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J Clin Med. 2024 Sep 21;13(18):5600. doi: 10.3390/jcm13185600.

ABSTRACT

Background: Thymic epithelial tumors (TETs) are uncommon malignancies uniquely associated with autoimmunity and immunodeficiency. Previous studies among patients with primary immunodeficiency diseases have shown that a low calculated globulin (CG) level, obtained by subtracting albumin from total protein level, is associated with infection risk. We investigated this association among patients with TET. Methods: A cross-sectional retrospective study was performed based on electronic medical records of patients with TET treated during 2002-2024 at a tertiary care institution. For each patient, their lowest CG level and the date of occurrence were identified. The incidence of serious infection requiring hospitalization during 6 months before and 6 months after the index date was recorded. Multivariable Poisson regression models were constructed. Results: Among 101 TET patients, 96 patients (95%) had the information available to derive at least one CG level. The median lowest CG level was 2.65 g/dL (range 1.0-4.2). There were 33 serious infection episodes. Pneumonia was the most prevalent type of infection in 52% of episodes. In a multivariable analysis, a CG level below 2.0 was independently associated with the prevalence of infection with a prevalence ratio of 6.18 (95% CI: 3.12-12.23, p < 0.001). Furthermore, thymectomy was significantly associated with infection. Conclusions: Among patients with TET, a low CG level was associated with an increased prevalence of serious infections. Our limited experiences suggest that it is feasible to derive the CG level for most patients during routine clinical care.

PMID:39337087 | PMC:PMC11432503 | DOI:10.3390/jcm13185600

J Allergy Clin Immunol Pract. 2024 Sep 25:S2213-2198(24)00944-9. doi: 10.1016/j.jaip.2024.09.018. Online ahead of print.

ABSTRACT

Female X-linked chronic granulomatous disease (XL-CGD) carriers may develop severe clinical disease including infections with CGD-defining pathogens and inflammatory disorders. Similar to males with XL-CGD, female carriers warrant ongoing evaluation and prophylaxis where indicated.

PMID:39332496 | DOI:10.1016/j.jaip.2024.09.018

J Intern Med. 2024 Oct;296(4):311-326. doi: 10.1111/joim.20008.

ABSTRACT

Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)-driven kallikrein-kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first-line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa-targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long-term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE.

PMID:39331688 | DOI:10.1111/joim.20008

J Clin Immunol. 2024 Sep 27;45(1):18. doi: 10.1007/s10875-024-01809-3.

ABSTRACT

INTRODUCTION: This study investigates the frequency of hospital attendances, emergency care attendances and geographical influences on service interaction in cohorts of patients with primary and secondary antibody deficiency, to inform future service planning and delivery.

METHODS: The COVID-19 in Antibody Deficiency (COV-AD) study was a United Kingdom study that enrolled 525 participants between April 2021 and September 2022. Data on health care utilisation was extracted from a screening cohort of participants at one participating site (Birmingham, UK). Hospital attendance (i.e. all outpatient and inpatient care episodes, including hospital-based IVIG treatment) and emergency care attendance patterns were analysed. Geographical differences in travel times to hospitals and associated costs were considered for all participants at all recruiting sites.

RESULTS: Individuals with antibody deficiency had a median of 7 hospital attendances per year. A diagnosis of secondary antibody deficiency, and antibody deficiency severe enough to require treatment with immunoglobulin replacement were associated with an increased frequency of hospital attendance. 12.7% of the cohort attended the Emergency Department at least once in the preceding twelve months. Individuals with secondary antibody deficiency were at greater risk of requiring emergency care over the preceding one-year and five-year periods. Individuals receiving subcutaneous immunoglobulin lived further from their local immunology centre and were more likely to engage with the COV-AD research study remotely, via dried blood spots sampling.

CONCLUSION: This study highlights the utilisation of emergency and secondary care usage amongst patient with immunodeficiency and may inform service adaptation and development to better accommodate patient needs and circumstances.

PMID:39331196 | PMC:PMC11436396 | DOI:10.1007/s10875-024-01809-3

Curr Opin Allergy Clin Immunol. 2024 Sep 26. doi: 10.1097/ACI.0000000000001035. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Liver disease has emerged as a major risk factor for increased mortality in patients with common variable immunodeficiency (CVID). This is mostly due to presinusoidal portal hypertension (PHTN) frequently secondary to nodular regenerative hyperplasia (NRH). Its pathogenesis is still poorly understood and treatment strategies for its various stages are often guided by trial and error. This review summarizes the most recent findings in the light of previous literature.

RECENT FINDINGS: In the last 2 years, different groups have addressed pathology, diagnostics, treatment, and liver transplantation. Histological examinations seem to support the pathogenetic sequence of T-cell mediated infiltration and damage of the sinusoidal space with secondary development of NRH, pericellular fibrosis, and the manifestation of PHTN. While markers of the early phase – beyond slight elevation of cholestatic enzymes – are still missing, elevated liver stiffness and splenomegaly above 16 cm longitudinal diameter have been suggested as warning signs for PHTN in CVID patients. Data on immunosuppressive treatment of this manifestation is still very heterogeneous, but a recent report on liver transplantation was encouraging for end stage liver disease.

