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Australas Emerg Care. 2025 Jul 15:S2588-994X(25)00048-X. doi: 10.1016/j.auec.2025.06.009. Online ahead of print.

ABSTRACT

AIMS: To identify, analyse, and synthesise retrospective data regarding the characteristics and risk factors that primary immune deficiencies (PIDs) inhibit to enhance patient outcomes and improve healthcare professional knowledge.

BACKGROUND: There is currently limited research regarding the management of this high-risk paediatric cohort when they present to an emergency department (ED). This review analyses clinical data in the management, treatment and outcomes for these patients.

DESIGN: This retrospective cohort review analysed patient characteristics, including the ED presentation and treatments, and hospital outcomes for children with a PID.

METHOD: Data from electronic medical records were extracted at a large tertiary paediatric hospital in South-East Queensland according to inclusion and exclusion criteria. Identified cases deidentified, analysed and reported. Baseline variables summarised using descriptive statistics.

RESULTS: Out of 789 ED presentations relating either to fever or PID, 126 cases met the inclusion criteria. Overall, the length of time to be seen by a clinician in ED was a mean of 83 min, 27.8 % did not receive any treatment. Eleven patients had no investigations performed at all, of those who did, 5 % returned positive blood cultures. The immunology team were not consulted for 52 % of patients, and among those admitted, 70.3 % were classed as having a complex medical history.

CONCLUSIONS: There is limited consistency surrounding the management of children with a PID who present to the ED with a fever. Further research and resources are needed to facilitate enhanced emergency management to increase positive outcomes for this rare, but at-risk cohort of paediatric patients.

PMID:40670256 | DOI:10.1016/j.auec.2025.06.009

J Allergy Clin Immunol Glob. 2025 Jun 2;4(3):100506. doi: 10.1016/j.jacig.2025.100506. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: The impact and burden of antibody deficiencies, especially secondary antibody deficiency (SAD), among adult patients remain largely understudied. Specifically, the health-related quality of life (HRQoL) of patients with SAD, compared to patients with primary antibody deficiency (PAD) remains unknown.

OBJECTIVE: Our aim was to characterize and compare the HRQoL of adult patients diagnosed with PAD and SAD.

METHODS: Clinical and HRQoL questionnaire survey data (from the SF-36v2 Health Survey [SF-36v2]) of all adult patients diagnosed with PAD or SAD at Queen Mary Hospital (the only adult immunology center in Hong Kong) were analyzed and compared to data on the general population.

RESULTS: Among the 33 adult patients with antibody deficiency, 22 (66.7%) and 11 (33.3%) had PAD and SAD, respectively. Compared to the general population, patients with PAD scored significantly lower in 3 of 8 domains of the SF-36v2, namely, Role-Physical (81.0 vs 90.4 [P = .020]), Bodily Pain (70.6 vs 84.0 [P = .013]), and Social Functioning (80.1 vs 91.2 [P = .024]). In comparison, patients with SAD scored significantly lower HRQoL in 5 of 8 domains of the SF-36v2, namely, Physical Functioning (64.1 vs 91.8 [P = .032]), Role-Physical (61.9 vs 90.4 [P = .018]), Bodily Pain (51.6 vs 84.0 [P = .003]), General Health (32.9 vs 56.0 [P = .006]), and Social Functioning (61.4 vs 91.2 [P = .027]), as well as in the Physical Component Summary (41.7 vs 53.0 [P = .004]). Upon direct comparison with patients with PAD, patients with SAD had significantly poorer HRQoL in the Physical Component Summary (41.7 vs 49.9 [P = .015]).

CONCLUSION: Patients with SAD reported significantly poorer HRQoL than patients with PAD. Despite significantly greater impairment in HRQoL, patients with SAD often remain underrepresented and may warrant particular attention in terms of physical support and resource allocation.

PMID:40656764 | PMC:PMC12246627 | DOI:10.1016/j.jacig.2025.100506

Eur J Immunol. 2025 Jul;55(7):e51466. doi: 10.1002/eji.202451466.

