Childhood Interstitial Lung Disease (ChILD) 

Updated: Feb 21, 2020
Author: Rebekah J Nevel, MD; Chief Editor: Girish D Sharma, MD, FCCP, FAAP 

Overview

Practice Essentials

Interstitial lung diseases (ILDs) in childhood are a diverse group of conditions that primarily involve the alveoli and perialveolar tissues, leading to derangement of gas exchange and diffuse infiltrates on radiographs. Because ILDs can involve the distal airspaces as well as the interstitium, the terms diffuse lung disease or diffuse infiltrative lung disease have been suggested. Although this nomenclature may be more accurate than ILD, childhood interstitial lung disease (chILD) has become the preferred term.

Important differences between ILD in children and ILD in adults include nomenclature, pathophysiology, classification, and management. In addition, the clinical significance of the histologic classification differs significantly between children and adults. Examples include desquamative interstitial pneumonitis (DIP), which is associated with steroid responsiveness and a better prognosis in adults, yet has a poor prognosis in infants and children, and pulmonary interstitial glycogenesis (PIG), which is a histologic pattern unique to pediatrics.[1]

Diagnosis

Considerations that influence the diagnostic approach to chILD include the following:

  • Age at presentation
  • Immunocompetence
  • Chronicity
  • Severity of disease
  • Duration of illness
  • Family history
  • Trend toward improvement

Some types of chILD may be diagnosed on the basis of genetic testing, and laboratory studies may provide clues for others, particularly in association with systemic disorders. For example, peripheral eosinophilia suggests parasitic disease, hypersensitivity, eosinophilic syndromes, or other immune dysfunction.

Chest computed tomography (CT) scanning, specifically high-resolution CT (HRCT), provides a noninvasive means for determining the patterns, extent, and distribution of changes associated with ILD. The imaging appearance of diffuse abnormalities varies by specific chILD diagnosis; findings include ground-glass attenuation, a tree-in-bud appearance, lobular air trapping, reticular attenuations, and centrilobular nodules.CT is especially useful in demarcating areas for tissue biopsy.

Most forms of chILD require surgical lung biopsy for definitive diagnosis. Histologic findings on routine hematoxylin and eosin staining remain the criterion standard for the diagnosis and classification of many types of ILD.

Treatment

Management of ILD in children differs from that in adults. Correct diagnosis is critical and requires a comprehensive search for possible underlying causes. Case reports that describe unique presentations and anecdotal responses to various therapeutic interventions abound. Definitive management of ILDs, particularly those of unknown etiology, is unclear at present. A growing national research network and the development of chILD registries in the United States, Europe, and elsewhere may facilitate the use of standardized diagnostic criteria, provide critical data on natural history, and create an infrastructure for clinical trials.

The heterogeneity of disease etiology and the lack of randomized clinical trials make offering specific recommendations regarding the treatment of chILD impossible. If the process is secondary to an underlying condition, patients should be treated for the underlying disease.

General recommendations include supportive care with nutritional, oxygen, and ventilator support as needed. Management of comorbid conditions, including atopic phenotypes, sleep apnea, dysphagia, and aspiration, is encouraged. More specific systemic disease treatments, such as immunomodulatory and immunosuppressive medications, are appropriate in patients with chILD related to vasculitis and connective tissue diseases.

The same principles that apply to all children with chronic pulmonary diseases apply to those with ILD. These include the following:

  • Meticulous attention to growth and nutrition
  • Immunizations (including respiratory syncytial virus [RSV], influenza, and pneumococcal prophylaxis)
  • Treatment of secondary infections

Pathophysiology

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.

Etiology

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:

Disorders with other known causes

Disorders with other known causes include the following:

Disorders of uncertain etiology

Disorders of uncertain etiology are listed below:

  • Neuroendocrine cell hyperplasia of infancy (NEHI)
  • Pulmonary interstitial glycogenosis (PIG)
  • 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
  • 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:

Epidemiology

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]

Prognosis

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.

 

Patient Education

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.

 

 

Presentation

History

Diagnosing childhood interstitial lung disease (chILD) requires a high index of suspicion. The delay between the onset of symptoms and the ultimate diagnosis is often months to years. Respiratory symptoms can be subtle in infants and children, and clinicians often treat ILD as asthma. A delay in referral can lead to clinically significant remodeling of the lung before diagnosis.

A clinical practice guideline from the American Thoracic Society outlines the classification, evaluation, and management of chILD.[20] Another guideline, which was published through the chILD-European Union (EU) Collaboration, includes diagnosis and treatment for chILD.[21]

The clinical history varies substantially by age. The onset of disease is often insidious, with caregivers or patients unsure when the illness actually began. Occasionally, patients present with relatively few symptoms but with abnormal findings on chest radiographs or pulmonary function tests (PFTs). Some patients, especially newborns with surfactant-dysfunction mutations, may present with respiratory failure.

The European Respiratory Task Force cohort of 185 patients with chILD reported the following symptoms[19] :

  • Tachypnea and dyspnea are common. Tachypnea is present in most patients (76%), particularly infants. Younger infants manifest retractions, difficulty in feeding, and diaphoresis with feeding; cyanosis may be evident during feeding or at rest. Exercise intolerance is often noted in older children.

  • A dry, nonproductive cough is frequently reported (78%) and can be the only symptom of interstitial lung disease (ILD), even in the newborn.

  • Failure to thrive and weight loss are common symptoms (37% overall, 62% in children aged < 2 years), which may result from anorexia, difficulty in feeding, and increased energy expenditure from the increased work of breathing.

