New clinical practice guidelines on the classification, evaluation and management of childhood interstitial lung disease in infants: what do they mean?

Abstract

The American Thoracic Society (ATS) recently published a clinical practice guideline regarding the classification, evaluation, and management of childhood interstitial lung disease in infancy (chILD). As disease entities among infants with ILD are often distinct from forms seen in older children and adults, the guideline encourages an age-based classification system and focuses on the diagnostic approach to neonates and infants <2 years of age. The guideline reviews current evidence and recommendations for the evaluation, relevant genetic studies, and management of symptomatic infants. Here, we summarize the ATS guideline, highlight the major concepts, and discuss future strategies aimed at addressing current gaps in knowledge.

Keywords::

• chest CT
• children
• interstitial lung disease
• lung biopsy
• surfactant

Historically, the medical literature on interstitial lung disease (ILD) in children has been sparse, largely filled with case reports and single-center case series utilizing the framework for ILD in adults. Over time, it has become evident that the terminology and classification intended for adults fail to inform disease pathogenesis and prognosis in children. In the past decade, genetic discoveries, multicenter and international collaborative efforts and patient advocacy have transformed the field of childhood ILD. It has been an inspiring time, indeed!

Recently, a committee convened by the American Thoracic Society (ATS) published ‘An Official ATS Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy (chILD)’ [1]. This document summarizes decades of work in the field of chILD, including recognition that ILD in infants is caused by entities that are often distinct from forms seen in older children and adults. Further, fundamental advances have included implementation of an age-based classification system focused on ILD in children [2], coupled with improved diagnostic approaches such as the availability of genetic testing.

The Guideline had broad input from neonatologists, pulmonologists, radiologists and pathologists, with a total of 63 authors from six countries. Because no controlled clinical trials were identified through the literature review process, observational evidence and clinical experience informed recommendations. With a depth and breadth of information on specific disease entities and diagnostic modalities, the ATS Guideline aims ‘to inform clinicians, patients, and organizations regarding the classification, evaluation, and management of childhood ILD’ [1]. While many of the principles detailed apply to older children, the ATS Guideline specifically focuses on neonates and infants <2 years of age. Here, we have chosen to highlight a few over-arching concepts.

Diagnosing ILD: when & where to start?

Although the clinical presentation of neonates and infants with ILD can be quite variable, common clinical findings include respiratory symptoms (cough, rapid breathing, exercise intolerance), respiratory signs (tachypnea, crackles, retractions, clubbing, failure to thrive, respiratory failure), hypoxemia and diffuse abnormalities on chest imaging. Prior to testing for specific forms of ILD, the ATS Guideline emphasizes that children with diffuse lung disease should first undergo testing to exclude more common diseases such as pulmonary infection, congenital heart disease, cystic fibrosis, immunodeficiency and primary ciliary dyskinesia. Most of these disorders can be excluded based on clinical history, newborn screening results, widely available laboratory studies (microbiologic cultures, immune testing) and echocardiography. Bronchoscopy is often required to evaluate for pulmonary infection and airway abnormalities that can present with signs and symptoms that overlap those of ILD, though the role of bronchoscopy in diagnosing and monitoring specific forms of ILD is not well established.

The goals of evaluation include achieving classification & a specific diagnosis, as it is not enough to just diagnose ILD

All childhood ILD is not the same. Evaluations should aim to identify the specific diagnosis, as prognosis, clinical course and outcomes are quite variable among different causes of ILD, ranging from resolution of symptoms to lung transplant or death. For example, respiratory symptoms in most children with neuroendocrine hyperplasia of infancy (NEHI) improve slowly with time and treatment is generally supportive [3]. In contrast, neonatal respiratory failure due to surfactant protein-B or ABCA3 deficiency is usually lethal with lung transplantation as the only available treatment option [4].

Genetic testing plays a growing role

The ATS Guideline solidifies that genetic testing now plays a prominent role in the diagnosis of ILD in children. Newborn infants with severe or progressive respiratory failure or a family history of ILD should undergo clinical sequencing of surfactant-associated genes SFTPB, SFTPC and ABCA3 that encode surfactant proteins B and C and the ATP-binding cassette transporter A3. Testing for NKX2-1/TTF1 mutations or deletions is recommended for neonates and older infants with respiratory disease and congenital hypothyroidism and/or hypotonia. Neonates presenting with respiratory failure and refractory pulmonary hypertension should be tested for mutations or deletions involving FOXF1, which have been associated with alveolar capillary dysplasia [5]. For infants presenting with ILD beyond the newborn period, sequencing of SFTPC and ABCA3 is recommended when other initial studies are non-diagnostic. The ATS Guideline emphasizes considerations of genetic counseling, limitations of current sequencing modalities and challenges in interpretation of results.

