The association of autoimmune cytopenia (AIC) and inflammatory bowel disease (IBD) has been reported in small series, but the incidence of and risk factors for IBD in children with AIC are not known. One thousand six hundred nine children with chronic immune thrombocytopenic purpura, autoimmune haemolytic anaemia or Evans syndrome from the prospective OBS\'CEREVANCE cohort are included in this study. Overall, 15 children were diagnosed with IBD, including 14 who developed IBD after AIC diagnosis (median delay: 21 months). The only risk factor for IBD development is age at AIC over 10 years. Out of 10 children genetically tested, germline variants associated with autoimmune disorders were identified in three (CTLA4: two, DOCK11: one). In children and adolescents monitored for AIC or past history of AIC, especially children over 10 years, gastro-intestinal (GI) symptoms (recurrent abdominal pains, GI bleeding, chronic diarrhoea, weight loss) should suggest IBD and deserve specific work-up and genetic studies. Identification of a causal germline variant will allow targeted therapy.

BACKGROUND: Hyper-IgE syndrome (HIES) constitutes a group of rare primary immunodeficiency disorders. The diagnosis relies on the National Institutes of Health (NIH) scoring system, incorporating clinical and laboratory data. Scores greater than or equal to 15 raise a strong suspicion of the disease. In an isolated Israeli population, Zinc Finger 341 deficiency, a subtype of HIES, has a carrier incidence of 1:20, but the prevalence of the clinical syndrome within this community remains unknown.
OBJECTIVE: To estimate the prevalence of potentially undiagnosed HIES cases within this population by using the NIH scoring criteria.
METHODS: This retrospective cohort study obtained requisite clinical and laboratory data for NIH score computation from the electronic medical records of Clalit Health Services for the isolated village under scrutiny in comparison to a neighboring village. Subsequently, clinical scores were assigned to each subject, enabling comparative analysis of suspected diagnosis rates between the 2 populations.
RESULTS: Among the 29,390 studied subjects, 12 had a documented diagnosis of HIES. All were in the study village, and none were from the control village (0.08% vs 0%, P < .01). Within the study village, 235 individuals (1.62%) had an NIH score greater than or equal to 15 and were suspected with having HIES almost doubled compared with the control group at 130 individuals (0.87%) (P < .001).
CONCLUSIONS: This is the first time the NIH clinical score system has been used for population screening. The significant disparity in the prevalence of suspected, undiagnosed cases between the study village and the control village strongly suggests the potential utility of this tool for preliminary screening.

There are approximately 500 congenital disorders that impair immune cell development and/or function. Patients with these disorders may present with a wide range of symptoms, including increased susceptibility to infection, autoimmunity, autoinflammation, lymphoproliferation, and/or atopy. Flow cytometry-based immune phenotyping of T and B lymphocytes plays an essential role in the evaluation of patients with these presentations. In this review, we describe the clinical utility of flow cytometry as part of a comprehensive evaluation of immune function and how this testing may be used as a diagnostic tool to identify underlying aberrant immune pathways, monitor disease activity, and assess infection risk.

BACKGROUND: Common variable immunodeficiency (CVID) is considered the most symptomatic type of inborn errors of immunity in humans. Along with infectious complications, which have numerous consequences, noninfectious complications are a major challenge among CVID patients.
METHODS: All CVID patients registered in the national database were included in this retrospective cohort study. Patients were divided into 2 groups based on the presence of B-cell lymphopenia. Demographic characteristics, laboratory findings, noninfectious organ involvement, autoimmunity, and lymphoproliferative diseases were evaluated.
RESULTS: Among 387 enrolled patients, 66.4% were diagnosed with noninfectious complications and 33.6% with isolated infectious presentations. Enteropathy, autoimmunity, and lymphoproliferative disorders were reported in 35.1%, 24.3%, and 21.4% of patients, respectively. Some complications, including autoimmunity and hepatosplenomegaly, were reported to be significantly more frequent among patients with B-cell lymphopenia. As for organ involvement, the dermatologic, endocrine, and musculoskeletal systems were predominantly affected in CVID patients with B-cell lymphopenia. Among autoimmune manifestations, the frequency of rheumatologic, hematologic, and gastrointestinal autoimmunity was reported to be higher than that of other types of autoimmunity not associated with B cell-lymphopenia. Furthermore, hematological cancers, particularly lymphoma, were the most common type of malignancy. The mortality rate was 24.5%, and respiratory failure and malignancies were the most common causes of death, with no significant differences between the 2 groups.
CONCLUSIONS: Considering that some of the noninfectious complications might be associated with B-cell lymphopenia, regular patient monitoring and follow-up with proper medication (in addition to immunoglobulin replacement therapy) are highly recommended to prevent sequelae and increase patient quality of life.

