Research

Blood Cancer J. 2024 Jul 25;14(1):124. doi: 10.1038/s41408-024-01107-6.

ABSTRACT

T cell engagers (TCE) such as chimeric antigen receptor (CAR) T cell therapy and bispecific antibodies (BiAbs) for the treatment of multiple myeloma (MM) have significantly improved clinical outcomes, but have also raised awareness for ensuing post-treatment secondary immunodeficiency and hypogammaglobulinemia (HG). As patients with MM live longer, recurrent infections become a significant component of therapy-associated morbidity and mortality. Treatment of HG with immunoglobulin G replacement therapy (IgG-RT) has been a mainstay of the primary immunodeficiency (PI) world, and extrapolation to MM has recently started to show promising clinical outcomes. However, IgG-RT initiation, dosing, route, timing, monitoring, and management in MM has not been standardized in the setting of TCE. Progress in MM treatment will involve greater recognition and screening of underlying secondary immunodeficiency, identification of risk-stratification markers, optimizing IgG-RT management, and implementing other approaches to decrease the risk of infection. In this review, we summarize infection risk, risk of HG, and management strategies for IgG-RT in patients with relapsed MM after TCE.

PMID:39054331 | DOI:10.1038/s41408-024-01107-6

Blood. 2024 Jul 25;144(4):462. doi: 10.1182/blood.2024024419.

NO ABSTRACT

PMID:39052266 | DOI:10.1182/blood.2024024419

Blood. 2024 Jul 25;144(4):354-355. doi: 10.1182/blood.2024024958.

NO ABSTRACT

PMID:39052271 | DOI:10.1182/blood.2024024958

Front Immunol. 2024 Jul 9;15:1414573. doi: 10.3389/fimmu.2024.1414573. eCollection 2024.

ABSTRACT

Dedicator of cytokinesis 8 (DOCK8) deficiency represents a primary immunodeficiency with a wide range of clinical symptoms, including recurrent infections, atopy, and increased malignancy risk. This study presents a case of a 6-year-old girl with DOCK8 deficiency, characterized by severe, treatment-resistant herpetic infections who was successfully treated with siltuximab and glucocorticoids. The successful use of siltuximab in achieving remission highlights the pivotal role of interleukin-6 (IL-6) in DOCK8 deficiency pathogenesis and suggests that IL-6 modulation can be critical in managing DOCK8 deficiency-related viral infections, which may inform future therapeutic strategies for DOCK8 deficiency and similar immunodeficiencies.

PMID:39044832 | PMC:PMC11263070 | DOI:10.3389/fimmu.2024.1414573

Front Oral Health. 2024 Jul 9;5:1427060. doi: 10.3389/froh.2024.1427060. eCollection 2024.

ABSTRACT

Medication-Related Osteonecrosis of the Jaw (MRONJ) is a challenging and evolving aspect of Oral and Maxillofacial Surgery. In recent years, several medications apart from those traditionally associated with MRONJ such as bisphosphates (BPs) and Denosumab (DMB) have been implicated in bony necrosis of the jaw. This aim of this report is to demonstrate a significant case of bone necrosis following dental extractions on a patient being treated with infliximab therapy for Crohn’s disease. Several cases in literature have reported MRONJ associated with infliximab but very few patients have developed as significant a form of the disease as seen in this report. Previous investigators have proposed pathophysiological pathways via which TNF-α inhibitors such as infliximab have a causative mechanism for MRONJ. When osteoclastic activity is restricted via these pathways, bone healing is impaired and MRONJ can occur. However, it remains a diagnostic challenge to differentiate between antiresorptive MRONJ and chronic osteomyelitis with bone necrosis in patients with acquired immunodeficiency. This case aims to illustrate why the antiresorptive effects of TNF-α inhibitors need to be considered as a possible primary driver of bone necrosis in such patients.

PMID:39045331 | PMC:PMC11263092 | DOI:10.3389/froh.2024.1427060

Front Immunol. 2024 Jul 8;15:1411141. doi: 10.3389/fimmu.2024.1411141. eCollection 2024.

ABSTRACT

Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency disease predominantly caused by gain-of-function variants in the CXCR4 gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4) leading to impaired leukocyte egress from bone marrow to peripheral blood. Diagnosis of WHIM syndrome continues to be challenging and is often made through clinical observations and/or genetic testing. Detection of a pathogenic CXCR4 variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants. Understanding the genotypic-phenotypic associations in WHIM syndrome has the potential to improve time to diagnosis and guide appropriate clinical management, resulting in a true example of precision medicine. This article provides an overview of the spectrum of CXCR4 variants in WHIM syndrome and summarizes the various lines of clinical and functional evidence that can support interpretation of newly identified variants.

