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Cureus. 2025 Dec 1;17(12):e98264. doi: 10.7759/cureus.98264. eCollection 2025 Dec.

ABSTRACT

Good’s syndrome (GS) is a primary immunodeficiency characterized by thymoma-associated hypogammaglobulinemia, leading to recurrent infections. A 71-year-old woman, with a history of oral and perineal lichen planus, chronic sinusitis, recurrent otitis, and thymoma excision in 2021, presented with fever and diarrhea after testing positive for SARS-CoV-2. On admission, she appeared stable but had bleeding lichen planus lesions and required supplemental oxygen for moderate respiratory insufficiency. Laboratory results revealed leukocytosis with neutrophil predominance and mild inflammation. A diagnosis of GS was made based on the history of thymoma, detection of hypogammaglobulinemia, and an imbalance in cellular immunity. Additionally, blood cultures grew Campylobacter coli, and she completed a 14-day regimen of azithromycin. After completing the antibiotic course, her respiratory condition worsened with progressive bilateral infiltrates seen on X-ray. The polymerase chain reaction-multiplex respiratory pathogen panel was positive only for SARS-CoV-2. Despite mechanical ventilation, treatment with broad-spectrum antibiotic therapy, and immunoglobulin replacement, her condition continued to deteriorate. The patient’s clinical deterioration was attributed to the combined immunodeficiency from GS and the co-infection of SARS-CoV-2 and C. coli bacteremia. At this point, SARS-CoV-2 remained detectable through the multiplex respiratory panel, and inflammatory markers were elevated, with a C-reactive protein of 21.13 mg/dL, procalcitonin of 0.69 ng/mL, and leukocytosis of 11.7 × 10⁹/L with neutrophilia (10.51 × 10⁹/L). This case emphasizes the risk of severe infections in patients with GS, as well as the importance of early detection and comprehensive management of concurrent bacterial and viral infections in immunocompromised individuals.

PMID:41480435 | PMC:PMC12755914 | DOI:10.7759/cureus.98264

Front Immunol. 2025 Dec 17;16:1683892. doi: 10.3389/fimmu.2025.1683892. eCollection 2025.

ABSTRACT

BACKGROUND: Primary immunodeficiencies (PIDs) comprise a heterogeneous group of disorders characterized by defects in the immune system, predisposing patients to recurrent and severe infections. Type 68 immunodeficiency, caused by biallelic pathogenic variants in MYD88, is rare; to date, at least 26 affected individuals have been reported in the literature, several of whom belong to the same families. This condition typically presents in early childhood with recurrent severe bacterial infections (SBIs), often accompanied by an absent or attenuated inflammatory response.

CASE PRESENTATION: We report a 3-month-old male patient admitted with multiple SBIs, including left-sided abscessing pyelonephritis, pyogenic liver abscess, and septic pneumonia complicated by tension pneumothorax. Initial immunological screening revealed normal leukocyte counts, immunoglobulin levels, lymphocyte subpopulations, and TREC (T-cell receptor excision circle)/KREC (kappa-deleting recombination excision circles) copy numbers. Congenital urinary tract anomalies were excluded. Despite clinical improvement, the patient subsequently developed a cold abscess of the cervical lymph node due to Staphylococcus aureus. Whole-exome sequencing identified two novel compound-heterozygous missense variants in MYD88 (p.Leu35Pro and p.Trp47Cys), both located in the death domain. In silico analysis suggested potential disruption of α-helical structure and MyD88-MyD88/IRAK4 interactions. Sanger sequencing confirmed parental heterozygosity, establishing the diagnosis of type 68 immunodeficiency. Prophylactic antibiotic therapy was initiated, and no further SBIs occurred during 8 months of follow-up.

CONCLUSION: This report expands the genetic spectrum of immunodeficiency 68 by identifying novel MYD88 mutations. Our findings highlight the value of genetic testing in severe, recurrent bacterial infections, irrespective of conventional laboratory results, and demonstrate improved outcomes achievable with modern management.

