Hypogammaglobulinemia Research Articles

P-2301. Predictors and clinical outcomes of hypogammaglobulinemia in liver transplant recipients: role of pre-transplant factors and graft volume

Abstract Background Hypogammaglobulinemia (HGG) is a common complication after liver transplantation and is associated with severe bacterial infections and mortality. Although hepatocytes synthesize immunoglobulins, how underlying liver disease affects immunoglobulin dynamics after liver transplantation has not been well evaluated. We evaluated differences in serum levels of immunoglobulin G (IgG) depending on pre-transplant model for end-stage liver disease (MELD) score.Table 1.Characteristics of liver transplantation recipients after propensity score matching Methods We prospectively enrolled patients who underwent liver transplantation between July 2016 and December 2022. Patients with pre-transplant MELD score < 30 and ≥30 were categorized as low and high MELD groups, respectively. Serum IgG levels were measured by enzyme-linked immunosorbent assay.Figure 1. Comparison of serum immunoglobulin G levels in liver transplant recipients between low and high MELD groups.ns, not significant; *, P < 0.05; **; P < 0.01; ***, P < 0.001. Results Of 559 liver transplant recipients, 444 were in the low MELD group and 111 were in the high MELD group. Propensity score matching was conducted between the two groups. The median serum IgG levels decreased significantly from 319.7 mg/dL pre-transplant to 201.3 mg/dL post-transplant at 1 month. The IgG levels at pre-transplant and post- transplant (1 month, 6 months, and 1 year) did not differ significantly between the low and high MELD groups. High MELD (adjusted hazard ratio [aHR], 3.71; 95% confidence interval [CI], 1.64–8.40; P = 0.002) and pre-transplant HGG (aHR, 2.16; 95% CI, 1.05–4.46; P = 0.037) were independently associated with overall mortality. In addition, hepatocellular carcinoma (aHR, 2.08; 95% CI, 1.07–4.03; P = 0.031), high MELD (aHR, 1.85; 95% CI, 1.01–3.37; P = 0.046) and post-transplant HGG (aHR, 2.35; 95% CI, 1.12–4.95; P = 0.023) were associated with bloodstream infections. Predictors for HGG were viral hepatitis (odds ratio [OR], 0.46; 95% CI 0.22­–0.90; P = 0.027) for pre-transplant, and hepatocellular carcinoma (OR, 0.34; 95% CI 0.12–0.79); P = 0.020) and graft to recipient weight ratio ≥ 0.8 (OR 0.26; 95% CI 0.07–0.90; P = 0.033) for post-transplant.Table 2.Multivariable cox proportional regression of effect of hypogammaglobulinemia in liver transplantation recipients on mortality and bloodstream infection. Hypogammaglobulinemia was defined as the lowest quartile of serum immunoglobulin G levels. Post-transplant hypogammaglobulinemia was assessed at post-operative 1 month. Post-transplant hypogammaglobulinemia was used as a time-varying variable. Conclusion Peri-transplant HGG was associated with poor outcomes including mortality and severe infections. There is no significant difference in HGG according to MELD score, however, it is associated with insufficient graft volume.Table 3.Univariable analysis for hypogammaglobulinemia in liver transplantation recipients Hypogammaglobulinemia was defined as the lowest quartile of serum immunoglobulin G levels. Post-transplant hypogammaglobulinemia was assessed at postoperative 1 month. Disclosures All Authors: No reported disclosures

P-2256. Clinical characteristics and outcomes of non-typhoidal Salmonellosis in patients with hematologic malignancy

