Treatment Strategies for GLILD in Common Variable Immunodeficiency: A Systematic Review

Abstract

IntroductionBesides recurrent infections, a proportion of patients with Common Variable Immunodeficiency Disorders (CVID) may suffer from immune dysregulation such as granulomatous-lymphocytic interstitial lung disease (GLILD). The optimal treatment of this complication is currently unknown. Experienced-based expert opinions have been produced, but a systematic review of published treatment studies is lacking.GoalsTo summarize and synthesize the published literature on the efficacy of treatments for GLILD in CVID.MethodsWe performed a systematic review using the PRISMA guidelines. Papers describing treatment and outcomes in CVID patients with radiographic and/or histologic evidence of GLILD were included. Treatment regimens and outcomes of treatment were summarized.Results6124 papers were identified and 42, reporting information about 233 patients in total, were included for review. These papers described case series or small, uncontrolled studies of monotherapy with glucocorticoids or other immunosuppressants, rituximab monotherapy or rituximab plus azathioprine, abatacept, or hematopoietic stem cell transplantation (HSCT). Treatment response rates varied widely. Cross-study comparisons were complicated because different treatment regimens, follow-up periods, and outcome measures were used. There was a trend towards more frequent GLILD relapses in patients treated with corticosteroid monotherapy when compared to rituximab-containing treatment regimens based on qualitative endpoints. HSCT is a promising alternative to pharmacological treatment of GLILD, because it has the potential to not only contain symptoms, but also to resolve the underlying pathology. However, mortality, especially among immunocompromised patients, is high.ConclusionsWe could not draw definitive conclusions regarding optimal pharmacological treatment for GLILD in CVID from the current literature since quantitative, well-controlled evidence was lacking. While HSCT might be considered a treatment option for GLILD in CVID, the risks related to the procedure are high. Our findings highlight the need for further research with uniform, objective and quantifiable endpoints. This should include international registries with standardized data collection including regular pulmonary function tests (with carbon monoxide-diffusion), uniform high-resolution chest CT radiographic scoring, and uniform treatment regimens, to facilitate comparison of treatment outcomes and ultimately randomized clinical trials.

Integrating Clinics, Laboratory, and Imaging for the Diagnosis of Common Variable Immunodeficiency-Related Granulomatous–Lymphocytic Interstitial Lung Disease

“…However, the definite diagnosis requires both radiological and histopathological assessment of the lung, mainly through techniques such as transbronchial biopsy or video-assisted thoracoscopic (VATS) biopsy that entails important morbidity. Furthermore, it has been revealed as a major cause of death in CVID patients with non-infectious comorbidities owing to the lack of tools aiding its early clinical suspicion and diagnosis, as well as undefined therapeutic strategies ( 12 ). There is still no worldwide consensus on GLILD treatment and data on patients’ overall survival, and quantitative well-controlled evidence is lacking ( 12 ).…”

“…Furthermore, it has been revealed as a major cause of death in CVID patients with non-infectious comorbidities owing to the lack of tools aiding its early clinical suspicion and diagnosis, as well as undefined therapeutic strategies ( 12 ). There is still no worldwide consensus on GLILD treatment and data on patients’ overall survival, and quantitative well-controlled evidence is lacking ( 12 ). Several immunosuppressants such as corticosteroids, cyclosporine, infliximab, azathioprine, and rituximab are being used, with variable efficacy ( 12 , 13 ).…”

“…There is still no worldwide consensus on GLILD treatment and data on patients’ overall survival, and quantitative well-controlled evidence is lacking ( 12 ). Several immunosuppressants such as corticosteroids, cyclosporine, infliximab, azathioprine, and rituximab are being used, with variable efficacy ( 12 , 13 ).…”

Granulomatous–lymphocytic interstitial lung disease: an international research prioritisation

“…The immune and inflammatory complications of CVID such as GLILD are important and associated with reduced survival [ 2 ]. However, as a rare manifestation of a rare disease, the scientific understanding and evidence basis to inform effective diagnosis and management of GLILD [ 3 ] are limited. There are challenges with the definition of GLILD presented above and the terminology more widely of ILD in people with CVID, which requires further consensus.…”

“…This process generated a list of seven suggestions for resource development and 27 research questions. From our knowledge of the literature, including a recent systematic review [ 3 ], none of the 27 questions had already been adequately addressed and, therefore, all 27 questions went forward to the final prioritisation.…”