PMID:41479884 | PMC:PMC12754000 | DOI:10.3389/fimmu.2025.1683892

Front Immunol. 2025 Dec 16;16:1687588. doi: 10.3389/fimmu.2025.1687588. eCollection 2025.

ABSTRACT

INTRODUCTION: Intravenous immune globulin 10% liquid (IVIG 10%) is used in the treatment of primary immunodeficiency (PID). Originally approved in 2012 and then voluntarily withdrawn in 2016, IVIG 10% (BIVIGAM^®) underwent manufacturing process improvements by a new manufacturer and was reintroduced to the US market in 2019. The purpose of this real-world study is to assess the tolerability of BIVIGAM in an outpatient setting.

METHODS: An observational, retrospective analysis was performed using a random sample of patients who initiated BIVIGAM from 8/2021-5/2022 in 15 US outpatient physician office infusion centers. Patient data collected from electronic medical records included baseline characteristics, BIVIGAM treatment details, adverse events (AEs) and clinical laboratory data for 6 months following initiation.

RESULTS: A total of 60 patients treated with BIVIGAM were included. The mean age was 74 ± 8.2 years, 82% were female, and 90% had prior experience with immune globulin therapy. Treatment diagnoses were PID-related in the majority of patients (58,97%).There were 346 BIVIGAM infusions (mean of 5.8 ± 2.6 infusions per patient, mean dose of 492 ± 200.8 mg/kg),titrated upward over a mean of 80 ± 27.9 minutes to a final maximum mean infusion rate of 158 ± 28.8 mL/hr. Pre-medications were used in 83% of patients during 266 infusions. Forty-six AEs were patients (38.3%), resulting in an overall AE rate per infusion of 0.13 per patient year.

DISCUSSION: BIVIGAM was well-tolerated within this real-world outpatient setting. Infusion-related adverse reactions were low. This study provides the largest real-world evaluation of reformulated BIVIGAM in outpatient practice.

PMID:41476964 | PMC:PMC12748259 | DOI:10.3389/fimmu.2025.1687588

Jugan Geongang Gwa Jilbyeong. 2025 Dec 18;18(49):1985-2001. doi: 10.56786/PHWR.2025.18.49.2. Epub 2025 Nov 18.

ABSTRACT

OBJECTIVES: To analyze data collected through the National Infectious Disease Surveillance System to provide information on infectious disease outbreaks and deaths for use in infectious disease prevention and management.

METHODS: On June 26, 2025, the status of infectious disease outbreaks and deaths reported in 2024 was analyzed and announced, based on the reporting scope and criteria for each statutory infectious disease.

RESULTS: In 2024, 40 of 66 infectious diseases under surveillance were reported, whereas 26 remained unreported. The number of reported infectious diseases under surveillance is 171,376, a significant decrease from 5,626,627 in 2023. However, excluding coronavirus disease 2019 (COVID-19) and syphilis, which had fluctuations in infectious disease levels between 2023 and 2024, the number increased by 54.5% from 109,087 in 2023 to 168,586 in 2024. The major infectious diseases that showed an increase were pertussis, scarlet fever, chickenpox, and Carbapenem-resistant Enterobacterales (CRE) infections, and those that decreased were mumps, tuberculosis, hepatitis C, and hepatitis A. Reported imported infectious diseases in 2024 totaled 606, including dengue fever, primary syphilis, malaria, chickenpox, and hepatitis C. The number of deaths reported in 2024 was 1,238, excluding tuberculosis, which is an 18.2% increase compared to that of 2023, when excluding COVID-19 deaths 2023; with the major infectious diseases being CRE, acquired immunodeficiency syndrome, and pneumococcal infection.

CONCLUSIONS: The statutory infectious disease surveillance system can be used to produce basic data and develop policies for infectious disease prevention and management.

PMID:41476667 | PMC:PMC12750143 | DOI:10.56786/PHWR.2025.18.49.2

Genome Med. 2025 Dec 31. doi: 10.1186/s13073-025-01593-8. Online ahead of print.

