Childhood Interstitial Lung Disease (ChILD)

Childhood ILD is not a single disease but a large and diverse group of disorders. Because most chILD entities present in a similar way, chILD syndrome has come to be defined in terms of clinical presentation (respiratory signs and symptoms; diffuse radiographic abnormalities, with or without hypoxemia, in the absence of other causes of diffuse lung disease, such as cystic fibrosis, aspiration, infection, and immunodeficiency). ^[1]

The classification and prevalence of different chILD entities differ between younger (aged 0-2 years) and older (aged 2-18 years) patients. ^{[1, 2]}  Thus, it is impossible to define pathophysiologic features that are shared across all the chILD disorders.

In general, one can think of ILD as structural remodeling of the tissues separating the distal airspaces (alveoli), leading to impaired gas exchange. Interstitial remodeling in chILD can result from a developmental abnormality or from genetic variants that cause cellular stress, leading to spontaneous remodeling or aberrant remodeling in response to injury. Remodeling may also result from particular types of injury, infection, inflammation, or immune dysregulation.

However, some diseases classified as chILD (most notably neuroendocrine cell hyperplasia of infancy [NEHI]) have little to no detectable remodeling, yet nonetheless manifest as respiratory signs and symptoms and impaired gas exchange. In this section, we will briefly discuss some pathophysiologic paradigms seen in numerous disorders classified as chILD.

Understanding the pathophysiology of chILD has been hampered by the rarity of most of the disorders and the lack of animal models in which to study mechanisms and possible treatments. With the rapid developments in regenerative medicine, next-generation genetic sequencing, genetic animal models, and gene-editing approaches, the biomedical research community is poised to make significant advancements in understanding and treating rare diseases.

Disordered lung growth and development

Alveolar development is a complex process that involves growth, differentiation, and interaction of multiple cell types within a complex geospatial orientation; this process is affected by thoracic volume, mechanical forces, and genetic and epigenetic programming. Alveoli begin to develop in the third trimester of fetal life and continue to develop into late adolescence/young adulthood.

Several entities classified within chILD syndrome are caused by abnormal growth and development of the alveolar structures, including diffuse developmental abnormalities, such as alveolar capillary dysplasia (ACD), and lung growth abnormalities, such as alveolar hypoplasia. The latter is the most prevalent abnormality in younger (aged 0-3 years) children with chILD syndrome, accounting for up to one third of cases, and is often associated with chromosomal abnormalities, such as trisomy 21, and with congenital heart defects.

Bronchopulmonary dysplasia (BPD) is a well-recognized type of lung growth abnormality.

Pulmonary interstitial glycogenosis (PIG) is a condition unique to infancy, which is characterized by the accumulation of abnormal glycogen-rich mesenchymal cells in the alveolar interstitial space. PIG can occur as an isolated entity, which is very rare, or as is more often the case, in association with lung growth abnormality, pulmonary hypertension, or congenital heart disease. ^[3] Because it occurs during a period of rapid alveolar development, generally resolves over time, and is associated with other abnormalities of lung development, PIG is considered a developmental abnormality.

Congenital pulmonary airway malformations (CPAMs) are also disorders of lung growth and development, but because they are typically localized and have a distinct clinical presentation and radiographic appearance, they are not usually classified as interstitial lung diseases.

NEHI is another entity restricted to infancy and childhood that resolves without specific treatment; thus, it is considered a developmental disorder. It is usually classified as a chILD because of its clinical presentation, although typical NEHI is not associated with structural remodeling or abnormality of the interstitium. Rather, excessive numbers of pulmonary neuroendocrine cells (PNECs) and neuroendocrine bodies (NEBs) are present in the distal airways. How this histologic abnormality leads to the observed clinical syndrome of tachypnea, hypoxemia, and crackles characteristic of NEHI is unknown.

