrates of unknown etiology [51-55]. Lung biopsy demonstrated interstitial proliferation of bland, nondescript histiocytic type cells and minimal or no inflammation. Electron microscopy demonstrated that these interstitial cells contained monoparticulate glycogen, called "pulmonary interstitial glycogenosis" by the authors [53]. P.I.G. is a histologic finding that typically accompanies abnormal lung development in infants rather than a singular specific diagnosis; the clinical course and management depend on individual patient characteristics, including any underlying and/or concurrent diagnoses.

The severity of the clinical presentation is highly variable and can include neonatal respiratory failure with pulmonary hypertension or more chronic tachypnea and hypoxemia. This histologic finding of P.I.G. virtually always occurs in young infants, typically less than six months of age. Many patients have associated alveolar growth abnormalities (simplification), pulmonary vascular disease, or congenital heart disease [56,57]. After one year of age, ongoing symptoms in patients with P.I.G. are likely related to the associated pulmonary or cardiac disease [57].

Case series have reported that chest radiographs have diffuse infiltrates or hazy opacities [53]. Lung biopsy is the only way to diagnose P.I.G. While historically, P.I.G. was reported as a disorder that rarely occurred as a diffuse isolated histologic entity, it is increasingly identified in a patchy distribution (termed "patchy P.I.G.") in the setting of other pulmonary conditions, most commonly lung growth abnormalities, including pulmonary hypoplasia and chronic neonatal lung disease due to prematurity [8,56]. On chest high-resolution computed tomography (HRCT), typical findings include diffuse or scattered, irregular ground-glass opacities, often with cystic lucencies or architectural distortion if lung growth abnormalities are present [56,58-60]. It is important to acknowledge that there is substantial overlap of radiologic findings in P.I.G. with those reported in other forms of DLD, and imaging findings have not been proven to be specific or sufficient for the diagnosis of P.I.G. The etiology of P.I.G. is unknown, though clearly related to lung development [61].

There is no known definitive therapy. Case reports and case series have suggested possible benefits from high-dose pulse glucocorticoids in some patients, but no controlled studies have been performed [53,56,62,63]. The possible benefits of glucocorticoids should be assessed in the context of the clinical severity and extent of histologic findings and weighed against the potential detrimental impact of glucocorticoids on postnatal alveolarization and neurodevelopment in this patient population. The clinical significance of patchy P.I.G. has been debated, and the role of empiric treatment is even less certain in patients with this histologic pattern [8,63]. When comorbidities such as congenital heart disease or complications of prematurity are present, these problems are often the focus of management. Before performing a trial of glucocorticoids, biopsy confirmation is recommended when feasible. Case reports and series suggest that clinical response is typically observed early, in the first days to months of therapy, if at all. Thus, long-term therapy is generally not advised, given the lack of evidence of P.I.G. in older infants.

The natural history of P.I.G. is not well described. Case series suggest that many patients will remain symptomatic but improve over time in the absence of concurrent disease [56]. In a series of nine infants with isolated P.I.G., all were reported asymptomatic in long-term follow-up (median follow-up 12 years) [64]. However, most had abnormalities on pulmonary function testing (either obstructive or restrictive pattern) and some persistent radiographic abnormalities. The prognosis is substantially worse for infants with P.I.G. accompanied by other comorbidities, which is often the case, including lung growth abnormalities, bronchopulmonary dysplasia, congenital heart disease, or pulmonary hypertension [8,56,63,65].

In our clinical practice, we use the abbreviation "P.I.G." rather than the acronym "PIG," which might have negative connotations to patients and their families. Further, we focus discussion of management and prognosis on the clinical context and any underlying and concurrent diagnoses.

Neuroendocrine cell hyperplasia of infancy — Neuroendocrine cell hyperplasia of infancy (NEHI) is a rare disorder that presents in infants in the first months to year of life with chronic hypoxemia, retractions, and crackles. In patients with typical clinical findings, the diagnosis can be established by chest HRCT, which shows relatively homogeneous ground-glass opacities in the right middle lobe, lingula, and central portions of the lung (image 1). The pulmonary symptoms and hypoxemia tend to improve with time but may persist for years [66,67]. The clinical features, diagnosis, and management of NEHI are discussed in a separate topic review. (See "Neuroendocrine cell hyperplasia of infancy (NEHI)".)

Genetic disorders of surfactant dysfunction — Genetic abnormalities of surfactant function have been described in infants with DLD [68-70]. Before these molecular defects were discovered, infants with these disorders were categorized according to their histopathologic appearance, which can include pulmonary alveolar proteinosis (PAP), chronic pneumonitis of infancy (CPI), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), or nonspecific pulmonary fibrosis [71-74]. These rare disorders may produce familial or sporadic lung disease, with clinical presentations ranging from neonatal respiratory failure to childhood- or adult-onset DLD. An overview of these disorders is presented in the table (table 4). (See "Genetic disorders of surfactant dysfunction".)