ABSTRACT

BACKGROUND: Copy number variation (CNV) is a class of genomic structural variation (SV) that contributes to genomic disorders and can significantly impact health. Short-read genome sequencing (sr-GS) enables genome-wide SV calling which has been shown to increase diagnosis in unsolved rare disease families. The growing number of large sequencing cohort projects with sr-GS data available requires open free analytical tools that provide visualization of CNV and SV integrated calls associated with gene annotation, proband-parent trio analysis to enable prioritization of de novo variants, B-allele frequency (BAF) plots to support CNV calls, parent of origin assessment and mosaicism detection.

METHODS: To support those needs, we developed VizCNV, an open-source platform that incorporates read depth and BAF to enable haplotype-aware CNV analysis. The tool incorporates multiple interactive view modes for SV concurrent calls and annotation tracks for analyzing chromosomal abnormalities [e.g., aneuploidy, segmental aneusomy, and chromosome translocations], gene exonic rearrangements and non-coding gene regulatory regions. In addition, VizCNV includes a built-in filter schema for trio genomes, prioritizing the detection of de novo CNVs. We optimized VizCNV using 1000 Genomes Project data and benchmarked its performance against a cohort containing CNVs validated by multiple technologies. Finally, we applied VizCNV to a molecularly unsolved primary immunodeficiency disease cohort (PIDD, n = 39) previously analyzed by exome sequencing.

RESULTS: Upon computational optimization, VizCNV achieved approximately 82.3% recall and 76.3% precision for deletions > 10 kb. VizCNV accurately detected all 71 validated copy number gains and correctly indicated potential underlying genomic complexities. Haplotype-aware CNV analysis identified a meiosis I non-disjunction event (trisomy 21), three de novo CNVs at two unique loci and 48 inherited candidate CNVs in the PIDD cohort of which 42% (20/48) were validated by integrated CNV/BAF analysis. Moreover, genotype-phenotype analyses revealed that a compound heterozygous combination of a paternal 12.8 kb deletion of exon 5 and a maternal missense variant allele of DOCK8 are the molecular cause of one proband diagnosed with Hyper-IgE syndrome.

CONCLUSIONS: VizCNV provides a robust and flexible platform for identification of aneuploidies, CNV, SV discovery and visualization of CNV and BAF data. It is also a useful tool to investigate features of genomic rearrangements such as parental origin which has implications for genetic counseling and mechanistic studies. The tool is freely available through https://doi.org/10.6084/m9.figshare.25869523.

PMID:41470026 | DOI:10.1186/s13073-025-01593-8

BMJ Case Rep. 2025 Dec 30;18(12):e269367. doi: 10.1136/bcr-2025-269367.

ABSTRACT

We present a school-aged girl with ataxia-telangiectasia (AT), a rare autosomal recessive neurodegenerative disorder. She presented with progressive cerebellar ataxia beginning at 12 months, ocular telangiectasias developing at 4 years and unusually extensive cutaneous telangiectasias on the dorsum of hands, feet and limbs emerging at 5 years. Laboratory investigations revealed elevated alpha-fetoprotein levels, decreased immunoglobulin A and G and cerebellar atrophy on MRI. The patient experienced recurrent sinopulmonary infections requiring monthly intravenous immunoglobulin therapy. This patient demonstrates the classical neurological manifestations of AT alongside an atypical distribution of prominent cutaneous telangiectasias, emphasising the importance of early recognition for appropriate management and genetic counselling.

PMID:41469184 | DOI:10.1136/bcr-2025-269367

Life (Basel). 2025 Nov 29;15(12):1838. doi: 10.3390/life15121838.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEIs) are a heterogeneous group of genetically determined disorders that lead to immune dysfunction, recurrent infections, and organ-specific complications. The lungs are among the most commonly affected organs, with both infectious and noninfectious manifestations that significantly contribute to morbidity and mortality. This study aimed to provide a comprehensive overview of pulmonary manifestations in IEI, with emphasis on pathophysiological mechanisms, diagnostic approaches, and therapeutic strategies.

