Pediatric Interstitial Lung Diseases: Emerging Perspectives in Diagnosis, Classification, and Advanced Therapies 

The Evolving Landscape of chILD 

Childhood interstitial lung diseases (chILD) represent a heterogeneous group of more than 200 rare respiratory disorders that continue to pose significant challenges in pediatric pulmonology (Fenu et al., 2023). Although historically considered extremely rare, recent investigations suggest that chILD may be less uncommon than previously thought. A recent study published in 2024 based on French population data reported a prevalence of 44 cases per million children, underscoring the growing need for awareness and research in this field (Bush & Nogee, 2024). Despite their rarity, chILD contribute substantially to pediatric morbidity and mortality, and our understanding of these conditions is rapidly evolving, as highlighted by numerous publications in 2024 and 2025 offering new insights into pathophysiology, disease progression, and therapeutic strategies (Cheng et al., 2025). 

Diagnostic challenges often stem from the non-specific nature of early symptoms and the limited familiarity of general pediatricians with this broad category of disorders (Bush & Nogee, 2024; Tsujioka et al., 2024). This emphasizes the urgent need to enhance early recognition and management to optimize long-term clinical outcomes. 

Classification and Diagnosis: A Renewed and Less Invasive Approach 

One of the most significant advancements concerns the recognition that adult interstitial lung disease classifications are not applicable to chILD, particularly in early-onset forms (Tsujioka et al., 2024). The Children’s Interstitial Lung Disease Research Cooperative Group and the European Union-ChILD Collaboration Network have proposed new age-based categories for pediatric ILD, differentiating between disorders occurring in children under 2 years of age and those not specific to infancy. This refinement better reflects the unique clinical, radiological, and molecular characteristics of pediatric disease (Fenu et al., 2023). 

Although diagnosis still relies heavily on histopathological findings from lung biopsies, molecular technologies are revolutionizing the diagnostic process. Advances in genetic testing have elucidated the molecular basis of many chILD disorders, making molecular diagnosis increasingly fundamental (Tsujioka et al., 2024). Identifying pathogenic variants is clinically relevant, as these findings can directly guide decision-making and may help avoid invasive procedures such as lung biopsy (Alrehaili et al., 2024, p. 151). This enhances diagnostic accuracy and enables the identification of newly recognized entities (Alrehaili et al., 2024, p. 151; Griese et al., 2024; Tsujioka et al., 2024). Nonetheless, high-resolution computed tomography remains the imaging gold standard for chILD and plays a crucial role alongside clinical and genetic information (Tsujioka et al., 2024). 

Pulmonary Fibrosis in Childhood: A Bridge to Adulthood 

An area of growing interest is pulmonary fibrosis, which may originate in childhood and progress into adulthood (Griese et al., 2024). Recent reports suggest that many children diagnosed with chILD continue to show progressive or fibrosing disease into adult life (Griese et al., 2024). A large prospective 2025 study from the European chILD-EU registry examined more than one thousand children and found that 11.6% had pulmonary fibrosis (Griese et al., 2025, p. 8). This study also highlighted the need for pediatric-specific fibrosis criteria, given the remarkable regenerative capacity of developing lungs, which extends into adolescence. Such plasticity offers the possibility of reversibility even in fibrotic processes, an important distinction from adult ILD (Griese et al., 2025, p. 10). This underscores the importance of careful monitoring and targeted interventions to preserve lung function during growth. 

New Therapeutic Frontiers: From Research to Clinical Practice 

Historical treatments for chILD have largely been empirical, but emerging research is paving the way toward more targeted and individualized therapies. Publications from 2024 and 2025 highlight notable advances in novel therapeutic strategies (Cheng et al., 2025). Among these, tyrosine kinase inhibitors, particularly nintedanib, are showing promising results. Already approved in adults for idiopathic pulmonary fibrosis, nintedanib has demonstrated an acceptable safety profile in children and appears to slow fibrosis progression and pulmonary function decline. Although not yet approved for pediatric use, its therapeutic potential is substantial (Faelli et al., 2024, p. 7). 

