Interstitial lung disease in newborns
Introduction
Interstitial lung disease (ILD) is a heterogeneous group of rare disorders of diverse and often unknown etiologies that cause acute or chronic respiratory signs and findings. Whereas the term ILD has become broadly accepted as a result of the pathologic changes observed in the pulmonary interstitium, these disorders often involve the airspaces, and the term ‘diffuse lung disease’ (DLD) may be more accurate. ILD/DLD has generally been classified in adults based upon the underlying histopathology, but the disorders seen in adults differ from those seen in children and even more so in neonates, and thus different approaches are needed. In the past ten years, collaborative efforts between clinicians, imagers, and pathologists have led to a classification system more appropriate for infants and children. Whereas this approach was based largely upon lung pathology, it is being increasingly recognized that many of the disorders affecting newborns and young infants have a genetic basis, which may allow for a specific diagnosis through non-invasive means. Recent advances in genetics based upon next-generation sequencing methods have allowed for more cost-effective genetic testing panels for known disorders and identification of new disorders through agnostic approaches using whole-exome or whole-genome sequencing. The approach to the diagnosis of ILD and understanding of the specific disorders is thus likely to continue to evolve rapidly. This review focuses on those disorders that typically present in the newborn period and which are likely to result in hypoxemic respiratory failure.
Section snippets
Classification of childhood interstitial lung disease (chILD)
A classification of ILD specific for infants aged <2 years was developed based upon review of clinical, imaging and lung biopsy data [1]. More than half (57%) needed supplemental oxygen at birth, and 21% had biopsies performed before age 2 months. Subsequent studies have utilized and expanded on this classification scheme, with the majority of included subjects having needed supplemental oxygen or respiratory support at birth, and disorders likely to present in the neonatal period have
Surfactant disorders
Mutations in genes encoding proteins needed for the production, function, and metabolism of pulmonary surfactant lipids and proteins account for ∼20% of ChILD disorders and often present in the newborn period. The typical presentation is a term infant with DLD that clinically and radiographically resembles respiratory distress syndrome in prematurely born infants *[22], [23], *[24], [25], [26], [27]. Disease onset in older infants and children without a history of neonatal lung disease also
Pulmonary alveolar proteinosis
An accumulation of proteinaceous material that fills distal air spaces may be a prominent finding in surfactant dysfunction disorders. The term pulmonary alveolar proteinosis (PAP) has been used because of the similarity in appearance to that observed in adults with a syndrome in which surfactant accumulates in distal airspaces and results in hypoxemia. However, PAP in adults is usually secondary to an auto-immune disorder, with neutralizing antibodies to granulocyte–macrophage
Neuroendocrine cell hyperplasia of infancy (NEHI; also known as persistent tachypnea of infancy, PTI)
This is a form of chILD that has accounted for ∼8% of cases in retrospective studies, and is being increasingly recognized ∗[1], [3], [5], [35]. The characteristic presentation is that of chronic tachypnea in a young infant, often accompanied by a need for supplemental oxygen and failure to thrive. Chest radiographic findings are non-specific and include hyperexpansion and increased perihilar markings. CT findings may be characteristic with ground-glass opacities in non-dependent lobes,
Primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD) is a disorder resulting from absent or abnormal ciliary function in the respiratory epithelia leading to poor mucous clearance with secondary complications of chronic sino-pulmonary disease. Almost half of affected subjects have situs inversus (Kartagener's syndrome) or other laterality defects. The disorder results from mutations in genes needed for normal ciliary development or function and is inherited in an autosomal recessive fashion. Mutations in more than
Other genetic causes of ILD in older children
With advances in DNA sequencing methods, genetic causes of disease are being identified at an increasing rate, including many involving the lungs (Table 2). Examples include COPA syndrome, which involves mutations in a gene encoding a protein involved in intracellular retrograde transport from the Golgi apparatus to the endoplasmic reticulum, and stimulator of interferon genes (STING)-associated vasculopathy of infantile-onset (SAVI), secondary to mutations in an endoplasmic reticulum
Diagnostic approach to ILD in newborns
Approaches to the diagnosis of chILD have been outlined *[49], *[50]. It is important to first exclude known causes of lung disease – including structural heart disease and pulmonary hypertension – by echocardiography. In older infants, cystic fibrosis and immunodeficiency should be excluded. Evaluation should generally include high-resolution CT, and bronchoscopy may be helpful to exclude anatomical issues, infection, and aspiration. In newborns, strong consideration should be given to early
Conclusion
ChILD disorders frequently present in the neonatal period and are associated with significant morbidity and mortality. Clinical presentations range from intractable hypoxemic respiratory failure to milder respiratory signs and findings that persist after discharge. An underlying genetic basis occurs frequently in chILD, and newer genetic methodologies are uncovering the basis for previously cryptogenic disorders. Genetic discoveries and testing allow for non-invasive diagnosis and the results
Conflict of interest statement
L.M.N. receives royalties for co-authorship of the section on “Surfactant Dysfunction Disorders” published in UpToDate.
Funding sources
L.M.N. has received funding from the US National Institutes of Health (NHLBI) (U01HL134745), American Thoracic Society, and the Eudowood Board, and is a co-investigator on a study sponsored by United Therapeutics Corporation. None of the sponsors had any role in the preparation of this manuscript.
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