Pediatric interstitial lung disease (ILD) represents a heterogeneous group of rare but potentially severe pulmonary disorders characterized by diffuse parenchymal involvement and impaired gas exchange. Among these, immune-mediated ILD constitutes a significant subgroup, often associated with autoimmune and inflammatory conditions, leading to progressive lung damage and substantial morbidity.

Early diagnosis and accurate prognostication of pediatric ILD remain challenging due to overlapping clinical presentations, nonspecific radiological findings, and the lack of reliable biomarkers. Consequently, there is an increasing need to identify measurable biological indicators that can aid in both diagnosis and prediction of disease progression.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that plays a central role in immune regulation and has been implicated in various inflammatory and autoimmune disorders. Elevated IL-6 levels have been associated with disease activity and severity in multiple pulmonary conditions. Similarly, matrix metalloproteinase-7 (MMP-7) is involved in extracellular matrix remodeling and has emerged as a promising biomarker in interstitial lung diseases, reflecting ongoing tissue injury and fibrosis.

The combined assessment of IL-6 and MMP-7 may provide valuable insights into both inflammatory activity and fibrotic processes in immune-mediated ILD. This dual role suggests their potential utility not only as diagnostic markers but also as prognostic indicators for disease progression and clinical outcomes.

This study aims to evaluate the diagnostic and prognostic utility of IL-6 and MMP-7 in children with immune-mediated interstitial lung disease, with the goal of improving early detection, risk stratification, and clinical management.

Inclusion Criteria:

• Children aged 2-18 years with immune-mediated interstitial lung disease, including:

  • Connective Tissue Disease-associated ILD (CTD-ILD), such as Juvenile Idiopathic Arthritis, according to ILAR Classification, 2019, Systemic Lupus Erythematosus, according to EULAR/ACR Classification, 2023, Juvenile Dermatomyositis, according to EULAR/ACR Classification for Juvenile Idiopathic Inflammatory Myopathies, 2017, Mixed Connective Tissue Disease, according to Kasukawa Criteria, 2019, and Systemic Sclerosis, according to ACR/EULAR Classification, 2013.
  • Pediatric vasculitis, according to EULAR/PRINTO/PReS Pediatric Vasculitis Classification Criteria, 2022 update.
  • Pediatric sarcoidosis, according to WASOG pediatric consensus, 2019

• Children with newly diagnosed or previously diagnosed cases in whom IL-6 and MMP- 7 biomarker levels can be obtained according to standardized procedures.

• Children whose guardians have provided written informed consent, according to institutional ethical guidelines.

Exclusion Criteria:

• • ILD caused by infectious, environmental, drug-induced, or post-injury etiologies, rather than immune-mediated mechanisms, according to ERS/ATS chILD guidelines, 2025.

  • Patients with incomplete diagnostic documentation preventing confirmation according to recognized criteria, as per disease-specific guidelines mentioned above.
  • Children with other chronic lung diseases unrelated to immune-mediated pathology, such as congenital malformations or cystic fibrosis, according to pediatric pulmonology consensus, 2024.
  • Cases in which biomarker samples cannot be obtained or processed reliably, according to laboratory standards for IL-6 and MMP-7 measurement

Group 1: Immune-mediated ILD

Pediatric patients with confirmed interstitial lung disease associated with immune-mediated disorders, including:

• Connective tissue diseases (CTD) such as SLE, juvenile idiopathic arthritis, juvenile dermatomyositis, mixed connective tissue disease, systemic sclerosis
• Vasculitis-associated ILD
• Sarcoidosis-associated ILD
• Autoimmune musculoskeletal disorders with ILD Group 2: Immune-mediated disease without ILD Pediatric patients with immune-mediated diseases (CTD, vasculitis, sarcoidosis, autoimmune musculoskeletal disorders) but without ILD.

This group serves as a comparison to determine whether elevations in IL-6 and MMP-7 are specific to ILD rather than the underlying immune disease itself.

Group 3: Healthy Controls Age- and sex-matched healthy children without immune-mediated disease or lung disease used as a baseline reference for biomarker levels.