  • Hemoptysis may indicate a vasculitic process or a pulmonary hemorrhage syndrome.

  • Chest pain has been reported in older children.

  • Fever may be present (20%), which suggests infectious or inflammatory causes.

  • Wheezing occurs in approximately 20% of patients.

A careful family history is critical because some forms of chILD may have a genetic basis, which may be associated with neonatal deaths, unexplained childhood respiratory disease, or ILD in adults.

Physical Examination

General physical findings include the following:

  • Growth retardation, signs of weight loss, and failure to thrive
  • Hypoxemia on room air
  • Desaturation during sleep, during feeding (infants), or with exercise (eg, 6-minute walk test in older children and adolescents)

Auscultation may reveal normal findings or dry crackles that sound like Velcro being pulled apart; these are present in only a subset of patients (44%).[35]

Deformity of the chest has been reported and may indicate lung hypoplasia, as well the effects of prolonged illness. A study of 9 children with ABCA3 deficiency reported pectus excavatum as a frequent finding.[25]  Signs of hyperinflation, such as increased chest diameter, or a palpable liver and spleen may be evident.

Signs consistent with pulmonary hypertension may be present. Examples include an active precordium, which signifies right ventricular hypertrophy, and a loud pulmonary component to the second heart sound.

Cyanosis occurs in 28% of patients. Clubbing is a late manifestation of ILD, which is evident in 13% of patients.[35]

Stigmata of collagen vascular diseases, vasculitides, and other systemic disorders should be carefully sought.

 

DDx

 

Workup

Laboratory Studies

General diagnostic approach

The process and pace of evaluation depend on several factors, and no single algorithm applies to the diverse clinical settings in which interstitial lung disease (ILD) can occur. Considerations influencing the diagnostic approach include age at presentation, immunocompetence, chronicity, severity of disease, duration of illness, family history, and trend toward improvement. For example, the full-term newborn with respiratory failure is approached differently from the young child with tachypnea of insidious onset and hypoxemia with feeding or sleep.

As outlined below, some types of ILD may be diagnosed on the basis of genetic testing, and laboratory studies may provide clues for others, particularly in association with systemic disorders. Chest CT patterns may suggest certain diagnoses, although most forms of ILD require surgical lung biopsy for definitive diagnosis.

The following laboratory studies may be included in the workup:

  • Complete blood cell (CBC) count and differential: Anemia and reticulocytosis are seen in pulmonary hemorrhage. Polycythemia may be seen in chronic hypoxia. Peripheral eosinophilia suggests parasitic disease, hypersensitivity, eosinophilic syndromes, or other immune dysfunction.

  • Urinalysis may indicate coincident glomerulonephritis in patients with pulmonary-renal syndromes.

  • Stool Hemoccult results may be positive in patients with idiopathic pulmonary hemorrhage, celiac disease, or inflammatory bowel disease.

  • Sweat chloride test and cystic fibrosis (CF) genotyping may be required to exclude CF.

  • Serologic testing for Mycoplasma pneumoniae may be used.

  • Fungal serologic testing may be used.

  • Respiratory viral studies may be used.

  • Markers of inflammation, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, may be elevated in inflammatory disorders.

Workup for immunodeficiency

The workup for immunodeficiency includes testing for immunoglobulins, immunoglobulin G (IgG), IgG subclasses, specific antibodies to vaccine antigens (tetanus, diphtheria, polyvalent pneumococcal vaccine, and Haemophilus influenzae type B), complement (C3, C4, CH50), and lymphocyte subsets.

The following tests may be included in the workup:

  • An anergy skin test panel should be considered.

  • Lymphocyte markers may be useful.

  • Immunoglobulin E (IgE) may be used to evaluate for parasitic disease, allergic bronchopulmonary aspergillosis (ABPA), and eosinophilic syndromes.

  • Human immunodeficiency virus (HIV) testing is indicated if lymphocytic interstitial pneumonia (LIP), Pneumocystis carinii pneumonia (PCP), or disseminated histoplasmosis is present.

  • Markers of rheumatic disorders, including rheumatoid factor (RF), antinuclear antibody (ANA)/anti–double-stranded DNA (anti-dsDNA) antibody, antineutrophil cytoplasmic antibodies (ANCAs), and anti–basement membrane antibodies, should be measured to determine connective tissue disease or autoimmune etiologies.

  • Levels of angiotensin-converting enzyme (ACE) and lysozyme may be elevated in patients with sarcoidosis, but these findings are neither sensitive nor specific.

  • Serum precipitin results may be positive in patients with hypersensitivity pneumonitis but do not prove disease causality.

Genetic testing

Genetic testing is evolving rapidly, and consultation with a geneticist or ILD specialist is recommended. Genetic testing is increasingly used for identification of mutations resulting in altered surfactant production (SFTPB, SFTPC, ABCA3, and NKX2.1) or surfactant catabolism (CSF2FA, CSF2RB, SLC7A7, MARS, GATA2, and OAS1).

Testing for SFTPB and ABCA3 mutations should be performed in infants with unexplained severe neonatal respiratory distress, particularly if a family history of respiratory disease is known. Testing for SFTPC and ABCA3 mutations should be considered in infants and children with childhood interstitial lung disease (chILD) syndrome, particularly if they exhibit digital clubbing, diffuse ground-glass opacities, or reticular changes on high-resolution computed tomography (HRCT) or if they have a family history of chronic lung disease.