Abstract Background Non-typhoidal salmonellosis is a significant cause of foodborne illness in the US, especially in immunocompromised host. Previous studies report a higher incidence in cancer patients; however, advancements in cancer therapy and rising antibiotic resistance have reshaped this association. Salmonellosis in patients with hematologic malignancy (HM) remains poorly characterized. Characteristics of HM patients with non-typhoidal Salmonella infection *Only for those who were not receiving intravenous immunoglobulin therapy **Included culture from splenic abscess, lymph node, soft tissue, and bone Methods We identified non-typhoidal salmonella infections in HM patients from 1/1/2016 to 12/31/2023 at 2 institutions. Clinical, microbiologic and treatment outcomes were collected. Hypogammaglobulinemia (HGG) was defined as having immunoglobulin G (IgG) level < 500 IU/dL or receiving intravenous immunoglobulin for past diagnosis of low IgG. Relapse was defined as confirmed Salmonella infection with symptoms recurring after clinical resolution with an initial antibiotic course. Chi square and Mann-Whitney U tests were used to examine the relationship between clinical parameters and relapse.Table 2.Demographic and clinical characteristics of HM patients by relapse of Salmonella infection * Four patients did not have enough follow-up to determine relapse ** p<0.05 *** Only for those who were not receiving intravenous immunoglobulin therapy Results We identified 53 HM patients with non-typhoidal salmonellosis. Clinical and microbiological variables are shown in Table1. Most individuals were male (54.7%) with median age of 63 years [20-88]. Multiple myeloma was the most common diagnosis (39.6%), followed by acute leukemia/myelodysplastic syndrome (32.1%); 18 patients underwent hematopoietic cell transplantation and 8 patients received chimeric antigen T-cell therapy. Twenty-six patients (45.3%) had HGG. Salmonella was isolated from stool cultures (62.3%), blood cultures (17%), both (13.2%) or another specimen (7.5%). Four patients (7.5%) had musculoskeletal involvement. Relapse occurred in 14 cases (26.4%). In a bivariate analysis (Table 2), HGG was associated with relapse (p=0.002) and those with relapse had a lower median IgG level (p=0.032). Among patients with extraintestinal infection, those who experienced relapse received a shorter initial duration of antimicrobials to those without relapse (p=0.004; figure 1). Duration of antibiotic therapy in days for patients with extra-intestinal salmonella infection Conclusion HM patients are at high risk for non-typhoidal salmonellosis. HGG and shorter course of antibiotics are associated with an increased relapse risk, particularly in those with extraintestinal involvement. Extended duration of antibiotic therapy could be considered for these high-risk patients. Disclosures Elizabeth Hohmann, MD, Astra Zeneca: Grant/Research Support|Laguna Biotherapeutics: Grant/Research Support|MicrobiomeX/Tend: Grant/Research Support Sarah P. Hammond, MD, Cidara: Grant/Research Support|F2G: Grant/Research Support|GSK: Grant/Research Support|Melinta: Advisor/Consultant|Pfizer: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Grant/Research Support|Seres Therapeutics: Advisor/Consultant

P-1054. BTK drives neutrophil activation for sterilizing antifungal immunity

Abstract Background Bruton’s tyrosine kinase (BTK) is a critical component of B-cell receptor signaling and regulates B-cell proliferation and survival. Ibrutinib is an irreversible inhibitor of BTK and is successfully used in treatment of various B-cell malignancies. However, it has been associated with increased risk for invasive aspergillosis (IA). Model of BTK-dependent responses promoting neutrophil activation in response to Aspergillus fumigatus. Methods To shed light in the susceptibility of ibrutinib-treated patients, we studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Results In response to fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, leading to oxidative burst. BTK inhibition selectively impaired neutrophils’ capacity to damage Aspergillus hyphae, release primary granules and induce oxidative burst by impeding the activation of NADPH oxidase subunit p40phox and GTPase RAC2. Similarly, we found impaired neutrophil function in Aspergillus-infected, neutrophil-specific Btk deficient mice, whereas neutrophil recruitment and survival were spared. These defects were partially mitigated by GM-CSF via enhancing p47phox activation, supporting a role for GM-CSF use in susceptible patients. The presence of the BTK rs5951308 (T >C; E24G) in donors of allogeneic hematopoietic transplant recipients was independently associated with increased risk of IA. Conclusion Our data uncover a previously unappreciated role for BTK in fungal immune surveillance against Aspergillus fumigatus. Disclosures All Authors: No reported disclosures

One hundred thirty-four germ line PU.1 variants and the agammaglobulinemic patients carrying them.