Mutations causing surfactant dysfunction should be considered in infants with the following clinical presentations [13,75]:

Severe unexplained lung disease in the newborn period

HRCT imaging showing diffuse disease including ground-glass opacities involving both lungs

Histopathology that demonstrates findings of congenital PAP, CPI, DIP, or NSIP (see 'Implications of histopathologic patterns in childhood DLD' below)

Bronchoscopy findings of PAP in a young child (see "Pulmonary alveolar proteinosis in children")

Electron microscopy demonstrating abnormal or absent lamellar bodies

The genetic defects that cause surfactant dysfunction include mutations in the SFTPB, SFTPC, ABCA3, and NXK2-1/TTF1 genes, as well as RAB5B, which is involved in surfactant processing [76]. Gene deletions have also been reported for the SFTPC, ABCA3, and NKX2-1/TTF1 genes [42,77]. In addition, mutations in the CSF2RA and MARS1 (methionyl-tRNA synthetase) genes cause phenotypes that include PAP [78-80].

DISORDERS NOT SPECIFIC TO INFANCY — Some forms of childhood DLD are similar to disorders seen in adults. The childhood classification system groups these diverse disorders, in large part, according to clinical associations (table 1).

Disorders of the presumed immunocompetent host — This overarching category has been proposed to facilitate classification of a broad collection of disorders that occur in children who are presumed immunocompetent, ie, without a known immunodeficiency or systemic disorder. The pathophysiology of many of these disorders reflects acute and chronic airway injury, including a spectrum of infectious and postinfectious processes, disorders related to environmental agents including hypersensitivity pneumonitis and toxic inhalation, aspiration syndromes, and eosinophilic pneumonia. The category provides a useful organizational framework to approach the differential diagnosis of such cases and is a starting point to facilitate additional testing aimed at establishing a specific diagnosis. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)".)

Bronchiolitis obliterans — Bronchiolitis obliterans (BO) is a DLD phenotype that can result from a large number of both infectious and noninfectious injuries to the lung. The more current classification structure enables BO to be classified in either the "immunocompetent host" or the "immunocompromised host" category, depending on the clinical context.

The predominant cause of BO in children is adenovirus infection [81]. Other infectious causes of BO that have been reported in children include influenza, parainfluenza, measles, respiratory syncytial virus, varicella, and mycoplasma [82]. These are collectively grouped as postinfectious BO.

Noninfectious etiologies of BO in children include connective tissue disease, toxic fume inhalation, chronic hypersensitivity pneumonitis, aspiration, drug reaction, and Stevens-Johnson syndrome [83,84]. BO is also a common complication of lung transplantation, in which it is a manifestation of chronic graft rejection (see "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome"). It is also seen as a complication following hematopoietic stem cell transplantation and is a form of chronic graft versus host disease. (See "Pulmonary complications after autologous hematopoietic cell transplantation" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

Characteristic findings on chest high-resolution computed tomography (HRCT) include mosaic perfusion, air trapping, vascular attenuation, and central bronchiectasis (image 2). These findings may obviate the need for lung biopsy in a compatible clinical context [85,86]. When lung biopsy is performed, histologic features include a spectrum of obliterative bronchiolitis, constrictive bronchiolitis, and cryptogenic organizing pneumonia, with extension of granulation tissue into the alveoli. Because the disease process can be patchy, lung biopsies may not always be diagnostic or reflect the severity of the disease.

Infectious and postinfectious processes — Postinfectious lung inflammation and injury may appear in a myriad of histologic patterns, including bronchiolitis (see 'Bronchiolitis obliterans' above), interstitial pneumonitis, and organizing pneumonia. (See 'Implications of histopathologic patterns in childhood DLD' below.)

Disorders related to environmental agents — This category includes hypersensitivity pneumonitis and toxic inhalations.

Hypersensitivity pneumonitis occurs in children of all ages, as it does in adults. When an environmental exposure is noted, demonstration of serum immunoprecipitations (immunoglobulin G [IgG] antibodies) specific to a species of bird or a particular organic dust can support the diagnosis of hypersensitivity pneumonitis [87,88]. Without this history, screening with a precipitin panel that includes common antigens and environmental contaminants may still be useful, although there are high rates of false-positive and false-negative results with this technology. Skin testing and immunoglobulin E (IgE)-based immunoassays for allergic disease are not helpful in the diagnosis of hypersensitivity pneumonitis. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

Toxicity from inhaled substances also can cause DLD without the typical features of hypersensitivity pneumonitis. Reported triggers include humidifier disinfectant, which was responsible for an epidemic of DLD in Korea in 2006 through 2011 [89,90]; mineral particles; nitric oxide gas; and various industrial exposures. Use of e-cigarettes or vaping products has also been associated with acute or subacute lung injury in some patients. (See "E-cigarette or vaping product use-associated lung injury (EVALI)".)

