Abstract
Children with diffuse and interstitial lung disease (chILD) comprise a group of rare disorders with significant morbidity and mortality. Individually these disorders are rare but collectively they create a sizable group of children with complex disease who present challenges to families, multiple different pediatric specialties, and the health care system. Tremendous progress continues around the globe to classify disease in children, organize quality systems of care, and search for new treatment and cures. More chILD diseases continue to be discovered and defined with improving genetic technology. This chapter provides an overview of the field as an introduction to the more in-depth discussions for each of the sections that follow.
Keywords
diffuse lung disease, children’s interstitial lung disease
The field of children’s interstitial and diffuse lung disease (chILD) has undergone tremendous development over the past decade, driven by new genetic discoveries, improved techniques in imaging and lung biopsy, and organized efforts to better define clinical phenotypes ( Table 54.1 ). This progress has resulted in recognition of new disorders, the definition of a diffuse lung disease pediatric classification system, and formation of the chILD Foundation [ http://child-foundation.org/ (USchILD); http://www.childlungfoundation.org/ (UKchILD)] and chILD research networks around the world. Research networks in the USA and the European Union now have prospective multicenter registries. Chapters in this section have been organized to align with these new developments and to provide the reader with a new framework to care for these children.
| Classification Category | Specific Disorders | Common Age Presentation |
|---|---|---|
| Disorders More Common in Infancy | ||
| Developmental Disorders | Alveolar capillary dysplasia with misalignment of pulmonary veins | Birth |
| Growth Abnormality Disorders (alveolar simplification) | Pulmonary hypoplasia, chronic neonatal lung disease associated with chromosomal disorders, associated with congenital heart disease | Birth |
| Specific Conditions of Unknown Etiology | Neuroendocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG) | Birth—1 month (PIG) Infancy—24 months (NEHI) |
| Surfactant Dysfunction Mutations | Surfactant protein B (SFTPB), surfactant protein C (SFTPC), ATP-binding cassette A3 (ABCA3); NKX2.1 (thyroid transcription factor 1); and histology consistent with a surfactant mutation | Birth (SFTPB) Birth—Adulthood (SFTPC, ABCA3 NKX2.1) |
| Disorders Related to Systemic Disease | Immune-mediated collagen vascular disease, storage disease, sarcoidosis, and Langerhans cell histiocytosis. | Childhood—Adolescence |
| Disorders of the Normal Host/Environment Exposure | Infectious or postinfectious process, hypersensitivity pneumonitis, aspiration, eosinophilic pneumonia. | Infancy—Adolescence |
| Disorders of the Immunocompromised Host | Opportunistic infections, transplantation and rejection, therapeutic interventions | Infancy—Adolescence |
| Disorders Masquerading as Interstitial Lung Disease | Pulmonary hypertension, cardiac dysfunction, veno-occlusive disease, lymphatic disorders | Birth—Adolescence |
| Unknown | Pulmonary biopsy tissue that cannot be classified |
The cliché that “children are not little adults” is a good paradigm to explain the confusing early literature on children with ILD. Although adult patients with desquamative interstitial pneumonitis (DIP) were found to have a good prognosis, children with DIP had high mortality. DIP in children is now a recognized pathologic phenotype, which is consistent with congenital surfactant mutations that have significant mortality. Conversely, children with severe ILD were frequently labeled as cases of idiopathic pulmonary fibrosis (IPF), which is synonymous histologically with usual interstitial pneumonia (UIP), a leading cause of mortality in adult ILD. However, on further review, the histologic diagnostic criteria for UIP characterized by fibroblast foci have not been seen in infants and young children, and have been seen in only one older adolescent. New disorders in young children less than 2 years of age—not previously described in adult patients—were also reported. There were disorders, such as neuroendocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). The differences in diagnosis highlighted the fact that forcing children with ILD into adult classification systems did not serve their interests and signaled the need to reorganize thinking in this area, and to create a pediatric-specific diffuse lung disease classification system.