Leukopoiesis is lethally arrested in mice lacking the master transcriptional regulator PU.1. Depending on the animal model, subtotal PU.1 loss either induces acute myeloid leukemia or arrests early B cell and dendritic cell development. Although humans with absolute PU.1 deficiency have not been reported, a small cadre of congenital agammaglobulinemia patients with sporadic, inborn PU.1 haploinsufficiency were recently described. To better estimate the penetrance, clinical complications, immunophenotypic features, and malignancy risks of PU.1-mutated agammaglobulinemia (PU.MA), a collection of 134 novel or rare PU.1 variants from publicly available databases, institutional cohorts, previously published reports, and unsolved agammaglobulinemia cases were functionally analyzed. In total, 25 loss of function (LOF) variants were identified in 33 heterozygous carriers from 21 kindreds across 13 nations. Of subjects harboring LOF PU.1 variants, 22 were agammaglobulinemic, 5 displayed antibody deficiencies, and 6 were unaffected, indicating an estimated disease penetrance of 81.8% with variable expressivity. In a cluster of patients, disease onset was delayed, sometimes into adulthood. All LOF variants conveyed effects via haploinsufficiency, either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription. PU.MA patient immunophenotypes consistently demonstrated B-cell, conventional dendritic-cell, and plasmacytoid dendritic-cell deficiencies. Associated infectious and non-infectious symptoms hewed closely to X-linked agammaglobulinemia and not monogenic dendritic cell deficiencies. No carriers of LOF PU.1 variants experienced hematologic malignancies. Collectively, in vitro and clinical data indicate heterozygous LOF PU.1 variants undermine humoral immunity but do not convey strong leukemic risks.

Gut microbial dysbiosis, IgA, and Enterococcus in common variable immunodeficiency with immune dysregulation

BackgroundCommon variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Significant morbidity and mortality are caused by immune dysregulation complications (CVIDid), which affect around one-third of CVID patients and have a poorly understood etiology. Here, we investigate the hypothesis that gut microbial dysbiosis contributes to the inflammation underlying CVIDid.ResultsBacterial invasion of colonic crypts was observed in CVID (3/15) and X-linked agammaglobulinemia (XLA, 1/3), but not in healthy control (HC, 0/9) biopsies. Fecal gut microbiota was characterized using 16S rRNA-targeted amplicon sequencing. Increased bacterial load, decreased alpha diversity and distinct beta diversity were observed in CVIDid (n = 42) compared to HC (n = 48), and similar results were seen in CVID with IgA deficiency (n = 40) compared to HC. CVIDid and CVID-IgA showed enrichment of the genus Enterococcus, and in vitro studies confirmed the inflammatory potential of Enterococcus gallinarum and Enterococcus hirae in patient monocytes. ConclusionsThis study further supports the hypothesis that a dysregulated gut microbiota, with IgA deficiency as an important driving factor, contributes to systemic inflammation in primary antibody deficiency, and introduces enterococci as potential pathobionts in CVIDid.EQUitBFVXYmTZpXE6XWtg9Video

Advancing Newborn Screening in Washington State: A Novel Multiplexed LC-MS/MS Proteomic Assay for Wilson Disease and Inborn Errors of Immunity.

For many genetic disorders, there are no specific metabolic biomarkers nor analytical methods suitable for newborn population screening, even where highly effective preemptive treatments are available. The direct measurement of signature peptides as a surrogate marker for the protein in dried blood spots (DBSs) has been shown to successfully identify patients with Wilson Disease (WD) and three life-threatening inborn errors of immunity, X-linked agammaglobulinemia (XLA), Wiskott-Aldrich syndrome (WAS), and adenosine deaminase deficiency (ADAD). A novel proteomic-based multiplex assay to detect these four conditions from DBS using high-throughput LC-MS/MS was developed and validated. The clinical validation results showed that the assay can accurately identify patients of targeted disorders from controls. Additionally, 30,024 newborn DBS samples from the Washington State Department of Health Newborn Screening Laboratory have been screened from 2022 to 2024. One true presumptive positive case of WD was found along with three false positive cases. Five false positives for WAS were detected, but all of them were premature and/or low-birth-weight babies and four of them had insufficient DNA for confirmation. The pilot study demonstrates the feasibility and effectiveness of utilizing this multiplexed proteomic assay for newborn screening.