Familial NEHI has been associated with a sequence variant of the NKX2.1 gene, although this finding has not been reported in sporadic NEHI. ^[4] In a few reported cases, PIG in infants has been associated with the excessive numbers of PNECs characteristic of NEHI, usually with other histopathologic abnormalities; this association further supports the idea that these disorders are developmental abnormalities. ^[3]

Alveolar lipoproteinosis

Accumulation of excessive surfactant in the alveolar airspaces can occur in a broad range of congenital and acquired conditions. ^[5]  Pulmonary alveolar proteinosis (PAP) is not a specific diagnosis, but a clinical syndrome. In many of the disorders classified as chILD, alveolar proteinosis is a prominent feature of the histopathology, especially in infants.

Pathologic variants of the surfactant-associated genes SFTPB, SFTPC, ABCA3, and NKX2.1 often are associated with alveolar lipoproteinosis with varying degrees of cellular derangements and interstitial remodeling. Other rare chILD entities (eg, MARS mutations, Niemann-Pick disease) have prominent alveolar proteinosis, as do many types of immunodeficiency and immune dysregulation–associated ILDs. Accumulated proteinaceous material in the airspaces, either from excessive surfactant production or from macrophage dysfunction, causes impaired gas exchange and diffuse radiographic abnormalities.

Immune dysregulation

Immunodeficiency syndromes, autoimmune disorders, and other forms of immune dysregulation (eg, those associated with malignancy or immunosuppressive therapies) account for a large proportion of chILD diagnoses, particularly in childhood and adolescence, although they can occur in infancy as well. The spectrum of pathophysiologic mechanisms for immunodeficiency-related lung disease is broad and includes chronic infection, granulomatous disease, numerous patterns of interstitial remodeling, lymphoproliferative disorders, and malignancy. ^{[6, 7]}  

Hereditary autoinflammatory disorders are characterized by bouts of mainly interleukin-1–driven systemic inflammation with various patterns of tissue and organ involvement. ILD can be prominent, severe, and progressive in a few of these disorders, most notably in STING (stimulator of interferon genes)-associated vasculopathy with onset in infancy (SAVI), which is caused by gain-of-function mutations in the TMEM173 gene that encodes the STING protein. ^[8]

Numerous patterns of lung disease are associated with autoimmune (collagen-vascular) diseases. ^[9]  Follicular bronchiolitis, lymphocytic interstitial pneumonia (LIP), cryptogenic organizing pneumonia (COP), and nonspecific interstitial pneumonia (NSIP) are patterns associated with immune-mediated lung disease, but other patterns can be seen, such as alveolar proteinosis (eg, in association with systemic juvenile inflammatory arthritis) and alveolar hemorrhage (eg, in COPA syndrome, an autosomal dominant disorder associated with mutations in the COPA gene, with both immunodeficiency and autoinflammatory features). ^[10] Granulomatous-lymphocytic interstitial lung disease (GLILD) is the consensus pattern of lung disease associated with common variable immunodeficiency disorders. ^[11]

Airway remodeling

Most diseases that feature chronic airway remodeling (eg, asthma, bronchiectasis) are clinically distinct from chILD; however, diffuse lung diseases with prominent airway involvement, such as post-infectious bronchiolitis obliterans, can be difficult to distinguish from chILD, and conditions with overlapping airway and interstitial involvement, such as lung involvement associated with immunodeficiencies, can manifest with both bronchiectasis and interstitial remodeling. Although NEHI does not manifest as tissue remodeling per se, the observed pathologic alteration (increase in neuroendocrine cells) occurs in the airways.

Interstitial remodeling

Many types of ILD follow an injury to or dysfunction of cells in the distal airspaces. The initial "insult" may be intrinsic, as in surfactant-associated genetic disorders, or extrinsic and overt, as in the alveolar remodeling that follows acute lung injury. In many forms of chILD (eg, PIG), the inciting cellular or molecular "event" and the subsequent steps to remodeling are unknown.

Much of the interstitial remodeling in different forms of ILD is thought to recapitulate wound healing. The lung has a remarkable capacity to heal and recover following many types of injury (eg, bacterial pneumonia). In ILD, the “wound healing” events are persistent, excessive, or inappropriate, resulting in anatomic abnormalities (blocked airways, collapsed alveoli, excessive extracellular matrix, and cells between the airspaces and the capillaries) that cause physiologic dysfunction, which manifests as signs and symptoms.