METHODS: A narrative review and synthesis of current literature and clinical guidelines were conducted, focusing on pulmonary involvement in IEI as classified by the International Union of Immunological Societies (IUIS). The analysis included data on infectious and noninfectious complications, imaging findings, immunological assessments, and management strategies, supported by clinical evidence and expert consensus.

RESULTS: Pulmonary manifestations in IEI encompass a wide spectrum of conditions. Infectious complications include recurrent bacterial pneumonias, bronchitis, and opportunistic infections, frequently resulting in irreversible lung damage such as bronchiectasis. Noninfectious complications, including granulomatous-lymphocytic interstitial lung disease (GLILD) and interstitial lung disease (ILD), are common in disorders such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). Early diagnosis using high-resolution computed tomography (HRCT) and immunological testing, combined with the timely initiation of immunoglobulin replacement therapy and anti-biotic prophylaxis, significantly improves prognosis.

CONCLUSIONS: Pulmonary complications are key clinical indicators of IEI and often precede systemic manifestations. Early, integrated, and interdisciplinary diagnostic and therapeutic management are crucial for preventing irreversible lung damage and improving patient outcomes. Regular monitoring and individualized therapy, including immunoglobulin replacement, targeted immunosuppression, and vaccination, are the cornerstones of effective long-term care in IEI.

PMID:41465777 | DOI:10.3390/life15121838

Genes (Basel). 2025 Dec 2;16(12):1445. doi: 10.3390/genes16121445.

ABSTRACT

Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted. We present a pediatric case from Kazakhstan to broaden the clinical and molecular spectrum of TYK2-related immunodeficiency and accentuate diagnostic challenges. Methods: The proband underwent clinical assessment, immunophenotyping, and biochemical analysis during episodes of active pathology and subsequent follow-up. Whole-exome sequencing (WES) was executed, followed by confirmatory Sanger sequencing and segregation analysis in first-degree kin. Functional assays for phagocyte oxidative burst and phagocytosis were conducted to exclude CGD. Results: WES identified two rare TYK2 variants (c.209_212del, pathogenic; c.2395G>A, previously reported as pathogenic in a Chinese patient with TYK2 deficiency) and a heterozygous MEFV duplication (c.761_764dup). Paternal DNA was unavailable; therefore, allelic phase could not be formally established, but the combined genotype and phenotype are consistent with autosomal recessive TYK2 deficiency. Sanger sequencing confirmed segregation of the frameshift TYK2 variant in the mother, while the clinically healthy brother carried only the wild-type allele. The missense alteration was exclusive to the proband. Conclusions: This case exemplifies the significance of contemplating TYK2 deficiency in pediatric patients with refractory mycobacterial infections, particularly in BCG-endemic locales. Genetic validation provided a definitive diagnosis, differentiating the condition from CGD and informing patient management. To our knowledge, this constitutes one of the inaugural genetically confirmed instances of TYK2 deficiency in Central Asia, enhancing regional epidemiological comprehension and emphasizing the role of molecular diagnostics in directing treatment and vaccination policies.

PMID:41465118 | DOI:10.3390/genes16121445

Immun Inflamm Dis. 2025 Dec;13(12):e70307. doi: 10.1002/iid3.70307.

ABSTRACT

OBJECTIVES: Pathogenic variants in IL2RG, encoding the common γ chain (γ_c/CD132), usually lead to T – B + NK- X-SCID but can, occasionally, generate a T – B + NK+ phenotype. We wanted to delineate potential mechanisms for this discrepancy.

METHODS: The immunological work-up of our patient comprised: whole genome sequencing and subsequent bioinformatics, flow-cytometry (lymphocyte surface receptor expression, STAT5 phosphorylation, NK cell proliferation and degranulation), lymphocyte stimulation (IL-2, IL-4 and IL-15) as well as restriction enzyme digestion and fragment size separation (evaluation of relative WT/variant expression).

