Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers

Abstract

Background: Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis.Methods: In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD.Results: In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97).Conclusions: we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.

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

“…A trend of lower absolute levels of IgA was also more frequently observed for cases. However, as in the work by Hartono and colleagues ( 14 ), it was not identified as an independent predictive factor itself, contrary to previous studies ( 13 , 16 ). The prevalence of polyarthritis in both groups of patients was similar.…”

“…Beyond these constraints, several important concerns arise from the model. On the one hand, according to our data and as previously described, splenomegaly and lymphadenopathies are associated with GLILD ( 13 – 16 ). Both lymphadenopathies and splenomegaly are easily detectable by physical examination and CT scan, making these variables extremely useful in defining determined subsets of CVID patients who may develop GLILD or present with compatible image findings in clinical practice.…”

“…The small sample size due to the low prevalence of the disease and the single-center approach raises the probability of type II error, and the statistical potency is limited; therefore, this study was conceived exploratory in nature. As no prospective analyses have been performed to date, our work shares the limitation of a retrospective design with previous studies ( 14 – 16 ). Moreover, there may be a selection bias as a result of including patients from a tertiary care referral unit with potentially different characteristics from those of patients in the general population.…”

“…At the time of enrolment, both GLILD cases and controls were required to have at least one HRCT scan; IgG, IgA, IgM, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels at last follow-up prior to diagnosis or GLILD immunosuppressant therapy; one abdominal ultrasound; clinical history regarding cancer, enteropathy, autoimmune cytopenia, and lymphoproliferation; and B- and T-cell subpopulation count by flow cytometry, similar to previously described ( 16 ).…”

“…Some authors have demonstrated a significant association between GLILD and other dysimmune phenomena such as immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and lymphatic hyperplasia of the spleen, liver, and lymphadenopathies (14)(15)(16). Similarly, ITP and AIHA have been related to the development of granulomas in any tissue (6,17); and therefore, GLILD may not be exclusively considered as a localized form of lymphoproliferation, as it has been suggested in some works evaluating the features of the disease using 18 F-FDG PET/CT (18,19).…”