Blog

Ecancermedicalscience. 2024 Jul 30;18:1733. doi: 10.3332/ecancer.2024.1733. eCollection 2024.

ABSTRACT

Scarce data is available regarding primary immunodeficiency-associated cancers in children in low-middle-income countries. This study aimed to determine the incidence, clinical features and outcomes of primary immunodeficiencies (PIDs)-associated cancers in children presenting to Pakistan’s largest public-sector specialised pediatric oncology center. Among 5,748 children with cancers registered over 5 years, only eight patients were found to have PID-associated pediatric malignancies with an incidence of 1.4 per 1,000 cases. The median age at the time of diagnosis was 6.5 years with a male-to-female ratio of 7:1. Only four types of PIDs were found to be associated with cancer in children at our center: Ataxia Telangiectasia in 37.5% (n = 3), hyper-IgE syndrome and IgG deficiency in 25% (each n = 2) and one case (12.5%) of common variable immune deficiency. Six different types of pediatric cancers were associated with PID with a predisposition towards hematological malignancies (n = 7, 87.5%). Only two patients (25%) survived. The median survival of the cohort was 3.5 months. Infection-related mortality was the cause of death in four patients (66%), and the type of PID was the only statistically significant factor associated with the outcome. It is concluded that a lesser proportion of PID-associated pediatric cancers are found in our center as compared to the reported data from high-income countries. PID-associated cancers in children have an abysmal prognosis and infection-related mortality is the major cause of treatment failure. Sensitisation of oncologists to look for any underlying PID, the introduction of PID-screening programs in children and consideration of PID-associated malignancies as a high-risk group for treatment may help improve the outcomes.

PMID:39421168 | PMC:PMC11484680 | DOI:10.3332/ecancer.2024.1733

Pediatr Allergy Immunol. 2024 Oct;35(10):e14259. doi: 10.1111/pai.14259.

NO ABSTRACT

PMID:39418167 | DOI:10.1111/pai.14259

Sci Rep. 2024 Oct 16;14(1):24247. doi: 10.1038/s41598-024-71673-z.

ABSTRACT

Immunodeficiency 11B with atopic dermatitis (IMD11B, OMIM:617638) is rare primary immunodeficiency disease caused by germline dominant negative (DN) mutations in the CARD11 gene. Affected patients present with immune dysfunction, recurrent infections and atopic dermatitis. In this study, we sought to identify and characterize the genetic variant in one patient with periodic fever, recurrent infections, and eczema. Trio whole-exome sequencing (WES) was employed in this patient and her parents, and Sanger sequencing validated the potential pathogenic variant. In vitro functional study was performed to evaluate the pathogenicity of genetic variant identified. A very rare missense mutation (c.2324C > T, p.S775L) in CARD11 gene (NM_032415) was identified by WES in the patient but not her parents. Luciferase reporter assays and co-immunoprecipitation demonstrated mutation exerts a dominant-interfering effect on wild-type CARD11, inhibiting the activity of NF-κB. RNA sequencing analysis also confirmed that mutant CARD11 inhibited down-stream transcriptional activity of NF-κB. A review of literature doesn’t found significant genotype-phenotype correlation. We identified a vary rare DN CARD11 mutation, expanding the genetic and phenotypic spectrum of CARD11.

PMID:39414811 | DOI:10.1038/s41598-024-71673-z

Front Immunol. 2024 Oct 2;15:1456769. doi: 10.3389/fimmu.2024.1456769. eCollection 2024.

ABSTRACT

INTRODUCTION: Early diagnosis of Severe Combined Immunodeficiency (SCID) increases survival outcomes and quality of life while significantly minimizing healthcare burden and costs. Despite growing evidence supporting the benefits and cost-effectiveness of SCID detection through newborn screening (NBS), it has yet to be implemented in Malaysia. This study aims to explore experts’ opinions on the current status, challenges, and crucial strategies needed for the successful implementation of SCID NBS.

METHODOLOGY: A guided, structured interview was employed to explore opinions on the current status, barriers, and strategies for implementing SCID NBS in Malaysia. All 13 invited experts participated in this study, indicating complete participation from the entire Malaysian immunology fraternity (consisting of eight clinical immunologists and five immunopathologists).

KEY FINDINGS: Several initiatives are ongoing to establish SCID NBS in Malaysia. Hindrances such as low immunologist-to-patient ratio, unequal placements of immunologists throughout Malaysia, society’s low disease awareness, national health prioritization, lack of stakeholder engagement, and inadequacy of local study/data were highlighted. Pilot research on SCID NBS, advocacy workshops, and promotion materials are among the ongoing activities outlined in the blueprint, paving the way for this nationwide NBS program to be achievable in the near future.