Aim: To assess a patient empowerment program (PEP) for children/adolescents with primary immunodeficiency (PID) on IgG replacement therapy regarding quality of life (QoL) in patients and proxy. Patients & methods: Health-related QoL was assessed using KIDSCREEN-27 and DISABKIDS-37 before and 6 months after PID-PEP kids in 19 children/adolescents and their parents. Results: The following three dimensions of the KIDSCREEN-27 significantly increased in children/adolescents after PID-PEP kids as compared with baseline: Psychological Well-Being, Parents & Autonomy and School Environment. Total DISABKIDS-37 index, as well as 5 of the 6 DISABKIDS-37 dimensions, significantly increased, in other words, Independence, Emotion, Social Inclusion, Social Exclusion and Physical. Evaluation of proxy instruments showed comparable results. Conclusion: PID-PEP kids significantly improved QoL in patients with PID.
What is this study about? This study evaluated a patient empowerment program (PEP) for children and adolescents with primary immunodeficiency (PID) on immunoglobulin replacement therapy. The goal was to see if the program improved quality of life (QoL). Two commonly administered questionnaires were used to measure QoL before and 6 months after participating in the program.What were the results? Significant improvements were found in several dimensions including Psychological Well-Being, Parents & Autonomy and School Environment. Additionally, overall QoL scores and dimensions such as Independence, Emotion, Social Inclusion, Social Exclusion and Physical also improved. Assessments by the parents confirmed these findings.What do the results mean? The PID-PEP kids program significantly improved the QoL for these young patients.

UNASSIGNED: Tixagevimab-cilgavimab is a combination of 2 mAbs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In December 2021, the Food and Drug Administration issued Emergency Use Authorization for intramuscular injection of tixagevimab-cilgavimab for prophylaxis against SARS-CoV-2 in immunocompromised patients. Shortly thereafter, our clinic distributed tixagevimab-cilgavimab to patients with common variable immunodeficiency.
UNASSIGNED: We sought to evaluate the effectiveness and tolerability of tixagevimab-cilgavimab in a common variable immunodeficiency clinic.
UNASSIGNED: A retrospective chart review from February 1, 2022, to August 1, 2022, of 47 patients with common variable immunodeficiency who were offered tixagevimab-cilgavimab was carried out. Comparative outcomes of treatment and nontreatment groups examined the occurrence of SARS-CoV-2 infection, severity of SARS-CoV-2 infection, and other non-SARS-CoV-2 infections.
UNASSIGNED: Seventy percent of the patients were female; mean age was 49 years. Twenty-three patients received tixagevimab-cilgavimab, and 24 did not receive prophylaxis. In the tixagevimab-cilgavimab group, all were vaccinated for SARS-CoV-2 and 22 were receiving immunoglobulin replacement. One patient was infected with SARS-CoV-2, no patients required emergency care, and 7 patients had non-SARS-CoV-2 infection. In the cohort that did not receive prophylaxis, 21 were vaccinated, and all received immunoglobulin replacement. Two patients tested positive for SARS-CoV-2, 1 patient required emergency care due to SARS-CoV-2 disease severity, and 4 patients had a non-SARS-CoV-2 infection. None of the results showed statistical significance.
UNASSIGNED: Although there is evidence that tixagevimab-cilgavimab can be protective against SARS-CoV-2 in immunocompromised individuals, our data suggest that this benefit may be blunted in patients with common variable immunodeficiency on immunoglobulin replacement. The additional benefit of tixagevimab-cilgavimab in immunocompromised patients already receiving replacement therapy requires further exploration.

In order to maintain the polio eradication status, it has become evident that the surveillance of cases with acute flaccid paralysis and of environmental samples must be urgently supplemented with the surveillance of poliovirus excretions among individuals with inborn errors of immunity (IEI). All children with IEI were screened for the excretion of poliovirus during a collaborative study conducted by the ICMR-National Institute of Virology, Mumbai Unit, ICMR-National Institute of Immunohaematology, and World Health Organization, India. A seven-month -old male baby who presented with persistent pneumonia and lymphopenia was found to have severe combined immune deficiency (SCID) due to a missense variant in the RAG1 gene. He had received OPV at birth and at 20 weeks. Four stool samples collected at 4 weekly intervals yielded iVDPV type 1. The child\'s father, an asymptomatic 32-year-old male, was also found to be excreting iVDPV. A haploidentical hematopoietic stem cell transplant was performed, but the child succumbed due to severe myocarditis and pneumonia three weeks later. We report a rare case of transmission of iVDPV from an individual with IEI to a healthy household contact, demonstrating the threat of the spread of iVDPV from persons with IEI and the necessity to develop effective antivirals.

