OBJECTIVE: To investigate predictors of hypogammaglobulinemia (HGG) and severe infection event (SIE) in patients with autoimmune disease (AID) receiving rituximab (RTX) therapy.
METHODS: This was a retrospective study conducted in a tertiary medical center in China. Predictors of HGG or SIE were assessed using Cox analysis. Restricted cubic spline (RCS) analysis was applied to examine the correlation between glucocorticoid (GC) maintenance dose and SIE.
RESULTS: A total of 219 patients were included in this study, with a cumulative follow-up time of 698.28 person-years. Within the study population, 117 patients were diagnosed with connective tissue disease, 75 patients presented with ANCA-associated vasculitis, and 27 patients exhibited IgG4-related disease. HGG was reported in 63.3% of the patients, where an obvious decline in IgG and IgM was shown three months after RTX initiation. The rate of SIE was 7.2 per 100 person-years. An increase in the GC maintenance dose was an independent risk factor for both hypo-IgG (HR 1.07, 95% CI 1.02-1.12, p = 0.003) and SIE (HR 1.06, 95% CI 1.02-1.1, p = 0.004). Further RCS analysis identified 7.48 mg/d prednisone as a safe threshold dose for patients who underwent RTX treatment to avoid a significantly increased risk for SIE.
CONCLUSIONS: HGG was relatively common in RTX-treated AID patients. Patients with chronic lung disease or who were taking ≥ 7.5 mg/d prednisone during RTX treatment were at increased risk for SIE and warrant attention from physicians.

BACKGROUND: Infection remains a relevant complication after kidney transplantation (KT). A well-established strategy in modern medicine is the application of bundles of evidence-based practice in clinical settings. The objective of this study is to explore the application of a personalized bundle of measures aimed to reduce the incidence of infection in the first 12 months after KT.
METHODS: A single-center prospective cohort of 148 patients undergoing KT between February 2018 and September 2019 that received an individualized infection prevention strategy was compared to a preintervention cohort (n = 159). The bundle comprised a review of the patient\'s immunization history, infection risk by country of origin, screening for latent tuberculosis infection (LTBI), antimicrobial prophylaxis, and immunological assessment. Individualized recommendations were accordingly provided at a scheduled visit at day +30 after transplantation.
RESULTS: The intervention cohort showed a higher compliance rate with the recommended vaccine schedule, screening for geographically restricted infections and LTBI, and intravenous immunoglobulin and vitamin D supplementation (p values <.001). The 1-year incidence rate of infection was lower in the intervention cohort (42.6% vs. 57.9%; p value = .037), as was the rate of infection-related hospitalization (17.6% vs. 32.1%; p value = .003) and the incidence of severe bacterial infection. There were no differences in graft rejection or mortality rates between groups.
CONCLUSIONS: A multifaceted intervention, including a bundle of evidence-based practices, enhanced compliance with recommended preventive measures and was correlated with a reduction in the 12-month incidence of infection after KT.

Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. \"Fair or poor\" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoimmune and inflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported \"fair or poor\" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD.

Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. \"Fair or poor\" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoinflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported \"fair or poor\" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD.

BACKGROUND: We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7.
METHODS: Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents.
RESULTS: The variant led to increased outward currents, indicating it underlies the patient\'s phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH.
CONCLUSIONS: Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7\'s critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for various hematological, immunological and metabolic diseases, replacing the patient\'s hematopoietic system with donor-derived healthy hematopoietic stem cells. HSCT can be complicated by early and late events related to impaired immunological recovery such as prolonged hypogammaglobulinemia post-HSCT. We present a 16-year-old female patient with sickle-cell disease who underwent HSCT with stem cells from a human leukocyte antigen (HLA) class-II mismatched family donor. While cellular recovery was good post-HSCT, the patient developed mixed chimerism and suffered from cervical lymphadenopathy, recurrent airway infections and cutaneous SLE. She presented with hypogammaglobulinemia and was started on immunoglobulin substitution therapy and antibiotic prophylaxis. B-cell phenotyping showed that she had increased transitional and naïve mature B cells, reduced memory B cells, and diminished marginal zone/natural effector cells. In-depth immunophenotyping and B-cell receptor repertoire sequencing ruled out an intrinsic B-cell defect by expression of activation-induced cytidine deaminase (AID), presence of somatic hypermutations and differentiation into IgG- and IgA-producing plasma cells in vitro. Immunohistochemistry and flow cytometry of lymph node tissue showed a clear block in terminal B-cell differentiation. Chimerism analysis of sorted lymph node populations showed that exclusively patient-derived B cells populated germinal centers, while only a minor fraction of follicular helper T cells was patient-derived. Given this discrepancy, we deduced that the HLA class-II disparity between patient and donor likely hinders terminal B-cell differentiation in the lymph node. This case highlights that studying disturbed cognate T-B interactions in the secondary lymphoid organs can provide unique insights when deciphering prolonged hypogammaglobulinemia post-HSCT.