Respiratory system evaluation of adult primary immunodeficiency patients: a tertiary care center experience

Abstract Introduction Primary immunodeficiencies (PIDs) are rare diseases in which chronic pulmonary diseases are common. Chronic pulmonary complications affect the long-term survival of these patients. The aim of this study was to evaluate the accompanying lung diseases and respiratory functions in adult PID patients in the Turkish population. Materials and Methods Patients’ files who applied to the immunology clinic between 2015 and 2020 were evaluated retrospectively. The respiratory system was evaluated by physical examination, and if necessary, computed tomography, chest radiography, and pulmonary function test (PFT) were performed. The diagnosis of PIDs was based on the European Society of Immunodeficiency’s (ESID) criteria. Results A total of 186 patients were included in the study. The median age of the patients was 38 years. The distribution of the diseases included in the study in order of frequency is: Common Variable Immunodeficiency (CVID) (47.8%), Severe Combined Immunodeficiency (SCID) (22.6%), Selective IgA deficiency (SIgAD) (10.8%), X-Linked Agammaglobulinemia (XLA) (10.2%), Chronic Granulomatous Disease (CGD) (8.6%). The most common findings on chest radiology were bronchiectasis (37.1%), parenchymal nodule (32.8%), ground glass opacity (31.2%), lymphadenopathy (24.7%), fibrotic changes (24.8%), reticular opacities (23.7%) and bronchial wall thickening (23.1%). PFT’s results were lower in patients with CGD. Bronchiectasis (37.1%), asthma (22%), and tuberculosis (9.7%) were the most common lung complications. Conclusion We think that the frequency of other lung complications, especially asthma and bronchiectasis, is higher in adult patients with PIDs, and patient management is poor as there are no guidelines for the follow-up, diagnosis, and treatment of pulmonary complications.

A Case of X-Linked Agammaglobulinemia and COVID-19 in a Japanese Infant

An infant was diagnosed as having X-linked agammaglobulinemia (XLA) at age 3 months and was receiving immunoglobulin replacement therapy. He developed SARS-CoV-2 infection at age 7 months and was treated with intravenous immunoglobulin, remdesivir, and dexamethasone. His respiratory symptoms improved quickly, and the infection resolved. Viral disappearance was confirmed via PCR, and the result of a SARS-CoV-2 test was negative on day 67 of illness, as a result of antiviral therapy. Immunoglobulin administered to the patient did not contain anti-SARS-CoV-2 antibodies, and no seroconversion of anti-SARS-CoV-2 antibodies was observed after healing. These findings suggest that humoral immunity did not contribute to infection in our patient. Thus, the importance of cellular immunity against COVID-19 was confirmed. In the future, it is hoped that testing companies will be able to use the ELISPOT assay to check cellular immunity in order to confirm the effectiveness of vaccines and the history of infection.

The effect of rituximab therapy and the risk of hypogammaglobulinamea on immunoglobulin levels in patients with rheumatoid arthritis

Background. Rituximab (RTX) is a biological monoclonal antibody targeting the CD20 antigen on B cells, effectively decreasing disease activity and progression in patients with rheumatoid arthritis (RA). RTX treatment can lead to a decline in plasma cells that produce immunoglobulin, potentially resulting in hypogammaglobulinemia (HGG). This study aims to assess the effect of RTX on immunoglobulin levels and determine the prevalence of HGG in RA patients after receiving different doses and cycles of RTX. Additionally, immunoglobulin levels were compared between patients treated with RTX and those treated with traditional disease-modifying antirheumatic drugs (DMARDs). We also sought to identify patient, disease, and therapy factors associated with HGG to evaluate the importance of monitoring immunoglobulin levels. Method. A single-center observational cross-sectional study was conducted at Baghdad Teaching Hospital between November 2023 and May 2024. Patients with RA were recruited and divided into two groups. The first group consisted of 45 RA patients receiving RTX, and the second group included 45 patients receiving DMARDs. All patients met the American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism (EULAR) 2010 classification criteria for RA. Patients were excluded if they had received RTX for conditions other than RA or if they had been treated with RTX for less than six months. Quantitative IgG and IgA levels were measured via enzyme-linked immunosorbent assay (ELISA) to evaluate the effect of RTX on immunoglobulin levels and compare it with the effect of DMARDs. HGG was defined as an immunoglobulin level below two standard deviations from the mean of age-matched healthy controls. Results. Ninety patients were enrolled in the study, 45 of whom were treated with RTX. The mean number of RTX cycles was 3.67, ranging from 2 to 10 cycles. A significant decrease in immunoglobulin levels was observed post-RTX therapy, with 84.4% of patients exhibiting low IgG levels (<5 μg/ml), leading to HGG. The IgG levels in RTX-treated patients ranged from 4.3 to 22.0 μg/ml, with a mean of 7.28 ± 3.95 μg/ml. In contrast, patients treated with DMARDs maintained normal immunoglobulin levels similar to healthy individuals, with IgG levels ranging from 19.7 to 43.7 μg/ml. RTX also affected IgA levels, but to a lesser extent than IgG. Conclusion. Lower immunoglobulin levels following RTX therapy frequently result in HGG, emphasizing the importance of immunologic surveillance before and after treatment. DMARD therapy did not affect immunoglobulin levels, and concurrent use of DMARDs with RTX offered no protection against HGG. Additionally, HGG was not associated with an increased incidence of infections.