Aspiration syndromes — Chronic and recurrent aspiration is a common cause of DLD in children and may be caused by either swallowing dysfunction (antegrade aspiration) or gastroesophageal reflux (retrograde aspiration). Infants with tachypnea are particularly prone to swallowing dysfunction, but it can be quite challenging to determine whether aspiration is the primary cause of the lung disease or is a secondary contributor (see "Aspiration due to swallowing dysfunction in children"). Similarly, gastroesophageal reflux is common in children with DLD, occurring in up to 50 percent of cases by clinical reports, but it is often difficult to establish with certainty whether the reflux is causing aspiration and, if so, the degree to which the aspiration is causing or contributing to the lung disease. It is important to remember that increased numbers of lipid-laden macrophages also occur due to abnormalities of surfactant production or clearance, including with surfactant protein or ABCA3 mutations. Lipoid pneumonia caused by aspiration of mineral oil has been reported, usually in children with neurodevelopmental abnormalities or gastroesophageal reflux [91,92]; a similar phenomenon has been reported in an adolescent using lip gloss [93].

Other disorders — Other DLDs that affect the immunocompetent host are categorized by their histopathologic appearance. These include eosinophilic pneumonia, acute interstitial pneumonia (AIP), and nonspecific interstitial pneumonia (NSIP) (see 'Acute interstitial pneumonia' below and 'Nonspecific interstitial pneumonia' below). Eosinophilic pneumonia is a rare disorder characterized by marked accumulation of eosinophils in the interstitium and alveolar spaces of the lung, which usually presents in mid-adulthood but has been reported in children. (See "Chronic eosinophilic pneumonia".)

Disorders of the immunocompromised host — Patients who are immunocompromised because of a known immunodeficiency (eg, common variable immunodeficiency), organ or bone marrow transplantation, or chemotherapy for malignancy are at risk for a spectrum of DLDs, including those caused by infectious processes. In a series of 191 children 2 to 18 years old undergoing lung biopsy for DLD, 41 percent of cases were in immunocompromised children. Immunosuppression was also associated with increased mortality (53 percent), especially in children with pulmonary hypertension [10].

The histologic patterns of follicular bronchiolitis and lymphocytic interstitial pneumonia (LIP) are most commonly seen in children with immunodeficiency states and should prompt aggressive evaluation for underlying immune dysfunction if not already recognized [8,94-96]. Children with immune dysfunction may have signs of systemic lymphoproliferative disease or autoimmune disease. LIP has most commonly been associated with HIV infection, but Epstein-Barr virus and human herpesvirus 6 have also been implicated. Familial cases also have been reported [97,98]. Other reports indicate a good prognosis and apparent absence of underlying systemic disease in children presenting with LIP [99]. LIP in children is discussed in detail separately. (See "Lymphocytic interstitial pneumonia in children".)

A growing number of genetic etiologies are associated with a spectrum of pulmonary disease in children with immunodeficiencies and immune dysfunction, including mutations in the STAT3, GATA2, COPA, and LRBA genes [100-104]. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Genetic testing'.)

Disorders related to systemic disease processes — DLD is a relatively rare but well-recognized feature of connective tissue (rheumatic) disorders in children, and connective tissue disease underlies a prominent proportion of DLD in older children [10,11,105]. DLD has been reported in particular association with systemic lupus erythematosus, polymyositis/dermatomyositis, systemic sclerosis, mixed connective tissue disease, and systemic juvenile idiopathic arthritis. A cellular, fibrotic, or mixed NSIP pattern predominates in children, but patterns of LIP/follicular bronchiolitis, BO, pulmonary alveolar proteinosis (PAP), or alveolar hemorrhage also occur [94,95]. As in adults, mixed compartment patterns seem to suggest underlying connective tissue disease. Because pulmonary disease onset may precede the overt symptoms of the underlying systemic disease, these histologic patterns warrant a diligent search for underlying connective tissue disease. Therapeutic approaches are empirically focused on the systemic disease process, and prognosis is not well established. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Pulmonary' and "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis".)

A variety of metabolic or storage diseases associated with DLD, including Niemann–Pick disease, mucopolysaccharidosis, and glycogen storage disease, are also classified in this category. (See "Overview of Niemann-Pick disease" and "Mucopolysaccharidoses: Complications" and "Overview of inherited disorders of glucose and glycogen metabolism".)