Other innovative approaches include mesenchymal stem cell therapy for respiratory failure associated with surfactant protein C dysfunction (Faelli et al., 2024, p. 7) and gene therapy using viral vectors for surfactant protein B deficiency in murine models (Faelli et al., 2024, p. 7). High-throughput drug screening has identified cyclosporine A as a potential molecular corrector for specific ABCA3 variants, offering a therapeutic alternative when hydroxychloroquine fails. Advances in gene therapy further expand opportunities for personalized treatment strategies (Tang et al., 2025, p. 12). These emerging therapeutic approaches aim to target the underlying cause of disease rather than merely addressing symptoms, marking a shift toward precision medicine in chILD. 

Future Perspectives: Toward Personalized and Collaborative Medicine 

Despite significant progress, major challenges remain, including disease heterogeneity and the need to bridge pediatric and adult ILD care (Griese et al., 2024). International collaboration is essential for assembling large patient cohorts and developing robust clinical trials, given the rarity of these disorders (Manali et al., 2024; Schlapbach et al., 2024). Networks such as the European Union–ChILD Collaboration Network play a pivotal role in this effort, contributing to updated classifications and facilitating prospective multicenter data collection (Fenu et al., 2023; Griese et al., 2025, p. 8). The ultimate goal is to develop targeted treatments capable of significantly improving quality of life and long-term prognosis for affected children, with growing emphasis on biomarkers, innovative drugs, and optimized therapeutic strategies. Recent literature indicates a promising future in which molecular understanding and advanced therapies—supported by strong international collaboration—transform the management of pediatric interstitial lung diseases, offering renewed hope to children and their families.

Key Clinical Questions & Evidence-Based Answers

What are childhood interstitial lung diseases (chILD)?

Childhood interstitial lung diseases (chILD) are a heterogeneous group of more than 200 rare pediatric respiratory disorders, characterized by diffuse lung involvement and high clinical complexity. Although historically considered extremely rare, recent data suggest that chILD are less uncommon than previously thought, with a reported prevalence of 44 cases per million children in France.

Why is early diagnosis of chILD challenging?

Diagnosis is often delayed due to non-specific early symptoms and limited familiarity among general pediatricians. These factors contribute to late referral and highlight the need for improved awareness and structured diagnostic pathways.

Why are adult ILD classifications not applicable to children?

Adult ILD classifications fail to capture the distinct clinical, radiological, and molecular features of pediatric disease, particularly in early-onset forms. Pediatric-specific, age-based classifications (e.g. <2 years vs non-infancy-specific disorders) better reflect disease biology in children.

What is the current diagnostic gold standard for chILD?

High-resolution computed tomography (HRCT) remains the imaging gold standard, integrated with clinical evaluation and increasingly with genetic and molecular diagnostics, which can refine diagnosis and reduce invasive procedures.

Can genetic testing reduce the need for lung biopsy?

Yes. Advances in molecular genetics allow identification of pathogenic variants that directly inform diagnosis and management, and in selected cases may avoid invasive lung biopsy, improving diagnostic accuracy and patient safety.

Can pulmonary fibrosis begin in childhood?

Yes. Pulmonary fibrosis can originate in childhood and persist into adulthood. Data from the chILD-EU registry (2025)show that 11.6% of over 1,000 children had fibrosing ILD, underscoring the need for pediatric-specific fibrosis criteria and long-term follow-up.

Which advanced therapies are emerging for chILD?

Emerging therapies include:

• Nintedanib (tyrosine kinase inhibitor), with acceptable pediatric safety data and potential to slow fibrosis progression (off-label).

• Mesenchymal stem cell therapy for surfactant protein C dysfunction.

• Gene therapy (preclinical) for surfactant protein B deficiency.