New Concepts, Terminology, and Classification
The field of diffuse lung disease is large and includes commonly recognized pediatric diseases. For example, diffuse lung diseases, such as cystic fibrosis, chronic lung disease of prematurity, and pulmonary infections have recognized clinical presentations and diagnostic testing. However, once these more recognized disorders have been ruled out, some children remain undiagnosed and are labeled with the general term ILD, as if this were a final diagnosis, or they are listed as having unknown lung disease. The concept of chILD syndrome was created to further define this subset of poorly diagnosed children with diffuse lung disease. chILD syndrome is defined as a child who has three to four of the following findings without a known underlying lung disease to fully explain the clinical condition: (1) respiratory symptoms, such as coughing, rapid breathing, or exercise intolerance; (2) physical signs, such as crackles, adventitial breathing sounds, digital clubbing, or intercostal retractions; (3) a low blood oxygen tension or hypoxemia; and (4) diffuse parenchymal abnormalities on chest imaging. chILD syndrome is a constellation of findings that should signal the clinician that further diagnostic evaluation is indicated to reach a definitive diagnosis. Using this definition, Van Hook reviewed two large data sets of young children with biopsy-proven diffuse lung disease and found this definition to be sensitive to make the diagnosis of chILD syndrome. Furthermore, if a child with a known diagnosis has symptoms out of proportion to the recognized disease, they may still have chILD syndrome and require further evaluation for a secondary diagnosis. This is an important nuance, as some chILD diseases occur in conjunction with other known conditions, such as congenital heart disease and chronic lung disease of prematurity or PIG. (See Chapter 56 for further discussion.)
The designation of a pediatric-specific classification system for diffuse lung disease was essential. Based on the expertise of Dr. Claire Langston and her extensive experience reviewing lung biopsies in children with diffuse lung disease, a new clinical and pathologic classification system was proposed, which incorporated features unique to children, especially the category “disorders more common in infancy” (see Table 54.1 ). A landmark study, published in 2007, reported on the application of this classification system by a multidisciplinary cooperative that reviewed more than 180 lung biopsies over a 5-year period in children less than 2 years of age at 11 children’s hospitals in North America. This review further established that the Langston classification system could realistically be applied, and was appropriate, for infants and young children. Chapters in the chILD section are organized loosely around these categories, and should provide a diagnostic framework for children with diffuse lung disease. The Europeans have used a similar classification with minor differences. Refinements of this classification system are evolving and will continue to evolve as more genetic disease associations are identified with the increased use of exome and genome sequencing for the diagnoses of unknown disease.
Retrospective studies in North America and Europe illustrate that children with chILD syndrome are overly represented in infants and younger children. The application of the Langston classification system and an adapted version in Europe also demonstrated that over half the patients reviewed could be classified in the category “disorders more prevalent in infancy.” It is less clear if the Langston pediatric classification system is appropriate for older children. A recently published review of more than 180 lung biopsies in children older than 2 years of age at multiple centers in North America, using the same methodologies as the previous under 2 years of age retrospective review, suggests that the classification system does work well for these older children. Biopsies in older children were rarely classified in the category “disorders more common in infancy”; older children had significantly more biopsies classified in the categories “disorders related to system disease” (see Chapters 57 and 58 ) and “disorders related to the immunocompromised host” (see Chapter 64 ). This is further illustrated in the chapters that deal with these categories.
General Diagnostic Approach
The evaluation of chILD can be complicated, expensive, and associated with a risk for significant morbidity. To address these concerns, clinical guidelines focused on infants and young children have been published.
Any newborn or child presenting with diffuse lung disease should have a complete history and physical (H&P) performed. Although most diagnoses are not established with an H&P, specific clues can be uncovered that may be suggestive. Important history questions should include: birth history, a complete family history for use of oxygen or pulmonary deaths in any age family member to suggest genetic disease, previous pulmonary infections to suggest lung injury, family history of autoimmune disease, and a thorough environmental history to evaluate for hypersensitivity pneumonitis. A complete physical examination should evaluate for nutritional indices, sinopulmonary disease, chest wall deformities, skin rash, clubbing, and neurologic disorders.
Other noninvasive testing should then be completed to rule out known causes of lung disease, such as cystic fibrosis, primary ciliary dyskinesia, aspiration, immunodeficiency, hypersensitivity pneumonitis, pulmonary infections, or autoimmune disease. An echocardiogram should be obtained to rule out masqueraders of lung diseases, such as congenital heart disease and pulmonary vein abnormalities, and to identify the presence of pulmonary hypertension, which may require more aggressive treatment, and may be associated with a worse prognosis.