Immune-mediated diseases associated with DLD include pulmonary vasculitis syndromes and antiglomerular basement membrane antibody (Goodpasture) disease, which is characterized by glomerulonephritis and is often accompanied by diffuse alveolar hemorrhage. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis".)

Lung disease associated with systemic juvenile idiopathic arthritis is associated with high morbidity and mortality [106,107]. Presentation may include distinctive acute erythematous clubbing. The histologic spectrum may include a component of alveolar proteinosis or lipoid pneumonia as well as interstitial and vascular pathology.

Dyskeratosis congenita may be associated with pulmonary fibrosis, which has occasionally presented during late childhood or early adolescence [108]. The key feature of the disorder is bone marrow hypoplasia or failure; other common features are reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia (picture 1), with or without hepatic disease, immunodeficiencies, or early hair graying. (See "Dyskeratosis congenita and other telomere biology disorders".)

Disorders masquerading as interstitial disease — Arterial, venous, or lymphatic abnormalities masquerading as DLD by clinical and imaging criteria are known to account for a proportion of cases that come to lung biopsy (approximately 5 percent in one series) [8].

Unclassified — The classification system includes this category to acknowledge that some cases remain unclassifiable for a variety of reasons. In one study, predominant reasons included end-stage disease, nondiagnostic biopsies, and those with inadequate material [8].

IMPLICATIONS OF HISTOPATHOLOGIC PATTERNS IN CHILDHOOD DLD — Certain histopathologic patterns previously described in adults are now known to be associated with specific types of DLD. Thus, identification of these patterns should prompt additional etiologic investigations if not already done. These histopathologic patterns and clinical considerations are described below and summarized in the table (table 3).

Pulmonary alveolar proteinosis — Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of granular, periodic acid-Schiff (PAS)-positive, lipoproteinaceous material within the alveoli. PAP in young children has been associated with genetic disorders of surfactant dysfunction (particularly SFTPB and ABCA3 gene mutations) (see 'Genetic disorders of surfactant dysfunction' above), lysinuric protein intolerance, and mutations in components of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (CSF2RA and CSF2RB genes). In adults and, occasionally, in older children and adolescents, PAP is usually an autoimmune disease, mediated by antibodies to GM-CSF. (See "Pulmonary alveolar proteinosis in children".)

An acquired (secondary) form of PAP can be seen in children or adults in association with infections (eg, mycobacterium tuberculosis or HIV), hematologic malignancies and immune deficiencies, or exposure to inhaled chemicals.

Chronic pneumonitis of infancy — Chronic pneumonitis of infancy (CPI) occurs in term or late preterm infants who appear well initially and then develop tachypnea or other respiratory symptoms and hypoxemia with diffuse interstitial infiltrates on imaging studies [2]. Characteristic pathologic findings include alveolar septal thickening; pneumocyte hyperplasia; and an alveolar exudate containing numerous macrophages, occasional eosinophilic globules, and rare cholesterol clefts [54,109,110]. Although this pattern has been associated with gastroesophageal reflux and lysinuric protein intolerance in the past [55], it is now recognized that CPI largely is a manifestation of genetic abnormalities of surfactant function. Genetic testing should be considered in children with this histologic pattern on lung biopsy. (See "Genetic disorders of surfactant dysfunction".)

Desquamative interstitial pneumonia — Desquamative interstitial pneumonia (DIP) is a histologic pattern that has been previously utilized to describe DLD in children. In contrast with DIP in adults (which is associated with smoking), most cases of DIP in children are caused by an inborn error in surfactant metabolism, including mutations in the SFTPB, SFTPC, and ABCA3 genes. DIP is just one of many histologic expressions of these mutations (others include PAP, CPI, nonspecific interstitial pneumonia [NSIP], and, very rarely, usual interstitial pneumonia [UIP]). (See "Genetic disorders of surfactant dysfunction".)

Acute interstitial pneumonia — Acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome and accelerated interstitial pneumonia, is an acute, severe, and rapidly progressive process with a high fatality rate. Histologically, AIP is identical to the organizing or proliferative stage of diffuse alveolar damage, which is the histologic lesion seen in acute respiratory distress syndrome. It is characterized by an active diffuse interstitial process consisting of multiplying fibroblasts and myofibroblasts within thickened alveolar septae. The histologic features of AIP are described in detail separately. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Acute interstitial pneumonia'.)

Lymphocytic interstitial pneumonia — Lymphocytic interstitial pneumonia (LIP) is a form of pulmonary lymphoproliferative disease and tends to occur in association with autoimmune disease and immunodeficiencies, including HIV. It is characterized by a diffuse infiltrate of mature and immature lymphocytes, plasma cells, and histiocytes in the alveolar septae and pulmonary interstitium (picture 2). A form of LIP, known as granulomatous and lymphocytic interstitial lung disease (GLILD), has been described in patients with certain immunodeficiencies, especially common variable immunodeficiency. LIP and GLILD are discussed in detail separately. (See "Lymphocytic interstitial pneumonia in children" and "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease'.)