PMID:39040098 | PMC:PMC11260667 | DOI:10.3389/fimmu.2024.1411141

Front Immunol. 2024 Jul 8;15:1419748. doi: 10.3389/fimmu.2024.1419748. eCollection 2024.

ABSTRACT

Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34⁺-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34⁺/CD43⁺/CD45⁺ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.

PMID:39040103 | PMC:PMC11260623 | DOI:10.3389/fimmu.2024.1419748

Am J Clin Nutr. 2024 Jul 20:S0002-9165(24)00613-0. doi: 10.1016/j.ajcnut.2024.07.016. Online ahead of print.

ABSTRACT

BACKGROUND: Early enteral nutrition (EN) is recommended for patients with critical illness to maintain intestinal immunity. However, the optimal timing of the commencement of EN remains unclear, particularly after cardiovascular surgery.

OBJECTIVE: We herein focused on Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) as a predisposing immunodeficiency, and investigated its association with very early EN (<24 hours) in patients who underwent cardiovascular surgery.

DESIGN: In this retrospective study, we used an administrative claims database with laboratory examinations between 2008 and 2021 to identify adult patients admitted to the intensive care unit after cardiovascular surgery. Patients who received EN the day after surgery were assigned to the EN <24 h group, while those who received EN on day 2 or 3 were assigned to the control group. The primary outcome was a composite of the incidence of PICS and mortality on day 14 after surgery. We defined PICS as patients hospitalized for >14 days and meeting at least two of the following conditions: a lymphocyte count <800/μL, albumin <3.0 g/dL, and CRP >2.0 mg/dL. We compared the two groups using a propensity score analysis.

RESULTS: Propensity score matching generated 2,082 pairs. The primary outcome was significantly lower in the EN <24 h group than in the control group on days 14 (risk difference [95% CI], -3.1% [-5.9%, -0.3%]) and 28 (risk difference [95% CI], -2.1% [-3.7%, -0.4%]). Mortality did not significantly differ between the two groups. The length of hospital stay was significantly shorter in the EN <24 h group: the difference (95% CI) was -2.2 (-3.7, -0.7) days.

CONCLUSIONS: Among patients who underwent cardiovascular surgery, very early EN provided on the day after surgery was associated with a lower incidence of PICS and a shorter length of hospital stay than EN provided two or three days after surgery.

PMID:39038737 | DOI:10.1016/j.ajcnut.2024.07.016

J Paediatr Child Health. 2024 Jul 21. doi: 10.1111/jpc.16614. Online ahead of print.

ABSTRACT

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is used in critically ill children with cardiac and/or respiratory failure. Use is increasing in children with high-risk comorbidities. Reasons children do not survive ECMO are poorly described.

AIMS: Describe characteristics and cause of death, compare mortality in children with high-risk comorbidities, evaluate mortality trends over a decade.

METHOD: All children <18 years old who received ECMO at this institution from 1 January 2011 to 31 December 2020 were described and categorised by outcome: died on or <48 h post-ECMO, died ≥48 h post-ECMO, survived to hospital discharge. Children who did not survive ECMO (DNSE) were categorised to: ECMO withdrawal for irrecoverable original condition, withdrawal for poor prognosis neurological condition, brain death, withdrawal for poor prognosis with multiple complex conditions, and unsupportable. Poison regression was used to analyse survival trends.

RESULTS: Four hundred twenty-eight children received ECMO, 19% DNSE, 14% died ≥48 h post-ECMO and 67% survived. ECMO was electively withdrawn for irrecoverable original condition (39%), poor prognosis for neurological condition (32%) or multiple complex conditions (18%). One hundred twenty-two children had ≥1 high-risk comorbidity. Children with genetic syndromes (58%), risk-adjusted congenital heart surgery score-1 ≥4 (53%), primary immunodeficiency (50%) had lower hospital survival. No children with malignancy/bone marrow transplant survived to hospital discharge. Overall hospital survival was 67%, with no significant change during the study period (P-trend = 0.99).

CONCLUSION: Children who DNSE have therapy electively withdrawn for irrecoverable disease or poor prognosis. Children with high-risk comorbidities have a reasonable chance of survival. This study informs clinicians ECMO may be a therapeutic option.

PMID:39034664 | DOI:10.1111/jpc.16614

Front Immunol. 2024 Jul 5;15:1406532. doi: 10.3389/fimmu.2024.1406532. eCollection 2024.

ABSTRACT

Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.

PMID:39035006 | PMC:PMC11257845 | DOI:10.3389/fimmu.2024.1406532