Imaging is often ordered to determine the pattern of diffuse lung disease. Chest radiographs are nonspecific and not helpful for specific diagnoses. Volume-controlled inspiratory and expiratory high-resolution computerized topography (HRCT) has been the most helpful way to obtain quality images for children with chILD syndrome, and may suggest bronchiolitis obliterans, pulmonary alveolar proteinosis, hypersensitive pneumonitis, or neuroendocrine cell hyperplasia. The lowest amount of radiation possible should always be used. In children less than 4 years of age, or in those neurologically impaired, HRCTs will likely require sedation for optimal scans unless newer fast scanners are used, and some children may require prone positioning if atelectasis is seen posteriorly. Though HRCT scanning is available at most hospitals around the country, it is highly recommended that scans in newborns, infants, and young children be completed at centers with expertise and protocols developed to optimize HRCTs for children with chILD using the lowest radiation dose possible. Newer imaging modalities are also emerging, such as hyperpolarized 3He ventilation magnetic resonance imaging (MRI), which may be more sensitive for early lung disease and is done without radiation.
Infant pulmonary function testing is currently used to evaluate children with cystic fibrosis and chronic lung disease of prematurity. Limited, but important, data exist for children with chILD syndrome. Infant pulmonary functions can be completed reliably in children with NEHI at centers experienced in these techniques, and may be helpful because a classic pattern of airway obstruction and gas trapping has been reported in infants and young children. Data suggest that the severity of small airway obstruction may correlate to the prominence of bombesin staining (a marker for neuroendocrine cells) in the lung tissue, and that measures of small airway obstruction also may trend toward correlation with lower weight. Some experienced chILD centers currently use infant pulmonary function data in conjunction with other testing (HRCT imaging, bronchoscopy, and clinical findings) to determine the need for a diagnostic lung biopsy in a child with classic findings for NEHI. The American Thoracic Society (ATS) consensus guidelines address the ideal timing and use for infant pulmonary function tests (PFTs). New techniques with a lung clearance index have not yet been tested in children with chILD.
Genetic testing has emerged as a significant consideration in the evaluation of children with chILD, especially for inborn errors of surfactant metabolism. Any child with chILD syndrome without a clear etiology, and especially those who present with a family history of infant deaths, prolonged oxygen use, or family members with IPF, should have testing for abnormalities in surfactant metabolism. Clinical testing is available through clinical laboratory improvement amendments (CLIA)–certified laboratories. A useful site for genetic information and laboratory testing is GeneTests ( https://www.genetests.org/ ). The type of genetic testing is related to clinical presentation, so that those who present immediately in the newborn period with respiratory failure and pulmonary hypertension may be more likely to have surfactant protein B (SFTPB) and ATP-binding cassette A3 (ABCA3) mutations, while those who present later may be more likely to have surfactant protein C (SFTPC) mutations. Genetic testing for (ABCA3) mutations has become very important for prognosis, as mutations that are null/null are associated with death or transplant at 1 year. For those infants who present with respiratory failure and congenital hypothyroidism, investigations for mutations in the NKX2.1 or thyroid transcription factor-1 (TTF-1) gene should be performed because this is a more recently recognized gene that regulates surfactant proteins. NKX2.1 can also present with the complete triad of “Brain, Thyroid, Lung Syndrome” or a combination of any two organs. Children with chorea should be checked for NKX2.1 and evaluated for lung disease. As the time to sequence these genes has decreased and test results can become available in weeks (instead of months), many centers wait for test results before proceeding to lung biopsy if the child’s clinical status is stable. If test results are unclear or if testing is negative, a lung biopsy may be indicated. There is still a great deal to learn about both genetic and environmental modifiers for these genes. Chapter 57 provides a more detailed discussion of disease associated with abnormal surfactant metabolism. Recently, the forkhead box transcription factor (FOXF) gene has been associated with familial cases of children with ACDMPV, and testing may be indicated for this fatal disorder. Finally, more genetic mutations are likely to be found in children with chILD, such as NEHI, which has been shown to occur in families, and some surfactant genetic abnormalities may be important modifiers of more common diseases such as respiratory distress of the newborn, and adult diseases, such as chronic obstructive pulmonary disease (COPD). Exome and whole genome technologies are becoming more available in a timely manner and at more reasonable price points. Also, there are pulmonary genetic panels that examine many genes. Genetics will clarify how many unknown chILD conditions exist and allow better mechanistic understanding of the disease. Many new diseases are being defined, and this will only grow with enhanced genetic techniques. Table 54.2 provides a list of recently described serious chILD diseases with genetic causes, such as mutations in filamin A (FLNA), coatomer subunit alpha (COPA), GATA-2 transcription factor, Methionyl-tRNA synthetase (MARS), lipopolysaccharide-responsive and beigelike anchor protein (LRBA) and CTLA4.