Vaccine challenge responses are an integral component in the diagnostic evaluation of patients with primary antibody deficiency, including Common Variable Immunodeficiency Disorders (CVID). There are no studies of vaccine challenge responses in primary hypogammaglobulinemia patients not accepted for subcutaneous/intravenous immunoglobulin (SCIG/IVIG) replacement compared to those accepted for such treatment. Vaccine challenge responses in patients enrolled in two long-term prospective cohorts, the New Zealand Hypogammaglobulinemia Study (NZHS) and the New Zealand CVID study (NZCS), were compared in this analysis. Almost all patients in the more severely affected SCIG/IVIG treatment group achieved protective antibody levels to tetanus toxoid and H. influenzae type B (HIB). Although there was a highly significant statistical difference in vaccine responses to HIB, tetanus and diphtheria toxoids, there was substantial overlap in both groups. In contrast, there was no significant difference in Pneumococcal Polysaccharide antibody responses to Pneumovax® (PPV23). This analysis illustrates the limitations of evaluating vaccine challenge responses in patients with primary hypogammaglobulinemia to establish the diagnosis of CVID and in making decisions to treat with SCIG/IVIG. The conclusion from this study is that patients with symptoms attributable to primary hypogammaglobulinemia with reduced IgG should not be denied SCIG/IVIG if they have normal vaccine responses.

While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine.

OBJECTIVE: Common Variable Immunodeficiency Disorders (CVID) and Large Granular Lymphocytes leukemia (LGLL) exhibit diverse clinical manifestations including infections, dysimmunity, and lymphoproliferation. Recent decades have seen the discovery of new genes in the lymphopoiesis pathway, such as JAK-STAT. This case series supplemented by a literature review aims to describe clinical and biological characteristics of patients with both CIVD and LGLL.
METHODS: Patients were included through a call for comments to French and Belgian centers and through a literature review via PubMed. Clinical characteristics were compared to two large French cohort involving CVID and LGLL patients.
RESULTS: Twelve patients were included. In all cases, CVID precedes LLGL (median diagnosis delay for LLGL was 7 years). Most cases presented with splenomegaly and autoimmune cytopenia. Ten out of 12 patients underwent splenectomy during follow up.
CONCLUSIONS: Patients with LGLL and CVID differ from patients without immune deficiency in term of clinical presentation and prognosis. We suggest CVID may act as a trigger of LGL lymphocytosis, due to endogenous and exogenous antigenic pressure leading to the selection of a dominant LGL clone and stimulation of the JAK-STAT pathway. The role of splenomegaly and splenectomy in LGLL onset warrant further investigation in future studies.

Common variable immunodeficiency (CVID) is a primary B cell immunodeficiency disorder. Symptoms do not develop immediately after birth, and patients are often diagnosed in childhood and adulthood. These patients often develop autoimmune diseases and malignant tumors. We herein report a 50-year-old woman with severe hypogammaglobulinemia and recurrent respiratory tract infections who was diagnosed with CVID. Target sequencing showed a TNFRSF13B heterozygous frameshift variant. The patient had many comorbidities, probably caused by a CVID-induced immune imbalance. Physicians who treat adult patients are often unaware of CVID. CVID should be recognized as a differential diagnosis in hypogammaglobulinemia and recurrent infections.