ABSTRACT

Reticular dysgenesis (RD) is a rare genetic disorder caused by mutations in the adenylate kinase 2 (AK2) gene. It is characterized by a T^–B^– severe combined immunodeficiency, agranulocytosis, and sensorineural deafness. We established and characterized a haematopoiesis-specific conditional Ak2-knockout mouse model to provide a model system to study the molecular pathophysiology of RD. As expected from the human phenotype of RD, haematopoiesis-specific AK2-deficient embryos had a small, atrophic thymus consisting mainly of epithelial cells. No recognizable T-cell component was observed, but B-cell lineage precursor cells were present in the foetal liver. The effects of AK2 deficiency on myelopoiesis were less severe in mice than in humans. The absolute numbers of monocytes, macrophages, granulocytes and megakaryocytes in foetal liver as well as colony-forming precursors were not reduced. In contrast to humans, haematopoiesis-specific Ak2-knockout mice exhibit embryonic lethality between E13 and E15 due to severe anaemia caused by an early block in definitive erythropoiesis. Murine erythroid progenitors mainly express AK2 and only low levels of functionally related kinases, which are unable to compensate for AK2 deficiency, in contrast to human erythroid progenitors.

PMID:40654267 | DOI:10.1002/eji.202451466

J Clin Lab Anal. 2025 Jul 12:e70078. doi: 10.1002/jcla.70078. Online ahead of print.

ABSTRACT

BACKGROUND: Newborn screening (NBS) for severe combined immunodeficiency (SCID) relies on the measurement of T-cell receptor excision circle (TREC) for early diagnosis and intervention. However, considerable variation in TREC cutoff values across countries and testing platforms poses challenges for standardization and optimal screening performance. This study aimed to refine the TREC cutoff values in a large Russian pilot NBS cohort comprising 202,908 newborns, with a primary focus on improving SCID detection sensitivity.

METHODS: A retrospective analysis of 202,908 newborns from a pilot NBS project assessed TREC and KREC levels. Confirmed PID diagnoses were compared with TREC measurements in a group of 66 false-positive cases. The optimal TREC cutoff was established using ROC analysis, with validation across patients with SCID, 22q11.2 deletion syndrome (22q11.2DS), and syndromic forms of PID from an extended validation cohort of PID patients from the Dmitry Rogachev National Medical Research Center.

RESULTS: Receiver operating characteristic (ROC) analysis based on true-positive cases identified an optimal TREC cutoff of 150 copies/10⁵ cells. Values between 150-200 copies/10⁵ cells were found to identify high-risk newborns who require closer monitoring. This threshold was validated in an independent cohort, reducing missed SCID cases while improving the detection of 22q11.2 deletion syndrome and other syndromic primary immunodeficiencies (PIDs). Notably, elevated TREC levels in some SCID patients reflected “leaky” SCID phenotypes, which nonetheless required curative intervention. Additionally, syndromic PIDs and cases of transient idiopathic lymphopenia (TIL) were also more accurately identified, enabling timely clinical management.

CONCLUSION: These findings emphasize the need for broader evaluation of TREC cutoff values across diverse assay systems to improve the effectiveness, comparability, and global harmonization of NBS programs.

PMID:40650447 | DOI:10.1002/jcla.70078

Int J Mol Sci. 2025 Jun 25;26(13):6107. doi: 10.3390/ijms26136107.