Nonspecific interstitial pneumonia — NSIP is the designation for a heterogeneous group of interstitial pneumonias that fit specific histologic parameters. The main change in all cases is an interstitial pneumonitis characterized by expansion of alveolar septae by a variably dense infiltrate of predominantly mononuclear inflammatory cells, with or without associated fibrosis (picture 3) [6]. Although these changes may be patchy or diffuse, they appear to occur over a single time period. The uniformity distinguishes NSIP from UIP [4]. Focal areas of organizing pneumonia, patchy intraalveolar macrophages, lymphoid hyperplasia, and rare focal granulomas also may be seen in NSIP [6]. The histologic features of NSIP are described in detail separately. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Nonspecific interstitial pneumonia'.)

The incidence of NSIP in children is unknown, although it does occur. In one review of 25 lung biopsies in children with interstitial pneumonitis, seven were classified as NSIP [5]. As in adults, the NSIP histologic pattern is often seen in children with immune-mediated disorders and hypersensitivity pneumonitis [6]. An NSIP pattern has also rarely been associated with SFTPC mutations in children and adults [8,111].

Organizing pneumonia — Organizing pneumonia, previously called bronchiolitis obliterans (BO) organizing pneumonia, is a rare type of pediatric lung disease characterized by patchy areas of inflammation and organizing pneumonia with obstruction of airways by intraluminal polyps of fibrous tissue [112]. The characteristic histopathologic lesions include excessive proliferation of granulation tissue within small airways (proliferative bronchiolitis) and alveolar ducts, associated with chronic inflammation in the surrounding alveoli. It can be idiopathic, in which case, it is called cryptogenic organizing pneumonitis [113]. Organizing pneumonia may also occur as a complication of HIV infection [114], other infections, or chemotherapeutic regimens [112]; in association with dermatomyositis and other connective tissue diseases; or during bone marrow transplantation with graft-versus-host disease [115].

Usual interstitial pneumonia — UIP is characterized by an ongoing and progressive process with temporal heterogeneity of interstitial changes within the lung. The histologic hallmark and chief diagnostic criterion is a heterogeneous appearance with alternating areas of normal lung; distinct fibroproliferative lesions termed fibroblastic foci are present, as well as honeycomb change. The histologic features of UIP are described in detail separately. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia'.)

In adults, UIP is the histopathologic pattern of the clinical disease idiopathic pulmonary fibrosis (IPF; also called cryptogenic fibrosing alveolitis), which is associated with a poor prognosis. The histologic pattern of UIP can also be found in secondary types of DLD, such as connective tissue disorders and hypersensitivity pneumonitis. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis".)

For practical purposes, UIP and IPF do not occur in children. One case with UIP histology including fibroblastic foci has been reported in a 15-year-old boy with mutations in the ABCA3 gene, though this case did not have clinical or radiographic features consistent with IPF [116]. However, in prior literature, children reported to have possible UIP have experienced a clinical course different from that of adults with UIP [117-119]. Furthermore, many researchers consider fibroblast foci to be essential to the diagnosis of UIP [4], and this finding is almost never seen in the pediatric age group.

Respiratory bronchiolitis interstitial lung disease — Respiratory bronchiolitis ILD is related to smoking in most cases and, therefore, usually is not seen in children. (See "Respiratory bronchiolitis-associated interstitial lung disease".)

Pleuroparenchymal fibroelastosis — This disorder is now recognized to occur in children, with radiologic and histologic findings that are similar to those of adults. The majority of identified pediatric cases have occurred in children with a history of treatment for cancer or bone marrow transplantation [120]. (See "Nitrosourea-induced pulmonary injury", section on 'Late onset pleuroparenchymal fibroelastosis' and "Cyclophosphamide pulmonary toxicity".)

SUMMARY

Terminology – Diffuse lung disease (DLD), traditionally known as interstitial lung disease (ILD), consists of a diverse group of rare disorders that involve the pulmonary parenchyma and interfere with gas exchange. Because many of these disorders are associated with extensive alteration of alveolar and airway architecture in addition to changes in the interstitial compartment, we prefer the term DLD rather than ILD. (See 'Terminology' above.)

Classification – The classification system for childhood DLD is based on both clinical characteristics and histopathology and recognizes disorders that are only seen in infants or young children. Age at presentation is a key organizing principle, such that disorders more prevalent in infancy are grouped separately from those that are not specific to infancy (table 1). DLD can be further classified by whether it is primarily a pulmonary process or whether it occurs in association with a systemic disorder (table 2). (See 'Classification system' above.)