Other genetic etiologies of chILD syndromes include the following[36, 37, 38] :

  • FOXF1, which is associated with alveolar capillary dysplasia with misalignment of the pulmonary veins
  • COPA
  • FLNA (filamin A), which is associated with X-linked periventricular nodular heterotopia, alveolar simplification, and pulmonary hypertension
  • TBX4, which is  associated with lung development alterations

Clinical genetic testing is available through Clinical Laboratories Improvement Act (CLIA)–certified diagnostic laboratories.

Other laboratory tests

Serum and urine amino acids may be measured if metabolic conditions, such as lysinuric protein intolerance, are suspected. Brain natriuretic peptide (BNP) may be used in the screening and trending of right heart strain in the setting of pulmonary hypertension.

Imaging Studies

Chest radiography

Chest radiographs are often the first imaging study performed for evaluation of possible ILD. Although they rarely allow for a specific diagnosis, they can be useful in identifying other causes of respiratory symptoms that may present similarly to ILD.[39, 40] Findings on plain chest images may be normal in the presence of active disease and abnormal in the absence of symptoms. Numerous radiographic patterns are associated with ILD, including ground-glass opacities; reticular, nodular, or reticulonodular infiltrates; and honeycombing. The ground-glass appearance is consistent with active alveolitis, and honeycombing is consistent with advanced fibrosis.

Radiographic findings are usually described as interstitial infiltrates, although predominantly nodular (alveolar) and mixed reticulonodular patterns have been described, as have nonspecific findings (hyperinflation).

CT scanning

Computed tomography (CT) scanning, specifically high-resolution CT (HRCT), provides a noninvasive means for determining the patterns, extent, and distribution of changes associated with ILD. The imaging appearance of diffuse abnormalities varies by specific chILD diagnosis; findings include ground-glass attenuation, a tree-in-bud appearance, lobular air trapping, reticular attenuations, and centrilobular nodules.[41] CT is especially useful in demarcating the most appropriate areas for tissue biopsy.[22]

Disadvantages of traditional HRCT include the need for sedation in uncooperative infants and young children and the relatively high radiation exposure. Newer, more rapid acquisition algorithms have decreased these problems.

Long et al developed a method by using a combination of sedation and controlled ventilation providing a controlled pause in respiration to allow scanning of the lung with 1-mm sections.[42] Without controlled ventilation, respiratory motion may mimic ground-glass opacities, and dependent atelectasis may occur mimicking parenchymal changes. When possible, both inspiratory and expiratory images should be obtained, as expiratory images can be important to assess for air trapping and to evaluate the extent of ground-glass opacity.

Because imaging technology is changing rapidly, consultation with a radiologist who is knowledgeable about imaging children's lungs is highly advised. Whether serial HRCT provides any benefit in monitoring disease progression or response to therapy is unclear.

In a study of HRCT in 20 children with ILD, specific patterns were correlated with certain types of pathology, with little overlap.[23]  A characteristic CT pattern appears to be associated with neuroendocrine cell hyperplasia of infancy (NEHI).[43, 44] Consolidative patterns were seen in aspiration syndromes, cryptogenic organizing pneumonia (COP), and vasculitides. Characteristic thin-walled, heterogeneous cysts, alternating with small nodules, were seen only in patients with Langerhans cell histiocytosis (LCH).

In another study, investigators evaluated the ability of expert readers to correctly diagnose pediatric diffuse lung disease with HRCT.[40] The correct first-choice diagnosis of ILD was made in 61% of CT observations, and the conditions correctly diagnosed with greatest frequency were alveolar proteinosis, idiopathic pulmonary hemosiderosis, and pulmonary lymphangiectasia.

Studies in patients with NEHI or bronchiolitis obliterans suggest that characteristic HRCT patterns are often noted in these entities and may be used for diagnosis in the appropriate clinical context.[43, 44, 45]

Barium swallow studies

Barium swallow studies, videofluoroscopic swallow studies, or radionuclide "milk" scans may demonstrate evidence of dysphagia or aspiration.

Echocardiography

Echocardiography should be included in the initial diagnostic workup. Special attention should be paid to depiction of all four pulmonary veins, because partial anomalous pulmonary venous return may be present in patients with respiratory distress and chest radiograph findings of interstitial infiltrates.

Evidence of pulmonary hypertension (based on the tricuspid regurgitant jet velocity or septal geometry) and right ventricular hypertrophy may be evident. A systematic review found that the frequency of pulmonary hypertension in patients with chILD ranged from 1% to 64%.[34]

Magnetic resonance imaging

The use of thoracic magnetic resonance imaging (MRI) has been proposed, given the absence of ionizing radiation; however, because of the relatively low proton content of the lungs, conventional MRI has less utility for evaluating the pulmonary parenchyma than it has for assessing the mediastinal structures.[46]  MRI has been used specifically to evaluate sarcoidosis in children.[47]

MRI technology is rapidly evolving. Techniques such as the use of inhaled hyperpolarized gas for a contrast agent and ultrashort echo time MRI are increasingly applied in clinical settings.[46, 48, 49, 50]

 

Other Tests

Pulse oximetry

Decreased oxyhemoglobin saturation more often reflects ventilation-perfusion mismatching, rather than diffusion abnormalities, because of the remodeling of distal airspaces characteristic of most chILDs. In the early stages of ILD, oxyhemoglobin saturation may be relatively normal at rest but may worsen dramatically with exercise or sleep.