B-ALL in a 21-year-old male with X-linked agammaglobulinemia (XLA): a case report and review of B-cell malignancies in XLA

B-ALL in a 21-year-old male with X-linked agammaglobulinemia (XLA): a case report and review of B-cell malignancies in XLA

The dilemma of X-linked agammaglobulinemia carriers.

Many patients with X-linked agammaglobulinemia (XLA) nowadays have reached adulthood, as well as their sisters, possibly carriers of a deleterious Bruton tyrosine kinase variant. Studies on motherhood outcomes in families with XLA are lacking. We sought to investigate adherence to carrier status screening, interest in preconception and prenatal genetic counseling, and reproductive decisions in relatives with XLA. In this multicenter, retrospective cohort study, we collected a 3-generation pedigree and data on mothers and sisters of patients with XLA, including carrier status and pregnancy outcome. Data on 53 adults with XLA, 52 mothers, and 33 sisters were collected. All XLA sisters received genetic counseling. Forty percent of the sisters chose to undergo carrier status determination, and 60% of them chose invasive prenatal testing. The main reasons for the sisters to decide not to undergo genetic testing were their young age and the willingness to carry on with the pregnancy regardless of the outcome of the genetic test, followed by the willingness to postpone the decision at the time of pregnancy and the decision to not have children. Prenatal testing resulted in 5 XLA diagnoses, with 2 pregnancy terminations, 1 miscarriage, and 2 XLA live births. Three carriers refused prenatal testing and had 6 live births, including 3 XLA-affected sons. One sister was diagnosed as a carrier after the birth of an XLA-affected son. In total, 9 XLA diagnoses were made, including 6 live births. A number of XLA sister carriers decided to carry on with their pregnancy after receiving the diagnosis of an affected fetus or after refusing prenatal testing. We propose to initiate a more extensive collaborative study to verify the effect of genetic counseling on families with XLA in other cohorts from different countries.

Outcomes of X-Linked Agammaglobulinaemia Patients.

X-linked agammaglobulinaemia (XLA), caused by mutations in BTK, is characterised by low or absent peripheral CD19 + B lymphocytes and agammaglobulinaemia. The mainstay of treatment consists of immunoglobulin replacement therapy (IgRT). As this cannot fully compensate for the immune defects in XLA, patients may therefore continue to be at risk of complications. To describe the clinical outcomes of XLA patients in the United Kingdom and Hong Kong and evaluate current treatment strategies. Patients with a definitive diagnosis of XLA were included in this cross-sectional and retrospective analysis of clinical health outcomes. Data pertaining to diagnosis, infection incidence, IgG trough levels and lung function were collected and analysed. 99 patients with a median age of 29.02 years (IQR 12.83-37.41) and a total follow up of 1922 patient years, were included this study. The median age at diagnosis was 3.30 years (IQR 1.04-8.38) which decreased over time (p = 0.004). 40% of the cohort had radiological evidence of bronchiectasis. Risk of bronchiectasis was not significantly associated with clinical infection incidence (p = 0.880) or IgG trough levels (p = 0.407). Two patients demonstrated novel complications, namely persistent norovirus infection, leading to haemopoietic stem cell transplantation (HSCT). Despite modern therapy, most XLA patients continue to experience complications, most notably bronchiectasis, likely due to absence of IgA/M in current therapies, but lack of B lymphocytes may also lead to additional sequalae. These data strongly support the need for further research, particularly that of curative modalities including HSCT and gene therapy.