• Cyclosporine A as a molecular corrector in selected ABCA3 variants, particularly when hydroxychloroquine fails.

SCIENTIFIC SUMMARY BOX

Pediatric Interstitial Lung Diseases (chILD): Scientific Overview

Childhood interstitial lung diseases (chILD) comprise a broad and heterogeneous spectrum of rare pediatric lung disorders with significant morbidity and potential long-term consequences. Once considered exceptionally rare, recent epidemiological data indicate higher prevalence than previously assumed. Diagnostic challenges arise from non-specific early symptoms and limited awareness, leading to delayed recognition.

Modern classification systems emphasize pediatric-specific, age-based categories, reflecting unique developmental, radiological, and molecular features distinct from adult ILD. While lung biopsy has historically played a central role, HRCT combined with genetic and molecular diagnostics now represents the cornerstone of evaluation, enabling more precise and less invasive diagnosis.

Pulmonary fibrosis represents a critical disease trajectory that may begin in childhood and extend into adult life. Pediatric lungs exhibit unique regenerative capacity, necessitating dedicated pediatric fibrosis criteria and longitudinal monitoring.

Therapeutic strategies are evolving from empirical treatment toward precision medicine, including antifibrotic agents (e.g. nintedanib), cellular therapies, gene-based approaches, and targeted molecular correctors. International collaboration through networks such as EU-ChILD is essential to advance classification, research, and clinical trials, ultimately improving long-term outcomes for affected children.

Bibliografia:

• Schlapbach et al., 2024 Schlapbach, L. J., Ramnarayan, P., Gibbons, K. S., et al.. Building global collaborative research networks in paediatric critical care: a roadmap. The Lancet Respiratory Medicine.
• Tang et al., 2025 Tang, X., Zhao, S., Shen, Y., et al.. A comparative analysis of clinical phenotypes and outcomes in childhood interstitial lung disease due to surfactant dysfunction disorders: focusing on mutations in SFTPC, ABCA3, and NKX2-1 genes. Frontiers in Pediatrics.
• Cheng et al., 2025 Cheng, P. C., Liptzin, D. R., Garagozlo, K., et al.. Pediatric Pulmonology 2024 year in review: Rare and diffuse lung disease. Pediatric Pulmonology.
• Manali et al., 2024 Manali, E. D., Griese, M., Nathan, N., et al.. Childhood interstitial lung disease survivors in adulthood: a European collaborative study. The Lancet Respiratory Medicine.
• Tsujioka et al., 2024 Tsujioka, Y., Nishimura, G., Nishi, E., et al.. Childhood interstitial lung diseases: current understanding of the classification and imaging findings. Pediatric Radiology.
• Bush & Nogee, 2024 Bush, A., & Nogee, L. M.. Children’s interstitial lung disease (chILD): less rare than we thought?. Thorax.
• Fenu et al., 2023 Fenu, G., Astori, C., & Lombardi, E.. Childhood interstitial lung disease: When to suspect and what to do. Paediatric Respiratory Reviews.
• Faelli et al., 2024 Faelli, N., Chironi, F., Andrenacci, B., et al.. The lost chILD: a case report of delayed diagnosis of Surfactant Protein C Deficiency in a 15-year-old African male. Pediatric Pulmonology.
• Griese et al., 2025 Griese, M., Reu, S., Ley‐Zaporozhan, J., et al.. Fibrosing interstitial lung disease in childhood: prevalence and disease trajectories. Thorax.
• Alrehaili et al., 2024 Alrehaili, G., Kemppainen, J. L., Kalra, S., et al.. Genetic Testing Goes Beyond Imaging and Histological Evaluation in Pleuroparenchymal Fibroelastosis. Lung.
• Griese et al., 2024 Griese, M., Kurland, G., Cidon, M., et al.. Pulmonary fibrosis may begin in infancy: from childhood to adult interstitial lung disease. Thorax.

No metadata found.