Pulmonary function testing

In children and adolescents who can perform spirometry and plethysmography, total lung capacity (TLC), forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1) are all often reduced. Although TLC maybe reduced, functional residual capacity (FRC) and residual volume (RV) are often normal or elevated, resulting in increased FRC/TLC and RV/TLC ratios. Airflow limitation, as indicated by a reduced FEV1/FVC ratio, is present in as many as one half of children with ILD. Compliance of the respiratory system (Crs) is reduced.

Diffusing capacity for carbon monoxide is usually low, although this value often returns to normal when corrected for lung volume and hemoglobin. In pulmonary hemorrhage syndromes, diffusing capacity may be elevated because of the affinity of carbon monoxide for sequestered hemoglobin.

Pulmonary function tests (PFTs) have been safely performed in sedated infants at some pediatric centers. Results of PFTs in infants, if available, usually show reduced Crs using both multiple occlusion and end-inspiratory occlusion techniques. PFTs have been used to monitor the response to treatment in some studies.[51]

Additional markers of pulmonary function, including lung clearance index (LCI) and oscillometry, have been used in other pulmonary disorders; however, they have not been systematically studied in chILD.

Results of arterial blood gas analysis may be normal, but typical changes include decreased arterial partial pressure of oxygen (PaO2) and respiratory alkalosis.

Exercise testing

In children old enough to cooperate, exercise testing may reveal exercise-related desaturation, even when oxyhemoglobin saturation is normal during rest. Exercise testing, or a 6-minute walk test, may provide an objective indicator of disease progression.

pH/impedance probe testing

pH or impedance probe testing may be required to demonstrate gastroesophageal reflux (GER), predisposing patients to aspiration. GER may occur as a secondary complication of ILD.

Electrocardiography

Electrocardiography (ECG) readings may show evidence of cor pulmonale, specifically right atrial and ventricular enlargement, and right axis deviation.

Procedures

Bronchoalveolar lavage

Bronchoscopy with bronchoalveolar lavage (BAL) is useful in diagnosing certain conditions in the differential diagnosis of ILD, including alveolar proteinosis, aspiration syndromes, pulmonary hemosiderosis, eosinophilic syndromes, and various infections. Occasionally, results of cytologic analysis may be diagnostic—for example, when Langerhans cells are present, indicating histiocytosis. Most authorities believe BAL should precede biopsy.

Problems with the use of BAL include the lack of a standardized methodology in children, the paucity of reference values for differential cell counts, the variability of BAL findings at different times in a disease course, and the lack of correlation between BAL and histologic findings.

Fluid should be sent for differential cell counts, cultures and special staining for bacteria (including mycobacteria) and fungi, cytologic analysis (including oil red O staining for lipid-laden macrophages and staining for hemosiderin), pepsin levels, and viral diagnostic studies.

BAL findings can be diagnostic of pulmonary alveolar proteinosis (PAP), demonstrating a cloudy or milky appearance of the fluid with periodic acid-Schiff (PAS)–positive amorphous debris. Electron microscopy may reveal lamellar membranous structures in a fibrous and granular matrix with degenerative cells.[52] Increased eosinophils (>30% of total) are consistent with eosinophilic pneumonia syndromes, whereas predominant lymphocytosis can be associated with hypersensitivity pneumonitis. CD1a-positive cells are diagnostic for Langerhans cell histiocytosis.[53]

A study evaluated quantitation of levels of surfactant proteins B (SP-B) and C (SP-C) in BAL fluid for the diagnosis of chILD and reported that low SP-C levels may suggest diseases caused by mutations in NKX2.1, SFTPC, ABCA3, and other genes involved in surfactant metabolism. SP-B levels may be used to screen for SP-B deficiency; however, given the availability of genetic testing, this approach is not the standard of care for diagnosis.[54]

Lung biopsy

Analysis of tissue obtained during lung biopsy can be the best route to a diagnosis if it cannot be established by noninvasive means. For NEHI, an expert clinician can be confident of a presumptive diagnosis based on the clinical history and characteristic HRCT findings, but this is not true of most other chILD entities. An increasing number of chILDs can be diagnosed by genetic testing.

Much of the classification of ILD, especially in disorders of unknown cause, is based on histopathology. However, it is important to note that a histopathologic pattern is not synonymous with a diagnosis in many cases. To maximize the diagnostic yield, a pediatric lung biopsy protocol has been developed and supported by the ChILD Research Network.[55] However, a diagnosis is not reached in all patients, even after biopsy is performed.

The number of biopsy procedures performed and the method used (eg, open vs thoracoscopic) have little influence on diagnostic yield. Diagnostic yield may be enhanced if HRCT is used to direct the biopsy sites. The biopsy sample should be taken from a region of involvement. If diffuse involvement is found, any site (except the tip of the right middle lobe or lingua) is appropriate.

Communication between the clinician, surgeon, pathologist, and radiologist before the biopsy is useful and appropriate for determining biopsy sites and prioritizing use of the tissue.

Compared with open lung biopsy, thoracoscopic biopsy shortens the surgical time, duration of chest tube placement, and hospital stay without substantially altering the diagnostic yield. The choice between thoracoscopic and open approaches should be left to the consulting surgeon. Transbronchial biopsies are not recommended for chILDs.

Regardless of the method used, biopsy samples should be processed for bacterial, fungal, and mycobacterial cultures and staining, including special staining, light microscopy, immunofluorescence, and electron microscopy. Immunostains, such as bombesin for NEHI and vimentin for pulmonary interstitial glycogenesis (PIG), may aid in the diagnosis of specific forms of ILD.[56]

Cardiac catheterization

This procedure should be considered in any child with noninvasive evidence of pulmonary hypertension but especially in children with a history of hemoptysis or absence of crackles on examination. These findings have been correlated with pulmonary veno-occlusive disease.

