Novel Approaches to the Assessment and Management of Granulomatous Lymphocytic Interstitial Lung Disease (GLILD)

Abstract

Introduction: Granulomatous-lymphocytic interstitial lung disease (GLILD) is generally considered a manifestation of systemic immune dysregulation occurring in up to 20% of people with common variable immunodeficiency disorders (CVID). GLILD is associated with increased morbidity and mortality and presents a significant diagnostic and management challenge. There is a lack of evidence-based guidelines of GLILD despite its clinical significance. This thesis aimed to bridge knowledge gaps, offering new insights and methods to improve GLILD assessment and management. Methods: Several methods are employed. First, an international research prioritization exercise was conducted based on methodology developed by the James Lind Alliance. Subsequently, a systematic review was undertaken to summarise the current literature on diagnostic approaches in GLILD. Additionally, a national data analysis focusing on non-infectious complications (NICs) in CVID patients with and without GLILD was conducted to assess the variation in clinical features and the risk factors associated with this condition. Moreover, a clinicians survey was conducted to evaluate the current practice regarding lung biopsy in the work up of GLILD. A retrospective analysis was undertaken to assess three treatment regimens at our centre. Finally, a prospective study was conducted to evaluate the utility of the 6-minute walk test (6MWT) in GLILD. Results: The international research prioritization exercise identified key areas for future research. The systematic review suggested that high-resolution computed tomography (HRCT) and lung biopsy were required for definitive diagnosis of GLILD, emphasizing the need for standardized diagnostic criteria. In the CVID cohort with NICs, chronic lung diseases, particularly GLILD, were predominant, with lymphadenopathy associated with GLILD. The clinician survey underscored the complexity of diagnosing GLILD and highlighted varied opinions on the necessity and effectiveness of lung biopsies. Treatment outcomes varied, with corticosteroids demonstrating inducing remission but presenting challenges in long-term management, while mycophenolate showed promise in disease stabilization and corticosteroid sparing. Functional assessments, particularly the 6MWT and the King's Brief Interstitial Lung Disease (K-BILD) questionnaire, were valuable measures with good reproducibility in GLILD patients. Conclusion: This thesis contributes significantly to the understanding and management of GLILD in CVID. By addressing critical research priorities, elucidating diagnostic challenges, evaluating treatment modalities, and integrating functional assessments. Our findings inform clinical practice and guide future research. Ultimately, our efforts aim to improve patient outcomes and promote international collaboration.