Inflammation is present in many types of ILD, and many ILDs are triggered by inflammatory events, such as infection or hypersensitivity. Neutrophils and lymphocytes are prominent in bronchoalveolar lavage (BAL) samples in many types of ILD.

In so-called desquamative interstitial pneumonia (DIP), a pattern seen in some infantile presentations of surfactant-associated disorders, the airspaces are filled with cells that were initially believed to be desquamated epithelium but which are, in fact, activated macrophages. The mediators released by inflammatory cells, particularly interleukin-1 and transforming growth factor (TGF)-beta, are potent activators of fibroblast-mediated remodeling. Almost every type of inflammatory cell, including eosinophils and mast cells, has been described in various forms of ILD and can interact with fibroblasts and other parenchymal cells.

Interstitial remodeling can take many forms that result in different histopathologic patterns. Note that the histopathology findings, even though they may fit into a recognizable pattern, are usually not diagnoses in and of themselves (except in cases such as NEHI and some forms of bronchiolitis obliterans); however, certain patterns of remodeling may suggest etiologies or diagnostic categories. It is critically important to have lung biopsies in suspected chILD reviewed by pathologists experienced with these disorders, as subtle differences may provide valuable diagnostic clues.

Fibrosis

Fibrosis is defined as the deposition of cross-linked collagen by activated fibroblasts that results in architectural distortion, mechanical stiffness, and tissue/organ dysfunction. Fibrosis can be the end result of many types of interstitial lung remodeling and can lead to organ failure that requires long-term ventilatory support, transplantation, or death. However, it is important to understand that “ILD” is not synonymous with fibrosis and that fibrosis is not present in many (if not most) forms of chILD.

Wound healing and fibrosis are complex pathophysiologic processes that involve numerous cell types and cellular processes, such as adhesion; migration; proliferation; apoptosis; and a vast array of soluble mediators, extracellular matrix (ECM) molecules, and signaling intermediates. Detailed discussion of the pathophysiology of lung fibrosis can be found in several excellent reviews. ^{[12, 13, 14]} In chILD, these processes occur in an organ that is still developing, further complicating the pathophysiology.

Fibrotic remodeling is responsible for most of the morbidity and mortality associated with ILD. Remodeling of distal airspaces results in hypoxemia. Persistent hypoxemia causes pulmonary hypertension and vascular remodeling, leading to cor pulmonale. The increased work of breathing associated with reduced compliance raises energy expenditure, which, combined with the effects of inflammatory mediators, can result in cachexia. Portions of the lung may be replaced by fibrotic septa between dilated airspaces, the so-called honeycomb changes of end-stage interstitial disease.

Much of what is understood about the pathophysiology of fibrosis is derived from studies of idiopathic pulmonary fibrosis (IPF) characterized by usual interstitial pneumonia (UIP), which does not occur in children, with extremely rare exceptions. Animal studies have been carried out primarily using bleomycin-induced lung fibrosis in rodents, which spontaneously resolves and perhaps best recapitulates fibrosis following acute lung injury. The degree to which the biological paradigms derived from IPF and current animal models apply to chILD remains unclear.

Resolution of fibrotic remodeling involves a complex series of orderly steps, including matrix breakdown and restructuring, re-epithelialization, and apoptosis of fibroblasts and inflammatory cells. In most cases, the fibrosis is progressive and is thought to be irreversible.

The field of adult ILD has been energized in the past decade by the adoption of new antifibrotic therapies (eg, pirfenidone and nintedanib), which slow the progression of fibrosis. These agents have been tested primarily in IPF/UIP, which occurs almost exclusively in adults. Whether these antifibrotic agents will have a role in any chILDs remains to be seen and will require careful and complex clinical studies.

ILD in children can be classified in many ways. ^[15]  In several clinical series, the diagnosis remained undetermined in approximately 25% of cases. ^{[16, 17]}  Several important non-chILD disorders present with chronic respiratory symptoms and findings of diffuse radiographic infiltrates and must be considered in the differential diagnosis. ILD can also be classified based on histopathologic findings (see ILD classification systems below).