Histologic Findings

Histologic findings on routine hematoxylin and eosin staining remain the criterion standard for the diagnosis and classification of many types of ILD and may indicate the underlying cause, if a cause is present, or may suggest associated systemic illnesses (eg, noncaseating granulomas characteristic of granulomatous infections or sarcoidosis). However, this area has been rife with confusion because of different classification schemes, inexact nomenclature, and important differences between children and adults. Consultation with pathologists experienced in chILD is critical and ideally should be sought before biopsy specimens are obtained.

ILD classification systems

Adult histologic classifications for ILD are of questionable relevance to chILD, because particular patterns may have differing diagnostic and prognostic significance in adults and children. A classification system for infants with ILD that is based on a multicenter retrospective review of histopathology divides chILD entities into disorders more prevalent in infancy, disorders not unique to infancy, and unclassified disorders.[1]

Histologic Patterns of Interstitial Lung Diseases More Prevalent in Infancy

Follicular bronchitis/Bronchiolitis

Lung biopsy findings in follicular bronchiolitis demonstrate follicular lymphocytic infiltration surrounding and infiltrating the bronchial walls. This pattern may be seen in immunodeficiency disorders and connective tissue diseases.[43, 57, 58, 59]  See the image below.

Follicular bronchiolitis (A) Chest high-resolution Follicular bronchiolitis (A) Chest high-resolution CT (HRCT) scan from a patient with common variable immunodeficiency with history of anemia, thrombocytopenia, recurrent pneumonia, chronic cough, and exercise intolerance. Mosaic attenuation is present diffusely throughout the lungs. Extensive hilar and mediastinal lymphadenopathy is also present. Air-trapping was seen on expiratory images (not shown). (B) Lung histopathology demonstrates severe airway-centric lymphocytic inflammation with reactive follicles, which infiltrates and obscures most bronchioles.

Cellular interstitial pneumonitis/Pulmonary interstitial glycogenosis (PIG)

Lung biopsy findings reveal interstitial proliferation of histiocytic type cells with minimal to no infiltration.[57]  Electron microscopy demonstrates primitive interstitial cells with abundant cytoplasmic glycogen.[60]  PIG presents in infancy and is associated with alveolar growth abnormality.[61, 62]

Genetic abnormalities of surfactant function/Chronic pneumonitis of infancy

Biopsy findings reveal alveolar septal thickening, prominent pneumocyte hyperplasia, and alveolar exudates with numerous macrophages along with rare eosinophils and cholesterol clefts.[57, 63]

The typical histologic pattern for SP-B deficiency is interstitial thickening, abundant type II cell hyperplasia, and eosinophilic PAS-positive granular material in the alveolar space. The eosinophilic granular material is typical of PAP. Immunohistochemical staining may demonstrate the absence of SP-B.[64, 65]

Adults with SP-C deficiency can have biopsy findings consistent with those of usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), or nonspecific interstitial pneumonia (NSIP).[57, 66]

The histopathology of ABCA3 deficiency can widely vary and appears to be age-dependent, with infants exhibiting patterns consistent with PAP, chronic pneumonitis of infancy, or DIP, and older children exhibiting features of NSIP.[25]  The only well-documented case of UIP in a child was an adolescent with ABCA3 deficiency.[67]

Neuroendocrine cell hyperplasia of infancy (NEHI)

Lung biopsy in NEHI reveals mild, nonspecific changes, including airway smooth muscle hyperplasia, increased alveolar macrophages, and increased airway clear cells. Immunostaining of the cells demonstrates strong staining for bombesin and serotonin, which identifies these cells as pulmonary neuroendocrine cells (PNECs).

See the image below.

Neuroendocrine cell hyperplasia of infancy (NEHI) Neuroendocrine cell hyperplasia of infancy (NEHI) (A) Chest high-resolution CT (HRCT) scanning (at total lung capacity) in a 6-month-old infant with tachypnea, hypoxemia, and failure to thrive. Sharply defined areas of ground glass opacity are seen most prominently in the right middle lobe and lingula. Diffuse air-trapping was seen on expiratory images (not shown). No additional abnormalities were identified. (B) Hematoxylin and eosin staining of the lung biopsy specimen reveals near-normal lung architecture. (C) Bombesin immunostaining demonstrates increased numbers of neuroendocrine cells.

Histologic Patterns of Interstitial Lung Disease Not Limited to Children

Pulmonary alveolar proteinosis (PAP)

This histologic pattern may be seen in disorders of surfactant dysfunction, granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling dysfunction or autoantibodies, and lysinuric protein intolerance. On histologic examination, PAP appears as dilated air spaces and amorphous material with scattered pulmonary macrophages. Electron microscopy may demonstrate characteristic findings. Silver staining should be performed to rule out Pneumocystis pneumonia.

Desquamative interstitial pneumonia (DIP)

In adults, DIP is usually seen in cigarette smokers. In children, the DIP histologic pattern is associated with some of the surfactant dysfunction mutations, such as ABCA3 deficiency, and with chronic pulmonary hemorrhage syndromes.

The histologic pattern is uniform and diffuse. Alveoli are filled with accumulations of macrophages, which were originally believed to be desquamated alveolar epithelial cells, hence the name.

Nonspecific interstitial pneumonia (NSIP)

NSIP is a confusing term (a specific pattern despite the inclusion of “nonspecific”) for a microscopically homogeneous pattern of inflammation and fibrosis, although gross involvement may be patchy. Honeycomb changes are rare. Patchy ground-glass attenuations are depicted on HRCT scans. This histologic pattern may be seen in connective tissue diseases and rarely in SFTPC mutations. See the image below.