M630L MUTATION DISRUPTS THE STRUCTURE CONFORMATION OF BRUTON TYROSINE KINASE (BTK) DOMAIN IN PATIENT WITH X-LINKED AGAMMAGLOBULINEMIA: INSIGHTS FROM IN SILICO

X-Linked Agammaglobulinemia (XLA) is a rare inherited disease, attributed to mutations found in the Bruton Tyrosine Kinase (BTK) gene. This research outlines the application of Molecular Modelling and Simulation to predict the effects of a novel non-synonymous Single Nucleotide Polymorphism (nsSNP) reported in the BTK kinase domain protein of a male XLA patient. The mutation at position c.1888A>T causes a substitution of p.M630L within the kinase domain of the BTK protein. Functional assessment using in silico prediction tools (SIFT, Polyphen-2, PROVEAN, MutationAssessor, PANTHER, FATHMM, MutPred and MutationTaster) predicted the mutation to be deleterious, potentially disrupting both the structure and function of the protein. Nevertheless, the mutation is not located at the active site of the kinase domain. Consequently, the molecular dynamics (MD) simulations were performed to investigate the impact of amino acid substitution to the three-dimensional (3D) conformational structure of the BTK protein, contributing to the disease phenotype observed in the reported patient. MD analysis, clustering analysis and Principle Component Analysis (PCA) revealed that the 3D conformational structure of the kinase domain of mutant protein to be more compact and rigid compared to the wildtype. Given that the alterations in protein structure can influence their functional characteristics, the p.M630L mutation within the BTK protein kinase domain might disrupt the protein function, potentially impeding the maturation of B cells and contributing to the onset of XLA disease.

Comprehensive newborn screening for severe combined immunodeficiency, X-linked agammaglobulinemia, and spinal muscular atrophy: the Chinese experience

BackgroundNewborn screening (NBS) for severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), and spinal muscular atrophy (SMA) enables early diagnosis and intervention, significantly improving patient outcomes. Advances in real-time polymerase chain reaction (PCR) technology have been instrumental in facilitating their inclusion in NBS programs.MethodsWe employed multiplex real-time PCR to simultaneously detect T-cell receptor excision circles (TRECs), kappa-deleting recombination excision circles (KRECs), and the absence of the survival motor neuron (SMN) 1 gene in dried blood spots from 103,240 newborns in Zhejiang Province, China, between July 2021 and December 2022.ResultsOf all the samples, 122 were requested further evaluation. After flow cytometry evaluation and/or genetic diagnostics, we identified one patient with SCID, two patients with XLA, nine patients with SMA [one of whom also had Wiskott–Aldrich Syndrome (WAS)], and eight patients with other medical conditions. The positive predictive values (PPVs) of NBS for SCID, XLA, and SMA were 2.44%, 2.78%, and 100%, respectively. The estimated prevalence rates in the Chinese population were 1 in 103,240 for SCID, 1 in 51,620 for XLA, and 1 in 11,471 for SMA.ConclusionThis study represents the first large-scale screening in mainland China using a TREC/KREC/SMN1 multiplex assay, providing valuable epidemiological data. Our findings suggest that this multiplex assay is an effective screening method for SCID, XLA, and SMA, potentially supporting the universal implementation of NBS programs across China.Graphical abstract

Diversity in the Clinical Course and Outcome of COVID-19 in Patients with Different Inborn Errors of Immunity can be Associated with the Type of Error

Background: The relationship between inborn errors of immunity (IEIs) and COVID-19 severity and incidence rates remains unclear due to limited and diverse data. This study aimed to address this gap by identifying specific IEIs associated with an increased risk of severe COVID-19 or a predisposition to severe disease before vaccination. Materials and Methods: Data were collected from the medical records of 15 patients with various IEIs, supplemented by interviews with individuals from an IEIs registry who had experienced COVID-19 before vaccination. Results: Among the participants, only three patients (20%) experienced severe-prolonged COVID-19. Notably, this severity was predominantly observed in two male patients with Bruton’s disease (BD) and one female patient with autosomal recessive hypogammaglobinemia. Moderate and severe COVID-19 cases were equally distributed (13.33%). In the female subgroup, one patient with common variable immunodeficiency and another with combined immunodeficiency experienced moderate and severe COVID-19, respectively. Conversely, both male patients with moderate and severe COVID-19 had BD. Conclusion: Despite the limited number of severe cases, the absence of cytokine storm manifestation suggests potential protective mechanisms, possibly due to intravenous immunoglobulin therapy and inherent deficiencies within cytokine-producing cells (B and T cells). While IEIs may not be significant risk factors for COVID-19, they offer promising avenues for further research into therapeutic strategies targeting specific immune system components to mitigate severe COVID-19.