Classification systems vary internationally; however, a clinical classification of chILD is listed below. ^{[18, 19, 20, 21, 22, 23, 24]}

Diffuse developmental disorders

Diffuse developmental disorders include the following:

• Acinar dysplasia
• Congenital alveolar dysplasia
• Alveolar-capillary dysplasia with pulmonary vein misalignment

Lung growth abnormalities

Lung growth abnormalities are listed below:

• Pulmonary hypoplasia
• Chronic neonatal lung disease ( bronchopulmonary dysplasia [BPD])
• Associated with chromosomal disorders (ie, trisomy 21)
• Associated with congenital heart disease

Surfactant dysfunction mutations and related disorders

Surfactant dysfunction mutations and related disorders include the following:

• Mutations in  SFTPB, SFTPC, ABCA3, NKX2.1/TTF1, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor
• Histology consistent with surfactant dysfunction disorder but without recognized genetic etiology

Disorders related to systemic disease processes

Disorders related to systemic disease processes are listed below:

• Autoimmune-related and connective tissue disease–related disorders ( systemic lupus erythematosus [SLE],  polymyositis/ dermatomyositis, systemic sclerosis,  sarcoidosis,  mixed connective tissue disease)
• Pulmonary vasculitis ( polyarteritis nodosa, Wegener granulomatosis,  Churg-Strauss syndrome)
• Storage diseases ( Gaucher disease, Niemann-Pick disease)
• Metabolic disorders
• Langerhans cell histiocytosis
• Malignant infiltrates (lymphoma, leukemia)
• Liver disease (chronic active hepatitis,  primary biliary cirrhosis)
• Bowel disease ( ulcerative colitis,  Crohn disease)
• Amyloidosis
• Neurocutaneous disorders ( tuberous sclerosis, neurofibromatosis, ataxia-telangiectasia)
• Lymphoproliferative disorders

Disorders with other known causes

Disorders with other known causes include the following:

• Infection

  • Viral infection (eg, adenoviral or other post-infectious bronchiolitis obliterans, cytomegalovirus [CMV] infection, infection with Epstein-Barr virus [EBV])
  • Bacterial infection (eg, pertussis or infection due to Legionella, Mycoplasma, Chlamydia, or Mycobacteriumspecies)
  • Fungal infection (eg, infection due to Histoplasma, Aspergillus, or Pneumocystisspecies)
  • Parasitic infection (eg, visceral larva migrans)
• Environmental conditions

  • Exposure to organic dusts (hypersensitivity pneumonitis)
  • Exposure to inorganic particulates (eg, silica, asbestos, talc, zinc)
  • Exposure to chemical fumes (eg, sulfuric acid, hydrochloric acid, methyl isocyanate)
  • Exposure to gases (eg, oxygen, chlorine, nitrogen dioxide [silo-filler disease], ammonia)
  • Exposure to radiation
• Drugs

  • Use of antineoplastic agents (eg, cyclophosphamide, nitrosoureas, methotrexate, azathioprine, cytosine arabinoside, 6-mercaptopurine, vinblastine, bleomycin, busulfan)
  • Use of other drugs or elements (eg, penicillamine, nitrofurantoin, gold)
• Post-transplantation/rejection syndromes
• Chronic aspiration pneumonitis
• Resolving acute respiratory distress syndrome (ARDS)
• Degenerative disorders (eg, pulmonary microlithiasis)
• Immunodeficiency-associated ILD

  • COPA syndrome (mutation in the COPA gene encoding COPα protein)
• Autoinflammatory disorder–associated ILD

  • STING (stimulator of interferon genes)-associated vasculopathy with onset in infancy (SAVI)
• Immunodeficiency-related opportunistic infections
• DNA repair defects
• Other genetic/familial disorders

  • Familial hypocalciuric hypercalcemia
  • Lysinuric protein intolerance
  • Farber lipogranulomatosis
  • Hermansky-Pudlak syndrome
  • Filamin A (FLNA) mutation
  • Pulmonary alveolar proteinosis (PAP) with known genetic associations, such as methionyl-tRNA synthetase (MARS) mutations