FINDINGS: Our patient, hemizygous for a maternally derived, c.677 G > A IL2RG missense variant displayed a T – B + NK+ phenotype, no dysmorphic features and no thymus. The γ_c was surface expressed. In contrast to B cells from cord-blood and adults (including maternal B cells), only pre-gene therapy (patient) B cells did not decrease IL-4Rα surface expression upon IL-4 stimulation, consistent with compromised IL-4R (and γ_c) function. After gene therapy, patient B cells decreased IL-4Rα upon Il-4 stimulation. Pre-gene therapy NK cells displayed normal, K562 cell, induced degranulation and, in response to IL-2 and IL-15 and exhibited normal initial pSTAT5 kinetics but clearly attenuated activation and proliferation day six. By restriction enzyme digestion and fragment size separation, selected T and B cells from the healthy mother exhibited skewed expression (92% and 84%, respectively) of the WT IL2RG allele.

CONCLUSION: The selective WT IL2RG expression in maternal B cells was consistent with the compromised IL-4R signaling (and compromised IL-21R signaling) in her offspring (the patient), as both IL-4 and IL-21 are critical for normal human B cell germinal center reactions but not for peripheral B cell homeostasis. The c.677 G > A IL2RG variant permitted normal NK cell degranulation and initial STAT5 phosphorylation but was incapable of sustaining normal NK cell activation and proliferation in vitro. As IL-2 and IL-15 induced in-vitro NK cell proliferation is primarily mediated through the low affinity βγ_c (CD122-CD132) complex, our data indicate the importance of high affinity IL-15Rα and IL-2 Rα mediated signaling in-vivo for sustaining NK cell numbers in X-linked SCID. Consequently, we further hypothesize that in cases of X-linked SCID, where even initial IL-15 and IL-2 STAT5 phosphorylation is compromised, in-vivo trans-presentation of IL-15 (and IL-2), via the high affinity IL-15Rα and IL-2Rα receptor subunits, will not be able to sustain normal peripheral NK cell numbers”.

PMID:41462576 | DOI:10.1002/iid3.70307

Virchows Arch. 2025 Dec 29. doi: 10.1007/s00428-025-04378-x. Online ahead of print.

ABSTRACT

Patients with inborn errors of immunity/primary immunodeficiency (IEI/PID) frequently present with reactive lymphadenopathy which is biopsied to rule out lymphoma or infection. We asked whether reactive lymphoid tissue from an international cohort of 35 patients with IEI/PID contains diagnostic clues to the underlying immune dysfunction as compared to 13 control pediatric patients. To this end, we investigated abnormalities of B-cell follicle architecture and Immunoglobulin G (IgG) + class-switched (CS) versus IgM/IgD + non-IgG-CS Ig production. Abnormalities of B-cell follicles including absent or naked germinal centers (GCs) and/or increased T follicular helper(TFH) cells within GCs were seen in 45.7% (16/35) of IEI/PIDs and 15.4% (2/13) of controls (X² = 3.7520, p = 0.054). There was a statistically significant association of B-cell follicle abnormalities with infectious (X² = 5.148, p = 0.023) but not autoimmune history. Abnormal IgM + , IgD + , IgG + and/or CD138 + plasmablast/plasma cell (PB/PC) density was observed in 79.4% of IEI/PIDs (27/34) as compared to 7.7% of controls (1/13, X² = 20.085, p < 0.001). Isolated deficiency of IgG CS PB/PC was present in 42% (12/33) of IEI/PID biopsies and in no control patients, 0% (0/13, X² = 6.396, p = 0.011). There was a strong and highly statistically significant positive correlation between IgG + PB/PC density and serum IgG (Kendall’s tau-b 0.567, asymptotic standard error 0.129, approximate significance < 0.001). There was also a statistically significant association of PB/PC abnormalities with infectious (X² = 12.024, p < 0.001) but not autoimmune history. Assessment of B-cell follicle architecture and Ig production may play a role in identifying patients with unexplained reactive lymphadenopathy who would benefit from immunologic evaluation.

PMID:41460331 | DOI:10.1007/s00428-025-04378-x