BACKGROUND: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient outcomes. In 2013, Ontario became the first Canadian province to perform newborn screening (NBS) for SCID by T cell receptor excision circles (TRECs) analysis, a surrogate marker of thymic function and lymphocyte maturation.
METHODS: This retrospective study reports on nearly 10 years of NBS for SCID at a quaternary referral centre.
RESULTS: From August 2013 to April 2023, our centre\'s densely populated catchment area flagged 162 newborns with low TRECs levels, including 10 cases with SCID. Follow-up revealed other causes of low TRECs, including non-SCID T cell lymphopenia (secondary/reversible or idiopathic causes, and syndromic conditions) and prematurity. A small number of cases with normal repeat TRECs levels and/or T cell subsets were also flagged. Province-wide data from around this period revealed at least 24 diagnosed cases of SCID or Leaky SCID.
CONCLUSIONS: This is the first report of NBS outcomes in a Canadian province describing the causative genetic defects, and the non-SCID causes of a positive NBS for SCID.

The interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional regulator, functioning a transcriptional corepressor by interacting with the interferon regulatory factor-2. The ubiquitous expression of IRF2BP2 by diverse cell types and tissues suggests its potential involvement in different cell signalling pathways. Variants inIRF2BP2have been recently identified to cause familial common variable immunodeficiency (CVID) characterized by immune dysregulation. This study investigated three rare novel variants inIRF2BP2, identified in patients with primary antibody deficiency and autoimmunity by whole exome-sequencing (WES). Following transient overexpression of EGFP-fused mutants in HEK293 cells and transfection in Jurkat cell lines, we used fluorescence microscopy, real-time PCR and Western blotting to analyze their effects on IRF2BP2 expression, subcellular localization, nuclear translocation of IRF2, and the transcriptional activation of NFκB1(p50). We found altered IRF2BP2 mRNA and protein expression levels in the mutants compared to the wild type after IRF2BP2 overexpression. In confocal fluorescence microscopy, variants in the C-terminal RING finger domain showed an irregular aggregate formation and distribution instead of the expected nuclear localization compared to the variants in the N-terminal zinc finger domain and their wildtype counterpart. Immunoblotting revealed an impaired IRF2 and NFκB1 (p50) nuclear localization in the mutants compared to the IRF2BP2 wildtype counterpart. LPS stimulation reduced IRF2BP2 mRNA expression in the variants compared to the wild type. Our findings significantly contribute to understanding the clinical significance of IRF2BP2 mutations in the pathogenesis of immunodeficiency and immune dysregulation. We observed impairment of the nuclear translocation of IRF2 and NFκB1 (p50) due to the upregulation of IRF2BP2, potentially affecting specific gene expressions involved in immune regulation.

UNASSIGNED: Trichothiodystrophy-1 (TTD1) is an autosomal-recessive disease and caused by mutations in ERCC2, a gene coding for a subunit of the TFIIH transcription and nucleotide-excision repair (NER) factor. In almost half of these patients infectious susceptibility has been reported but the underlying molecular mechanism leading to immunodeficiency is largely unknown.
UNASSIGNED: The aim of this study was to perform extended molecular and immunological phenotyping in patients suffering from TTD1.
UNASSIGNED: Cellular immune phenotype was investigated using multicolor flow cytometry. DNA repair efficiency was evaluated in UV-irradiation assays. Furthermore, early BCR activation events and proliferation of TTD1 lymphocytes following DNA damage induction was tested. In addition, we performed differential gene expression analysis in peripheral lymphocytes of TTD1 patients.
UNASSIGNED: We investigated three unrelated TTD1 patients who presented with recurrent infections early in life of whom two harbored novel ERCC2 mutations and the third patient is a carrier of previously described pathogenic ERCC2 mutations. Hypogammaglobulinemia and decreased antibody responses following vaccination were found. TTD1 B-cells showed accumulation of γ-H2AX levels, decreased proliferation activity and reduced cell viability following UV-irradiation. mRNA sequencing analysis revealed significantly downregulated genes needed for B-cell development and activation. Analysis of B-cell subpopulations showed low numbers of naïve and transitional B-cells in TTD1 patients, indicating abnormal B-cell differentiation in vivo.
UNASSIGNED: In summary, our analyses confirmed the pathogenicity of novel ERCC2 mutations and show that ERCC2 deficiency is associated with antibody deficiency most likely due to altered B-cell differentiation resulting from impaired BCR-mediated B-cell activation and activation-induced gene transcription.