BTK and MMP9 regulate NLRP3 inflammasome-dependent cytokine and NET responses in primary neutrophils.

BackgroundInflammation is a double-edged state of immune activation required to resolve threats harmful to the host but can also cause severe collateral damage. Polymorphonuclear neutrophils (PMN) the primary leukocyte population in humans, mediate inflammation through the release of cytokines and neutrophil extracellular traps (NETs). Whilst the pathophysiological importance of NETs is unequivocal, the multiple molecular pathways driving NET release are not fully defined. Recently, NET release was linked to the NLRP3 inflammasome which is regulated by Bruton’s tyrosine kinase in macrophages. ObjectiveAs NLRP3 inflammasome regulation by BTK has not been studied in neutrophils, we here explored a potential regulatory role of BTK in primary murine and human neutrophils and matched monocytes or macrophages from Btk-deficient vs WT mice or healthy donors (HD) vs BTK-deficient X-linked agammaglobulinemia (XLA) patients, respectively. MethodsCytokine, MPO and MMP-9 release were quantified by ELISA, NET release and inflammasome formation by immunofluorescence microscopy. ResultsSurprisingly, in both mouse and human primary neutrophils, we observed a significant increase in NLRP3 inflammasome-dependent IL-1β and NETs when BTK was absent or inhibited, whereas IL-1β release was decreased in corresponding primary mouse macrophages or human PBMC, respectively. This suggests a novel negative regulatory role of BTK in terms of neutrophil NLRP3 activation. Both IL-1β and NET release in mouse and human primary neutrophils were strictly dependent of NLRP3, caspase-1 and, surprisingly, MMP-9. ConclusionThis highlights BTK and MMP-9 as novel and versatile inflammasome regulators and may have implications for the clinical use of BTK inhibitors.

Progressive Neurodegenerative Syndrome in a Patient with X-linked Agammaglobulinemia

Progressive Neurodegenerative Syndrome in a Patient with X-linked Agammaglobulinemia

Abnormal T Cells Function Associated With Intraspinal Cold Abscess Caused by Macrolide-resistant Mycoplasma pneumoniae in a Patient With X-linked Agammaglobulinemia.

Intraspinal cold abscesses caused by macrolide-resistant Mycoplasma pneumoniae in patients with X-linked agammaglobulinemia have not yet been described to our knowledge. Here we describe a patient with X-linked agammaglobulinemia who developed an intraspinal cold abscess caused by macrolide-resistant M. pneumoniae . Genetic analysis revealed a hemizygous c.1566 + 1G > C (IVS15 + 1G > C) mutation in BTK gene. The patient showed relatively naive T cells and a significant proliferative defect.

Carbapenem resistant Campylobacter jejuni bacteremia in a Bruton’s X-linked agammaglobulinemia patient

Immunocompromised patients are prone to recurrent Campylobacter infections. We report a case of recurrent multi-drug resistant Campylobactor jejuni bloodstream infections in a Bruton’s X-linked agammaglobulinemia patient with prolonged ertapenem treatment. The isolate from the fifth recurrence developed carbapenem resistance, which is associated with mutations in a porin gene porA, and promoter changes and duplication of chromosomal blaOXA-61 gene. Combination therapy using cefepime and doxycycline (later switched to moxifloxacin) cleared the infection.

Mycoplasma pneumonia in a patient with X-linked agammaglobulinemia

BackgroundX-linked agammaglobulinemia (XLA), also referred to as Bruton’s tyrosine kinase deficiency, is a rare genetic disorder that affects the immune system. We conducted genetic analysis on patients suffering from immunodeficiency by utilizing Next-Generation Sequencing techniques, as well as their closest relatives, to facilitate accurate diagnosis, offer genetic counseling services, and enhance our comprehension of XLA.