CONCLUSION: This article provides recommendations to policymakers in mandating SCID NBS. Strategies by key stakeholders are underway, particularly in advocacy programs and efforts to increase awareness among clinicians and the public.

PMID:39416794 | PMC:PMC11479922 | DOI:10.3389/fimmu.2024.1456769

Front Genet. 2024 Oct 2;15:1409754. doi: 10.3389/fgene.2024.1409754. eCollection 2024.

ABSTRACT

Common variable immunodeficiency (CVID) is a group of genetic disorders involving more than a dozen genetic loci and characterized by a deficiency in specific antibody isotypes leading to poor immune responses and recurrent infection. CVID affects approximately 1 in 10,000 to 1 in 50,000 people worldwide with substantial heterogeneity in disease severity, including asymptomatic individuals designated as hypogammaglobulinemia of undetermined significance (HGUS). As expected of humoral immunodeficiency, the molecular causes of CVID primarily affect the maturation, activation, or survival of B cells and plasma cells. In this retrospective analysis, we defined a cohort of 21 patients with a primary CVID or HGUS diagnosis in the v7 release of the All of Us Research Program database and performed gene annotation and variant effect prediction. Our analysis identified both known disease-causing variants and rare genetic variants overlapping with other immunodeficiency syndromes.

PMID:39415980 | PMC:PMC11479952 | DOI:10.3389/fgene.2024.1409754

Clin Exp Immunol. 2024 Oct 16:uxae089. doi: 10.1093/cei/uxae089. Online ahead of print.

ABSTRACT

Periodontitis is a frequent local inflammatory disease. The microbiota and repeated exposure to bacterial endotoxins triggers excessive inflammation through oral mucosal immunity, sometimes leading to a destructive effect on the supportive mucosal tissues around the teeth. Elimination of the pathogens and increasing the tolerance of the cellular immune response is crucial in addition to standard dental therapies like mechanical debridement. Based on our experience on immune-mediated diseases, especially primary immunodeficiency diseases (PIDs), we wrote this review to discuss the treatment alternatives for severe periodontal disease. Risk factors are malnutrition, vitamin deficiencies, smoking, systemic inherited and acquired immune-mediated diseases, infections, endocrinological diseases, and pharmacological agents may accompany periodontitis. The diagnosis and treatment of dietary deficiencies, as well as the addition of nutritional supplements, may aid in epithelial regeneration and immune system function. Recently, modifications to the therapeutic option for severe periodontitis have been made depending on the fact that the immune response against bacteria may modify the severity of periodontal inflammation. The anti-inflammatory therapies support or inhibit the host’s immune response. The clinical approach to severe periodontitis should extend beyond classical therapies. There is a need for a diverse therapeutic strategy that supports the epithelial barrier, which is the crucial component of innate immunity against microbiota. Leukocytes are the main cellular component in periodontal inflammation. Anti-inflammatory therapeutic options directed at leukocytes, such as IL-17 and IL-23-targeted therapies, could be the candidates for the treatment of severe periodontitis. Therapy against other inflammatory cytokines, IL-1, IL-6, IL12, IL23, TNF-alpha, PGE2, and cytokine receptors, could also be used in periodontal inflammation control.

PMID:39412215 | DOI:10.1093/cei/uxae089

Int J Mol Sci. 2024 Oct 9;25(19):10844. doi: 10.3390/ijms251910844.

ABSTRACT

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C>T variant in TP63, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly-Ectodermal Dysplasia-Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a TP63 mutation, highlighting the need for further investigation into the immunological aspects of TP63-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with TP63 mutations to better understand and manage potential immune dysfunctions.

PMID:39409174 | DOI:10.3390/ijms251910844

Int Forum Allergy Rhinol. 2024 Oct 15. doi: 10.1002/alr.23468. Online ahead of print.

ABSTRACT

BACKGROUND: There is clear evidence that prevalence of primary antibody deficiency (PAD) is higher in children with chronic rhinosinusitis (CRS) than in the general population. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on rhinosinusitis with PAD, summarize the existing evidence, and provide recommendations on the evaluation and management of rhinosinusitis in children with PAD.

METHODS: The PubMed, Embase, and Cochrane databases were systematically reviewed from inception through December 2023. Studies on the evaluation and management of rhinosinusitis in PAD patients were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on the evaluation and management principles for PAD were generated.