Disorders more prevalent in infancy – A number of unique forms of DLD have been described in infants and neonates (table 1). These include diffuse developmental lung disorders and alveolar growth abnormalities, pulmonary interstitial glycogenosis (P.I.G.), neuroendocrine cell hyperplasia of infancy (NEHI), and genetic disorders of surfactant dysfunction.

NEHI presents with tachypnea, crackles, and hypoxemia, with hyperinflation and ground-glass opacities in a characteristic distribution on chest high-resolution computed tomography (HRCT). NEHI may be diagnosed based on HRCT and clinical findings in many cases, but lung biopsy is needed in some cases. The symptoms tend to improve with time, though symptoms may persist for months to years. (See "Neuroendocrine cell hyperplasia of infancy (NEHI)".)

Genetic disorders of surfactant dysfunction typically present with neonatal respiratory failure, although they occasionally cause childhood- or adult-onset DLD (table 4). (See "Genetic disorders of surfactant dysfunction".)

Disorders seen in all age groups – Forms of DLD that are not specific to infancy include aspiration syndromes, bronchiolitis obliterans (BO; which may be caused by viral infections, especially adenovirus, as well as noninfectious causes), and hypersensitivity pneumonitis. Immunocompromised hosts are particularly prone to DLD. Similarly, a number of systemic disorders may be associated with DLD, especially connective tissue diseases. Immune deficiencies and connective tissues diseases should be considered during the evaluation of a child with DLD since DLD is occasionally a presenting feature of the systemic disease. (See 'Disorders of the immunocompromised host' above and 'Disorders related to systemic disease processes' above.)

Histopathologic patterns – Some forms of DLD have recognizable histopathologic patterns (table 3). Because each histopathologic pattern has been associated with certain causes of DLD or with underlying systemic disorders, identification of these patterns should prompt a focused evaluation for the underlying disorder. (See 'Implications of histopathologic patterns in childhood DLD' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Cynthia E Epstein, MD, and Leland Fan, MD, who contributed to an earlier version of this topic review.