Nonspecific interstitial pneumonitis. (A) Chest hi Nonspecific interstitial pneumonitis. (A) Chest high-resolution CT (HRCT) scanning from a 10-year-old with systemic sclerosis and progressive exercise intolerance. (B) Lung biopsy showed multiple abnormalities including a relatively diffuse interstitial process with mild chronic inflammation, abundant fibroblastic tissue and patchy dense interstitial fibrosis. Accumulation of alveolar macrophages is seen in the airspaces, with rare foci of organizing pneumonia. Pulmonary arteries demonstrated focal intimal hyperplasia and medial hypertrophy, and the pleura contains patchy chronic inflammation. This overall constellation of findings is generally classified as mixed cellular and fibrotic nonspecific interstitial pneumonia (NSIP) and is a pattern most commonly seen in the setting of underlying collagen vascular disease.

Diffuse alveolar damage (DAD)/Acute interstitial pneumonia (AIP)

AIP is seen following acute lung injury, with a histologic pattern of diffuse active fibrosis (many proliferating fibroblasts, little collagen) with uniform alveolar septal thickening. Features of acute lung injury and a proliferative state of DAD are present, such as hyaline membranes, acute inflammation, and bronchial epithelial atypia.

Organizing pneumonitis/Cryptogenic organizing pneumonitis (COP)

COP (previously bronchiolitis obliterans organizing pneumonia [BOOP]) appears as patchy areas of granulation tissue in conducting airways and alveolar ducts with inflammation (primarily macrophages) in the surrounding alveoli. In affected areas, the appearance is uniform without significant distortion of lung parenchyma. Buds of myofibroblasts in collagenous stroma (Masson bodies) may extend into adjacent airspaces, demonstrating a characteristic butterfly pattern. This pattern may be associated with a broad differential diagnosis (including HIV infection and bone marrow transplantation) and may occur with other histologic patterns. See the image below.

Bronchiolitis obliterans. (A) Chest CT scanning fr Bronchiolitis obliterans. (A) Chest CT scanning from an 8-year-old demonstrates irregular large mosaic regions of ground-glass opacity and air-trapping, as well as the presence of peribronchial thickening and bronchiectasis. (B) Pathology demonstrates focal areas of fibrosis with polypoid plugs of fibroblastic cells and fibrin filling distal bronchioles and airspaces (hematoxylin and eosin).

Lymphocytic interstitial pneumonia (LIP)

LIP is characterized by monotonous, diffuse, lymphoplasmacytic cell infiltrates in the interstitium and distal airspaces. Mononuclear cells and histiocytes are also seen. Occasionally, lymphoid aggregates are found in a lymphatic or angiocentric distribution. LIP has been described as a pulmonary manifestation of HIV infection in children. In addition, LIP is associated with Sjögren syndrome, chronic active hepatitis, and juvenile rheumatoid arthritis. Epstein-Barr virus (EBV)-genomic DNA occasionally can be identified in LIP. Lymphoproliferative diseases, lymphomas, and underlying immunodeficiency must be considered.

Usual interstitial pneumonitis (UIP)

UIP is the histopathologic pattern associated with idiopathic pulmonary fibrosis (IPF), a disease of adulthood. UIP is characterized by a heterogeneous appearance at low magnification, with alternating areas of normal lung, inflammation, fibrosis, and honeycomb changes, which are most prominent in the peripheral subpleural areas. Fibrotic areas contain dense collagenous deposits and characteristic foci of proliferating fibroblasts (fibroblastic foci), which have negative prognostic importance in IPF.

UIP is extremely rare in children, and its presence on a pediatric biopsy should be confirmed by a pathologist with significant expertise in chILD. There is only one well-characterized report of UIP in a child, an adolescent with ABCA3 deficiency.[67]  UIP at an early age has also been described in dyskeratosis congenita, with the onset of interstitial lung involvement in childhood in some cases.[68]

Staging

No widely used staging system is available for chILD, which is appropriate because the spectrum of possible diagnoses is large.

In adults, a scoring system is available for IPF, based on clinical, radiographic, and pathologic findings (ie, CRP scoring system).

Fan devised a simple scoring system for chILD. A score of 5 indicates the worst outcome, with a 38% survival rate at 60 months. A score of 2, 3, or 4 indicates a survival rate of 76%. Data from Cox proportional hazards modeling suggests a 140% increase in risk of death with each unit increase in score. The score can be applied to most ILD diagnoses with the likely exception of NEHI, which has a good eventual prognosis in the majority of cases.

The Fan severity scoring system is as follows[69] :

  1. Asymptomatic

  2. Symptomatic with normal oxyhemoglobin saturation

  3. Symptomatic with nocturnal or exercise-induced desaturation

  4. Desaturation at rest

  5. Pulmonary hypertension

 

Treatment

Medical Care

The heterogeneity of disease etiology and the lack of randomized clinical trials make offering specific recommendations regarding treatment of childhood interstitial lung disease (chILD) impossible. If the process is secondary to an underlying condition, patients should be treated for the underlying disease.

