Fatal liver mass rupture in a common-variable-immunodeficiency patient with probable nodular regenerating hyperplasia

Background Nodular regenerating hyperplasia (NRH) is the most common liver involvement in common variable immunodeficiency (CVID). Most patients are asymptomatic with gradually increasing alkaline phosphatase (ALP) and mildly elevated transaminase enzymes over the years. We report the first case of fatal liver mass rupture in a CVID patient with probable NRH. Case presentation A 24-year-old man was diagnosed with CVID at the age of 1.25 years. Genetic testing revealed a transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI) mutation. He had been receiving intravenous immunoglobulin (IVIg) replacement therapy ever since then. The trough level of serum IgG ranged between 750–1200 mg/dL. However, he still had occasional episodes of lower respiratory tract infection until bronchiectasis developed. At 22 years old, computed tomography (CT) chest and abdomen as an investigation for lung infection revealed incidental findings of numerous nodular arterial-enhancing lesions in the liver and mild splenomegaly suggestive of NRH with portal hypertension. Seven months later, he developed sudden hypotension and tense bloody ascites. Emergency CT angiography of the abdomen showed NRH with intrahepatic hemorrhage and hemoperitoneum. Despite successful gel foam embolization, the patient died from prolonged shock and multiple organ failure. Conclusions Although CVID patients with NRH are generally asymptomatic, late complications including portal hypertension, hepatic failure, and hepatic rupture could occur. Therefore, an evaluation of liver function should be included in the regular follow-up of CVID patients.

Retrospective Analysis of a Longitudinal Single Institution 219 Common Variable Immunodeficiency Patient Cohort

Common variable immunodeficiency is a heterogenous disorder of the immune system associated with immunodeficiency, lymphoproliferation, autoimmunity, and malignancy. Certain laboratory characteristics of common variable immunodeficiency patients can be associated with an increase of related clinical sequelae, though there is limited data on predictive characteristics for clinical sequelae in CVID patients. The purpose of this study was to analyze a unique large CVID patient cohort for predictive laboratory characteristics of clinical sequelae. A retrospective chart review was performed of a longitudinal cohort of CVID patients treated at a single institution, largely by a single provider with higher dose replacement immunoglobulin, that has not been previously described. 219 CVID patients were followed for 1,990 patient-years. 86% of the patients were on immunoglobulin with an average IgG trough of 1260 mg/dL. Low IgG at time of diagnosis, low CD19 absolute cell count, and poor mitogen induced lymphocyte proliferation were associated with increase of CVID clinical sequelae. In particular, this cohort demonstrates the novel finding that low IgG at time of diagnosis prior to immunoglobulin replacement is associated with a higher incidence of lymphoma, bronchiectasis, granulomatous disease, lymphoid hyperplasia, splenomegaly, and hepatic disease.

SARS-CoV-2-Associated T-Cell Responses in the Presence of Humoral Immunodeficiency

We report perhaps the most comprehensive study of subsets of CD4+ and CD8+ and subsets of B cells in a mild symptomatic SARS-CoV-2+ immunocompetent patient and a common variable immunodeficiency disease (CVID) patient who had normal absolute lymphocyte counts and remained negative for SARS-CoV-2 IgG antibodies. Naïve (T_N), central memory (T_CM), effector memory (T_EM), and terminally differentiated effector memory (T_EMRA) subsets of CD4+ and CD8+ T cells, subsets of T follicular helper cells (cT_FH, T_FH1, T_FH2, T_FH17, T_FH1/T_FH17, and T_FR), CD4 Treg, CD8 Treg, mature B cells, transitional B cells, marginal zone B cells, germinal center (GC) B cells, CD21^low B cells, antibody-secreting cells (plasmablasts), and Breg cells were examined in patients and age-matched controls with appropriate monoclonal antibodies and isotype controls using multicolor flow cytometry. Different patterns of abnormalities (often contrasting) were observed in the subsets of CD4+ T, CD8+ T, B-cell subsets, and regulatory lymphocytes among the immunocompetent patient and CVID patient as compared to corresponding healthy controls. Furthermore, when data were analyzed between the 2 patients, the immunocompetent patient demonstrated greater changes in various subsets as compared to the CVID patient. These data demonstrate different immunological responses to SARS-CoV-2 infection in an immunocompetent patient and the CVID patient. A marked decrease in GC B cells and plasmablasts may be responsible for failure to make SARS-CoV-2 antibodies. The lack of SARS-CoV-2 antibodies with mild clinical disease suggests an important role of T-cell response in defense against SARS-CoV-2 infection.

The Successful Vaccination of an IVIgG Naive CVID Patient with an mRNA COVID-19 Vaccine

Introduction Different subtypes of vaccines have been developed to help protect populations from COVID-19. Currently, three vaccines have been authorized by the United States Food and Drug Administration for emergency use to combat the COVID-19 pandemic. With COVID-19 vaccination rates increasing, it is important to know whether immunodeficient patients have the capacity to mount an immune response with the available vaccines. Case Report A 78-year-old female with Common Variable Immunodeficiency and anti-IgA antibodies who is naïve to IVIgG treatment responded positively to a COVID-19 mRNA vaccine. Successful seroconversion was proved by having positive COVID-19 spike protein IgG antibodies weeks after the vaccination. Her recent IgG, IgA, and IgM levels were all significantly reduced. Previously, she had no response to the polysaccharide pneumococcal vaccine, but did maintain titers afterTdap vaccination. Discussion Immunodeficient patients are a susceptible population during a pandemic. Unfortunately, there is a paucity of research on the infectivity, vaccination, and outcome of these patients during the COVID-19 outbreak. Our patient with CVID was able to respond to protein/toxoid vaccines, but did not respond to polysaccharide pneumococcal vaccine. After inoculation with an mRNA COVID-19 vaccine she was able to create COVID-19 spike protein IgG antibodies. Conclusion We present a case of successful vaccination to COVID-19 by an mRNA vaccine in an IVIgG naïve CVID patient.

Synergy in B-Cell Activation between Toll-Like Receptor 9 and Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor (TACI) in A181E/C104R Compound Heterozygous Siblings

Purpose. Approximately 9% of common variable immunodeficiency (CVID) patients harbor variants in the transmembrane activator and CAML interactor gene, TACI, which contribute to CVID development. We found identical compound heterozygous TACI variants (C104R and A181E) in kindred of which one sibling had severe CVID with refractory auto immunity, and a second sibling remained asymptomatic. This study investigated possible differences in B-cell phenotype and function that could explain this divergent clinical expression. Methods. C104R and A181E TACI variants were identified through Sanger sequencing. Phenotypic evaluation of the lymphocyte compartment was performed by flow cytometry analyses. Lymphoblastoid cell lines (LCL) from the index patient, asymptomatic sibling, and controls were generated. Intracellular TACI expression was determined, and activation-associated calcium flux capacity was measured. In vitro stimulation assays and RT PCR were performed. Results. Both intracellular levels and surface expressed TACI protein were higher in the asymptomatic sibling than the CVID patient as were TACI-triggering-induced mRNA expression AID and production of Ig class-switched antibodies. In analogy, the asymptomatic sibling displayed enhanced Toll-like receptor 9 expression and signaling, suggesting a compensatory immune mechanism. Conclusions. Posttranscriptional regulation of TACI protein and cross-talk with TLR9 signaling may contribute to phenotypic diversity between individuals with TACI variants.