ABSTRACT

DNA-deaminase AID plays a pivotal role in adaptive immunity, antibody diversification and epigenetic regulation. AID catalyzes cytidine deamination in immunoglobulin genes, facilitating somatic hypermutation (SHM), class-switch recombination (CSR) and gene conversion (GC). However, the dysregulation of AID activity can lead to oncogenic mutations and immune disorders such as hyper-IgM syndrome type 2 (HIGM2). At present the number of studies investigating the role of AID polymorphic variants in the promotion of pathology is low. The current review examines the structural and functional aspects of AID, focusing on the impact of amino acid substitutions-both natural polymorphisms and artificial mutations-on its catalytic activity, substrate binding and interactions with regulatory proteins. Additionally, a bioinformatic analysis of single-nucleotide polymorphisms of AID deposited in the dbSNP database was performed. SNPs leading to amino acid substitutions in the primary protein structure were analyzed. The bioinformatic analysis of SNPs in the AID gene predicts that among 208 SNPs causing amino acid substitutions in the primary protein structure, 62 substitutions may have significant negative impact on the functioning of AID. The integration of computational predictions with experimental data underscores the importance of AID regulation in maintaining immune homeostasis and highlights potential markers for immune-related pathologies. This comprehensive analysis provides insights into the molecular mechanisms of AID dysfunction and its implications for disease.

PMID:40649888 | DOI:10.3390/ijms26136107

Diagnostics (Basel). 2025 Jun 29;15(13):1659. doi: 10.3390/diagnostics15131659.

ABSTRACT

Background and Clinical Significance: Common variable immunodeficiency (CVID) is a primary B-cell immunodeficiency disorder, characterized by severe hypogammaglobulinemia and disturbed antibody production. In addition to increased susceptibility to recurrent respiratory and gastrointestinal infections, CVID can lead to a wide array of complications associated with immune dysregulation, which can also affect the liver. Liver involvement occurs in about 10% of patients with CVID, and can result from a range of causes, including infections, autoimmune disorders, lymphoproliferative conditions, granulomatous inflammation, and infiltrative processes. The most common liver manifestations include nodular regenerative hyperplasia, granulomatous or autoimmune hepatitis, and lymphocytic infiltration. The prevalence, pathophysiology, extent, and prognosis of liver involvement in CVID have not been systematically studied. Case Presentation: The object of this article is to present two patients with CVID-related liver disease and to illuminate the most relevant causes of liver involvement in CVID, describe the clinical features of their liver disease, and summarize the diagnostic and therapeutic approaches for its management. Conclusions: Liver involvement is an expected complication in patients with CVID syndrome. The delayed recognition of this pathology significantly worsens the disease prognosis, making the early detection of this potential complication crucial.

PMID:40647658 | DOI:10.3390/diagnostics15131659

Clin Exp Med. 2025 Jul 12;25(1):246. doi: 10.1007/s10238-025-01773-1.

ABSTRACT

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disease associated with heterogeneous manifestations, including recurrent infections, lymphoproliferation, and autoimmunity. This analysis sought to estimate the mean annual direct medical costs of manifestations associated with APDS. A burden-of-illness cost calculator was developed based on survey responses from the US clinical experts, published evidence, and the US cost sources (2023). Results from the survey provided estimates of mean annual prevalence of various manifestations associated with APDS and the mean number of times patients experienced recurrent manifestations in a year. In the base case analysis, the annual mean cost of manifestations associated with APDS per patient in the US was estimated to be $116,387 (range, $10,711-$417,455) with gastrointestinal-, infection-, and hematology-related manifestations being the largest contributing factors. The weighted average scenario analysis resulted in similar estimates of mean annual manifestation costs as the base case analysis. To our knowledge, our study is the first to provide estimates of annual prevalence of manifestations associated with APDS and to estimate the annual direct medical costs for patients with APDS in the US. The high mean annual cost associated with APDS contributes to the economic burden of patients and health care payers. Patients with APDS often require off-label, symptomatic treatments for various manifestations that do not target the root cause of the disorder. These treatments are associated with high costs that may not control symptoms. This analysis provides valuable support for discussions about resource utilization and the economic burden of APDS.

PMID:40652158 | DOI:10.1007/s10238-025-01773-1

Health Sci Rep. 2025 Jul 9;8(7):e71015. doi: 10.1002/hsr2.71015. eCollection 2025 Jul.

ABSTRACT

BACKGROUND AND AIMS: Registries are powerful tools for data management. Designing a minimum data set as the first step in registry development helps collect relevant and efficient data. The aim of this study was to develop a minimum data set for the primary immunodeficiency registry system.