RESULTS: A total of 50 studies were included in this evidence-based review. These studies were evaluated on the incidence of PAD in rhinosinusitis patients, the incidence of rhinosinusitis in PAD patients, and on the different treatment modalities used and their outcome. The aggregate quality of evidence varied across the reviewed domains.

CONCLUSION: Based on the currently available evidence, the incidence of PAD in children with recalcitrant CRS can be significantly elevated. Despite the presence of multiple studies addressing rhinosinusitis and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology. There is need for higher level studies that compare different treatments in children with PAD and rhinosinusitis.

PMID:39404739 | DOI:10.1002/alr.23468

Front Cell Infect Microbiol. 2024 Sep 30;14:1456672. doi: 10.3389/fcimb.2024.1456672. eCollection 2024.

ABSTRACT

The gut microbiota serves a crucial role in the development of host immunity. Immunocompromised patients are particularly vulnerable to dysbiosis not only by virtue of a defect in the immune system but also due to increased susceptibility to infection and multiple courses of antibiotic therapy. Fecal microbiota transplantation is by far the most effective option for restoring gastrointestinal homeostasis. However, it is contraindicated in patients with significant primary and secondary immunodeficiencies. This article presents the case of a 59-year-old patient with common variable immunodeficiency, after splenectomy at age 39 for primary immune thrombocytopenia, who manifested diarrhea of up to 10 stools per day accompanied by secondary malnutrition and cachexia. The patient was admitted to the hospital on multiple occasions due to this condition, with stool PCR tests confirming a HHV-5 (Cytomegalovirus, CMV) infection. Following the administration of valganciclovir, the patient’s complaints diminished, although, upon cessation of the drug, the symptoms recurred. In addition, the patient had an intestinal infection with C. difficile etiology. Given that the patient’s therapeutic options had been exhausted, after obtaining informed consent from the patient and approval from the bioethics committee to conduct a medical experiment, treatment of diarrhea was undertaken by fecal microbiota transplantation with the certified preparation Mbiotix HBI from the Human Biome Institute. The patient underwent two transplants, with a one-week interval between them. The initial procedure was performed using the endoscopic method, while the subsequent was conducted using the capsule method. Following the administration of the applied treatment, the patient’s symptoms were successfully alleviated, and no adverse effects were observed. A microbiological analysis of the intestinal microbiota was conducted prior to and following transplantation via next-generation sequencing (NGS). No recurrence of symptoms was observed during the two-year follow-up period. To the best of our knowledge, this is the first fecal microbiota transplantation in an adult patient with primary and secondary immunodeficiency.

PMID:39403201 | PMC:PMC11472351 | DOI:10.3389/fcimb.2024.1456672

Eur Ann Allergy Clin Immunol. 2024 Oct 14. doi: 10.23822/EurAnnACI.1764-1489.368. Online ahead of print.

ABSTRACT

Background. We aimed to describe the clinical heterogeneity (infectious and noninfectious manifestations) and the impact of immunoglobulin replacement therapy on the reduction of infections in patients given a diagnosis of common variable immunodeficiency. Methods. This was a descriptive case series study. Medical charts were retrospectively reviewed based on demographics, clinical presentation, immunoglobulin replacement therapy and laboratory findings at diagnosis. Results. Thirty six common variable immunodeficiency patients were enrolled. Nineteen of them were male (53%). The median age at onset of symptoms was 8 years and at common variable immunodeficiency diagnosis was 19 years. Family history for immunodeficiency was observed in 2 patients (5%). Recurrent infections were present in 35 patients (97%) and they were the first clinical manifestations in 31 patients (86%). Respiratory infections were the most frequent, followed by gastrointestinal infections. Noninfectious manifestations were present in 32 patients (89%), including bronchopulmonary disease, allergy, autoimmunity, lymphoproliferation, gastrointestinal disorders and malignancy. Chronic pulmonary disease and lymphoproliferation were the most common. There was an important reduction of infections 1 year after begining immunoglobulin replacement therapy, mainly pneumonia and sinusitis. Conclusions. Although the diagnosis of common variable immunodeficiency has improved over the last decade, many patients are still being referred and diagnosed late. Physicians must recognize that both infectious and noninfectious manifestations can be the initial signs of common variable immunodeficiency and are very common in these patients. Immunoglobulin replacement therapy significantly reduces respiratory infections.

PMID:39400126 | DOI:10.23822/EurAnnACI.1764-1489.368