  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. Vece TJ, Young LR. Update on Diffuse Lung Disease in Children. Chest 2016; 149:836.
  8. 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.
  9. 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.
  10. 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.
  11. Soares JJ, Deutsch GH, Moore PE, et al. Childhood interstitial lung diseases: an 18-year retrospective analysis. Pediatrics 2013; 132:684.
  12. Rice A, Tran-Dang MA, Bush A, Nicholson AG. Diffuse lung disease in infancy and childhood: expanding the chILD classification. Histopathology 2013; 63:743.
  13. Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol 2004; 38:369.
  14. 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.
  15. Fan LL, Langston C. Pediatric interstitial lung disease: children are not small adults. Am J Respir Crit Care Med 2002; 165:1466.
  16. Vincent M, Karolak JA, Deutsch G, et al. Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders. Am J Respir Crit Care Med 2019; 200:1093.
  17. 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.
  18. Melly L, Sebire NJ, Malone M, Nicholson AG. Capillary apposition and density in the diagnosis of alveolar capillary dysplasia. Histopathology 2008; 53:450.
  19. 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.
  20. Shankar V, Haque A, Johnson J, Pietsch J. Late presentation of alveolar capillary dysplasia in an infant. Pediatr Crit Care Med 2006; 7:177.
  21. Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary dysplasia. Am J Respir Crit Care Med 2011; 184:172.
  22. Towe CT, White FV, Grady RM, et al. Infants with Atypical Presentations of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins Who Underwent Bilateral Lung Transplantation. J Pediatr 2018; 194:158.
  23. Jourdan-Voyen L, Touraine R, Masutti JP, et al. Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study. Arch Dis Child Fetal Neonatal Ed 2020; 105:387.
  24. Galambos C, Sims-Lucas S, Ali N, et al. Intrapulmonary vascular shunt pathways in alveolar capillary dysplasia with misalignment of pulmonary veins. Thorax 2015; 70:84.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. Prothro SL, Plosa E, Markham M, et al. Prenatal Diagnosis of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. J Pediatr 2016; 170:317.
  32. Szafranski P, Gambin T, Dharmadhikari AV, et al. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Genet 2016; 135:569.
  33. 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.
  34. 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.
  35. Karolak JA, Liu Q, Xie NG, et al. Highly Sensitive Blocker Displacement Amplification and Droplet Digital PCR Reveal Low-Level Parental FOXF1 Somatic Mosaicism in Families with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. J Mol Diagn 2020; 22:447.
  36. Pradhan A, Dunn A, Ustiyan V, et al. The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia. Am J Respir Crit Care Med 2019; 200:1045.
  37. Karolak JA, Vincent M, Deutsch G, et al. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway. Am J Hum Genet 2019; 104:213.
  38. Rohmann E, Brunner HG, Kayserili H, et al. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet 2006; 38:414.
  39. Entesarian M, Matsson H, Klar J, et al. Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands. Nat Genet 2005; 37:125.
  40. Suhrie K, Pajor NM, Ahlfeld SK, et al. Neonatal Lung Disease Associated with TBX4 Mutations. J Pediatr 2019; 206:286.
  41. Cooney TP, Thurlbeck WM. Pulmonary hypoplasia in Down's syndrome. N Engl J Med 1982; 307:1170.
  42. 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.
  43. 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.
  44. 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.
  45. de Wit MC, Tiddens HA, de Coo IF, Mancini GM. Lung disease in FLNA mutation: confirmatory report. Eur J Med Genet 2011; 54:299.
  46. 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.
  47. Sasaki E, Byrne AT, Phelan E, et al. A review of filamin A mutations and associated interstitial lung disease. Eur J Pediatr 2019; 178:121.
  48. Burrage LC, Guillerman RP, Das S, et al. Lung Transplantation for FLNA-Associated Progressive Lung Disease. J Pediatr 2017; 186:118.
  49. Shelmerdine SC, Semple T, Wallis C, et al. Filamin A (FLNA) mutation-A newcomer to the childhood interstitial lung disease (ChILD) classification. Pediatr Pulmonol 2017; 52:1306.
  50. 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.
  51. Schroeder SA, Shannon DC, Mark EJ. Cellular interstitial pneumonitis in infants. A clinicopathologic study. Chest 1992; 101:1065.
  52. 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.
  53. 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.
  54. 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.
  55. 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.
  56. Liptzin DR, Baker CD, Darst JR, et al. Pulmonary interstitial glycogenosis: Diagnostic evaluation and clinical course. Pediatr Pulmonol 2018; 53:1651.
  57. Liptzin DR, Udoko MN, Pinder M, et al. Pulmonary interstitial glycogenosis after the first year. Pediatr Pulmonol 2021; 56:3056.
  58. Lanfranchi M, Allbery SM, Wheelock L, Perry D. Pulmonary interstitial glycogenosis. Pediatr Radiol 2010; 40:361.
  59. 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.
  60. Weinman JP, White CJ, Liptzin DR, et al. High-resolution CT findings of pulmonary interstitial glycogenosis. Pediatr Radiol 2018; 48:1066.
  61. Deutsch GH, Young LR. Lipofibroblast Phenotype in Pulmonary Interstitial Glycogenosis. Am J Respir Crit Care Med 2016; 193:694.
  62. Deutsch GH, Young LR. Histologic resolution of pulmonary interstitial glycogenosis. Pediatr Dev Pathol 2009; 12:475.
  63. Deutsch GH, Young LR. Pulmonary interstitial glycogenosis: words of caution. Pediatr Radiol 2010; 40:1471.
  64. Sardón O, Torrent-Vernetta A, Rovira-Amigo S, et al. Isolated pulmonary interstitial glycogenosis associated with alveolar growth abnormalities: A long-term follow-up study. Pediatr Pulmonol 2019; 54:837.
  65. Cutz E, Chami R, Dell S, et al. Pulmonary interstitial glycogenosis associated with a spectrum of neonatal pulmonary disorders. Hum Pathol 2017; 68:154.