SUMMARY: Liver disease deserves higher attention in the management of CVID. More studies are needed to understand its pathogenesis and optimal treatment.

PMID:39329167 | DOI:10.1097/ACI.0000000000001035

MedComm (2020). 2024 Sep 25;5(10):e747. doi: 10.1002/mco2.747. eCollection 2024 Oct.

ABSTRACT

Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4⁺ T cells have a Th2 effector fate. RNA-bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4⁺ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4⁺ T cells, which is related to the Akt/mTOR/S6/HIF-1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4⁺ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8-deficient patients.

PMID:39329018 | PMC:PMC11424684 | DOI:10.1002/mco2.747

Zhonghua Er Ke Za Zhi. 2024 Oct 2;62(10):1000-1004. doi: 10.3760/cma.j.cn112140-20240301-00140.

ABSTRACT

原发性免疫缺陷病（PID）是一组由基因变异引起的疾病，这些变异影响免疫系统的各个层面，导致免疫功能障碍。在PID患儿中，呼吸系统并发症非常普遍，特别是肺炎，对患儿的预后有重大的影响。现聚焦于几种常见的PID类型，探讨了PID的发病机制与肺炎并发症之间的联系，旨在为国内未来的研究和临床实践提供参考依据。.

PMID:39327970 | DOI:10.3760/cma.j.cn112140-20240301-00140

Australas Emerg Care. 2024 Sep 25:S2588-994X(24)00053-8. doi: 10.1016/j.auec.2024.09.001. Online ahead of print.

ABSTRACT

AIM: To identify, analyse, and synthesise existing research on the characteristics and risk factors associated with primary immune deficiencies (PIDs), with focus on understanding how factors impede patient outcomes.

BACKGROUND: There is currently limited research regarding the management of this cohort when they present to an emergency department with the presentation urgency often being overlooked.

METHOD: Three databases, google scholar, and citations were searched for relevant studies under the criteria. Included papers were analysed and reported following the PRISMA guideline, and then critically appraised using the Mixed Method Appraisal Tool.

RESULTS: After a review of 625 titles and abstracts, 20 studies met the inclusion criteria. The majority being mixed method (n = 8) and case studies (n = 8). All chosen studies reported some form of management of a child with a PID, and most made recommendations for improvement.

CONCLUSIONS: Further research is needed to facilitate an understanding of how to enhance emergency management, to increase positive outcomes.

RELEVANCE TO PRACTICE: There is a critical need for improved management strategies for children with a PID presenting to ED with fever. Creating protocols, increasing staff knowledge, and implementing patient specific interventions are essential in improving outcomes and reducing serious complications in this high-risk paediatric population.

PMID:39327126 | DOI:10.1016/j.auec.2024.09.001

Cureus. 2024 Aug 26;16(8):e67799. doi: 10.7759/cureus.67799. eCollection 2024 Aug.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary disorder characterized by impaired B cell differentiation and defective immunoglobulin production. This condition often presents with a wide range of clinical manifestations, including increased frequency and severity of infections, autoimmune diseases, and inflammatory disorders, which can lead to delays in diagnosis. Granulomatous involvement of the brain is an extremely rare but severe manifestation of CVID. We present a case of a woman in her 30s with a history of Evans syndrome and lymphocytic alveolitis who was admitted with persistent headache without neurological symptoms. Imaging revealed multiple infiltrative brain lesions. Despite the absence of recurrent infections, the patient’s history of autoimmune manifestations and immunoglobulin deficiencies led to the diagnosis of CVID without the need for a brain biopsy. Treatment with intravenous immunoglobulin and immunosuppressive therapy resulted in significant clinical improvement and resolution of brain lesions. This case highlights the importance of considering CVID in patients with autoimmune manifestations and the effectiveness of prompt immunoglobulin replacement and immunosuppression in managing severe presentations of this condition.

PMID:39323683 | PMC:PMC11423391 | DOI:10.7759/cureus.67799

Immunotherapy. 2024;16(13):895-905. doi: 10.1080/1750743X.2024.2382074. Epub 2024 Sep 26.

ABSTRACT

Immunoglobulin G (IgG) dosing in treating primary immunodeficiency diseases (PIDs) is individualized, which often involves regular monitoring of IgG levels, and considers patient experiences with immunoglobulin therapies, their clinical status and physician judgment. The frequency and dose(s) of intravenously (IVIG) and subcutaneously (SCIG) administered IgGs (including hyaluronidase-facilitated SCIG) require rigorous evaluation to maximize therapeutic benefits. Monitoring serum IgG levels represents an integral part of diagnosing primary immunodeficiency diseases and determining or adjusting IgG dosing strategies to meet individual patient needs, but cannot be conducted in isolation. This review discusses the current state and future perspectives on dosing strategies for different types of IgG therapies, as well as dosing considerations for specific patient populations, immunoglobulin-naive patients and patients switching between IVIG and SCIG.

PMID:39323406 | PMC:PMC11457668 | DOI:10.1080/1750743X.2024.2382074