Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency

Purpose About 20–30% of patients with common variable immunodefciency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodefciency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID. Methods We analyzed serum biomarkers related to infammation, pulmonary epithelium injury, fbrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n=16), patients with other non-infectious complications (n=37), and patients with infections only (n=20). Results We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, refecting T cell activation and exhaustion, compared to both CVID patients with other infammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. Conclusion GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients

Increased Plasma Levels of Triglyceride-Enriched Lipoproteins Associate with Systemic Inflammation, Lipopolysaccharides, and Gut Dysbiosis in Common Variable Immunodeficiency

Purpose: Triglycerides (TG) and their major transport lipoprotein in the circulation (VLDL) appear to be related to inflammation. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with gut microbial dysbiosis. We hypothesized that CVID patients have disturbed TG/VLDL profiles associated with these clinical characteristics. Methods: We measured plasma concentrations of TGs, inflammatory markers, and lipopolysaccharide (LPS) in 95 CVID patients and 28 healthy controls. Additionally, in 40 CVID patients, we explored plasma lipoprotein profiling, fatty acid, gut microbial dysbiosis, and diet. Results: TG levels were increased in CVID patients as compared to healthy controls (1.36 ± 0.53 mmol/l versus 1.08 ± 0.56 [mean, SD], respectively, P = 0.008), particularly in the clinical subgroup “Complications,” characterized by autoimmunity and organ-specific inflammation, compared to “Infection only” (1.41 mmol/l, 0.71[median, IQR] versus [1.02 mmol/l, 0.50], P = 0.021). Lipoprotein profile analyses showed increased levels of all sizes of VLDL particles in CVID patients compared to controls. TG levels correlated positively with CRP (rho = 0.256, P = 0.015), IL-6 (rho = 0.237, P = 0.021), IL-12 (rho = 0.265, P = 0.009), LPS (r = 0.654, P = 6.59 × 10−13), CVID-specific gut dysbiosis index (r = 0.315, P = 0.048), and inversely with a favorable fatty acid profile (docosahexaenoic acid [rho =  − 0.369, P = 0.021] and linoleic acid [rho =  − 0.375, P = 0.019]). TGs and VLDL lipids did not appear to be associated with diet and there were no differences in body mass index (BMI) between CVID patients and controls. Conclusion: We found increased plasma levels of TGs and all sizes of VLDL particles, which were associated with systemic inflammation, LPS, and gut dysbiosis in CVID, but not diet or BMI.publishedVersio

Real-World Experiences With Facilitated Subcutaneous Immunoglobulin Substitution in Patients With Hypogammaglobulinemia, Using a Three-Step Ramp-Up Schedule

Immunoglobulin replacement therapy with facilitated subcutaneous immunoglobulin (fSCIg) can be self-administrated at home and given at longer intervals compared to subcutaneous immunoglobulin (SCIg) therapy, but real-word experience of home-based fSCIg therapy is limited. Herein we present our real-word clinical experiences with home-based fSCIg therapy using a three-step ramp-up schedule. We registered data from all patients with immunodeficiency starting fSCIg from 01.01.2017 to 31.12.2019. For comparison we also included patients starting conventional SCIg training. Fifty-four patients followed for a median of 18 months (IQR 12, range 0–40), received fSCIg training, and 84 patients received conventional SCIg training. Out of 54 patients starting with fSCIg, 41 patients had previous experience with conventional SCIg therapy, and the main reason for starting fSCIg was ‘longer intervals between therapies’ (n=48). We found an increase in training requirement for fSCIg (3 ± 1 [2-9] days) compared to conventional SCIg (2 ± 0 [1-7] days), P < 0.001 (median ± IQR, [range]). For fSCIg training, IgG levels were stable from baseline (8.9 ± 2.3 g/L), 3-6 months (10.2 ± 2.2 g/L) and 9-12 months (9.9 ± 2.3 g/L), P = 0.11 (mean ± SD). The most common side-effect was: ‘rubor around injection site’ (n=48, 89%). No patients experienced severe adverse events (grade 3-4). Thirteen patients (24%) discontinued fSCIg therapy due to local adverse events (n=9), cognitive/psychological difficulties (n=6) and/or systemic adverse events (n=3). In conclusion, fSCIg training using a three-step ramp-up schedule is safe and well tolerated by the majority of patients, but requires longer training time compared to conventional SCIg

Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency—Features of CT and 18F-FDG Positron Emission Tomography/CT in Clinically Progressive Disease

Common variable immunodeficiency (CVID) is characterized not only by recurrent bacterial infections, but also autoimmune and inflammatory complications including interstitial lung disease (ILD), referred to as granulomatous-lymphocytic interstitial lung disease (GLILD). Some patients with GLILD have waxing and waning radiologic findings, but preserved pulmonary function, while others progress to end-stage respiratory failure. We reviewed 32 patients with radiological features of GLILD from our Norwegian cohort of CVID patients, including four patients with possible monogenic defects. Nineteen had deteriorating lung function over time, and 13 had stable lung function, as determined by pulmonary function testing of forced vital capacity (FVC), and diffusion capacity of carbon monoxide (DLCO). The overall co-existence of other non-infectious complications was high in our cohort, but the prevalence of these was similar in the two groups. Laboratory findings such as immunoglobulin levels and T- and B-cell subpopulations were also similar in the progressive and stable GLILD patients. Thoracic computer tomography (CT) scans were systematically evaluated and scored for radiologic features of GLILD in all pulmonary segments. Pathologic features were seen in all pulmonary segments, with traction bronchiectasis as the most prominent finding. Patients with progressive disease had significantly higher overall score of pathologic features compared to patients with stable disease, most notably traction bronchiectasis and interlobular septal thickening. 18F-2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography/CT (PET/CT) was performed in 17 (11 with progressive and six with stable clinical disease) of the 32 patients and analyzed by quantitative evaluation. Patients with progressive disease had significantly higher mean standardized uptake value (SUVmean), metabolic lung volume (MLV) and total lung glycolysis (TLG) as compared to patients with stable disease. Nine patients had received treatment with rituximab for GLILD. There was significant improvement in pathologic features on CT-scans after treatment while there was a variable effect on FVC and DLCO. Conclusion Patients with progressive GLILD as defined by deteriorating pulmonary function had significantly greater pathology on pulmonary CT and FDG-PET CT scans as compared to patients with stable disease, with traction bronchiectasis and interlobular septal thickening as prominent features

Elevated plasma sTIM-3 levels in patients with severe COVID-19

Background - The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. Objective - We examined the parameters of activation of different leukocyte subsets in COVID-19–infected patients in relation to disease severity. Methods - We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19–infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. Results - Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B–type natriuretic peptide. Conclusion - Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell–targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder