Clinical Features and Lymphocyte Immunophenotyping Analysis in Primary Immunodeficiency Patients With Non-transplant Lymphoproliferative Disorders

Purpose: Lymphoproliferative disorders (LPD) comprise a heterogeneous group of diseases and can be classified categorized into the category as being immune dysregulation diseases in primary immunodeficiency diseases (PID) that typically represent as monogenetic X-linked and autoimmune lymphoproliferative diseases (XLP and ALPS). The LPD phenotype extends to other categories in PID and its distribution remains scarce. Methods: The clinical course and lymphocyte immunophenotyping in PID patients with the LPD phenotype who were referred to the PICAR (Primary Immunodeficiency Care And Research) institute were investigated between 2004 and 2020.Results: Of the 96 enrolled patients, 31 (32.3%) (median age 144, range 3-252 months) developed the LPD phenotype mainly encompassing lymphadenopathy (in 10 patients), refractory inflammatory bowel disease (IBD)-like with intestinal lymphadenopathy in 8 and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). The LPD phenotype was most frequently present in the categories of antibody deficiency (in 7: 2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (in 6: 4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (in 6: 2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (in 5: 2 IL2RG, 1 CD40L, 1 ZAP70 and 1 unknown) and syndromic features (in 4: 2 STAT3-LOF, 1 WAS and 1 ATM) as well as three patients with anti-IFN-γ autoantibodies. Those with the LPD phenotype had a significantly higher mortality rate than those without (p=0.0016) despite a similar age at onset (median 66 vs 44 months) and follow-up duration (138 vs 144 months). EBV virus load was only detectable in the PIK3CD and HLH patient each. An increased senescent (CD8+CD57+) and CD21-low components, and disturbed transitional B (CD38+IgM++), plasamablast B (CD38++IgM-), memory B (CD19+CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping. However, except patients with CD40L and ZAP70 mutations, those with profound T cell defects who bear almost naïve (T and B cells) components and extreme low in the remaining subsets components trended to develop their LPD phenotype. Conclusion: The spectrum of the LPD phenotype in one third of the PID patients overriding the categorical boundaries had higher mortality and heterogeneous lymphocyte disturbances, especially higher senescent and CD21-low but lower memory B subpopulations. Large-scale longitudinal studies of PID patients are needed to validate the correlation between immunophenotype and the LPD status.

Predictive value of lymphocyte immunophenotyping (LIP) in primary central nervous system lymphoma (PCNSL).

2063 Background: Immunity plays an important role in PCNSL development. PCNSL predictive factors need to be improved. Objective: to evaluate the characteristics and predictive value of blood LIP in PCNSL patients. Methods: we prospectively analyzed blood LIP in all newly PCNSL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected. Results: fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). All patients presented with cerebral involvement, 13 (25%) with cerebrospinal fluid extension and 8 (15%) with ocular extension. Thirty-four patients (62%) benefited of steroid treatment at the time of LIP. Patients characteristics did not differ depending on steroid intake. Forty-eight patients (95%) benefited of polychemotherapy with high-dose methotrexate as first line treatment. We observed three (6%) lymphoproliferative syndromes on the LIP and 33 patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4/CD8 ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results, including CD4 (p = 0.475) or CD8 (p = 0.726) rates and CD4/CD8 ratio (p = 0.727). Complete or partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4/CD8 ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077). A ROC curve analysis was performed with an AUC of 0.684 allowing the selection of a CD4/CD8 ratio cutoff of 1.97 with a sensibility, specificity, positive predictive value, and negative predictive value to identify refractory patients of 90%, 55%, 35% and 95% respectively. Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI: 6.5-22.9) and 43.2 (95%CI: 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4/CD8 ratio > 1.97 was associated with poor PFS (p = 0.043, HR = 3.32 [1.02-4.88]) and tended to be associated with worse OS (p = 0.064). Conclusions: LIP at baseline may predict refractory disease and exhibits a prognostic value in PCNSL patients.

In vitro testing for allergic and immunologic diseases

In vitro tests are used to assist in the diagnosis of both allergic and immunologic diseases. Unfortunately, there is no single test that is pathognomonic for most allergic diseases. The most commonly ordered in vitro test by allergists is allergen specific IgE (sIgE), which is used to help diagnose IgE mediated hypersensitivity to foods, aeroallergens and venoms. Multiple assays exist, although none of these assays have been adopted as the industry standard. Epicutaneous skin test is also a fundamental test in the diagnosis of IgE mediated hypersensitivity. In addition, total IgE, basophil activation test (BAT), and serum tryptase may also be useful in elucidating allergic diseases. Immunologists rely on laboratory testing to diagnose primary immunodeficiency diseases. These tests include serum quantitative immunoglobulins, lymphocyte immunophenotyping by flow cytometry and immune cell functional testing. Furthermore, genetic testing is invaluable in the diagnosis of many primary Immunodeficiencies.