General treatment recommendations

General recommendations include supportive care with nutritional, oxygen, and ventilator support as needed. Management of comorbid conditions, including atopic phenotypes, sleep apnea, dysphagia, and aspiration, is encouraged. More specific systemic disease treatments, such as immunomodulatory and immunosuppressive medications, are appropriate in patients with chILD related to vasculitis and connective tissue diseases.[70, 71]

The same principles that apply to all children with chronic pulmonary diseases apply to those with interstitial lung disease (ILD). These include meticulous attention to growth and nutrition, immunizations (including respiratory syncytial virus [RSV], influenza, and pneumococcal prophylaxis), and treatment of secondary infections.

Treatment with bronchodilators, inhaled steroids, or both may be appropriate if any component of airway reactivity is demonstrated on pulmonary function testing (PFT). However, this therapy has not been proven to modify the clinical course of most types of ILD.

Oxygen therapy, either continuously or during sleep, may be necessary to provide symptomatic relief and to decrease the risk or halt the progression of pulmonary hypertension and cor pulmonale related to alveolar hypoxia.

Active and passive smoking, as well as exposure to electronic cigarette vapor, should be avoided. Smoking cessation should be actively pursued for caregivers who smoke.

Avoiding contact with persons who have symptomatic respiratory tract infections, especially during periods of high respiratory viral activity, is prudent.

Many medications have been used to treat different forms of ILD. No therapeutic regimen has been subjected to the rigors of a randomized control trial in the pediatric population. Numerous broad treatment strategies have been attempted, including anti-inflammatory and immunomodulatory medications (eg, steroids, hydroxychloroquine, intravenous immunoglobulin [IVIG], cytotoxic agents, immunosuppressive therapies, and biologic agents).

Treatment of specific conditions

Hypersensitivity pneumonitis is the most treatable condition among chILDs, with removal of the offending agent as an initial and definitive step in therapy. Fan et al reported 86 cases of pediatric hypersensitivity pneumonitis that had an excellent response to steroids.[57] Other conditions that have demonstrated a response to steroids in selected cases include nonspecific interstitial pneumonia (NSIP), lymphocytic interstitial pneumonia (LIP), cryptogenic organizing pneumonitis (COP), eosinophilic pneumonia syndromes, sarcoidosis, pulmonary hemosiderosis, and ILD associated with connective tissue disease.[31]

Treatment of specific conditions resulting in ILD includes antiviral agents against cytomegalovirus (CMV) and Epstein-Barr virus (EBV), antiretroviral therapy in addition to prednisolone for AIDS-associated LIP, a surgical approach for lymphangiomatosis, therapeutic bronchoalveolar lavage (BAL) for pulmonary alveolar proteinosis (PAP), proton pump inhibitor (PPI) therapy and gastric fundoplication for gastroesophageal reflux (GER)-associated chronic aspiration, and non-oral feeding for primary aspiration.

In patients with associated pulmonary arterial hypertension (PAH), sildenafil and anticoagulant therapy (if PAH is related to chronic thromboembolic disease) should be considered.

In patients with congenital PAP due to granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor mutation or acquired receptor dysfunction secondary to autoantibody formation, subcutaneous or inhaled GM-CSF treatment has been reported to be beneficial.[72, 73] Therapeutic whole lung lavage may be beneficial in autoimmune or GM-CSF–associated PAP, but its application in cases of alveolar proteinosis associated with an underlying ILD diagnosis has not been evaluated in clinical trials and may be of limited utility, except in rare cases.[74]

Surgical Care

Surgical consultation is usually sought for diagnostic biopsy.

Patients with end-stage progressive forms of ILD, severe neonatal lung disease associated with SFTPB or ABCA3 mutations, and some pulmonary veno-occlusive diseases may be candidates for lung or heart/lung transplantation. These patients are considered on an individual basis at the few centers specializing in pediatric lung transplantation.

The 2016 International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry Report shows that worldwide more than 100 pediatric lung transplantations are performed annually, although the majority of lung transplant centers perform fewer than 5 transplantations each year.[75]  According to the 2018 ISHLT Thoracic Transplant Registry Report, the median post-transplantation survival is 7 years.[76]

Rama et al compared children with diffuse lung disease, cystic fibrosis, and pulmonary vascular disorders who were undergoing lung transplantation. Children with diffuse lung disease had higher pre-transplant morbidity (lower forced expiratory volume in 1 second [FEV1], pulmonary hypertension, and hypercapnia). They also required more invasive ventilation and intensive care compared with patients with cystic fibrosis. No difference was noted in survival or in the frequency of infections and lymphoproliferative disease after transplantation.[77]

For some diseases, such as neonatal surfactant protein B (SP-B) and alveolar capillary dysplasia, lung transplantation remains the only effective treatment. The proportion of ChILD- and other rare disease–related lung transplants at pediatric transplant centers is likely to increase as the life expectancy and prognosis of patients with cystic fibrosis continue to improve.

Consultations

All children with ILD should be treated in consultation with a pediatric pulmonologist. In addition, referral to or telephone consultation with a center that has clinicians who specialize in chILD is advised.

Because cardiovascular diseases can masquerade as ILD, all patients should have an echocardiogram and may benefit from the involvement of a pediatric cardiologist. A pediatric rheumatologist should be involved in the management of ILD associated with connective tissue disease. For ILD associated with immunodeficiency and/or immune dysregulation, the involvement of a pediatric immunologist is advised.

Consult a pediatric radiologist regarding the interpretation of imaging studies. Consultation with a pathologist is recommended before tissue is obtained to ensure that adequate specimens are collected and that they are correctly processed. In many cases, consideration should be given to consultation with a pathologist who is knowledgeable about chILD diagnoses.

In addition, consider consultation with an infectious disease specialist and a transplantation specialist. The pretransplantation evaluation should be initiated before end-stage disease develops to allow sufficient time for assessment and donor identification.

Diet

No specific diet is necessary in most cases. In ILD associated with gastrointestinal disorders, dietary management should be planned in consultation with a gastroenterologist and an experienced dietitian.

As for patients with any chronic disease, patients with chILD should receive sufficient kilojoules to maintain adequate growth. ChILDs are associated with an increased risk of failure to thrive. Decreased lung compliance increases the work of breathing and energy expenditure. Energy supplementation should be undertaken with consideration to the added difficulty in handling high carbohydrate loads with chronic lung disease.

Consult a nutritionist experienced in the management of chronic pulmonary conditions in children. Young infants with feeding difficulties resulting from dyspnea may require a transpyloric or gastrostomic feeding tube.

Activity

Activity may be limited by the patient's degree of dyspnea. Oxygen saturation during exercise should be measured. A prescribed, monitored exercise program may be beneficial to prevent deconditioning in older children. Conditions that may exacerbate pulmonary symptoms (high levels of ozone or other environmental pollutants) should be avoided. Patients with hypersensitivity pneumonitis should be removed from exposure to the precipitating substances (eg, birds, organic dusts). Air travel or travel to high altitudes must be carefully planned in patients with arterial desaturation.

 

Medication

Medication Summary

The primary treatment focus in childhood interstitial lung disease (chILD) remains supportive care, including supplemental oxygen and ventilatory support, nutrition optimization, appropriate immunizations, and treatment of pulmonary exacerbations. No clinical trials of medications for chILD have been conducted to date.

Corticosteroids have been the mainstay of therapy in most children and adults with interstitial lung disease (ILD), despite little conclusive evidence of their efficacy. The medications commonly used for pharmacotherapy in chILD and common adverse effects are reviewed below.[70]

Glucocorticoids

Class Summary

These agents elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the immune response of the body to diverse stimuli. Suppression of immune-mediated alveolitis and repair mechanisms may reduce the progression of fibrosis. Data from small studies suggest that pulse administration with intravenous (IV) corticosteroids may improve survival and lessen toxicity compared with prolonged courses of oral steroids. Adverse effects of chronic systemic steroid treatment include adrenal suppression, decreased bone density and growth, glaucoma, and immunosuppression. Regular screenings such as annual dual-energy x-ray absorptiometry (DEXA) scans, blood pressure medications, and ophthalmologic evaluations are recommended.[70]

Prednisone/Prednisolone (Deltasone, Meticorten, Orasone, Sterapred)

Most widely used agent, particularly for usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), and hypersensitivity pneumonitis. May decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. Typical dosing is 1-2 mg/kg/day until disease symptoms are controlled, then is decreased to the lowest effective dose. Alternating days on therapy may reduce the risk of adverse effects.

IV Methylprednisolone (Solu-Medrol)

Decreases inflammation by suppressing migration of PMN leukocytes and reversing increased capillary permeability. Typically given in high-pulse doses (10-30 mg/kg/day) for 3 consecutive days monthly, then dosing frequency is reduced once the clinical course stabilizes.

Immunomodulating and immunosuppressive agents

Class Summary

Immunomodulatory drugs may be used as second-line therapy if a response to corticosteroids has not occurred, if a steroid-sparing effect is desired, or as an adjunctive agent to steroids in severe or rapidly progressive disease. Immunomodulatory medications used in patients with chILD include azathioprine, methotrexate, cyclophosphamide, cyclosporine, and mycophenolate mofetil.

Additionally, the biologic treatments most commonly used in chILDs include granulocyte-macrophage colony-stimulating factor (GM-CSF) for pulmonary alveolar proteinosis (PAP) due to alveolar macrophage neutralizing autoantibodies; monoclonal antibodies, such as rituximab, for autoimmune-related lung diseases; intravenous immunoglobulin (IVIG) for several off-label indications, including immune-mediated alveolar hemorrhage syndromes; and tumor necrosis factor (TNF)-alpha inhibitors, interleukin-1 (IL-1) antagonists, and IL-6 antagonists for some immune-mediated disorders, including lung disease related to juvenile idiopathic arthritis.[31, 78, 70]

For the use of these and other immunomodulatory medications and biologic agents, especially in the setting of systemic disorders such as connective tissue diseases, and vasculitides and immune dysregulation, consultation with a rheumatologist or an immunologist is recommended.

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. In addition to its anti-inflammatory properties, hydroxychloroquine is thought to inhibit intracellular processing of the precursor of surfactant protein C (SP-C), which may be the mechanism of action in SP-C deficiency. Hydroxychloroquine sulfate 200 mg equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. Dose and duration not tested in controlled trials, but case reports describe children receiving 6-10 mg/kg/day for years. Adverse effects of hydroxychloroquine include possible cardiomyopathy and conduction disorders (including QT prolongation), photosensitivity, retinal and corneal toxicity, and liver function abnormalities. Thus, regular ophthalmologic evaluations and liver enzyme monitoring are recommended.

Macrolides

Azithromycin (Zithromax, Zmax)

In other chronic lung diseases, azithromycin has been used regularly for anti-inflammatory and immunomodulatory effects. The typical dosing is 10 mg/kg up to 500 mg per dose 3 times per week. Adverse effects include risk of QT prolongation, pyloric stenosis (in early infancy), and gastrointestinal effects. Additionally, a study of azithromycin for prevention of bronchiolitis obliterans syndrome after bone marrow transplantation was terminated early because of the increased risk of hematologic relapses and worse airflow decline–free survival in the azithromycin group.