Disorders of uncertain etiology

Disorders of uncertain etiology are listed below:

• Neuroendocrine cell hyperplasia of infancy (NEHI)
• Pulmonary interstitial glycogenosis (PIG)
• Pulmonary alveolar proteinosis (PAP)
• Other pulmonary hemorrhage syndromes ( idiopathic pulmonary hemosiderosis, capillaritis)
• Lymphocytic interstitial pneumonitis (LIP; known acquired immunodeficiency syndrome [AIDS] cases are excluded; LIP is often associated with human immunodeficiency virus [HIV] infection or AIDS but can be idiopathic)
• Lymphangiomatosis
• Bronchiolitis obliterans
• Bronchocentric granulomatosis
• Nonspecific interstitial pneumonia (this pattern has been shown to correlate with surfactant dysfunction mutations, such as ABCA3 deficiency, in older children ^[25] )
• Acute interstitial pneumonitis (AIP)
• Unclassified/undetermined: conditions that do not clearly fit into a specific category (ie, end-stage disease, inadequate or nondiagnostic biopsy specimen)

Disorders with presenting features similar to those of ILD

Disorders with presenting features similar to those of ILD include the following:

• Pulmonary veno-occlusive disorders ( anomalous pulmonary venous return, pulmonary hemangiomatosis, hereditary hemorrhagic telangiectasia, pulmonary venous stenosis/atresia)
• Heart disease (left ventricular failure, left-to-right shunts)
• Cystic fibrosis
• Primary ciliary dyskinesia
• Lymphatic disorders

Overall, ILD is rare in children, and individual ILDs are extremely rare. Because of the different approaches to case ascertainment and definition, determining the incidence and prevalence of ILDs is difficult. In a systematic review of the literature, the incidence of chILD was estimated at 0.13-16.2 cases per 100,000 children per year. ^[26]

United States data

Most of the literature is composed of case reports and small series. One of the first relatively large series was a combined retrospective and prospective study by Fan et al performed over a 15-year period at a leading referral center for ILD. ^[27] The study included 99 patients, in whom the case definition included respiratory symptoms lasting longer than 1 month, diffuse infiltrates depicted on chest radiography, and the absence of known bronchopulmonary dysplasia (BPD), heart disease, malignancy, immunodeficiency, autoimmunity, cystic fibrosis (CF), aspiration, or acquired immunodeficiency syndrome (AIDS).

A retrospective study that attempted a relatively complete case ascertainment of children undergoing biopsy for ILD in 11 referral centers in the United States and Canada over a 5-year period reported 187 cases in children younger than 2 years old. ^[1]  Fan et al expanded this case ascertainment in a study of children aged 2-18 years undergoing lung biopsies over a 4-year period at 12 centers across North America; the completed study reported 191 cases of chILD. ^[28]  In a single-center study, chILD cases were retrospectively reviewed and classified according to the classification system used by Fan et al; 93 cases were identified and 91% were classifiable. ^[29]

The National Registry for Childhood Interstitial and Diffuse Lung Diseases was created in the United States to improve the understanding of chILDs. ^[30]

International data

A national survey of cases of chronic ILD in immunocompetent children aged 0-16 years in the United Kingdom and Ireland over a 3-year period yielded an estimated prevalence of 3.6 per million. ^[31]  Griese et al used data from the Surveillance Unit for Rare Paediatric Disorders to determine that the incidence of chILD in Germany is 1.32 new cases per 1 million children per year. ^[18]

In Europe, an international registry enrolled 575 patients over a 3-year period; the distribution of some of the diagnostic categories was as follows ^[32] :

• Diffuse developmental disorders, 2.6%
• Growth abnormalities, 6.4%
• Other diagnoses in infancy (eg, NEHI, PIG), 18.5%
• Surfactant dysfunction, 22.3%
• Respiratory distress syndrome in a mature or almost mature neonate, 4%
• Diffuse parenchymal lung disease (DPLD) related to systemic disease, 15.6%
• Exposure-related DPLD in an immune intact host, 13.3%
• DPLD in an immunocompromised host, 4.3%
• DPLD related to lung vessels, 4.6%; reactive lymphoid lesions, 1.2%; and airway disorders, 3.5%