  66. Deterding RR, Pye C, Fan LL, Langston C. Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia. Pediatr Pulmonol 2005; 40:157.
  67. Nevel RJ, Garnett ET, Schaudies DA, Young LR. Growth trajectories and oxygen use in neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol 2018; 53:656.
  68. 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.
  69. 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.
  70. 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.
  71. Osika E, Muller MH, Boccon-Gibod L, et al. Idiopathic pulmonary fibrosis in infants. Pediatr Pulmonol 1997; 23:49.
  72. Tal A, Maor E, Bar-Ziv J, Gorodischer R. Fatal desquamative interstitial pneumonia in three infants siblings. J Pediatr 1984; 104:873.
  73. Buchino JJ, Keenan WJ, Algren JT, Bove KE. Familial desquamative interstitial pneumonitis occurring in infants. Am J Med Genet Suppl 1987; 3:285.
  74. 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.
  75. Kunig AM, Parker TA, Nogee LM, et al. ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn. J Pediatr 2007; 151:322.
  76. Huang H, Pan J, Spielberg DR, et al. A dominant negative variant of RAB5B disrupts maturation of surfactant protein B and surfactant protein C. Proc Natl Acad Sci U S A 2022; 119.
  77. Henderson LB, Melton K, Wert S, et al. Large ABCA3 and SFTPC deletions resulting in lung disease. Ann Am Thorac Soc 2013; 10:602.
  78. 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.
  79. 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.
  80. Suzuki T, Sakagami T, Rubin BK, et al. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med 2008; 205:2703.
  81. Colom AJ, Teper AM, Vollmer WM, Diette GB. Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis. Thorax 2006; 61:503.
  82. Jerkic SP, Brinkmann F, Calder A, et al. Postinfectious Bronchiolitis Obliterans in Children: Diagnostic Workup and Therapeutic Options: A Workshop Report. Can Respir J 2020; 2020:5852827.
  83. Moonnumakal SP, Fan LL. Bronchiolitis obliterans in children. Curr Opin Pediatr 2008; 20:272.
  84. Kurland G, Michelson P. Bronchiolitis obliterans in children. Pediatr Pulmonol 2005; 39:193.
  85. 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.
  86. Liptzin DR, DeBoer EM, Giller RH, et al. Evaluating for Bronchiolitis Obliterans with Low-Attenuation Computed Tomography Three-Dimensional Reconstructions. Am J Respir Crit Care Med 2018; 197:814.
  87. Griese M, Haug M, Hartl D, et al. Hypersensitivity pneumonitis: lessons for diagnosis and treatment of a rare entity in children. Orphanet J Rare Dis 2013; 8:121.
  88. Zhang F, Yang T, Liu Z, et al. Clinical Features of Hypersensitivity Pneumonitis in Children: A Single Center Study. Front Pediatr 2021; 9:789183.
  89. 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.
  90. 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.
  91. 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.
  92. Bandla HP, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics 1999; 103:E19.
  93. Becton DL, Lowe JE, Falletta JM. Lipoid pneumonia in an adolescent girl secondary to use of lip gloss. J Pediatr 1984; 105:421.
  94. Langston C, Dishop MK. Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Pediatr Dev Pathol 2009; 12:421.
  95. 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.
  96. Prenzel F, Harfst J, Schwerk N, et al. Lymphocytic interstitial pneumonia and follicular bronchiolitis in children: A registry-based case series. Pediatr Pulmonol 2020; 55:909.
  97. Thomas H, Risma KA, Graham TB, et al. A kindred of children with interstitial lung disease. Chest 2007; 132:221.
  98. O'Brodovich HM, Moser MM, Lu L. Familial lymphoid interstitial pneumonia: a long-term follow-up. Pediatrics 1980; 65:523.
  99. Kinane BT, Mansell AL, Zwerdling RG, et al. Follicular bronchitis in the pediatric population. Chest 1993; 104:1183.
  100. 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.
  101. 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.
  102. 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.
  103. 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.
  104. Gothe F, Gehrig J, Rapp CK, et al. Early-onset, fatal interstitial lung disease in STAT3 gain-of-function patients. Pediatr Pulmonol 2021; 56:3934.
  105. Xia J, Jiang G, Jin T, et al. Respiratory symptoms as initial manifestations of interstitial lung disease in clinically amyopathic juvenile dermatomyositis: a case report with literature review. BMC Pediatr 2021; 21:488.
  106. Schulert GS, Yasin S, Carey B, et al. Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease: Characterization and Risk Factors. Arthritis Rheumatol 2019; 71:1943.
  107. Saper VE, Chen G, Deutsch GH, et al. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis 2019; 78:1722.
  108. 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.
  109. Abe K, Kamata N, Okazaki E, et al. Chronic pneumonitis of infancy. Eur Radiol 2002; 12 Suppl 3:S155.
  110. Kavantzas N, Theocharis S, Agapitos E, Davaris P. Chronic pneumonitis of infancy. An autopsy study of 12 cases. Clin Exp Pathol 1999; 47:96.
  111. 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.
  112. 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.
  113. Inoue T, Toyoshima K, Kikui M. Idiopathic bronchiolitis obliterans organizing pneumonia (idiopathic BOOP) in childhood. Pediatr Pulmonol 1996; 22:67.
  114. 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.
  115. 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.
  116. Young LR, Nogee LM, Barnett B, et al. Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest 2008; 134:192.
  117. Zapletal A, Houstĕk J, Samánek M, et al. Lung function in children and adolescents with idiopathic interstitial pulmonary fibrosis. Pediatr Pulmonol 1985; 1:154.
  118. Chetty A, Bhuyan UN, Mitra DK, et al. Cryptogenic fibrosing alveolitis in children. Ann Allergy 1987; 58:336.
  119. 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.
  120. Nguyen HN, Das S, Gazzaneo MC, et al. Clinico-radiologic features of pleuroparenchymal fibroelastosis in children. Pediatr Radiol 2019; 49:1163.
Topic 6381 Version 34.0

References