METHODS: This cross-sectional study was conducted at two stages in 2023. In the first stage, primary data elements were extracted from related literature. In the second stage, based on the data elements extracted from the first stage, a questionnaire was developed. Then, using the questionnaire and the Quantitative Delphi Method, the minimal data set on primary immunodeficiency was obtained from 10 asthma and allergy specialists.

RESULTS: In the first stage, the initial minimum data set consisted of 198 data elements, which were categorized into two categories: administrative and clinical. Administrative data were classified into two categories: demographic and patient index. Clinical data were categorized into four categories: patient history, physical examination, tests, and diagnosis. In the second stage, eight elements were removed during the first round of Delphi. One element was removed in the second round of Delphi. In the first round of Delphi, 13 elements were recommended. In the second round of Delphi, all the recommended elements were included in the final list of the minimum data set. Finally, 202 data elements were selected as the final minimum data set.

CONCLUSION: The created primary immunodeficiency minimum data set is expected to improve decision-making by clinicians and policymakers, and also improve scientific research in this field.

PMID:40642570 | PMC:PMC12241437 | DOI:10.1002/hsr2.71015

Hum Mutat. 2025 Jul 3;2025:7065233. doi: 10.1155/humu/7065233. eCollection 2025.

ABSTRACT

Bloom syndrome (BS) is a rare genetic disorder associated with an elevated risk of cancer. In a national multicentre study, nine paediatric patients with BS and cancer were analysed. Median age at cancer diagnosis was 12 years. Four of the nine patients were diagnosed with BS prior to cancer detection. Six presented with solid tumours, whilst three had haematological malignancies. Six received polychemotherapy, often with dose reductions. Complications included prolonged aplasia, sepsis and early treatment discontinuation. Two patients received radiotherapy. Four relapsed, and four died, including one toxic death. However, five achieved remission, highlighting the possibility of curative treatment despite significant toxicities.

PMID:40641635 | PMC:PMC12245492 | DOI:10.1155/humu/7065233

J Clin Immunol. 2025 Jul 10;45(1):112. doi: 10.1007/s10875-025-01911-0.

ABSTRACT

Streptococcus pneumoniae can be responsible for severe infections, especially in patients with primary antibody deficiencies like selective anti-polysaccharide antibodies deficiency (SPAD). The reference method recommaned by the World Health Organization for assessment of anti-pneumococcal capsular polysaccharides (PCPs) IgG antibodies is a standardized serotype-specific ELISA (WHO-SSA), but this manual method is time-consuming and limit the number of evaluated PCPs. We aim to evaluate the performance values of a multiplex assay based on electrochemiluminescence (ECL-plex). A panel of 164 sera from 82 patients sampled before and 4-8 weeks after immunization by the 23-valent pneumococcal polysaccharide vaccine (PPV23) were assessed by the reference WHO-SSA (7 to 13 serotypes) and by an 18-plex ECL assay (18 serotypes). All patients had normal serum Ig/subclasses levels and were classified as good (n = 43) or poor responders (n = 39, i.e. SPAD patients) according to the American Academy of Asthma, Allergy and Immunology’s (AAAAI) current guidelines. We observed excellent correlations between the two methods for anti-PCPs titers against 7 serotypes (r = 0.88 [95% CI: 0.87-0.90], n = 124 sera) and 13 serotypes (r = 0.87 [0.87-0.89], n = 40 sera). Using the AAAAI’s guidelines for interpretation, the test performance of the 18-plex ECL assay for SPAD diagnosis showed a sensitivity of 95% and specificity of 84%, positive and negative predictive values of 84% and 95%, respectively. The percentage of agreement was 89% between the SSA and the 18-plex ECL assay. The 18-plex ECL assay is a reliable, rapid, and simple method for evaluating anti-PCPs response and screening for SPAD diagnosis.

PMID:40637813 | DOI:10.1007/s10875-025-01911-0