A study from Australia and New Zealand of patients aged 0-18 years with a diagnosis of chILD gathered questionnaire data from clinical providers and data from reference genetics laboratories; the investigators calculated the prevalence at 1.5 cases per million. ^[33]

Sex- and age-related demographics

There appears to be a slight male predominance (53-60%) in reported cases of chILD. This male predominance is found primarily in cohorts of children younger than 2 years; the male:female ratio is close to 50:50 in the diagnoses that cluster in the older ages. ^{[1, 28, 32, 33]}

ILD can present at any age from birth to adulthood. Some diagnoses cluster in infancy, such as NEHI and PIG, while other forms of chILD present throughout childhood and adolescence. A lung biopsy review of 378 chILD cases in children aged 0-2 years versus those aged 2-18 years demonstrated significant differences in the distribution and spectrum of diseases based on age. ^[28]  A European task force described 185 cases of ILDs in immunocompetent children; they demonstrated a significant clustering of cases among children younger than 2 years. ^[19]  In an 18-year retrospective review of 93 cases identified at a single institution, the median age at diagnosis was 90 months. ^[29]

The prognosis for patients with chILD is dependent on the specific diagnosis. Disorders such as NEHI improve over time with no reported mortality, whereas SFTPB mutation and alveolar-capillary dysplasia with pulmonary vein misalignment have high early mortality rates. Increased mortality has also been reported in patients with pulmonary hypertension, in whom the risk of death is up to 7 times higher than in children with ILD who do not have pulmonary hypertension. ^{[27, 34]}

Morbidity/mortality

The same factors that make estimating the incidence of ILD difficult (ie, the different approaches to case ascertainment and definition) make estimating its mortality rates difficult. In cohorts with chILD diagnoses, the reported mortality ranged from 7% to 13%. ^{[18, 33]}

In a series of 99 patients, the probability of surviving 24, 48, or 60 months was 83%, 72%, and 64%, respectively. ^[1]  The mean survival interval from onset in this group of patients was 47 months. In a study from Germany (which collected incident cases between 2005 and 2006), the reported survival was 87% at the end of a 2-year observation period. ^[18]  In a study from Australia and New Zealand, the mortality rate was 7% in cases between 2003 and 2013. ^[33]

In general, an accurate definitive diagnosis should be pursued before attempting to predict associated morbidity or mortality. Certain specific histologic diagnoses in newborns adversely influence prognosis; these include diffuse developmental disorders and patterns associated with certain surfactant protein mutations. Without lung transplantation, the prognosis for most of these conditions is poor. ^[1]  However, for other types of ILD, such as NEHI, significant morbidity but no mortality has been reported.

Complications

Superinfection can be life-threatening, particularly if the patient is receiving immunosuppressive medications, which can mask signs and symptoms of infection. Prevention and careful monitoring are crucial.

Drug toxicity causes much of the morbidity associated with ILD. Again, prevention and monitoring are the keys to management.

Hemoptysis may occur in some types of ILD and suggests vasculitis or veno-occlusive disease as possible underlying causes.

Death is usually the result of respiratory failure or cor pulmonale and right heart failure.

Stress the importance of compliance with medication and nutritional regimens, rehabilitation, and regular follow-up visits.

Carefully instruct patients and parents about the need to report possible adverse effects of medications and to monitor for signs and symptoms of superinfection.

Counsel patients and caregivers of patients with hypersensitivity pneumonitis to avoid precipitating exposures.

Strongly advise smoking cessation and prevention, and inform patients and caregivers about specific support programs.

Caregivers and patients should receive education and counseling appropriate for families of children with chronic respiratory diseases, including financial counseling and transplantation preparedness. Encourage involvement in support groups for rare disorders such as the Children’s Interstitial Lung Disease (chILD) Foundation.