Evaluating children with suspected ILD often requires a multidisciplinary approach

While a chest radiograph is a standard part of the initial diagnostic evaluation of any child with respiratory symptoms, additional information regarding disease character and distribution is generally needed from high-resolution thin-section chest CT scan. With proper technique, chest CT imaging patterns may sufficiently suggest a diagnosis so as to avoid the need for surgical lung biopsy. When lung biopsy is needed, chest CT is important in guiding the selection of biopsy sites. Surgical lung biopsy using video-assisted thoracoscopy (VATS) is recommended for infants with clinical urgency to identify the specific form of ILD or in whom other diagnostic evaluations have not yielded a specific diagnosis. Lung biopsy specimens should be handled according to established protocols, with sections available for histopathology, immunohistochemistry, microbiologic culture, electron microscopy, immunofluorescence or other special studies, in consultation with a pediatric pathologist experienced in childhood ILD [6]. Implementation of these ATS Guideline recommendations therefore remains predicated on the foundational capability to provide inter-disciplinary specialized respiratory care to neonates and young children, including access to flexible bronchoscopy, advanced chest imaging, genetic testing and pediatric surgical and pathology expertise.

Evaluation of neonates & infants with ILD should be focused

As reflected in the childhood diffuse lung disease classification structure, genetic and lung developmental disorders predominate among neonates and infants with ILD [2] Growth disorders including pulmonary hypoplasia and chronic lung disease related to prematurity are most common and usually diagnosed based on historical and radiographic findings. Lung biopsy is currently required to diagnose pulmonary interstitial glycogenosis, a form of childhood ILD which may present with hypoxemic respiratory insufficiency and pulmonary hypertension in infants [2]. To evaluate for other forms of ILD in infants, relevant genetic testing should be sent based on clinical presentation, associated findings and family history. As sequencing results may not be available for several weeks, a lung biopsy may still be necessary to make a diagnosis in severe or progressive cases.

ILD due to genetic disorders of surfactant dysfunction should be suspected in term or near-term neonates (≥36 weeks gestation) with severe, persistent respiratory failure that does not improve after 7–10 days, after exclusion of more common etiologies including infection and congenital cardiac anomalies. Neonates with recessive, loss-of-function mutations in SFTPB and ABCA3 present with severe respiratory failure at birth and have chest radiograph findings of diffuse ground glass opacities and superimposed air bronchograms, similar to premature neonates with surfactant deficiency. While individuals with dominant mutations in SFTPC typically present in later infancy or childhood, some develop respiratory symptoms at birth or within the first months of life. Notably, extra-pulmonary anomalies among infants with surfactant-associated gene mutations are uncommon. The presence of hypothyroidism or neurologic findings such as hypotonia or choreoathetosis in combination with ILD may suggest deletions or mutations in NKX2-1/TTF1 (brain–lung–thyroid disease) [7].

Alveolar capillary dysplasia (ACD) typically presents with neonatal respiratory failure, severe pulmonary hypertension and hypoxemia. Chest radiograph findings among infants with ACD are non-specific. Most infants with ACD have anomalies of the gastrointestinal, cardiovascular or genitourinary systems including intestinal malrotation, hydronephrosis or left ventricular outflow tract malformations [8]. Mutations or deletions involving FOXF1 have been identified in about half of neonates with ACD, and most cases are sporadic, although families with multiple affected children have been identified [8].

Management considerations

As no controlled trials of therapeutic interventions for childhood ILD have been performed, clinical management is guided by indirect evidence, case reports and clinical experience. While immunosuppressive therapies have been empirically utilized for many forms of childhood ILD, little evidence exists regarding clinical benefits, and negative side effects are well described. The ATS Guideline therefore emphasizes the need for decisions made on a case-by-case basis, discussions with families and close monitoring for side effects [1]. Neonates and infants with severe, progressive disease may be referred for lung transplantation evaluation after discussion with their family. All patients with childhood ILD should receive supportive and preventive care including nutritional support and monitoring, supplemental oxygen when needed and interventions to prevent serious infections such as immunizations. Families should receive education and support from care providers. Additionally, genetic counseling should be available to family members of patients with identified genetic disorders to address future reproductive planning and follow-up, especially if asymptomatic family members carry dominant mutations in SFTPC or NKX2-1/TTF1.

Future directions

In summary, there is growing recognition of the impact that childhood ILDs have on children and their families, as well as implications for the health care system. As such, childhood ILD has become a well-established component of neonatal and pediatric pulmonary practice. The ATS Guideline not only provides a comprehensive approach to the evaluation and management of ILD in infancy, but it also outlines an ambitious agenda for the future. Significant gaps remain in the implementation of standardized diagnostic approaches and the recommendations proposed in the ATS Guideline. Recommendations graded as ‘weak’ due to insufficient quality of evidence may be strengthened by future controlled studies. Further, additional work is needed to extend this work to older children with ILD.

Childhood ILDs remain among the vast majority of rare diseases for which there is no effective therapy. Efforts to define the epidemiology, natural history and pathogenesis of childhood ILDs are viewed as essential to enabling therapeutic advances and improved care for patients. There are several international collaborative efforts underway that aim to improve case ascertainment and develop registries, biobanks and clinical trials to establish evidence-based approaches [9]. With scientific discovery and patient advocacy, these efforts provide great promise that this ATS Guideline will therefore provide a foundation for much needed additional progress in this field.

Acknowledgement

We wish to thank all the individuals who participated in the development of the ATS Clinical Guideline that is discussed in this commentary. The views presented here do not necessarily represent those of the American Thoracic Society.

Financial & competing interests disclosure

LR Young is an author for Up-To-Date. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.