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

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 [10-14].

●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 [8,15,16].

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 [17].

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 [18].

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 [19-24].

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 [25]. 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 [26].

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 [24,27-34]. 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 [35-37].

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 [38].

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 [39].

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 [40,41]. It is likely that additional genetic mechanisms will be identified in the future [39,42].

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 (BPD): Clinical features and diagnosis") 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 [43]. 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 [44]. 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 [45-49]. 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 [50].

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 [51].

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 [52-56]. 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 [54]. P.I.G. is a histologic finding that typically accompanies abnormal lung development in infants rather than a singular specific diagnosis [57]; 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 [58,59]. After one year of age, ongoing symptoms in patients with P.I.G. are likely related to the associated pulmonary or cardiac disease [59].

Case series have reported that chest radiographs have diffuse infiltrates or hazy opacities [54]. 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 [8,58]. 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 [58,60-62]. 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 [57,63].

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 [54,58,64,65]. 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 [8,65]. 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 [58]. 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) [66]. 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 [8,58,65,67].

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 [68,69]. 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 [70-72]. 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 [73-76]. 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 [15,77]:

●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 [78]. Gene deletions have also been reported for the SFTPC, ABCA3, and NKX2-1/TTF1 genes [44,79]. In addition, mutations in the CSF2RA and MARS1 (methionyl-tRNA synthetase) genes cause phenotypes that include PAP [80-82].

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 [83]. Other infectious causes of BO that have been reported in children include influenza, parainfluenza, measles, respiratory syncytial virus, varicella, and mycoplasma [84]. 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 [85,86]. 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 [87,88]. 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 [89,90]. 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 [91,92]; 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 [93,94]; a similar phenomenon has been reported in an adolescent using lip gloss [95].

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 lymphoid 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 [8,96-98]. Children with immune dysfunction may have signs of systemic lymphoproliferative disease or autoimmune disease. (See 'Lymphoid interstitial pneumonia' below.)

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 [99-103]. (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 [10,11,104]. 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 [96,97]. 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 [105,106]. 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 [107]. 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 human immunodeficiency virus [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 [55,108,109]. Although this pattern has been associated with gastroesophageal reflux and lysinuric protein intolerance in the past [56], 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'.)

Lymphoid interstitial pneumonia — Lymphoid interstitial pneumonia (LIP), also known as lymphocytic interstitial pneumonia, describes a histologic pattern of pulmonary lymphoproliferation on lung biopsy. LIP appears to be part of a spectrum with other lymphoid disorders of the lung, which include follicular bronchiolitis and granulomatous and lymphocytic interstitial lung disease (GLILD). It is probably the result of various pathologic processes rather than a unique disease entity.

●Causes – In children, this pathologic spectrum usually occurs in patients with various forms of immune dysfunction, including [98]:

•Systemic inflammatory diseases – Especially juvenile idiopathic arthritis and Sjögren's disease. (See "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications" and "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis".)

•Acquired immunodeficiencies – HIV infection (sometimes associated with Epstein-Barr virus). In children with perinatally acquired HIV infection, LIP typically presents in the second or third year of life. LIP also has been reported after solid organ transplant. (See "Pediatric HIV infection: Classification, clinical manifestations, and outcome".)

•Inborn errors of immunity – LIP is often associated with primary immunodeficiencies including common variable immunodeficiency [110]. In these patients, the common histologic finding is GLILD [111]. (See "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease' and "Common variable immunodeficiency in children".)

•Monogenic disorders – The combination of LIP or other pulmonary disease and immune dysfunction has been associated with pathogenic variants in STAT3, GATA2, COPA, LRBA, STING1 (TMEM173), and CTLA4 [98-102]. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Genetic testing'.)

●Diagnosis – On lung biopsy, LIP is characterized by a diffuse infiltrate of mature and immature lymphocytes, plasma cells, and histiocytes in the alveolar septae and pulmonary interstitium (picture 2). When evaluating the lung biopsy, it is important to assess for presence of bronchiolitis obliterans, constrictive bronchiolitis, or fibrotic remodeling, which may have implications for treatment approach.

●Management – Children with LIP or GLILD should be carefully evaluated for an underlying immunodeficiency or autoimmune disease (outlined above). If one of these is identified, the first step is to optimize treatment for that disorder. For children with apparent idiopathic LIP, treatment decisions are based on clinical severity, evidence of disease progression, and considerations of risks versus benefits. A time-limited treatment trial of corticosteroids, typically of three months' duration, should be followed by objective reassessments of oxygenation, pulmonary function, exercise tolerance, and radiologic imaging.

LIP in adults and GLILD are discussed in detail separately. (See "Lymphoid interstitial pneumonia" 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 [8,112].

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 [113]. 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 [114]. Organizing pneumonia may also occur as a complication of HIV infection [115], other infections, or chemotherapeutic regimens [113]; in association with dermatomyositis and other connective tissue diseases; or during bone marrow transplantation with graft-versus-host disease [116].

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 [117]. However, in prior literature, children reported to have possible UIP have experienced a clinical course different from that of adults with UIP [118-120]. 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 [121]. (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.