Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immune Deficiency (CVID): an in-depth clinical, immunological, functional and radiological exploration with a focus on its management, challenged by chronic CMV infection

Mattia Moratti^1,2Gioacchino Schifino^3*Francesco Baccelli^4,5Simona Ferrari⁶Elisabetta Magrini⁷Mirna Bassi⁷Aldo Guerrieri⁸Maurizio Zompatori⁹Marcello Lanari^10,5Francesca Conti^10,5

• ¹Specialty School of Paediatrics - University of Bologna, Bologna, Emilia-Romagna, Italy
• ²Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
• ³Unità Operativa di Pneumologia - Clinica delle Malattie dell'apparato respiratorio - Arcispedale Sant’Anna – Azienda Ospedaliero Universitaria di Ferrara, Ferrara, Italy
• ⁴Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁵Department of Medical and Surgical Sciences, University of Bologna, Bologna, Emilia-Romagna, Italy
• ⁶Genetic Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁷Laboratory of immuno-haematology - Laboratorio Unico Metropolitano, Azienda USL, Bologna, Emilia-Romagna, Italy
• ⁸Respiratory and Critical Care Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
• ⁹Radiologia, Villa Erbosa, Gruppo San Donato, Bologna, Italy
• ¹⁰Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Emilia-Romagna, Italy

Background Common Variable Immune Deficiency (CVID) is the most prevalent inborn error of immunity (IEI), marked by diverse clinical-immunological phenotypes and significant immunedysregulation, including granulomatous lymphocytic interstitial lung disease (GLILD). GLILD is a severe manifestation of CVID, contributing to reduced life expectancy and challenging diagnosis due to its insidious and nonspecific clinical course. Current management strategies for GLILD rely on expert opinion due to a lack of randomized controlled trials (RCTs).Objectives This study aims to provide a comprehensive immunophenotypical characterization of CVID patients with and without GLILD, investigate predictive biomarkers for GLILD development, and explore therapeutic strategies, particularly during concomitant SARS-CoV-2 and chronic CMV infections. Sources Primary data were collected from a cohort of 25 CVID patients undergoing high-resolution computed tomography (HRCT), immunophenotyping, and serum immunoglobulin analysis at diagnosis and after immunoglobulin replacement therapy. Existing literature on CVID and GLILD biomarkers, immunological profiles, and therapeutic interventions informed comparative analyses.Content Patients with GLILD exhibited distinct immunophenotypical features, including reduced regulatory T-cells, CD8+ naïve, central memory T-cells, and B-cell subsets (memory and switched memory), alongside increased CD21low B-cells and naïve B-cells, indicative of chronic inflammation-driven immune activation. IgA and IgG4 concentrations were significantly lower in GLILD patients at diagnosis. Immunosuppressive therapy, predominantly mycophenolate mofetil (MMF), demonstrated favorable clinical and functional outcomes, though radiological progression persisted in some cases. CMV infection in GLILD patients on immunosuppressants resulted in favorable outcomes, underscoring the importance of personalized treatment strategies.This study highlights novel immunological markers and clinical-radiological patterns as potential predictors for GLILD, advocating for their integration into diagnostic and monitoring frameworks to reduce reliance on invasive histopathology. Future research should focus on validating biomarkers and conducting RCTs to establish evidence-based guidelines for GLILD management.